The Role of Urban Morphology Design on Enhancing Physical Activity and Public Health.
Along with environmental pollution, urban planning has been connected to public health. The research indicates that the quality of built environments plays an important role in reducing mental disorders and overall health. The structure and shape of the city are considered as one of the factors influencing happiness and health in urban communities and the type of the daily activities of citizens. The aim of this study was to promote physical activity in the main structure of the city via urban design in a way that the main form and morphology of the city can encourage citizens to move around and have physical activity within the city. Functional, physical, cultural-social, and perceptual-visual features are regarded as the most important and effective criteria in increasing physical activities in urban spaces, based on literature review. The environmental quality of urban spaces and their role in the physical activities of citizens in urban spaces were assessed by using the questionnaire tool and analytical network process (ANP) of structural equation modeling. Further, the space syntax method was utilized to evaluate the role of the spatial integration of urban spaces on improving physical activities. Based on the results, consideration of functional diversity, spatial flexibility and integration, security, and the aesthetic and visual quality of urban spaces plays an important role in improving the physical health of citizens in urban spaces. Further, more physical activities, including motivation for walking and the sense of public health and happiness, were observed in the streets having higher linkage and space syntax indexes with their surrounding texture.


High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy.
Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.


Msx1 and Msx2 regulate survival of secondary heart field precursors and post-migratory proliferation of cardiac neural crest in the outflow tract.
Msx1 and Msx2 are highly conserved, Nk-related homeodomain transcription factors that are essential for a variety of tissue-tissue interactions during vertebrate organogenesis. Here we show that combined deficiencies of Msx1 and Msx2 cause conotruncal anomalies associated with malalignment of the cardiac outflow tract (OFT). Msx1 and Msx2 play dual roles in outflow tract morphogenesis by both protecting secondary heart field (SHF) precursors against apoptosis and inhibiting excessive proliferation of cardiac neural crest, endothelial and myocardial cells in the conotruncal cushions. During incorporation of SHF precursors into the OFT myocardium, ectopic apoptosis in the Msx1-/-; Msx2-/- mutant SHF is associated with reduced expression of Hand1 and Hand2, which from work on Hand1 and Hand2 mutants may be functionally important in the inhibition of apoptosis in Msx1/2 mutants. Later during aorticopulmonary septation, excessive proliferation in the OFT cushion mesenchyme and myocardium of Msx1-/-; Msx2-/- mutants is associated with premature down-regulation of p27(KIP1), an inhibitor of cyclin-dependent kinases. Diminished accretion of SHF precursors to the elongating OFT myocardium and excessive accumulation of mesenchymal cells in the conotruncal cushions may work together to perturb the rotation of the truncus arteriosus, leading to OFT malalignment defects including double-outlet right ventricle, overriding aorta and pulmonary stenosis.


[Experimental efficacy of IgY antibodies produced in eggs against the venom of the Peruvian snake Bothrops atrox].
To develop an immunization protocol in order to produce avian IgY immunoglobulins against Bothrops atrox Peruvian snake venom and to evaluate its neutralizing capacity. Six Hy Line Brown hens were immunized each two weeks using 500μg/doses of B. atrox venom in a period of two months. Each week, eggs were collected for IgY isolation from yolk using two consecutive steps with caprilic acid and ammonium sulfate. Detection of IgY anti-B. atrox were performed by double immunodiffusion, whereas title and cross-reactivity were analyzed using ELISA and Western Blot technics, respectively. Furthermore, letal dose (DL(50)) and Medium Effective Dose (DE(50)) were obtained by Probit analysis. As a result of this protocol, chicken IgY's were obtained in a concentration of 8,5 ± 1,35 mg/yolk mL. DE50 from avian antivenom was 575 μL/venom mg. Cross-reactivity studies showed Bothrops atrox venom share more commom epitopes with Bothrops brazili (47%) than others Bothrops venoms showing Lachesis muta (19%) and Crotalus durissus (12%) venoms a low crossing reactivity, instead. Using this procedure, we could purify chicken IgY with a neutralizant capacity of B. atrox venom which is comparable to the antivenom of equine origin and demonstrate its capacity as a immunoanalitical tool to evaluate the cross reactivity with others peruvian snakes.


Structural characteristics of compounds that can be activated to chemically reactive metabolites: use for a prediction of a carcinogenic potential.
Many mutagens and carcinogens act via covalent interaction of metabolic intermediates with DNA in the target cell. This report groups those structural elements which are often found to form the basis for a metabolism to such chemically reactive metabolites. Compounds which are chemically reactive per se and which do not require metabolic activation form group 1. Group 2 comprises of olefins and aromatic hydrocarbons where the oxidation via an epoxide can be responsible for the generation of reactive species. Aromatic amines, hydrazines, and nitrosamines form group 3 requiring an oxidation of a nitrogen atom or of a carbon atom in alpha position to a nitrosated amine. Group 4 compounds are halogenated hydrocarbons which can either give rise to radicals or can form an olefin (group 2) upon dehydrohalogenation. Group 5 compounds depend upon some preceding enzymatic activity either not available in the target cell or acting on positions in the molecule which are not directly involved in the subsequent formation of electrophilic atoms. Examples for each group are taken from the "List of Chemicals and Industrial Processes Associated with Cancer in Humans" as compiled by the International Agency for the Research on Cancer, and it is shown that 91% of the organic carcinogens would have been detected on the basis of structural elements characteristic for group 1-5. As opposed to this very high sensitivity, the specificity (the true negative fraction) of using this approach as a short-term test for carcinogenicity is shown to be bad because detoxification pathways have so far not been taken into account. These competing processes are so complex, however, that either only very extensive knowledge about pharmacokinetics, stability, and reactivity will be required or that in vivo systems have to be used to predict, on a quantitative basis, the damage expected on the DNA. DNA-binding experiments in vivo are presented with benzene and toluene to demonstrate one possible way for an experimental assessment and it is shown that the detoxification reaction at the methyl group available only in toluene gives rise to a reduction by at least a factor of forty for the binding to rat liver DNA. This quantitative approach available with DNA-binding tests in vivo, also allows evaluation as to whether reactive metabolites and their DNA binding are always the most important single activities contributing to the overall carcinogenicity of a chemical.(ABSTRACT TRUNCATED AT 400 WORDS)


