Role of glucagon-like peptide-1 and its agonists on early prevention of cardiac remodeling in type 1 diabetic rat hearts.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from intestinal L cells upon nutrients ingestion, and is currently used for treating diabetes mellitus. It plays an important role in receptor modulation and cross talk with insulin at the coronary endothelium (CE) and cardiomyocytes (CM) in diabetic type 1 rat heart model. We studied the effects of insulin, GLP-1 analogues (exendin-4), and dipeptidyl peptidase-IV (DPP-IV) inhibitor on GLP-1 cardiac receptor modulation. The binding affinity of GLP-1 to its receptor on CE and CM was calculated using a rat heart perfusion model with [(125)I]-GLP-1(7-36). Tissue samples from the heart were used for immunostaining and Western blot analyses. GLP-1 systemic blood levels were measured using ELISA. GLP-1 binding affinity (τ) increased on the CE (0.33 ± 0.01 vs. 0.25 ± 0.01 min; p < 0.001) and decreased on the CM (0.29 ± 0.02 vs. 0.43 ± 0.02 min; p < 0.001) in the diabetic non-treated rats when compared to normal. There was normalization of τ back to baseline on the CE and CM levels with insulin and DPP-IV inhibitor treatment, respectively. Histological sections and immunofluorescence showed receptor up-regulation in diabetic rats with significant decrease and even normalization with the different treatment strategies. Systemic GLP-1 levels increased after 14 days of diabetes induction (10 ± 3.7 vs. 103 ± 58 pM; p = 0.0005). In conclusion, there is a significant GLP-1 receptor affinity modulation on the CE and CM levels in rats with diabetes type 1, and a cross talk with GLP-1 analogues in early prevention of cardiac remodeling.


Discrete wavelet transform coefficients for emotion recognition from EEG signals.
In this paper, we propose to use DWT coefficients as features for emotion recognition from EEG signals. Previous feature extraction methods used power spectra density values dervied from Fourier Transform or sub-band energy and entropy derived from Wavelet Transform. These feature extracion methods eliminate temporal information which are essential for analyzing EEG signals. The DWT coefficients represent the degree of correlation between the analyzed signal and the wavelet function at different instances of time; therefore, DWT coefficients contain temporal information of the analyzed signal. The proposed feature extraction method fully utilizes the simultaneous time-frequency analysis of DWT by preserving the temporal information in the DWT coefficients. In this paper, we also study the effects of using different wavelet functions (Coiflets, Daubechies and Symlets) on the performance of the emotion recognition system. The input EEG signals were obtained from two electrodes according to 10-20 system: F(p1) and F(p2). Visual stimuli from International Affective Picture System (IAPS) were used to induce two emotions: happy and sad. Two classifiers were used: Extreme Learning Machine (ELM) and Support Vector Machine (SVM). Experimental results confirmed that the proposed DWT coefficients method showed improvement of performance compared to previous methods.


[The characteristics of rat behavioral reactions in exposure to constant electrical fields of varying intensities].
Spontaneous motor orientation, the character of trained reflex responses to food and pain were studied in rats exposed to constant electrical fields (30-160 kV/m, 4 hrs daily for 30 days). A deceleration of responses, abolition of reflex extinction processes, decrease in the level of locomotor and orientation activity occurred along with increasing voltage. The system of negative emotional response seems to be most sensitive to CEF.


Exploring the ability of frozen-density embedding to model induced circular dichroism.
In this study, we present calculations of the circular dichroism (CD) spectra of complexes between achiral and chiral molecules. Nonzero rotational strengths for transitions of the nonchiral molecule are induced by interactions between the two molecules, which cause electronic and/or structural perturbations of the achiral molecule. We investigate if the chiral molecule (environment) can be represented only in terms of its frozen electron density, which is used to generate an effective embedding potential. The accuracy of these calculations is assessed in comparison to full supermolecular calculations. We can show that electronic effects arising from specific interactions between the two subsystems can reliably be modeled by the frozen-density representation of the chiral molecule. This is demonstrated for complexes of 2-benzoylbenzoic acid with (-)-(R)-amphetamine and for a nonchiral, artificial amino acid receptor system consisting of ferrocenecarboxylic acid bound to a crown ether, for which a complex with l-leucine is studied. Especially in the latter case, where multiple binding sites and interactions between receptor and target molecule exist, the frozen-density results compare very well with the full supermolecular calculation. We also study systems in which a cyclodextrin cavity serves as a chiral host system for a small, achiral molecule. Problems arise in that case because of the importance of excitonic couplings with excitations in the host system. The frozen-density embedding cannot describe such couplings but can only capture the direct effect of the host electron density on the electronic structure of the guest. If couplings play a role, frozen-density embedding can at best only partially describe the induced circular dichroism. To illustrate this problem, we finally construct a case in which excitonic coupling effects are much stronger than direct interactions of the subsystem densities. The frozen density embedding is then completely unsuitable.


Cerebral CT in fatal courses of resuscitated sudden infant death.
Three children revived after sudden infant death syndrome were observed by cerebral computed tomography (CT). The scans were correlated with clinical and electroencephalographic findings of brain deterioration. The salient features of the CT presentations are described. Necropsies performed in two of the three cases revealed liquefactive necrosis.


Modulation of rat B cell differentiation in vivo by the administration of an anti-mu monoclonal antibody.
We have previously described that the administration of an anti-mu mAb to adult rats results in the total depletion of circulating IgM. In the present study we analyzed the cellular mechanisms involved in the depletion of circulating IgM by the administration of an anti-mu mAb to adult rats. Administration of an anti-mu mAb to adult rats led to the cross-linking and internalization of membrane IgM (mIgM) but not mIgD on the surface of B cells. This correlated with the depletion in spleen and bone marrow of immature and short-lived Thy-1+ CD45RB+ B cells and with the specific depletion of the number of IgM but not IgA-, IgG1-, IgG2a-, and IgG2b-secreting cells in the spleen, which paralleled the depletion of circulating IgM but not IgA, IgG1, IgG2a, and IgG2b. In contrast to the other IgG subclasses, IgG2c-secreting cells as well as circulating IgG2c were increased by 10-fold in anti-mu-treated rats as compared with controls. Finally, anti-mu-treated rats showed an inhibition in the generation of primary thymus-dependent as well as thymus-independent Ab responses as compared with controls. In conclusion, the data presented suggests that anti-mu administration in adult rats results in the early arrest of B cell differentiation in the bone marrow, which causes the down-regulation of IgM production. Furthermore, anti-mu mAb administration directly or indirectly activates a particular subset of mature B cells, which differentiates into IgG2c-secreting cells.


Maize host requirements for Ustilago maydis tumor induction.
The biotrophic pathogen Ustilago maydis causes tumors by redirecting vegetative and floral development in maize (Zea mays L.). After fungal injection into immature tassels, tumors were found in all floral organs, with a progression of organ susceptibility that mirrors the sequential location of foci of cell division in developing spikelets. There is sharp demarcation between tumor-forming zones and areas with normal spikelet maturation and pollen shed; within and immediately adjacent to the tumor zone, developing anthers often emerge precociously and exhibit a range of developmental defects suggesting that U. maydis signals and host responses are restricted spatially. Male-sterile maize mutants with defects in anther cell division patterns and cell fate acquisition prior to meiosis formed normal adult leaf tumors, but failed to form anther tumors. Methyl jasmonate and brassinosteroid phenocopied these early-acting anther developmental mutants by generating sterile zones within tassels that never formed tumors. Although auxin, cytokinin, abscisic acid and gibberellin did not impede tassel development, the Dwarf8 mutant defective in gibberellin signaling lacked tassel tumors; the anther ear1 mutant reduced in gibberellin content formed normal tumors; and Knotted1, in which there is excessive growth of leaf tissue, formed much larger vegetative and tassel tumors. We propose the hypothesis that host growth potential and tissue identity modulate the ability of U. maydis to redirect differentiation and induce tumors.


Two-year follow-up of the 'Families for Health' programme for the treatment of childhood obesity.
The high prevalence of obesity in children in the UK warrants continuing public health attention. 'Families for Health' is a family-based group programme for the treatment of childhood obesity. Significant improvements in body mass index (BMI) z-score (-0.21, 95% CI: -0.35 to -0.07, P = 0.007) and other health outcomes were seen in children at a 9-month follow-up. To undertake a 2-year follow-up of families who attended 'Families for Health' in Coventry, to assess long-term outcomes and costs. 'Families for Health' is a 12-week programme with parallel groups for parents and children, addressing parenting skills, healthy lifestyles and emotional well-being. The intervention was delivered at a leisure centre in Coventry, England, with 27 overweight or obese children aged 7-13 years (18 girls, 9 boys) and their parents, from 21 families. A 'before-and-after' evaluation was completed with 19 (70%) children followed up at 2 years. The primary outcome was change in BMI z-score from baseline; secondary outcomes were children's quality of life, parent-child relationships, eating/activity habits and parents' mental health. Costs to deliver the intervention and to families were recorded. Mean change in BMI z-score from baseline was -0.23 (95% CI: -0.42 to -0.03, P = 0.027) at the 2-year follow-up and eight (42%) children had a clinically significant reduction in BMI z-score. Significant improvements were seen in children's quality of life and eating habits in the home, while there were sustained reductions in unhealthy foods and sedentary behaviour. Fruit and vegetable consumption and parent's mental health were not significantly different at 2 years. Costs of the programme were £517 per family (£402 per child), equivalent to £2543 per unit reduction in BMI z-score. Improvements in BMI z-score and certain other outcomes associated with the 'Families for Health' programme were sustained at the 2-year follow-up. 'Families for Health' is a promising new childhood obesity intervention, and a randomized controlled trial is now indicated.