Impaired everyday memory associated with encephalopathy of severe malaria: the role of seizures and hippocampal damage.
Seizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage. An everyday memory battery was administered on 152 children with cerebral malaria (CM) (mean age, 7 y 4 months [SD 13 months]; 77 males) 156 children (mean age, 7 y 4 months [SD, 14 months]; 72 males) with malaria plus complex seizures (MS) and 179 children (mean age, 7 y 6 months [SD, 13 months]; 93 males) unexposed to either condition. CM was associated with poorer everyday memory [95% CI, -2.46 to -0.36, p = 0.004] but not MS [95% CI, -0.91 to 1.16, p = 1.00] compared to unexposed children. Children with exposure to CM performed more poorly in recall [95% CI, -0.79 to -0.04, p = 0.024] and recognition subtests [95% CI, -0.90 to -0.17, p = 0.001] but not in prospective memory tests compared to controls. The health factors that predicted impaired everyday memory outcome in children with exposure to CM was profound coma [95% CI, 0.02 to 0.88, p = 0.037] and multiple episodes of hypoglycaemia [95% CI, 0.05 to 0.78, p = 0.020], but not seizures. The findings show that exposure to CM was associated with a specific impairment of everyday memory. Seizures commonly observed in severe malaria may not have a causal relationship with poor outcome, but rather be associated with profound coma and repeated metabolic insults (multi-hypoglycaemia) that are strongly associated with impaired everyday memory.


Stem cell- and growth factor-based regenerative therapies for avascular necrosis of the femoral head.
Avascular necrosis (AVN) of the femoral head is a debilitating disease of multifactorial genesis, predominately affects young patients, and often leads to the development of secondary osteoarthritis. The evolving field of regenerative medicine offers promising treatment strategies using cells, biomaterial scaffolds, and bioactive factors, which might improve clinical outcome. Early stages of AVN with preserved structural integrity of the subchondral plate are accessible to retrograde surgical procedures, such as core decompression to reduce the intraosseous pressure and to induce bone remodeling. The additive application of concentrated bone marrow aspirates, ex vivo expanded mesenchymal stem cells, and osteogenic or angiogenic growth factors (or both) holds great potential to improve bone regeneration. In contrast, advanced stages of AVN with collapsed subchondral bone require an osteochondral reconstruction to preserve the physiological joint function. Analogously to strategies for osteochondral reconstruction in the knee, anterograde surgical techniques, such as osteochondral transplantation (mosaicplasty), matrix-based autologous chondrocyte implantation, or the use of acellular scaffolds alone, might preserve joint function and reduce the need for hip replacement. This review summarizes recent experimental accomplishments and initial clinical findings in the field of regenerative medicine which apply cells, growth factors, and matrices to address the clinical problem of AVN.


An open study comparing manual therapy with the use of cold packs in the treatment of post-traumatic headache.
One year after head trauma, 23 patients with post-traumatic headache entered a prospective clinical controlled trial to find out if specific manual therapy on the neck could reduce the headache. The study was completed by 19 patients (83%). Ten patients were treated twice with manual therapy and nine patients were treated twice with cold packs on the neck. The pain index was calculated blindly. Two weeks after the last treatment the mean pain index was significantly reduced to 43% in the group treated with manual therapy compared with the pretreatment level. At follow-up five weeks later, the pain index was still lower in this group compared with the group treated with cold packs, but this difference was not statistically significant. The pain index for all 19 patients was significantly correlated to the use of analgesics as well as to the frequency of associated symptoms (number of days per week with dizziness, visual disturbances and ear symptoms). It is concluded that the type of manual therapy used in this study seems to have a specific effect in reducing post-traumatic headache. The result supports the hypothesis of a cervical mechanism causing post-traumatic headache and suggests that post-traumatic dizziness, visual disturbances and ear symptoms could be part of a cervical syndrome.


A children's acute respiratory illness scale (CARIFS) predicted functional severity and family burden.
The Canadian Acute Respiratory Illness and Flu Scale (CARIFS) was developed to measure illness severity in children with acute respiratory infection. The objective of this study was to evaluate its performance in a European primary care setting. 178 children (median age 3 years) with cough and fever were recruited in UK general practice. Perceived severity of illness at recruitment was recorded by parents, doctors, and nurses. Parents also completed an illness diary, including the CARIF scale, until their child had recovered. In-depth interviews were conducted with 24 parents. Parents found CARIFS relatively easy and quick to complete (78% of parents returned a fully completed diary covering the duration of the illness), internal consistency was high (minimum item correlation with total score 0.22; overall Cronbach's alpha statistic 0.85), and responsiveness to improvement in health was good (observed effect size of 0.45 at 8 h). At presentation, however, neither the overall CARIFS score nor the clinical element of the score correlated with physician assessment of clinical severity. Of the three recognized domains of illness severity, CARIFS appears to be a good and valid measure of functional severity and burden of illness to the parent but it may not be a good measure of physiological severity.


Refinement of a radioreceptor binding assay for nicotinic acid adenine dinucleotide phosphate.
The measurement of changes in nicotinic acid adenine dinucleotide phosphate (NAADP) levels in cells has been, and remains, key to the investigation of the functions of NAADP as a Ca2+ -releasing second messenger. Here we provide details of how to isolate NAADP from cells by extraction with perchloric acid and then measure the NAADP using a radioreceptor assay. We demonstrate that NAADP is neither generated nor broken down during sample processing conditions and that radioreceptor assay is highly selective for the detection of NAADP under cell extract conditions. Furthermore, a number of improvements, such as solid-state detection of the radioactivity, are incorporated to enhance the safety of the procedure. Finally, we have developed a new method to prevent the endogenous metabolism of NAADP by chelating Ca2+ with bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), thereby reducing the difficulty of catching a small transient rise in NAADP levels. In summary, we have refined and improved a method for measuring NAADP levels and presented it in a manner accessible to a wide range of laboratories. It is expected that this will enhance research in the NAADP field.


Adelta nociceptor response to laser stimuli: selective effect of stimulus duration on skin temperature, brain potentials and pain perception.
To disclose a possible effect of duration of pulsed laser heat stimuli on Adelta nociceptor responses, skin temperature profiles, brain evoked potentials and pain perception. We used a laser stimulator which works in the millisecond range and allows us to change the duration of the pulse while keeping the total energy of the stimulus constant. In 10 healthy volunteers, we measured the intensity of perceived pain with a 0-10 scale and the latency and amplitude of the early N1 and late N2 components of the scalp potentials evoked by laser pulses of equal energy and three different stimulus durations (2, 10, and 20 ms). Using a specifically developed pyrometer with a temporal resolution lower than 1 ms we also measured stimulus-induced changes of skin temperature. Stimulus duration significantly influenced temperature rise times, pain perception, and brain potentials. Shorter stimulus durations yielded steeper slopes in the skin temperature profiles and higher pain ratings, shortened the latency of the N1 and N2 components, and increased the amplitude of N1. The shorter stimulus duration shortens receptor activation times and yields a more synchronous afferent volley, thus providing a stronger spatial-temporal summation at central synapses that enhances intensity of first pain and brain potentials. This may prove useful in clinical applications.


Pemphigus foliaceus masquerading as IgA pemphigus and responding to dapsone.
A 14-year-old male presented with seven years history of recurrent episodes of fluid filled, itchy and eroded lesions over the body not responding to oral corticosteroids and azathioprine. Dermatological examination revealed crusted plaques and erosions in a seborrheic distribution. Histopathology of skin lesions and direct immunofluorescence were characteristic of pemphigus foliaceus. He was treated with dexamethasone pulse therapy with inadequate response. However, relapsing skin lesions revealed a circinate arrangement with a predilection to trunk and flexures. In view of clinical features suggestive of IgA pemphigus, he was started on dapsone, to which he responded dramatically in four weeks. However, repeat biopsy continued to reveal features of pemphigus foliaceus and ELISA for anti-desmoglein 1 antibodies was positive.


Masking residues using context-specific evolutionary conservation significantly improves short linear motif discovery.
Short linear motifs (SLiMs) are important mediators of protein-protein interactions. Their short and degenerate nature presents a challenge for computational discovery. We sought to improve SLiM discovery by incorporating evolutionary information, since SLiMs are more conserved than surrounding residues. We have developed a new method that assesses the evolutionary signal of a residue in its sequence and structural context. Under-conserved residues are masked out prior to SLiM discovery, allowing incorporation into the existing statistical model employed by SLiMFinder. The method shows considerable robustness in terms of both the conservation score used for individual residues and the size of the sequence neighbourhood. Optimal parameters significantly improve return of known functional motifs from benchmarking data, raising the return of significant validated SLiMs from typical human interaction datasets from 20% to 60%, while retaining the high level of stringency needed for application to real biological data. The success of this regime indicates that it could be of general benefit to computational annotation and prediction of protein function at the sequence level. All data and tools in this article are available at http://bioware.ucd.ie/~slimdisc/slimfinder/conmasking/.


Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling.
Ubiquitin ligases (E3s) embedded in the endoplasmic reticulum (ER) membrane regulate essential cellular activities including protein quality control, calcium flux, and sterol homeostasis. At least 25 different, transmembrane domain (TMD)-containing E3s are predicted to be ER-localised, but for most their organisation and cellular roles remain poorly defined. Using a comparative proteomic workflow, we mapped over 450 protein-protein interactions for 21 stably expressed, full-length E3s. Bioinformatic analysis linked ER-E3s and their interactors to multiple homeostatic, regulatory, and metabolic pathways. Among these were four membrane-embedded interactors of RNF26, a polytopic E3 whose abundance is auto-regulated by ubiquitin-proteasome dependent degradation. RNF26 co-assembles with TMEM43, ENDOD1, TMEM33 and TMED1 to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway. This RNF26 complex represents a new modulatory axis of STING and innate immune signalling at the ER membrane. Collectively, these data reveal the broad scope of regulation and differential functionalities mediated by ER-E3s for both membrane-tethered and cytoplasmic processes.