Diagnostic Accuracy of a Two-Stage Sequential Screening Strategy Implemented by Community Health Workers (CHWs) to Identify Individuals with COPD in Rural India.
Undiagnosed Chronic Obstructive Pulmonary Disease (COPD) results in high morbidity, disability and mortality in India. Effective strategies for active COPD screening in community settings are needed to increase early identification, risk reduction and timely management. The objective of this study was to test the diagnostic accuracy of a sequential two-step screening strategy to detect COPD, implemented by community health workers (CHWs), among adults aged ≥40 years in a rural area of North India. Trained CHWs screened all consenting (n=3256) eligible adults in two villages using the Lung Function Questionnaire (LFQ) to assess their COPD risk and conducted pocket spirometry on 268 randomly selected (132 with high risk ie LFQ score ≤18 and 136 with low risk ie LFQ score >18) individuals. Subsequently, trained researchers conducted post-bronchodilator spirometry on these randomly selected individuals using a diagnostic quality spirometer and confirmed the COPD diagnosis according to the Global Initiative for Obstructive Lung Disease (GOLD) criteria (FEV1/FVC ratio <0.7). This strategy of using LFQ followed by pocket spirometry was sensitive (78.6%) and specific (78.8%), with a positive predictive value of 66% and negative predictive value of 88%. It could accurately detect 67% of GOLD Stage 1, 78% of GOLD Stage 2, 82% of GOLD Stage 3 and 100% of GOLD Stage 4 individuals with airflow limitation. COPD can be accurately detected by trained CHWs using a simple sequential screening strategy. This can potentially contribute to accurate assessment of COPD and thus its effective management in low-resource settings.


Lung function in asthma: relation to clinics, challenge tests and immunotherapy.
In the last few years the consensus on asthma, guidelines and GINA have introduced a classification based on clinical criteria, PFR or FEV1 values and reversibility. However the relation of clinical classification with the functional data is not well defined. To correlate the clinical evaluation of asthma with the most usual parameters of larger and smaller airways bronchial obstruction, PFR and FEV1.n 153 patients have been studied by spirometry on absence of bronchodilator or anti inflammatory therapy in the last few days. Clinically, they were classified following the 2002 revised strategy for asthma management (NIH), 66 as mild intermitent, 61 mild persistent and 26 moderate persistent asthmas. In mild intermitent asthma PFR was decreased in 53 patients (80.3%) and FEV1 in 51 (77.2%). In mild persistent PFR and FEV1 were decreased in 59 (96.7%). In medium persistent asthma PFR was decreased in 25 (96.0%) and FEV1 in 24 (92%). The values of PFR and FEV1 were statistically different in intermitent and persistent asthma. For PFR square chi X2 = 8.91, p < 0.01 and for FEV1 X2 = 9.0 p < 0.01. In contrast there were no statistically differences between mild and moderate persistent asthmas. For PFR X2 = 0.02 p < 0.8 and for FEV1 X2 = 0.039, p < 0.9 (tables 1, 2, 3, 4). The occurrence of 77.2% and 80.3% of decreased FEV1 and PFR values in non dyspnea as reported by the patients. There were also no functional differences between patients in the different groups of persistent asthma. Clinical and functional data must be correlated, case by case in order to establish a correct classification of asthmatic patients and improve therapy and the relation between lung function and clinic reevaluate.


Immunostimulating Effect of Inactivated Parapoxvirus Ovis on the Serological Response to Equine Influenza Booster Vaccination.
Equine influenza virus (EIV) is responsible for recurring outbreaks that are detrimental to the equine industry. Vaccination is key for prevention, but the effectiveness and duration of protection provided by existing vaccines is often insufficient. In order to improve vaccine efficacy, we evaluated the benefit of immune stimulation with inactivated Parapoxvirus ovis (iPPVO) on the antibody response induced by a vaccine boost against EIV. A whole inactivated ISCOMatrix-adjuvanted equine influenza vaccine was administered alone (n = 10) or combined with iPPVO injections at D0, D2 and D4 post vaccination (n = 10) to adult horses that required a vaccine boost 6 months after the last immunization, as now recommended by the WOAH. Antibody levels were measured with the single radial haemolysis (SRH) assay at 1, 3 and 6 months post-vaccination. Results revealed that horses that received iPPVO had higher antibody levels than the control group injected with the EI vaccine alone. Although the vaccine used contains only a clade 1 and European lineage strain, the increase in protective antibodies was also observed against a clade 2 strain. Thus, immune stimulation with iPPVO, a substance already marketed as an immunostimulant, could be used to improve vaccination protocols in horses and potentially other species.


Cytogenetic screening of livestock populations in Europe: an overview.
Clinical animal cytogenetics development began in the 1960's, almost at the same time as human cytogenetics. However, the development of the two disciplines has been very different during the last four decades. Clinical animal cytogenetics reached its 'Golden Age' at the end of the 1980's. The majority of the laboratories, as well as the main screening programs in farm animal species, presented in this review, were implemented during that period, under the guidance of some historical leaders, the first of whom was Ingemar Gustavsson. Over the past 40 years, hundreds of scientific publications reporting original chromosomal abnormalities generally associated with clinical disorders (mainly fertility impairment) have been published. Since the 1980's, the number of scientists involved in clinical animal cytogenetics has drastically decreased for different reasons and the activities in that field are now concentrated in only a few laboratories (10 to 15, mainly in Europe), some of which have become highly specialized. Currently between 8,000 and 10,000 chromosomal analyses are carried out each year worldwide, mainly in cattle, pigs, and horses. About half of these analyses are performed in one French laboratory. Accurate estimates of the prevalence of chromosomal abnormalities in some populations are now available. For instance, one phenotypically normal pig in 200 controlled in France carries a structural chromosomal rearrangement. The frequency of the widespread 1;29 Robertsonian translocation in cattle has greatly decreased in most countries, but remains rather high in certain breeds (up to 20-25% in large beef cattle populations, even higher in some local breeds). The continuation, and in some instances the development of the chromosomal screening programs in farm animal populations allowed the implementation of new and original scientific projects, aimed at exploring some basic questions in the fields of chromosome and/or cell biology, thanks to easier access to interesting biological materials (germ cells, gametes, embryos ...).


Corporate preparedness for pandemic influenza: a survey of pharmaceutical and biotechnology companies in Montgomery County, Maryland.
We conducted a survey of corporate preparedness for pandemic influenza among biotechnology and pharmaceutical companies in Montgomery County, Maryland, to determine the level of preparedness for this industry and geographic region. The survey, based on the HHS Business Pandemic Influenza Planning Checklist, established whether a company had a preparedness plan specific to pandemic influenza, the contents of its plan, or its reasons for a lack of a plan. A total of 50 companies participated in the survey. Of these, 40 did not have any type of preparedness plan, 3 were drafting plans, 6 had general preparedness plans that could be applied to an influenza pandemic, and only 1 company had a preparedness plan specifically designed to address pandemic influenza. Biotechnology and pharmaceutical companies in this geographic region are currently not well prepared for pandemic influenza. Public health officials should offer more help, possibly in the form of a model small business preparedness plan, and collaboration between companies should be encouraged to foster sharing of preparedness plans.


Are Members of Long-Lived Families Healthier Than Their Equally Long-Lived Peers? Evidence From the Long Life Family Study.
The Long Life Family Study (LLFS) is a multicenter longitudinal study of exceptional survival among members of long-lived sibships (probands), their offspring, and spouses of either group. For these four "roles", we asked: Does membership in a long-lived family protect against disease? We used 2008-2010 Beneficiary Annual Summary Files from the Centers for Medicare & Medicaid Services (CMS) to compare prevalences of 17 conditions among 781 LLFS participants in Medicare with those of 3,227 non-LLFS matches from the general Medicare population. Analyses accounted for nesting within LLFS families. Seven conditions were significantly less common among LLFS probands than their matches: Alzheimer's, hip fracture, diabetes, depression, prostate cancer, heart failure, and chronic kidney disease. Four diseases not strongly linked to mortality (arthritis, cataract, osteoporosis, glaucoma) were significantly more common for LLFS probands. Despite fewer people and less disease in those roles, LLFS offspring and LLFS spouses of either generation also had significantly lower risk for Alzheimer's, diabetes, and heart failure. Common, severe mortality-associated diseases are less prevalent among LLFS probands and their offspring than in the general population of aging Americans. Quality-of-life-limiting diseases such as arthritis and cataract are more prevalent, potentially through more diagnosing of milder forms in otherwise healthy and active individuals. LLFS spouses are also relatively healthy. As the younger cohorts age into Medicare and develop more conditions, it will be important to see whether these tentative findings strengthen.


Regularization parameter estimation for feedforward neural networks.
Under the framework of the Kullback-Leibler (KL) distance, we show that a particular case of Gaussian probability function for feedforward neural networks (NNs) reduces into the first-order Tikhonov regularizer. The smooth parameter in kernel density estimation plays the role of regularization parameter. Under some approximations, an estimation formula is derived for estimating regularization parameters based on training data sets. The similarity and difference of the obtained results are compared with other work. Experimental results show that the estimation formula works well in sparse and small training sample cases.


Binary ultrasonography for the internist: yes or no, that's the question!
The authors discuss the pros and cons with regard to ultrasound for the internist. They state that ultrasonography is seldom used by internists and they suggest several reasons for this. After a brief review of the literature they conclude that using ultrasound would probably benefit patients and would lead to a more rapid diagnosis and an increase in safety while performing invasive diagnostic and therapeutic interventions. The authors suggest that internists use ultrasound in a different way compared with radiologists, cardiologists, etc. They introduce the term binary ultrasound: ultrasound should be used to answer clinical questions with a yes or a no.


Synesthesia improves sensory memory, when perceptual awareness is high.
Empirical evidence suggests that synesthesia is associated with enhanced sensory processing. A separate body of empirical literature suggests that synesthesia is linked to a specific profile of enhanced episodic and working memory performance. However, whether sensory (iconic) memory performance is also affected by synesthesia remains unknown. Therefore, we tested 22 grapheme-color synesthetes and compared their performance in a partial-report paradigm with 22 individually matched non-synesthete controls. Participants were briefly presented with a circular-letter array and required to report the identity of the letter at a probed target location after various delays. Furthermore, they were required to indicate the subjective clarity of the target letter after every trial. The results suggest that sensory memory performance is enhanced in synesthesia, but only when subjective clarity of the target letter is high. Additional exploratory analyses revealed that synesthetic consistency, which is widely used to confirm the genuineness of synesthesia, correlated significantly with performance in the partial report paradigm. We conclude that synesthesia does not generally enhance sensory memory performance, but that synesthetic experiences may enhance sensory memory performance when perceptual awareness of the target is high. Furthermore, the stability of synesthetic associations may be linked to sensory memory performance.