Effects of yoga on inner-city children's well-being: a pilot study.
To examine yoga's effects on inner-city children's well-being. This pilot study compared fourth- and fifth-grade students at 2 after-school programs in Bronx, New York. One program offered yoga 1 hour per week for 12 weeks (yoga) and the other program (non-yoga) did not. Preintervention and postintervention emotional well-being was assessed by Harter's Global Self-Worth and Physical Appearance subscales, which were the study's primary outcome measures. Secondary outcomes included other measures of emotional well-being assessed by 2 new scales: Perceptions of Physical Health and Yoga Teachings (including Negative Behaviors, Positive Behaviors, and Focusing/relaxation subscales). Preintervention and postintervention, physical wellbeing was assessed by measures of flexibility and balance. Subjective ratings ofyoga's effects on well-being were evaluated by an additional questionnaire completed by the yoga group only. Data were collected from 78% (n=39) and 86.5% (n=32) of potential yoga and non-yoga study enrollees. No differences in baseline demographics were found. Controlling for preintervention well-being differences using analysis of covariance, we found that children in the yoga group had better postintervention Negative Behaviors scores and balance than the non-yoga group (P < .05). The majority of children participating in yoga reported enhanced wellbeing, as reflected by perceived improvements in behaviors directly targeted by yoga (e.g., strength, flexibility, balance). Although no significant differences were found in the study's primary outcomes (global self-worth and perceptions of physical well-being), children participating in yoga reported using fewer negative behaviors in response to stress and had better balance than a comparison group. Improvements in wellbeing, specifically in behaviors directly targeted by yoga, were reported. These results suggest a possible role of yoga as a preventive intervention as well as a means of improving children's perceived well-being.


High precision quantum control of single donor spins in silicon.
The Stark shift of the hyperfine coupling constant is investigated for a P donor in Si far below the ionization regime in the presence of interfaces using tight-binding and band minima basis approaches and compared to the recent precision measurements. In contrast with previous effective mass-based results, the quadratic Stark coefficient obtained from both theories agrees closely with the experiments. It is also shown that there is a significant linear Stark effect for an impurity near the interface, whereas, far from the interface, the quadratic Stark effect dominates. This work represents the most sensitive and precise comparison between theory and experiment for single donor spin control. Such precise control of single donor spin states is required particularly in quantum computing applications of single donor electronics, which forms the driving motivation of this work.


Implementation of preventive mental health services for children of physically ill parents: experiences in seven European countries and health care systems.
Parental physical disease is a family issue, but families' minor children are seldom considered. The current study analyzed experiences with implementation of counseling for families with physically ill parents and minor children during a European multisite pilot project. Implementation protocols of seven European partner centers collaborating in a joint research project were analyzed by Mayring's qualitative content analysis. Both an inductive approach and a deductive approach were chosen. Satisfaction of families and therapists was considered based on information from three partner centers. Satisfaction with counseling was rather high. Mentioned problems referred to aspects related to liaison partners, family-related aspects and physicians' concerns. Recommendations related to contacting families, liaising with other professions, implementing counseling together with a research project, and training. Results are integrated in the current dissemination literature. Successful implementation was mostly determined by aspects of interdisciplinary cooperation and communication, perceived relative advantage and organizational premises. With regard to this kind of innovative child-centered family mental health services, top-down and bottom-up implementation strategies should be combined, and strategies of maintenance and sustainability should be considered from the very beginning.


Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial.
Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00-5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5-78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7-80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89-1·25, p=0·54). The most common grade 3-4 adverse events were hand-foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27%] of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 [11%] vs 104 [11%]), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 [33%] vs 75 [8%]), proteinuria (197 [21%] vs 49 [5%]), and wound healing problems (30 [3%] vs 17 [2%]). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used. Roche.


Supraliminal but not subliminal distracters bias working memory recall.
Information of which observers are not consciously aware can nevertheless influence perceptual processes. Whether subliminal information might exert an influence on working memory (WM) representations is less clear, and relatively few studies have examined the interactions between subliminal and supraliminal information in WM. We present 3 experiments examining this issue. Experiments 1a and b replicated the finding that orientation stimuli can influence behavior subliminally in a visuomotor priming task. Experiments 2 and 3 used the same orientation stimuli, but participants had to remember a target orientation and report it back by adjusting a probe orientation after a memory delay. Before or after presentation of the target orientation, a subliminal or supraliminal distracter orientation was presented that was either irrelevant for task completion and never had to be reported (Experiment 2), or was relevant for task completion because it had to be reported on some trials (Experiment 3). In both experiments, presentation of a supraliminal distracter influenced WM recall of the target orientation. When the distracter was presented subliminally, however, there was no bias in orientation recall. These results suggest that information stored in WM is protected from influences of subliminal stimuli, while online information processing is modulated by subliminal information.


Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.


The scientific impact of the Structural Genomics Consortium: a protein family and ligand-centered approach to medically-relevant human proteins.
As many of the structural genomics centers have ended their first phase of operation, it is a good point to evaluate the scientific impact of this endeavour. The Structural Genomics Consortium (SGC), operating from three centers across the Atlantic, investigates human proteins involved in disease processes and proteins from Plasmodium falciparum and related organisms. We present here some of the scientific output of the Oxford node of the SGC, where the target areas include protein kinases, phosphatases, oxidoreductases and other metabolic enzymes, as well as signal transduction proteins. The SGC has aimed to achieve extensive coverage of human gene families with a focus on protein-ligand interactions. The methods employed for effective protein expression, crystallization and structure determination by X-ray crystallography are summarized. In addition to the cumulative impact of accelerated delivery of protein structures, we demonstrate how family coverage, generic screening methodology, and the availability of abundant purified protein samples, allow a level of discovery that is difficult to achieve otherwise. The contribution of NMR to structure determination and protein characterization is discussed. To make this information available to a wide scientific audience, a new tool for disseminating annotated structural information was created that also represents an interactive platform allowing for a continuous update of the annotation by the scientific community.


Cost-effectiveness of lipid lowering with statins and ezetimibe in chronic kidney disease.
Statin-based treatments reduce cardiovascular disease (CVD) risk in patients with non-dialysis chronic kidney disease (CKD), but it is unclear which regimen is the most cost-effective. We used the Study of Heart and Renal Protection (SHARP) CKD-CVD policy model to evaluate the effect of statins and ezetimibe on quality-adjusted life years (QALYs) and health care costs in the United States (US) and the United Kingdom (UK). Net costs below $100,000/QALY (US) or £20,000/QALY (UK) were considered cost-effective. We investigated statin regimens with or without ezetimibe 10 mg. Treatment effects on cardiovascular risk were estimated per 1-mmol/L reduction in low-density lipoprotein (LDL) cholesterol as reported in the Cholesterol Treatment Trialists' Collaboration meta-analysis, and reductions in LDL cholesterol were estimated for each statin/ezetimibe regimen. In the US, atorvastatin 40 mg ($0.103/day as of January 2019) increased life expectancy by 0.23 to 0.31 QALYs in non-dialysis patients with stages 3B to 5 CKD, at a net cost of $20,300 to $78,200/QALY. Adding ezetimibe 10 mg ($0.203/day) increased life expectancy by an additional 0.05 to 0.07 QALYs, at a net cost of $43,600 to $91,500/QALY. The cost-effectiveness findings and policy implications in the UK were similar. In summary, in patients with non-dialysis-dependent CKD, the evidence suggests that statin/ezetimibe combination therapy is a cost-effective treatment to reduce the risk of CVD.


Human extrastriate visual cortex and the perception of faces, words, numbers, and colors.
Electrophysiological correlates of the processing of visual information were studied in epileptic patients with electrodes chronically implanted on the surface of striate and extrastriate cortex. In separate experiments patients viewed faces, letter strings (words and non-words), numbers, and control stimuli. A negative potential, N200, was evoked by faces, letter strings, and numbers, but not by the control stimuli. N200 was recorded bilaterally from discrete regions of the fusiform and inferior temporal gyri. These category-specific face, letter-string, and number "modules" vary in location. In most cases there was no overlap in the location of face and letter-string modules, suggesting a mosaic of functionally discrete regions. In some cases letter-string and number N200s were recorded from the same location, suggesting that these modules may be less spatially and functionally discrete. Face N200-like potentials can be recorded from temporal scalp, allowing the possibility of studying early face processing in normal subjects. Longer-latency face-specific potentials were recorded from the inferior surface of the anterior temporal lobe. Potentials evoked by colored checkerboards were recorded from a region of the fusiform gyrus posterior to the fusiform region from which category-specific N200s were recorded. These results suggest that there are several processing streams in inferior extrastriate cortex. In addition to object recognition systems previously proposed for faces and words, our preliminary results suggest a separate system dealing with numbers. Postulated systems dealing with larger manipulable objects and animals have not been detected.


Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo.
gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors. GABA(B) receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABA(B) receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABA(B) receptors is unclear. In order to elucidate the functional relevance of GABA(B) receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABA(B1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABA(B1)-/- mice). Lack of the GABA(B1) subunit precludes the assembly of functional GABA(B) receptor. We analyzed SNS-GABA(B1)-/- mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABA(B1)-/- mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1)-/- animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABA(B1) expression in nociceptors. This study addressed contribution of GABA(B) receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABA(B) agonist was significantly changed upon a specific deletion of GABA(B) receptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABA(B) receptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain.


Differential engagement of anterior cingulate and adjacent medial frontal cortex in adept meditators and non-meditators.
This study investigated differences in brain activation during meditation between meditators and non-meditators. Fifteen Vipassana meditators (mean practice: 7.9 years, 2h daily) and fifteen non-meditators, matched for sex, age, education, and handedness, participated in a block-design fMRI study that included mindfulness of breathing and mental arithmetic conditions. For the meditation condition (contrasted to arithmetic), meditators showed stronger activations in the rostral anterior cingulate cortex and the dorsal medial prefrontal cortex bilaterally, compared to controls. Greater rostral anterior cingulate cortex activation in meditators may reflect stronger processing of distracting events. The increased activation in the medial prefrontal cortex may reflect that meditators are stronger engaged in emotional processing.


Oesophageal variceal banding: report of the first eight cases in Kenya.
Twenty variceal banding sessions were performed in eight patients between February 1995 and September 1996. A total of 69 rings were used to band the varices and at each session between two to six rings were used. Two of the eight had active bleeding and both underwent variceal banding to successfully arrest their bleeding as inpatients. Sixteen other variceal banding sessions were performed on an outpatient basis to obliterate their varices. Four of the eight patients had had sclerotherapy before and varices were still present. No acute or long term complications were noted. In one patient, variceal banding could not be performed as he developed stridor upon placement of the overtube. All the patients had advanced varices (Grade III or IV) and extended for more than 15 cms in the oesophagus. Endoscopic variceal obliteration remains the treatment of choice for patients with portal hypertension with variceal bleeding. Variceal banding is associated with a superior outcome when compared with sclerotherapy; the variceal kill time is shorter, infective complications less, rebleeding occurs less commonly and transfusion requirements are lower.