Urea and short-chain fatty acids metabolism in Holstein cows fed a low-nitrogen grass-based diet.
Three ruminally cannulated and multicatheterised lactating dairy cows were used to investigate the effect of different supplement strategies to fresh clover grass on urea and short-chain fatty acid (SCFA) metabolism in a zero-grazing experiment with 24-h blood and ruminal samplings. Fresh clover grass was cut every morning and offered from 0800 to 1500 h. Maize silage was fed at 1530 h. The three treatments, arranged in a Latin square, differed by timing of feeding rolled barley and soya-bean hulls relative to fresh clover grass. All diets had the same overall composition. Treatments were soya-bean hulls fed at 0700 h and barley fed at 1530 h (SAM), barley fed at 0700 h and soya-bean hulls fed at 1530 h (BAM), and both soya-bean hulls and barley fed at 1530 h (SBPM). The grass had an unexpectedly low content of crude protein (12.7%) and the cows were severely undersupplied with rumen degradable protein. The treatment effects were numerically small; greater arterial ammonia concentration, net portal flux of ammonia and net hepatic flux of urea during part of the day were observed when no supplementary carbohydrate was fed before grass feeding. A marked diurnal variation in ruminal fermentation was observed and grass feeding increased ruminal concentrations of propionate and butyrate. The net portal fluxes of propionate, butyrate, isovalerate and valerate as well as the net hepatic uptake of propionate, butyrate, valerate and caproate increased after feeding at 0700 h. The hepatic extraction of butyrate showed a relatively large depression with grass feeding with nadir at 1200 to 1330 h. The increased net portal absorption and the decreased hepatic extraction resulted in an approximately six-fold increase in the arterial blood concentration of butyrate. The gut entry rate of urea accounted for 70 ± 10% of the net hepatic production of urea. Saliva contributed to 14% of the total amount of urea recycled to the gut. Urea recycling to the gut was equivalent to 58% of the dietary nitrogen intake. Despite the severe undersupply of rumen degradable protein, the portal-drained viscera did not extract more than 4.3% of the urea supplied with arterial blood. This value is in line with the literature values for cows fed diets only moderately deficient in rumen degradable protein and indicates that cows maximise urea transfer across gut epithelia even when the diet is moderately deficient in rumen degradable protein.


Mechanism of antitumor activity of tumor necrosis factor alpha with hyperthermia in a tumor necrosis factor alpha-resistant tumor.
Cells from a radiation-induced fibrosarcoma (RIF-1) are exceedingly resistant to tumor necrosis factor alpha (TNF-alpha) in vitro. We tested whether the addition of mild hyperthermia (42.5 degrees C, 30 minutes) could enhance TNF-alpha activity against RIF-1 tumors growing in syngeneic hosts (C3H mice). TNF-alpha was administered intratumorally. Tumor cell killing essentially was not measurable following TNF-alpha, hyperthermia, or a combination of the two. Single-modality treatments also had no effect on tumor growth delay or on the x-ray dose (given 24 hours after the primary treatment) required to sterilize 50% of the tumors. The combination of TNF-alpha and hyperthermia, however, resulted in a marked increase in tumor doubling time and a highly significant reduction in the x-ray dose required to sterilize the tumors. Syngeneic lymph nodal lymphocytes and blood leukocytes did not appear to mediate the action of TNF-alpha on RIF-1 cells in vitro. Necrosis and hemorrhage were the most prominent histopathological alterations in the treated tumors. Electron microscopic studies 6 hours after therapy showed increased damage to capillary endothelial cells and accumulation of neutrophils in the capillaries of tumors treated with TNF-alpha with or without heat, suggesting that neutrophils may mediate the endothelial cell injury. These observations indicate a greater than additive tumoricidal effect of TNF-alpha with hyperthermia. Furthermore, they support the concept that the interaction between the two agents damages the vasculature, compromising the microcirculation and ultimately causing ischemic tumor necrosis.


Should the indications for laparascopic live donor nephrectomy of the right kidney be the same as for the open procedure? Anomalous left renal vasculature is not a contraindiction to laparoscopic left donor nephrectomy.
The left kidney is preferred for live donation. In open live donor nephrectomy, the right kidney is selected if the left kidney has multiple renal arteries or anomalous venous drainage. With laparoscopic live donor nephrectomy (LLDN), there is reluctance to procure the right kidney because of the more difficult exposure and further shortening of the right renal vein (RRV) after a stapled transection. An experience with LLDN is reviewed to determine whether the right kidney should be procured laparoscopically. From February 1995 to November 1999, 227 patients underwent live donor renal transplants with allografts procured by LLDN. The results of these transplants were analyzed. Of the 227 kidneys transplanted, 17 (7.5%) were right kidneys. In the early experience, three (37.5%) of the eight right renal allografts developed venous thrombosis, two of which had duplicated RRV. Based on these initially unacceptable results, donor evaluation and LLDN techniques were modified. Spiral computerized tomography (CT) replaced conventional angiography to define better the venous anatomy. LLDN was modified in one of three ways: (1) changing the stapler port placement such that the RRV was transected in a plane parallel to the inferior vena cava, (2) relocation of the incision for open division of RRV, or (3) lengthening of the donor RRV with a panel graft constructed of recipient greater saphenous vein. Finally, the recipient operation enjoined complete mobilization of the left iliac vein with transposition lateral to the iliac artery. With these modifications, there were no vascular complications with the subsequent nine right renal allografts (P<0.05). Of the left kidneys transplanted, 31 had multiple renal arteries, 14 had retroaortic or circumaortic veins, 4 had both multiple arteries and venous anomalies, and 1 had a duplicated IVC draining the left renal vein. There were no vascular complications with left renal allografts that had multiple arteries or venous anomalies. LLDN of the left kidney is technically easier. Left kidneys with multiple arteries or anomalous venous drainage are not problematic. The right kidney can be procured with LLDN; however, a rational approach to preoperative angiographic imaging, donor operation, and recipient operation is crucial.


Oviposition site selection by the dengue vector Aedes aegypti and its implications for dengue control.
Because no dengue vaccine or antiviral therapy is commercially available, controlling the primary mosquito vector, Aedes aegypti, is currently the only means to prevent dengue outbreaks. Traditional models of Ae. aegypti assume that population dynamics are regulated by density-dependent larval competition for food and little affected by oviposition behavior. Due to direct impacts on offspring survival and development, however, mosquito choice in oviposition site can have important consequences for population regulation that should be taken into account when designing vector control programs. We examined oviposition patterns by Ae. aegypti among 591 naturally occurring containers and a set of experimental containers in Iquitos, Peru. Using larval starvation bioassays as an indirect measure of container food content, we assessed whether females select containers with the most food for their offspring. Our data indicate that choice of egg-laying site is influenced by conspecific larvae and pupae, container fill method, container size, lid, and sun exposure. Although larval food positively influenced oviposition, our results did not support the hypothesis that females act primarily to maximize food for larvae. Females were most strongly attracted to sites containing immature conspecifics, even when potential competitors for their progeny were present in abundance. Due to strong conspecific attraction, egg-laying behavior may contribute more to regulating Ae. aegypti populations than previously thought. If highly infested containers are targeted for removal or larvicide application, females that would have preferentially oviposited in those sites may instead distribute their eggs among other suitable, previously unoccupied containers. Strategies that kill mosquitoes late in their development (i.e., insect growth regulators that kill pupae rather than larvae) will enhance vector control by creating "egg sinks," treated sites that exploit conspecific attraction of ovipositing females, but reduce emergence of adult mosquitoes via density-dependent larval competition and late acting insecticide.


Increased expression of receptor phosphotyrosine phosphatase-β/ζ is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes.
Schizophrenia is a serious and chronic mental disorder, in which both genetic and environmental factors have a role in the development of the disease. Neuregulin-1 (NRG1) is one of the most established genetic risk factors for schizophrenia, and disruption of NRG1 signaling has been reported in this disorder. We reported previously that NRG1/ErbB4 signaling is inhibited by receptor phosphotyrosine phosphatase-β/ζ (RPTP β/ζ) and that the gene encoding RPTPβ/ζ (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTPβ/ζ in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTPβ/ζ (PTPRZ1-transgenic mice), which showed reduced NRG1 signaling, and molecular and cellular changes implicated in the pathogenesis of schizophrenia, including altered glutamatergic, GABAergic and dopaminergic activity, as well as delayed oligodendrocyte development. Behavioral analyses also demonstrated schizophrenia-like changes in the PTPRZ1-transgenic mice, including reduced sensory motor gating, hyperactivity and working memory deficits. Our results indicate that enhanced RPTPβ/ζ signaling can contribute to schizophrenia phenotypes, and support both construct and face validity for PTPRZ1-transgenic mice as a model for multiple schizophrenia phenotypes. Furthermore, our results implicate RPTPβ/ζ as a therapeutic target in schizophrenia.


Differentiation of O-H and C-H bond scission mechanisms of ethylene glycol on Pt and Ni/Pt using theory and isotopic labeling experiments.
Understanding and controlling bond-breaking sequences of oxygenates on transition metal catalysts can greatly impact the utilization of biomass feedstocks for fuels and chemicals. The decomposition of ethylene glycol, as the simplest representative of biomass-derived polyols, was studied via density functional theory (DFT) calculations to identify the differences in reaction pathways between Pt and the more active Ni/Pt bimetallic catalyst. Comparison of the computed transition states indicated three potentially feasible paths from ethylene glycol to C1 oxygenated adsorbates on Pt. While not important on Pt, the pathway to 1,2-dioxyethylene (OCH(2)CH(2)O) is favored energetically on the Ni/Pt catalyst. Temperature-programmed desorption (TPD) experiments were conducted with deuterated ethylene glycols for comparison with DFT results. These experiments confirmed that decomposition of ethylene glycol on Pt proceeds via initial O-H bond cleavage, followed by C-H and the second O-H bond cleavages, whereas on the Ni/Pt surface, both O-H bonds are cleaved initially. The results are consistent with vibrational spectra and indicate that tuning of the catalyst surface can selectively control bond breaking. Finally, the significant mechanistic differences in decomposition of polyols compared to that of monoalcohols and hydrocarbons serve to identify general trends in bond scission sequences.