A review on metaanalysis of biomarkers: promises and pitfalls.
The last 30 years have seen an exponential increase in metaanalyses. By combining multiple studies, metaanalysis can provide an overview of the totality of evidence on a particular question and the statistical power needed to reduce random error and produce precise estimates of even modest effect sizes. This capability is of particular value when many small studies address similar questions [such as in the investigation of novel cardiovascular disease (CVD) biomarkers]. To provide reliable evidence, however, metaanalyses must be undertaken robustly. In this review, we describe the major issues to consider when designing and conducting metaanalyses, including the design of constituent studies, selection criteria, assessment of exposures and disease outcomes, and control of bias and confounding. Some of the potential challenges and pitfalls associated with metaanalysis are examined, and their consequences are considered. We use 2 examples of novel biomarkers for CVD-homocysteine and triglycerides-to illustrate how metaanalyses of observational studies have contributed to, and on occasion hindered, our understanding; and how subsequent work has built upon these findings. Metaanalyses of observational studies, particularly metaanalyses of individual-participant data, have the power to provide robust evidence to support our understanding of the role of novel biomarkers for disease. The characteristic limitations and challenges of these studies, including their inability to detect causal associations, must be considered, however, and additional evidence from randomized controlled trials and genetic studies is frequently required to elucidate fully the role of novel biomarkers in predicting cardiovascular risk.


Functional connectivity in the basal ganglia network differentiates PD patients from controls.
To examine functional connectivity within the basal ganglia network (BGN) in a group of cognitively normal patients with early Parkinson disease (PD) on and off medication compared to age- and sex-matched healthy controls (HC), and to validate the findings in a separate cohort of participants with PD. Participants were scanned with resting-state fMRI (RS-fMRI) at 3T field strength. Resting-state networks were isolated using independent component analysis. A BGN template was derived from 80 elderly HC participants. BGN maps were compared between 19 patients with PD on and off medication in the discovery group and 19 age- and sex-matched controls to identify a threshold for optimal group separation. The threshold was applied to 13 patients with PD (including 5 drug-naive) in the validation group to establish reproducibility of findings. Participants with PD showed reduced functional connectivity with the BGN in a wide range of areas. Administration of medication significantly improved connectivity. Average BGN connectivity differentiated participants with PD from controls with 100% sensitivity and 89.5% specificity. The connectivity threshold was tested on the validation cohort and achieved 85% accuracy. We demonstrate that resting functional connectivity, measured with MRI using an observer-independent method, is reproducibly reduced in the BGN in cognitively intact patients with PD, and increases upon administration of dopaminergic medication. Our results hold promise for RS-fMRI connectivity as a biomarker in early PD. This study provides Class III evidence that average connectivity in the BGN as measured by RS-fMRI distinguishes patients with PD from age- and sex-matched controls.


Calculating the cost of acting in frontal cortex.
To make informed and successful decisions, it is vital to be able to evaluate whether the expected benefits of a course of action make it worth tolerating the costs incurred to obtain them. The frontal lobe has been implicated in several aspects of goal-directed action selection, social interaction, and optimal choice behavior. However, its exact contribution has remained elusive. Here, we discuss a series of studies in rats and primates examining the effect of discrete lesions on different aspects of cost-benefit decision making. Rats with excitotoxic lesions of the anterior cingulate cortex became less willing to invest effort for reward but showed no change when having to tolerate delays. Orbitofrontal cortex-lesioned rats, by contrast, became more impulsive, yet were just as prepared as normal animals to expend energy to obtain reward. The sulcal region of primate anterior cingulate cortex was also shown to be essential for dynamically integrating over time the recent history of choices and outcomes. Selecting a particular course of action may also come at the expense of gathering important information about other individuals. Evaluating social information when deciding whether to respond was demonstrated to be a function of the anterior cingulate gyrus. Taken together, this indicates that there may be dissociable pathways in the frontal lobe for managing different types of response cost and for gathering social information.


Notification of changes in taxonomic opinion previously published outside the IJSEM.
The Bacteriological Code deals with the nomenclature of prokaryotes. This may include existing names (the Approved Lists of Bacterial Names) as well as new names and new combinations. In this sense the Code is also dealing indirectly with taxonomic opinions. However, as with most codes of nomenclature there are no mechanisms for formally recording taxonomic opinions that do not involve the creation of new names or new combinations. In particular, it would be desirable for taxonomic opinions resulting from the creation of synonyms or emended descriptions to be made widely available to the public. In 2004, the Editorial Board of the International Journal of Systematic and Evolutionary Microbiology (IJSEM) agreed unanimously that it was desirable to cover such changes in taxonomic opinions (i.e. the creation of synonyms or the emendation of circumscriptions) previously published outside the IJSEM, and to introduce a List of Changes in Taxonomic Opinion [Notification of changes in taxonomic opinion previously published outside the IJSEM; Euzeby et al. (2004). Int J Syst Evol Microbiol 54, 1429-1430]. Scientists wishing to have changes in taxonomic opinion included in future lists should send one copy of the pertinent reprint or a photocopy or a PDF file thereof to the IJSEM Editorial Office or to the Lists Editor. It must be stressed that the date of proposed taxonomic changes is the date of the original publication not the date of publication of the list. Taxonomic opinions included in the List of Changes in Taxonomic Opinion cannot be considered as validly published nor, in any other way, approved by the International Committee on Systematics of Prokaryotes and its Judicial Commission. The names that are to be used are those that are the 'correct names' (in the sense of Principle 6) in the opinion of the bacteriologist, with a given circumscription, position and rank. A particular name, circumscription, position and rank does not have to be adopted in all circumstances. Consequently, the List of Changes in Taxonomic Opinion must be considered as a service to bacteriology and it has no 'official character', other than providing a centralized point for registering/indexing such changes in a way that makes them easily accessible to the scientific community.


Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.
The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.


Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity.
Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (Val158Met) that alters enzyme activity and influences PFC function. It has also been linked with cognition and anxiety, but the findings are mixed. We therefore developed a novel mouse model of altered COMT activity. The human Met allele was introduced into the native mouse COMT gene to produce COMT-Met mice, which were compared with their wild-type littermates. The model proved highly specific: COMT-Met mice had reductions in COMT abundance and activity, compared with wild-type mice, explicitly in the absence of off-target changes in the expression of other genes. Despite robust alterations in dopamine metabolism, we found only subtle changes on certain cognitive tasks under baseline conditions (eg, increased spatial novelty preference in COMT-Met mice vs wild-type mice). However, genotype differences emerged after administration of the COMT inhibitor tolcapone: performance of wild-type mice, but not COMT-Met mice, was improved on the 5-choice serial reaction time task after tolcapone administration. There were no changes in anxiety-related behaviors in the tests that we used. Our findings are convergent with human studies of the Val158Met polymorphism, and suggest that COMT's effects are most prominent when the dopamine system is challenged. Finally, they demonstrate the importance of considering COMT genotype when examining the therapeutic potential of COMT inhibitors.


The Oxford shoulder score revisited.
The validated, patient-reported Oxford shoulder score (OSS) was introduced around 10 years ago, primarily for the assessment of outcomes of shoulder surgery (excluding shoulder stabilisation) in randomised trials. Its uptake has steadily increased in a number of countries and its use has also been extended. Recently a number of issues have been raised in relation to other related patient-reported outcome measures which were devised around the same time as the OSS. This included recommendations to change the scoring system. This paper reviews issues concerning patient-reported outcome measures that apply to the OSS and makes some recommendations (including changes to the scoring system) as to how it should be used.


Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A.
Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. Importantly, results from a large number of biomonitoring studies are at odds with the results from two toxicokinetic studies. We examined several possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions. We examined > 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism. The > 80 biomonitoring studies examined included measurements in thousands of individuals from several different countries, and these studies overwhelmingly detected BPA in individual adults, adolescents, and children. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Some regulatory agencies have relied solely on these toxicokinetic models in their risk assessments. Available data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes.


MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling.
MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.


A systematic review of the effect of red blood cell transfusion on mortality: evidence from large-scale observational studies published between 2006 and 2010.
To carry out a systematic review of recently published large-scale observational studies assessing the effects of red blood cell transfusion (RBCT) on mortality, with particular emphasis on the statistical methods used to adjust for confounding. Given the limited number of randomised trials of the efficacy of RBCT, clinicians often use evidence from observational studies. However, confounding factors, for example, individuals receiving blood generally being sicker than those who do not, make their interpretation challenging. Systematic review. We searched MEDLINE and EMBASE for studies published from 1 January 2006 to 31 December 2010. We included prospective cohort, case-control studies or retrospective analyses of databases or disease registers where the effect of risk factors for mortality or survival was examined. Studies must have included more than 1000 participants receiving RBCT for any cause. We assessed the effects of RBCT versus no RBCT and different volumes and age of RBCT. -32 studies were included in the review; 23 assessed the effects of RBCT versus no RBCT; 5 assessed different volumes and 4 older versus newer RBCT. There was a considerable variability in the patient populations, study designs and level of statistical adjustment. Overall, most studies showed a higher rate of mortality when comparing patients who received RBCT with those who did not, even when these rates were adjusted for confounding; the majority of these increases were statistically significant. The same pattern was observed in studies where protection from bias was likely to be greater, such as prospective studies. Recent observational studies do show a consistently adverse effect of RBCT on mortality. Whether this is a true effect remains uncertain as it is possible that even the best conducted adjustments cannot completely eliminate the impact of confounding.


Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.
Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.


Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging.
Evidence concerning anatomical connectivities in the human brain is sparse and based largely on limited post-mortem observations. Diffusion tensor imaging has previously been used to define large white-matter tracts in the living human brain, but this technique has had limited success in tracing pathways into gray matter. Here we identified specific connections between human thalamus and cortex using a novel probabilistic tractography algorithm with diffusion imaging data. Classification of thalamic gray matter based on cortical connectivity patterns revealed distinct subregions whose locations correspond to nuclei described previously in histological studies. The connections that we found between thalamus and cortex were similar to those reported for non-human primates and were reproducible between individuals. Our results provide the first quantitative demonstration of reliable inference of anatomical connectivity between human gray matter structures using diffusion data and the first connectivity-based segmentation of gray matter.


TakeTwo: an indexing algorithm suited to still images with known crystal parameters.
The indexing methods currently used for serial femtosecond crystallography were originally developed for experiments in which crystals are rotated in the X-ray beam, providing significant three-dimensional information. On the other hand, shots from both X-ray free-electron lasers and serial synchrotron crystallography experiments are still images, in which the few three-dimensional data available arise only from the curvature of the Ewald sphere. Traditional synchrotron crystallography methods are thus less well suited to still image data processing. Here, a new indexing method is presented with the aim of maximizing information use from a still image given the known unit-cell dimensions and space group. Efficacy for cubic, hexagonal and orthorhombic space groups is shown, and for those showing some evidence of diffraction the indexing rate ranged from 90% (hexagonal space group) to 151% (cubic space group). Here, the indexing rate refers to the number of lattices indexed per image.