Comparison of resonator-originated and external beam shaping.
The spatial shaping of laser beams is a subject of research in modern optics. Recently the introduction of diffractive elements in laser resonators has offered an alternative to external beam-shaping optics by mode shaping within the resonator. We describe the specification of the laser resonator mirrors to obtain by means of internal mode shaping a desired beam outside the resonator. Modal discrimination of the modified resonator and the mirror alignment sensitivity is discussed. Basic features of resonator-originated and external beam shaping are compared.


Adjuvant Anthracyclines in Breast Cancer: What Is Their Role?
Anthracyclines have been a mainstay of breast cancer therapy for decades, with strong evidence demonstrating their impact on breast cancer survival. However, concerns regarding rare but serious long-term toxicities including cardiotoxicity and hematologic malignancies have driven interest in alternative adjuvant therapy options with more favorable toxicity profiles. This article provides an update of data that help inform clinicians of the role anthracyclines should play in adjuvant breast cancer therapy. Two recently reported large randomized trials-the Anthracycline in Early Breast Cancer and Western German Study Plan B studies-compared a taxane and cyclophosphamide regimen with an anthracycline, taxane, and cyclophosphamide regimen. Although the studies had conflicting results, together these studies suggest that the benefit of adjuvant anthracycline therapy over a nonanthracycline taxane-containing regimen is modest at best and may be primarily seen in patients with especially high-risk disease (i.e., triple-negative breast cancer, involvement of multiple lymph nodes). A third study-the MINDACT study-compared an anthracycline-based regimen to a nonanthracycline regimen, with similar outcomes in both groups. Despite the toxicities, no adjuvant breast cancer regimen has been shown to be superior to an anthracycline-taxane regimen in high-risk patients. These data can directly inform clinical decision-making in determining which patients warrant use of adjuvant anthracycline therapy. Future research may focus on confirming subgroups for whom it is reasonable to forgo adjuvant anthracyclines and validating predictive biomarkers or scores for anthracycline benefit. In patients with early breast cancer, the choice of adjuvant chemotherapy should be based on its effectiveness in reducing breast cancer recurrences and its short- and long-term toxicities. Although adjuvant anthracycline and taxane chemotherapy has the most data supporting its effectiveness, anthracyclines carry a small but important increased risk for cardiotoxicity and leukemia. Two recent clinical trials help describe the degree of benefit with adjuvant anthracycline therapy compared with taxane therapy alone. They suggest that in patients with hormone receptor-positive breast cancer and limited lymph node involvement, nonanthracycline taxane-based adjuvant therapy may be adequate.


Vidarabine therapy of neonatal herpes simplex virus infection.
Vidarabine (adenine arabinoside) was evaluated for treatment of neonatal herpes simplex virus infection in a randomized controlled study. Of 56 infected newborns, 13 had infection of skin, eye, or mouth only, 16 had localized brain disease (CNS), and 27 had disseminated disease. Both treatment and placebo groups were comparable by disease distribution and for major population characteristics. Because of the severity of CNS and disseminated disease, these groups were combined for mortality assessment. Mortality was significantly reduced in babies with CNS and disseminated disease from 74% to 38% with drug therapy, P = .014. Outcome in babies with disseminated disease alone, although improved, was poor. Death rate was reduced from 85% to 57% with therapy. Only 14% of drug and 8% of placebo recipients were assessed as normal at 1 year of age. Outcome was better with localized CNS disease; mortality was reduced from 50% to 10%. With treatment, 50% of infected newborns were normal and without only 17%. With skin, eye, or mouth infection death did not occur; however, severe sequelae occurred in 38% of placebo and minor sequelae in 25% of drug recipients. No evidence of acute toxicity was identified in this study. Thus, a beneficial effect of vidarabine therapy on neonatal herpes simplex infection is similar to that evident with therapy of herpes simplex encephalitis occurring in older individuals. Nevertheless, improvement in the mode of therapy or the development of more potent antiviral drugs is essential.


A study of the endocrine manifestations of hepatic cirrhosis.
The clinical features and hormonal abnormalities were surveyed in 117 men with cirrhosis of the liver. Compared with healthy men of similar ages, the patients had significantly lower metabolic clearance rates, plasma production rates and total and free levels of testosterone, reduced testosterone responses to human chorionic gonadotrophin stimulation, higher oestradiol, luteinizing hormone and follicle stimulating hormone levels and higher binding capacities of sex steroid binding globulin. The peripheral conversion of testosterone to oestradiol was also found to be significantly increased. However, the metabolic clearance and plasma production rates of oestradiol were not significantly different from those of healthy men. Patients who were severely ill with liver failure and one with haemochromatosis had low levels of luteinizing hormone and follicle stimulating hormone and sub-normal responses to clomiphene and luteinizing hormone-releasing hormone. Higher plasma oestradiol levels were found in patients with gynaecomastia and spider naevi than in those without these signs. However, the clinical features of androgen deficiency--that is, testicular atrophy, impotence and loss of secondary sex hair--were only poorly related to the low testosterone levels, and production rates and longtitudinal studies indicated that the hormonal levels, endocrine features and severity of the liver disease could change independently. It is concluded that the clearance of oestradiol from plasma is not limited by liver disease in all patients, and that reduced degradation of oestrogens is not the initial event in the sequence leading to the hormonal abnormalities of cirrhosis. While gonadotrophin deficiency occurs with liver failure and in some patients with haemochromatosis, the more usual findings are of elevated gonadotrophin levels and a poor Leydig cell response to chorionic gonadotrophin. These suggest that the hypogonadism is primary in most patients with cirrhosis. The causes of the high oestradiol levels were not discovered. Increased peripheral conversion of precursors to oestradiol or increased testicular secretion of oestradiol are possibilities. The high binding capacities of sex steroid binding globulin were not significantly correlated with either the low testosterone or high oestradiol level and the cause of this abnormality remains uncertain. The low metabolic clearance rates of testosterone appeared to result from the increased plasma protein binding of testosterone. The discrepancies in the expected relationships between the hormone and clinical changes suggest that factors other than those studied are also involved in the genesis of the endocrine features of hepatic cirrhosis.


A model checking method for the proportional hazards model with recurrent gap time data.
Recurrent events are the natural outcome in many medical and epidemiology studies. To assess covariate effects on the gaps between consecutive recurrent events, the Cox proportional hazards model is frequently employed in data analysis. The validity of statistical inference, however, depends on the appropriateness of the Cox model. In this paper, we propose a class of graphical techniques and formal tests for checking the Cox model with recurrent gap time data. The building block of our model checking method is an averaged martingale-like process, based on which a class of multiparameter stochastic processes is proposed. This maneuver is very general and can be used to assess different aspects of model fit. Numerical simulations are conducted to examine finite-sample performance, and the proposed model checking techniques are illustrated with data from the Danish Psychiatric Central Register.


Tobacco price boards as a promotional strategy-a longitudinal observational study in Australian retailers.
Price boards in tobacco retailers are one of the few forms of tobacco promotion remaining in Australia. This study aimed to examine how these boards were used to promote products over a period of rapidly rising taxes. Observations were made in a panel of 350 stores in Melbourne, Australia, in November of 2013 (just before) and in 2014 and 2015 (after 12.5% increases in tobacco duty). Fieldworkers unobtrusively noted the presence and characteristics of price boards, and the brand name, size and price of the product at the top of each board. Price boards were common in all store types apart from newsagent/lottery agents. The characteristics of the top-listed product changed notably over time: premium brands accounted for 66% of top-listed products in 2013, significantly declining to 43% in 2015, while packs of 20 cigarettes increased in prominence from 32% to 45%. The prevalence of packs of 20 cigarettes in budget market segments tripled from 2013 (13%) and 2014 (11%) to 32% in 2015, with no change in the proportion of packs that were under $A20 from 2014 (37%) to 2015 (36%). The rate of increase in the average price of the top-listed pack correspondingly flattened from 2014 to 2015 compared with 2013-2014. Price boards promote tobacco products in ways that undermine the effectiveness of tax policy as a means of discouraging consumption. Communication to consumers about prices should be restricted to information sheets provided to adult smokers on request at the point of sale.


Knowledge, attitudes, beliefs, and practices in registered nurses and care aids about urinary incontinence in Korean nursing homes: a cross-sectional survey.
The purpose of this study was to describe knowledge, attitudes, beliefs, and practices about urinary incontinence among Korean RNs and care aids and to identify correlates of continence care practices. A cross-sectional survey was used to gather self-reported data from 338 nursing staff, including 135 RNs and 203 care aids, from 61 nursing homes in Korea by using an existing instrument adapted for Korean nursing staff. The instrument consists of 18 items designed to measure knowledge about urinary incontinence, 18 items querying attitudes toward continence care, 17 items focusing on beliefs about undesirable consequences to older adults with urinary incontinence, and 28 items querying on continence care practice. Registered nurses had higher knowledge about urinary incontinence and they had more positive attitudes toward continence care practice than care aids. Attitudes, facility bed capacity, and continuing education on urinary incontinence were significantly related (P < .05) to RNs' continence care practice scores (R = 0.285; P < .001), while care aids' practice scores were associated with knowledge and attitudes (R = 0.163; P < .001). Attitude plays an important role in continence care practice for both RNs and care aids in Korean nursing homes. In addition, continence care practice of RNs may be influenced by updating clinical competencies. For care aids, continence care practice can be influenced by improving basic knowledge of urinary incontinence.


Construction of a tobacco master line to improve Rubisco engineering in chloroplasts.
The inability to assemble Rubisco from any photosynthetic eukaryote within Escherichia coli has hampered structure-function studies of higher plant Rubisco. Precise genetic manipulation of the tobacco chloroplast genome (plastome) by homologous recombination has facilitated the successful production of transplastomic lines that have either mutated the Rubisco large subunit (L) gene, rbcL, or replaced it with foreign variants. Here the capacity of a new tobacco transplastomic line, (cm)trL, to augment future Rubisco engineering studies is demonstrated. Initially the rbcL was replaced with the selectable marker gene, aadA, and an artificial codon-modified (cm)rbcM gene that codes for the structurally novel Rubisco dimer (L(2), approximately 100 kDa) from Rhodosprillum rubrum. To obtain (cm)trL, the aadA was excised by transiently introducing a T-DNA encoding CRE recombinase biolistically. Selection using aadA enabled transplantation of mutated and wild-type tobacco Rubisco genes into the (cm)trL plastome with an efficiency that was 3- to 10-fold higher than comparable transformations into wild-type tobacco. Transformants producing the re-introduced form I tobacco Rubisco variants (hexadecamers comprising eight L and eight small subunits, approximately 520 kDa) were identified by non-denaturing PAGE with fully segregated homoplasmic lines (where no L(2) Rubisco was produced) obtained within 6-9 weeks after transformation which enabled their Rubisco kinetics to be quickly examined. Here the usefulness of (cm)trL in more readily examining the production, folding, and assembly capabilities of both mutated tobacco and foreign form I Rubisco subunits in tobacco plastids is discussed, and the feasibility of quickly assessing the kinetic properties of those that functionally assemble is demonstrated.


Chronic hepatitis: role of diffusion-weighted imaging and diffusion tensor imaging for the diagnosis of liver fibrosis and inflammation.
To determine the diagnostic performance of liver apparent diffusion coefficient (ADC) measured with conventional diffusion-weighted imaging (CDI) and diffusion tensor imaging (DTI) for the diagnosis of liver fibrosis and inflammation. Breathhold single-shot echo-planar imaging CDI and DTI with b-values of 0 and 500 second/mm(2) was performed in 31 patients with chronic liver disease and 13 normal volunteers. Liver biopsy was performed in all patients with liver disease with a median delay of two days from MRI. Fibrosis and inflammation were scored on a 5-point scale (0-4). Liver ADCs obtained with CDI and DTI were compared between patients stratified by fibrosis stage and inflammation grade. Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the utility of the ADC measures for prediction of fibrosis and inflammation. Patients with liver fibrosis and inflammation had significantly lower liver ADC than subjects without fibrosis or inflammation with CDI and DTI. For prediction of fibrosis stage > or = 1 and stage > or = 2, area under the ROC curve (AUC) of 0.848 and 0.783, sensitivity of 88.5% to 73.7%, and specificity of 73.3% to 72.7% were obtained, for ADC < or =1.40 x 10(-3) mm(2)/second and < or =1.30 x 10(-3) mm(2)/second (using CDI), respectively. For prediction of inflammation grade > or = 1, AUC of 0.825, sensitivity of 75.0%, and specificity of 78.6% were obtained using ADC < or = 1.30 x 10(-3) mm(2)/second (using CDI). CDI performed better than DTI for diagnosis of fibrosis and inflammation. Liver ADC can be used to predict liver fibrosis and inflammation with acceptable sensitivity and specificity.


Ethical issues in the health care system.
The purposes of this article are to discuss ethics and ethical principles as bases for decision making by health care professionals and to encourage dialogue among these professionals. Most people who begin a study of philosophy and ethics have philosophical beliefs; they have formed opinions about values and what constitutes ethical and moral behavior; they have ideas about autonomy and its place in the social structure. Advances in modern medical technology have, however, introduced new concerns among health care providers and consumers. Increased costs of provider services have tended to focus attention on costs and benefits of care, using monetary terms only. This article addresses the relation of ethics and morals to autonomy and the intertwining of specific concepts with costs and benefits to the consumer where costs to personal dignity and self-image are of particular importance. Included are a brief discussion of philosophical bases for decision making and definitions of terms common to the study of ethics.


An exploration of hypotheses that explain herbivore and pathogen attack in restored plant communities.
Many hypotheses address the associations of plant community composition with natural enemies, including: (i) plant species diversity may reduce enemy attack, (ii) attack may increase as host abundance increases, (iii) enemy spillover may lead to increased attack on one host species due to transmission from another host species, or enemy dilution may lead to reduced attack on a host that would otherwise have more attack, (iv) physical characteristics of the plant community may influence attack, and (v) plant vigor may affect attack. Restoration experiments with replicated plant communities provide an exceptional opportunity to explore these hypotheses. To explore the relative predictive strengths of these related hypotheses and to investigate the potential effect of several restoration site preparation techniques, we surveyed arthropod herbivore and fungal pathogen attack on the six most common native plant species in a restoration experiment. Multi-model inference revealed a weak but consistent negative correlation with pathogen attack and host diversity across the plant community, and no correlation between herbivory and host diversity. Our analyses also revealed host species-specific relationships between attack and abundance of the target host species, other native plant species, introduced plant species, and physical community characteristics. We found no relationship between enemy attack and plant vigor. We found minimal differences in plant community composition among several diverse site preparation techniques, and limited effects of site preparation techniques on attack. The strongest associations of community characteristics with attack varied among plant species with no community-wide patterns, suggesting that no single hypothesis successfully predicts the dominant community-wide trends in enemy attack.


[Donor outcomes after nephrectomy. Operative and postoperative morbidity--mortality and long-term impact of nephrectomy].
The increase of living donor kidney transplants has prompted new interest for better knowledge of the risks of mobidity and mortality and long-term consequences of nephrectomy Peroperative morbidity varies in revised series, partially in relation to surgical technique: laparoscopic or open nephrectomy. We review the most frequent complications by surgical technique. In the long term, the causes of mortality among donors are similar to general population with aging.


Assessment of the robustness of a serendipitous zinc binding fold: mutagenesis and protein grafting.
Zinc binding motifs have received much attention in the area of protein design. Here, we have tested the suitability of a recently discovered nonnative zinc binding structure as a protein design scaffold. A series of multiple alanine mutants was created to investigate the minimal requirements for folding, and solution structures of these mutants showed that the original fold was maintained, despite changes in approximately 50% of the sequence. We next attempted to transplant binding faces from chosen bimolecular interactions onto one of these mutants, and many of the resulting "chimeras" were shown to adopt a native-like fold. These results both highlight the robust nature of small zinc binding domains and underscore the complexity of designing functional proteins, even using such small, highly ordered scaffolds as templates.


Potential roles in rhinitis for protease and other enzymatic activities of allergens.
Exposure to airborne pollen, fungal allergens, and dust mite allergens is associated with the development of allergic rhinitis. Biologic function of allergens is considered to be a key determinant for allergenicity, and many clinically important allergens have been shown to possess enzymatic activity. It is proposed that by enabling allergens to breach the integrity of the airway epithelial barrier, proteolytic activity plays an adjuvant pro-allergic role influencing immunogenicity. In this review, current evidence regarding enzymatic activity of aeroallergens is described, and the potential role of aeroallergens in allergic rhinitis is discussed.


The neurology of parasitic diseases and malaria.
Neurologists should be aware of parasitic diseases occurring in travelers and recent migrants because the world has become a global village as a result of tourism and immigration. Global warming is changing the distribution of diseases formerly confined to the tropics. The two most common parasitic diseases of the nervous system are Plasmodium falciparum malaria presenting as a febrile encephalopathy with normal CSF and neurocysticercosis causing seizures with focal MRI lesions or with intracranial hypertension. Numerous parasites may cause larva migrans with eosinophilic meningitis. Spinal cord involvement is the signature presentation of schistosomiasis. Trypanosoma cruzi, the agent of Chagas disease in the Americas, may cause myocardiopathy and embolic stroke. Sleeping sickness remains the most common manifestation of African trypanosomiasis. These conditions are challenging to diagnose unless a history of travel is elicited. Prospective travelers should be advised of preventive measures to avoid potentially severe infections of the nervous system.


Novel de novo mutation in ZBTB20 in a Chinese Primrose syndrome family and a review of the literature.
Primrose syndrome is an autosomal dominant disorder characterized by craniofacial dysmorphism, mental retardation, developmental delay, progressive muscle atrophy and calcification of the earlobe due to a mutation in the ZBTB20. We reported a case of a Chinese boy with clinical symptoms resembling Primrose Syndrome, and performed genetic etiology analysis of the proband's family through Trio whole exome sequencing. A novel missense variant c.1927T>A(p.F643I) in exon 14 of the ZBTB20 (NM_001348803) was identified in the proband. This is the first report case of primrose syndrome in China, and our case extends the variant spectrum of ZBTB20 and further strengthens the understanding of primrose syndrome. However, there are no formal clinical guidelines for the management of this disease, and research on treatment and prognosis remains a challenge and focus in future.


Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent.
Chemical libraries paired with phenotypic screens can now readily identify compounds with therapeutic potential. A central limitation to exploiting these compounds, however, has been in identifying their relevant cellular targets. Here, we present a two-tiered CRISPR-mediated chemical-genetic strategy for target identification: combined genome-wide knockdown and overexpression screening as well as focused, comparative chemical-genetic profiling. Application of these strategies to rigosertib, a drug in phase 3 clinical trials for high-risk myelodysplastic syndrome whose molecular target had remained controversial, pointed singularly to microtubules as rigosertib's target. We showed that rigosertib indeed directly binds to and destabilizes microtubules using cell biological, in vitro, and structural approaches. Finally, expression of tubulin with a structure-guided mutation in the rigosertib-binding pocket conferred resistance to rigosertib, establishing that rigosertib kills cancer cells by destabilizing microtubules. These results demonstrate the power of our chemical-genetic screening strategies for pinpointing the physiologically relevant targets of chemical agents.


Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry and aggregation.
The Blood-brain barrier (BBB) controls brain supply with oxygen and nutrients, and protects the brain from toxic metabolites, such as beta-amyloid (Aβ) peptides. The neurovascular unit (NVU) couples vascular and neuronal functions by controlling BBB parameters based on brain needs. As such, NVU/BBB dysfunction, associated to irregularities in cerebral blood flow (CBF), has been proposed to contribute in the pathogenesis of Alzheimer's disease (AD), mainly by impairing cerebral Aβ clearance. However, the spatiotemporal contribution of the NVU/BBB in the neurodegenerative cascades remains elusive. By using C57BL/6J mice subjected to right common carotid artery (rCCA) permanent ligation in order to induce mild chronic cerebral hypoperfusion, we show here that cerebral hypoperfusion induced NVU dysfunction by reducing ABCB1 protein expression in brain capillaries. ABCB1 reduction was mainly triggered by an enhanced Glycogen Synthase Kinase 3 (GSK3β) activation, which decreased β-catenin nuclear abundance. Moreover, cerebral hypoperfusion triggered early vascular deposition of peripherally applied human Aβ1-42 peptides, which has shifted from highly vascular to the parenchyma 6 weeks later, forming small stable Aβ deposits. Hypoperfusion induced a deregulation in glucose metabolism, as brain reperfusion, or the administration of a high dose of glucose, diminished GSK3β activation, recuperated β-catenin nuclear abundance, reestablished ABCB1 protein expression, and prevented Aβ vascular early deposition. These results demonstrate that mild chronic cerebral hypoperfusion creates a metabolically deregulated microenvironment, thus triggering the brain entry and aggregation of peripherally applied human Aβ1-42 peptides. Our study offers new insights on the initiation of the neurodegenerative cascades observed in AD, which could be valuable in developing adequate treatment strategies.


Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients.
We evaluated specimens obtained from the biopsy of spontaneously ruptured tendons in 891 patients who were treated between 1968 and 1989. The specimens, which were removed at the time of repair, included 397 Achilles tendons, 302 biceps brachii tendons, forty extensor pollicis longus tendons, eighty-two quadriceps tendons and patellar ligaments, and seventy other tendons. Age and sex-matched control specimens, from 445 tendons taken at the time of death from the cadavera of previously healthy individuals who died accidentally, also were obtained and evaluated. The histopathological analyses of the specimens included light and polarized light microscopy and scanning and transmission electron microscopy. A healthy structure was not seen in any spontaneously ruptured tendon, but two-thirds of the control tendons were structurally healthy (p less than 0.001). There were characteristic histopathological patterns in the spontaneously ruptured tendons. Most (97 per cent) of the pathological changes were degenerative; they included hypoxic degenerative tendinopathy, mucoid degeneration, tendolipomatosis, and calcifying tendinopathy, either alone or in combination. These changes were also found in 34 per cent of the control tendons, but significantly less frequently (p less than 0.001). In the other twenty-six ruptured tendons (3 per cent), the pathological change was an intratendinous foreign body, rheumatoid tendinitis, a xanthoma, a tumor, or a tumor-like lesion such as an intratendinous ganglion. The findings clearly indicate that, at least in an urban population, degenerative changes are common in the tendons of people who are older than thirty-five years and that these changes are associated with spontaneous rupture.


Manipulating root water supply elicits major shifts in the shoot proteome.
Substantial reductions in yield caused by drought stress can occur when parts of the root system experience water deficit even though other parts have sufficient access to soil water. To identify proteins associated to drought signaling, rice (Oryza sativa L. cv. IR64.) plants were transplanted into plastic pots with an internal wall dividing each pot into two equal compartments, allowing for equal distribution of soil and the root system between these compartments. The following treatments were applied: either both compartments were watered daily ("wet" roots), or water was withheld from both compartments ("dry" roots), or water was withheld from only one of the two compartments in each pot ("wet" and "dry" roots). The substantial differences in physiological parameters of different growth conditions were accompanied by differential changes in protein abundances. Label-free quantitative shotgun proteomics have resulted in identification of 1383 reproducible proteins across all three conditions. Differentially expressed proteins were categorized within 17 functional groups. The patterns observed were interesting in that in some categories such as protein metabolism and oxidation-reduction, substantial numbers of proteins were most abundant when leaves were receiving signals from "wet" and "dry" roots. In yet other categories such as transport, several key transporters were surprisingly abundant in leaves supported by partially or completely droughted root systems, especially plasma membrane and vacuolar transporters. Stress-related proteins behaved very consistently by increasing in droughted plants but notably some proteins were most abundant when roots of the same plant were growing in both wet and dry soils. Changes in carbohydrate-processing proteins were consistent with the passive accumulation of soluble sugars in shoots under drought, with hydrolysis of sucrose and starch synthesis both enhanced. These results suggest that drought signals are complex interactions and not simply the additive effect of water supply to the roots.


Hydroxychloroquine-induced erythroderma.
Erythroderma is characterized by diffuse erythema and scaling of the skin involving more than 90% of the total body skin surface area. Drug-induced erythroderma has rarely been reported with hydroxychloroquine. We report a case of a 50-year-old female patient, with systemic lupus erythematosus, who developed itchy lesions all over the body 1 month after starting treatment with hydroxychloroquine. Drug-induced erythroderma was suspected. Hydroxychloroquine was withdrawn and the patient was treated with emollients, mid-potency corticosteroids, and oral antihistamines. A biopsy was done which confirmed the diagnosis of erythroderma. She recovered with treatment and was discharged. A careful history and clinical examination to search for potential causative factors will help prevent disabling sequelae in erythroderma.


Qualitative study on maternal referrals in rural Tanzania: decision making and acceptance of referral advice.
The aim of this study was to describe perceptions of maternal referrals in a rural district in Tanzania. Focus group discussions (FGDs) with health workers and community members, stratified by age and gender, were conducted. The FGDs revealed that husbands and relatives are the decision makers in maternal referrals, whereas the women had limited influence, especially on emergency referrals. The process in deciding to seek referral care is envisaged within community perception of seriousness of the condition, difficulty to access and cost involved in transport, living expenses at the hospital, and perceived quality of care at facility level. The hospitals were seen as providing acceptable quality of care, whereas, the health centres had lower quality than expected. To improve maternal referral compliance and reduce perinatal and maternal morbidity and mortality, community views of existing referral guidelines, poverty reduction, women's empowerment and male involvement in maternal care are necessary.


Marked hyperthermia as a manifestation of hypoglycemia in long-standing diabetes mellitus.
Hyperthermia has recently been recognized as a manifestation of hypoglycemia. We describe two episodes of hypoglycemia associated with nausea, vomiting, chills, and impaired consciousness which were followed by marked hyperthermia. We suggest that the hyperthermia may result from excessive reaction to preceding hypothermia caused by the hypoglycemia. We would like to alert the clinician to the possibility of a previous, severe hypoglycemic episode in any diabetic patient with hyperthermia and coma.


Arginine and asymmetric dimethylarginine in puromycin aminonucleoside-induced chronic kidney disease in the rat.
Reduced renal L-arginine (L-Arg) synthesis/transport, induction of arginases and increased endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) will inhibit NO production. This study investigated pathways of L-Arg synthesis/uptake/utilization, ADMA degradation and oxidant/antioxidants in puromycin aminonucleoside (PAN) chronic kidney disease (CKD). Rats were given low- (LD) or high-dose (HD) PAN and followed for 11 weeks for proteinuria. BP was measured and blood and tissues were harvested and analyzed for abundance of argininosuccinate synthase (ASS) and lyase (ASL), arginase, cationic amino acid transporter (CAT1) and dimethylargininedimethylaminohydrolase (DDAH) in kidney, cortex, aorta and liver. Arginase and DDAH activity, plasma L-Arg and ADMA, renal pathology and creatinine clearances were also measured. PAN caused dose-dependent kidney damage and hypertension and creatinine clearance fell in HD-PAN. Renal ASS fell in HD-PAN, renal cortex and aortic ASL and membrane CAT1 fell in both PAN groups. There was no activation of renal arginase, but aortic arginase increased in LD-PAN. Renal DDAH activity fell moderately in LD-PAN and markedly in HD-PAN where hepatic DDAH activity also fell. Plasma L-Arg was unchanged while ADMA rose moderately and dose-dependently with PAN. There were several indices of oxidative stress which was most prominent in HD-PAN. Reduction in renal ASS/ASL and loss of renal cortex CAT1 compromises renal L-Arg synthesis and release. Loss of aortic CAT1 impairs L-Arg uptake. Increased plasma ADMA was associated with progressive loss of renal DDAH activity. However, loss of renal clearance and falls in hepatic DDAH activity in HD-PAN did not have additive effects on plasma ADMA.


Functional Activation During a Cognitive Control Task in Healthy Youth Specific to Externalizing or Internalizing Behaviors.
Externalizing behaviors are negative behaviors expressed outwardly, including rule breaking, aggression, and risk taking; internalizing behaviors are expressed inwardly, including depression, withdrawal, and anxiety. Such behavior can cause problems in early life and predict difficulties across the lifespan. There is evidence for a relationship between executive function and both externalizing and internalizing. However, although these behaviors occur along a spectrum, there is little neuroimaging research on this relationship in typically developing youth. We assessed 41 youth (10-19 years of age) using the Multi-Source Interference Task during functional magnetic resonance imaging and related the findings to self-reported externalizing and internalizing scores as measured by the Youth Self-Report. We performed a general linear model using FSL software; externalizing, internalizing, age, and sex were included in the model. Compared to the control condition, the more difficult Multi-Source Interference Task interference condition was associated with greater engagement of the frontoparietal cognitive control system and decreased engagement of regions in the default mode network, based on a cluster threshold of Z > 3.1 (p = .01). When we examined regions uniquely associated with either internalizing or externalizing, we found that within the same group of subjects, higher externalizing behavior was associated with hyperactivity in the parietal lobe; in contrast, higher internalizing behavior was associated with increased activation in the medial prefrontal cortex. These findings suggest that externalizing and internalizing may be associated with altered, but different, patterns of activation during cognitive control. This has implications for our understanding of the relationship between cognitive control and behavioral problems in youth.


Interleukin 1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells.
The cytokine interleukin 1 (IL-1) inhibits contractile responses in rat aorta by causing endothelium-independent and prolonged activation of soluble guanylate cyclase. The present study tested whether IL-1 activates guanylate cyclase by inducing prolonged production of nitric oxide in cultured rat aortic vascular smooth muscle cells (VSMC). IL-1 induced a marked time-dependent increase in cyclic guanosine monophosphate (cGMP) in VSMC which was significant at 6 h, and increased progressively for up to 36 h. This effect of IL-1 was abolished when protein synthesis was inhibited with cycloheximide or actinomycin D, suggesting that the effect of IL-1 involves new protein synthesis. IL-1-induced cGMP accumulation was inhibited by the soluble guanylate cyclase inhibitors, methylene blue, LY83583, and hemoglobin and by the L-arginine analogue NGmonomethyl-L-arginine (L-NMMA). The inhibitory effect of L-NMMA was reversed by a 10-fold excess of L-arginine, but not by D-arginine. Nitrite, an oxidation product of nitric oxide, accumulated in the media of VSMC incubated with IL-1 for 24 h in the presence of L-arginine, whereas both IL-1-induced cGMP accumulation and nitrite production were attenuated in VSMC incubated in L-arginine-deficient medium. In L-arginine-depleted VSMC, IL-1-induced cGMP accumulation was restored to control levels by a 15-min incubation with L-arginine. These results demonstrate that IL-1 activates guanylate cyclase in rat VSMC by inducing production of nitric oxide via a pathway dependent on extracellular L-arginine.


Caries inhibiting and remineralizing effect of xylitol in vitro.
This study aimed to determine the effect of xylitol on the development and remineralization of caries in vitro, and to compare this effect with that of fluoride alone and in combination. Two experiments were devised. In experiment 1, bovine incisors were each sectioned into 4 portions which were randomly assigned to 4 demineralizing agents: A) acidic buffer (x), B) x + 0.5 ppm fluoride, C) x + 20% xylitol, and D) x + 20% xylitol + 0.5 ppm fluoride. Caries-like lesions were produced in specimens. In experiment 2, carious lesions were produced in teeth. Five lesion-bearing slabs were cut from each tooth. While one was reserved as control (UN), others were randomly assigned to 4 remineralizing agents: 1) artificial saliva (y), 2) y + 0.05 ppm fluoride, (3) y + 20% xylitol, and 4) y + 20% xylitol + 0.05 ppm fluoride. Mineral loss (delta Z) and lesion depth (ld) were quantified after 4-week remineralization. In experiment 1, numerical values of delta Z and ld observed can be ranked as A > C > B > D. These differences were significant only in B and D when compared with A for delta Z, but not between any group for ld. In experiment 2, the numerical values of delta Z and ld for control UN (unremineralized) and remineralized groups (1-4) ranked as UN > 3 > 4 > 1 > 2. Compared with UN, this difference was significant in all groups with ld, but not in any group with delta Z. We concluded that tolerable levels of xylitol alone may not show a significant caries inhibiting and remineralizing effect, but may act as a caries inhibitor additively with fluoride.


Allee effect and self-fertilization in hermaphrodites: reproductive assurance in demographically stable populations.
The fact that selfing increases seed set (reproductive assurance) has often been put forward as an important selective force for the evolution of selfing. However, the role of reproductive assurance in hermaphroditic populations is far from being clear because of a lack of theoretical work. Here, I propose a theoretical model that analyzes self-fertilization in the presence of reproductive assurance. Because reproductive assurance directly influences the per capita growth rate, I developed an explicit demographic model for partial selfers in the presence of reproductive assurance, specifically when outcrossing is limited by the possibility of pollen transfer (Allee effect). Mating system parameters are derived as a function of the underlying demographical parameters. The functional link between population demography and mating system parameters (reproductive assurance, selfing rate) can be characterized. The demographic model permits the analysis of the evolution of self-fertilization in stable populations when reproductive assurance occurs. The model reveals some counterintuitive results such as the fact that increasing the fraction of selfed ovules can, in certain circumstances, increase the fraction of outcrossed ovules. Moreover, I demonstrate that reproductive assurance per se cannot account for the evolution of stable mixed selfing rates. Also, the model reveals that the extinction of outcrossing populations depends on small changes in population density (ecological perturbations), while the transition from outcrossing to selfing can, in certain cases, lead the population to extinction (evolutionary suicide). More generally, this paper highlights the fact that self-fertilization affects both the dynamics of individuals and the dynamics of selfing genes in hermaphroditic populations.


Repair of pectus excavatum. Anesthetic considerations.
The majority of patients undergoing pectus excavatum repair can be safely anesthetized with routine clinical preoperative evaluation and chest radiography. Electrocardiography, echocardiography, arterial blood gas, and pulmonary function tests should be reserved for patients with suspected coexisting conditions, such as mitral valve prolapse, skeletal abnormalities, Marfan's syndrome, and pulmonary disease. The choice of surgical repair and the advisability of placement of an epidural catheter or intercostal blocks for perioperative pain management should be discussed with the surgical team. Postoperatively, patients should be carefully monitored for signs of tension pneumothorax and pneumonia.


Simultaneous saccharification and cofermentation of dilute-acid pretreated yellow poplar hardwood to ethanol using xylose-fermenting Zymomonas mobilis.
Simultaneous saccharification and cofermentation (SSCF) was carried out at approximately 15% total solids using conditioned dilute-acid pretreated yellow poplar feedstock, an adapted variant of National Renewable Energy Laboratory (NREL) xylose-fermenting Zymomonas mobilis and either commercial or NREL-produced cellulase enzyme preparations. In 7 d, at a cellulase loading of 12 filter paper units per gram cellulose (FPU/g), the integrated system produced more than 3% w/v ethanol and achieved 54% conversion of all potentially available biomass sugars (total sugars) entering SSCF. A control SSCF employing Sigmacell cellulose and a commercial cellulase at an enzyme loading of 14 FPU/g achieved 65% conversion of total sugars to ethanol.


Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study.
To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response. DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.


The logic, experimental steps, and potential of heterologous natural product biosynthesis featuring the complex antibiotic erythromycin A produced through E. coli.
The heterologous production of complex natural products is an approach designed to address current limitations and future possibilities. It is particularly useful for those compounds which possess therapeutic value but cannot be sufficiently produced or would benefit from an improved form of production. The experimental procedures involved can be subdivided into three components: 1) genetic transfer; 2) heterologous reconstitution; and 3) product analysis. Each experimental component is under continual optimization to meet the challenges and anticipate the opportunities associated with this emerging approach. Heterologous biosynthesis begins with the identification of a genetic sequence responsible for a valuable natural product. Transferring this sequence to a heterologous host is complicated by the biosynthetic pathway complexity responsible for product formation. The antibiotic erythromycin A is a good example. Twenty genes (totaling >50 kb) are required for eventual biosynthesis. In addition, three of these genes encode megasynthases, multi-domain enzymes each ~300 kDa in size. This genetic material must be designed and transferred to E. coli for reconstituted biosynthesis. The use of PCR isolation, operon construction, multi-cystronic plasmids, and electro-transformation will be described in transferring the erythromycin A genetic cluster to E. coli. Once transferred, the E. coli cell must support eventual biosynthesis. This process is also challenging given the substantial differences between E. coli and most original hosts responsible for complex natural product formation. The cell must provide necessary substrates to support biosynthesis and coordinately express the transferred genetic cluster to produce active enzymes. In the case of erythromycin A, the E. coli cell had to be engineered to provide the two precursors (propionyl-CoA and (2S)-methylmalonyl-CoA) required for biosynthesis. In addition, gene sequence modifications, plasmid copy number, chaperonin co-expression, post-translational enzymatic modification, and process temperature were also required to allow final erythromycin A formation. Finally, successful production must be assessed. For the erythromycin A case, we will present two methods. The first is liquid chromatography-mass spectrometry (LC-MS) to confirm and quantify production. The bioactivity of erythromycin A will also be confirmed through use of a bioassay in which the antibiotic activity is tested against Bacillus subtilis. The assessment assays establish erythromycin A biosynthesis from E. coli and set the stage for future engineering efforts to improve or diversify production and for the production of new complex natural compounds using this approach.


[Methods for the costing process in the field of economic evaluation of a rehabilitation program for patients with chronic obstructive lung diseases].
Studies in health economics especially economic evaluations of health care technologies and programmes are getting more and more important. However, in Germany there are no established, validated and commonly used instruments for the costing process. For the economic evaluation of a rehabilitation programme for patients with chronic lung diseases such as asthma and chronic bronchitis we developed methods for identification, measurement and validation of resource use during the inpatient rehabilitation programme and during the outpatient follow-up period. These methods are based on methodological considerations as well as on practical experience from conducting a pilot study. With regard to the inpatient setting all relevant diagnostic and therapeutic resource uses could be measured basing on routine clinical documentation and validated by using the cost accounting of the clinic. For measuring the use of resources during the follow-up period in an outpatient setting no reliable administrative data are accessible. Hence, we compared a standardised retrospective patient questionnaire used in a 20-minute interview (n = 50) and a cost diary for the continuing documentation by the patient over a period of 4 weeks (n = 50). Both tools were useful for measuring all relevant resource uses in sufficient detail, but because of higher participation rates and lower dropouts the structured interview appears to be more suitable. Average total costs per month were 1591 DM (interview), respectively 1867 DM (cost diary). Besides productivity loss, costs for medication and GP visits caused the relatively highest resource uses. Practicable instruments were developed for the costing process as part of an economic evaluation in a German rehabilitation setting for pulmonary diseases. After individual modification, these could also be used for different indications and in other institutional settings.


Impact of frontal lobe lesions on rehabilitation and recovery from acute brain injury.
The frontal lobe has been viewed historically in very different ways, ranging from enigmatic and mystifying to the crucial neural substrate for higher cognition and social behavior. Frontal lobe damage poses a unique and difficult set of challenges to the patient, their family and the neurorehabilitation team. Because of the role of the frontal lobe in adaptation and adjustment, such damage adversely affects a patient's participation in the process and content of rehabilitation. To aid diagnosis and treatment planning, a model of frontal lobe organization is outlined, focusing on the specific cognitive and behavioral symptom clusters associated with superior mesial, inferior mesial, dorsolateral and orbital frontal lesions. A taxonomy of social executive processes is presented for identifying impairments in social behavior and personality, based upon the domains of social self-regulation, social self-awareness, social-sensitivity (empathy), and social-salience. Specific interventions are described that encompass dopamine agonist therapy for blunted affect, mutism and akinesia, cognitive strategies for improving organization and planning deficits, and evolving treatments for social impairments.


Segmental aneuploidy and the genetic gross structure of the Drosophila genome.
By combining elements of two Y-autosome translocations with displaced autosomal breakpoints, it is possible to produce zygotes heterozygous for a deficiency for the region between the breakpoints, and also, as a complementary product, zygotes carrying a duplication for precisely the same region. A set of Y-autosome translocations with appropriately positioned breakpoints, therefore, can in principle be used to generate a non-overlapping set of deficiencies and duplications for the entire autosomal complement.-Using this method, we have succeeded in examining segmental aneuploids for 85% of chromosomes 2 and 3 in order to assess the effects of aneuploidy and to determine the number and location of dosage-sensitive loci in the Drosophila genome (Figure 5). Combining our data with previously reported results on the synthesis of Drosophila aneuploids (see Lindsley and Grell 1968), the following generalities emerge.-1. The X chromosome contains no triplo-lethal loci, few or no haplo-lethal loci, at least seven Minute loci, one hyperploid-sensitive locus, and one locus that is both triplo-abnormal and haplo-abnormal. 2. Chromosome 2 contains no triplo-lethal loci, few or no haplo-lethal loci, at least 17 Minute loci, and at least four other haplo-abnormal loci. 3. Chromosome 3 contains one triplo-lethal locus that is also haplo-lethal, few or no other haplo-lethal loci, at least 16 Minute loci, and at least six other haplo-abnormal loci. 4. Chromosome 4 contains no triplo-lethal loci, no haplo-lethal loci, one Minute locus, and no other haplo-abnormal loci.-Thus, the Drosophila genome contains 57 loci, aneuploidy for which leads to a recognizable effect on the organism: one of these is triplo-lethal and haplo-lethal, one is triplo-abnormal and haplo-abnormal, one is hyperploid-sensitive, ten are haplo-abnormal, 41 are Minutes, and three are either haplo-lethals or Minutes. Because of the paucity of aneuploid-lethal loci, it may be concluded that the deleterious effects of aneuploidy are mostly the consequence of the additive effects of genes that are slightly sensitive to abnormal dosage. Moreover, except for the single triplo-lethal locus, the effects of hyperploidy are much less pronounced than those of the corresponding hypoploidy.


Family physicians' involvement and self-reported comfort and skill in care of children with behavioral and emotional problems: a population-based survey.
Little is known about general and family practitioners' (GP/FPs') involvement and confidence in dealing with children with common psychosocial problems and mental health conditions. The aims of this study were to ascertain GP/FPs' preferred level of involvement with, and perceived comfort and skill in dealing with children with behavioral problems, social-emotional difficulties, attention-deficit/hyperactivity disorder (ADHD), and mood disorders; and to identify factors associated with GP/FPs' involvement, comfort and skill. Postal survey of a representative sample of 801 GP/FPs in British Columbia, Canada, which enquired about level of involvement (from primarily refer out to deal with case oneself); ratings of comfort/skill with assessment/diagnosis and management; beliefs regarding psychosocial problems in children; basic demographics; and practice information. Surveys were completed by 405 of 629 eligible GP/FPs (64.4%). Over 80% of respondents reported collaborative arrangements with specialists across problem and condition types, although for children with behavior problems or ADHD, more physicians primarily refer (chi2 (1) = 9.0; P < 0.005; and chi2 (1) = 103.9; P < 0.001, respectively). Comfort/skill levels (mean +/- s.d) were higher for mood disorders (4.4 +/- 1.3) than behavior problems (3.6 +/- 1.1; F [3, 1155] = 84.0, P < .0001; effect size = 0.67), but not different from social-emotional difficulties (3.8 +/- 1.1) or ADHD (3.9 +/- 1.3). Taking primary responsibility for a case was consistently related to self-reported comfort/skill with each condition type (34% to 61% of variance across condition types), while comfort/skill ratings for each condition were related to exposure to relevant continuing medical education (all P < or = 0.001), and beliefs that these problems are significant and that GP/FPs have a role to play in dealing with them (P values ranged from 0.01 to < 0.001). Supporting GP/FPs in their care for children with common psychosocial and mental health problems should include efforts to bolster their confidence and modify attitudes in relation towards these problems, especially behavior problems and ADHD, possibly within innovative continuing education programs.


Gene expression profiling identifies pathways involved in seed maturation of Jatropha curcas.
Jatropha curcas, a tropical shrub, is a promising biofuel crop, which produces seeds with high content of oil and protein. To better understand the maturation process of J. curcas seeds and to improve its agronomic performance, a two-step approach was performed in six different maturation stages of seeds: 1) generation of the entire transcriptome of J. curcas seeds using 454-Roche sequencing of a cDNA library, 2) comparison of transcriptional expression levels using a custom Agilent 8x60K oligonucleotide microarray. A total of 793,875 high-quality reads were assembled into 19,382 unique full-length contigs, of which 13,507 could be annotated with Gene Ontology (GO) terms. Microarray data analysis identified 9111 probes (out of 57,842 probes), which were differentially expressed between the six maturation stages. The expression results were validated for 75 selected transcripts based on expression levels, predicted function, pathway, and length. Result from cluster analyses showed that transcripts associated with fatty acid, flavonoid, and phenylpropanoid biosynthesis were over-represented in the early stages, while those of lipid storage were over-represented in the late stages. Expression analyses of different maturation stages of J. curcas seed showed that most changes in transcript abundance occurred between the two last stages, suggesting that the timing of metabolic pathways during seed maturation in J. curcas occurs in late stages. The co-expression results showed that the hubs (CB5-D, CDR1, TT8, DFR, HVA22) with the highest number of edges, associated with fatty acid and flavonoid biosynthesis, are showing a decrease in their expression during seed maturation. Furthermore, seed development and hormone pathways are significantly well connected. The obtained results revealed differentially expressed sequences (DESs) regulating important pathways related to seed maturation, which could contribute to the understanding of the complex regulatory network during seed maturation with the focus on lipid, flavonoid and phenylpropanoid biosynthesis. This study provides detailed information on transcriptional changes during J. curcas seed maturation and provides a starting point for a genomic survey of seed quality traits. The results highlighted specific genes and processes relevant to the molecular mechanisms involved in Jatropha seed maturation. These data can also be utilized regarding other Euphorbiaceae species.


Evaluation of cholesterol and triglyceride concentrations in differentiating chylous and nonchylous pleural effusions in dogs and cats.
Serum and pleural fluid cholesterol and triglyceride concentrations and cholesterol/triglyceride ratios were determined in 9 dogs and 9 cats with pleural effusion (8 nonchylous, 10 chylous). The pleural fluid triglyceride concentrations were significantly higher (P less than 0.05) and the pleural cholesterol/triglyceride ratios were significantly lower (P less than 0.05) in chylous effusions than in nonchylous effusions in all animals. There were no differences in serum cholesterol and triglyceride concentrations and serum cholesterol/triglyceride ratios for chylous and nonchylous effusions in either species. There also were no differences in pleural fluid cholesterol concentrations between the 2 groups in the dog or cat. It was concluded that determinations of cholesterol/triglyceride ratios may be an accurate method for helping distinguish chylous from nonchylous effusions in dogs and cats.


[Pilot scheme to gain young professionals in orthopedics and trauma surgery. A new optional subject for students at the medical school in Göttingen (Germany)].
The Young Forum of the German Society of Orthopedics and Traumatology is an interest group of young orthopedics and trauma surgeons in Germany. Besides dealing with topics of political interest, the group tries to arouse enthusiasm and interest for musculoskeletal surgery by means of new lectures and teaching methods.An example is the newly invented optional subject for students at the Medical School in Göttingen (Germany). The idea for such a new teaching offer was built by the Young Forum itself. The optional subject was on the syllabus for the first time this year and the organization was done by the university Department of Trauma Surgery, Plastic and Reconstructive Surgery. The course is divided in two main parts: a theoretical (16 hours) and a practical (10 hours) one. A good ratio of lectures, skills stations and workshops was on choice. This article explains the course in detail and shows a first evaluation result.


Mutations within DR2 independently reduce the amount of both minus- and plus-strand DNA synthesized during duck hepatitis B virus replication.
The initial aim of this study was to examine the role of complementarity between the plus-strand primer and the minus-strand DNA template for translocation of the plus-strand primer in hepadnaviral replication. We show that when a 5-nucleotide substitution was placed in either DR1 or DR2, translocation of the primer at a detectable level did not occur. Placing the mutation in both DR1 and DR2 did not restore primer translocation, which indicates that complementarity is not the sole determinant for primer translocation. These mutants, in which primer translocation has been inhibited, have been additionally informative. The mutation in DR1 led to efficient synthesis of plus-strand DNA, albeit primed in situ. In contrast, the mutation in DR2 resulted in a reduction in the amount of plus-strand DNA synthesized per unit of minus-strand DNA. These findings were interpreted as indicating that a mutation at DR2, the primer acceptor site, can inhibit both primer translocation and in situ priming. Lastly, we show that mutations within DR2 can result in a reduction in the synthesis of minus-strand DNA and that this reduction is occurring at an early phase of the process. We speculate that this reduction in the amount of minus-strand DNA synthesized could be due to an inhibition of the template switch during minus-strand DNA synthesis.