Effect of erythritol formulation on the mortality, fecundity and physiological excretion in Drosophila suzukii.
Previously, we studied various combinations of non-nutritive sugars including erythritol and erythrose having a potentially insecticidal effect on Drosophila suzukii. The study suggested two potential physiological changes causing fly mortality: 1) starvation from the feeding of non-metabolizable erythritol and erythrose; 2) abnormal osmotic pressure increased in the hemolymph with erythritol transported from the midgut. In the present study, sucrose and erythritol were applied to blueberries and effects of these combinations on fly mortality and fecundity were monitored in the lab and greenhouse. In the lab, two sucrose/erythritol formulations (0.5M sucrose/2M erythritol, 1M sucrose/2M erythritol) resulted in the highest mortality and the lowest fecundity among D. suzukii adults. Two formulations, therefore, were selected for further evaluation with blueberry bushes and fruits in the greenhouse; fly survival with 0.5M sucrose/2M erythritol was significantly lower than 1M sucrose/2M erythritol for 7days. Unlike the smaller container, mortality occurred faster in the greenhouse probably because flies moved more in the bigger cage accelerating the exhaustion of energy reserves in the body. We examined presence of erythritol in the hemolymph and frass to determine the nutritional metabolism and absorption of erythritol in D. suzukii. Unlike sucrose, a large amount of erythritol was observed in the hemolymph of the fly that ingested 0.5M sucrose/0.5M erythritol. Erythritol was also found in the frass of the same fly. The results imply that erythritol might be directly transported from the midgut without being metabolized and stored, but is accumulated in the hemolymph which in turn elevates the osmotic pressure in the fly hemolymph. For practical application, the sucrose/erythritol combination would be more effective than erythritol alone because the combination tastes sweeter to elicit more feeding. This erythritol formulation can be a potential insecticide used alone or as a delivery agent combined with conventional or biological insecticides to enhance their efficacy.


Efficacy of Sphenopalatine Ganglion Radiofrequency in Refractory Chronic Cluster Headache.
In the literature, there are only short series of radiofrequency of the sphenopalatine ganglion (SPG) to treat chronic refractory cluster headache (CCHr) with variable results. Furthermore, there is no consensus on which methodology to use: radiofrequency ablation (RFA) or pulsed radiofrequency (PRF). We conducted a prospective analysis of 37 patients with CCHr who underwent RFA or PRF of the SPG in our center between 2004 and 2015. The mean age of the patients was 40 years (range, 26-59 years). PRF was performed in 24 patients, and RFA was performed in 13 patients. A total of 5 patients (13.5%) experienced complete clinical relief of both pain and parasympathetic symptoms, 21 patients (56.8%) had partial and transient relief, and 11 patients (29.7%) did not improve. There was no evidence of significant superiority of one radiofrequency modality over the other (P = 0.48). There were no complications associated with the technique. The passage of time tended to decrease the efficacy of both techniques (P < 0.001). The mean follow-up was 68.1 months (range, 15-148 months). To our knowledge, this is the series with the largest number of patients and the longest follow-up period published in the literature. Radiofrequency of the SPG is a safe, fast, and partially effective method for the treatment of CCHr. Given its low rate of complications and its low economic cost, we think it should be one of the first invasive treatment options, prior to techniques with greater morbidity and mortality, such as neuromodulation.


The Evaluation of Syncope in a Predominantly Black Population: Focus on Neuroimaging.
Current guidelines do not support the routine use of computed tomography (CT) scan of the head in the diagnostic workup of syncope. There is a lack of research to support whether these guidelines apply to the Black population. This study aims to evaluate the yield of neuroimaging in the evaluation of Syncope in a predominantly Black patient population and to test whether current guidelines based on studies conducted in other populations hold true in this group. A retrospective review of records of 151 patients admitted to a University Hospital with Syncope from 2011 to 2014 was performed. Data collected include CT head, magnetic resonance imaging of the brain, magnetic resonance angiogram, electroencephalogram, and orthostatic vital signs. Demographic data, admitting service, and comorbid conditions were identified. Syncope was classified as cardiogenic, orthostatic, vasovagal, situational, or undetermined. Statistical analysis was performed to determine which diagnostic tools were useful in identifying the potential causes of syncope. Data analysis was conducted using the Statistical Analysis System software 9.3 (SAS Institute, Cary, NC) and Statistical Analysis and Graphics (NCSS 9.0.7, Kaysville, UT). One hundred and twenty eight (84.8%) of the patients were Black. The average age was 56.62 ± 18.78 standard deviation and 68.2% (103) were female. One hundred and fourteen patients (75.5%) had a CT brain. Five out of 114 patients had an acute abnormality on CT (4.4%). Only 1 of these 5 patients had an abnormality that was related to syncope. CT brain (P = 0.978) was not found to be predictive of underlying etiology of syncope despite high frequency of use. CT head was not useful in determining the etiology of syncope in a predominantly Black population. Current guidelines and studies conducted in other populations have detected similar findings.


Purinergic receptors influence the differentiation of human mesenchymal stem cells.
Adult stem cells, including adipose tissue-derived mesenchymal stem cells (MSCs) or ectomesenchymal dental follicle cells (DFCs), attract considerable attention for their potential to differentiate into lineages, which are of major interest in the field of Regenerative Medicine. Purinergic receptors exert a wide range of biological actions in many cell and tissue types through extracellular nucleotides. Little is known about P2 receptors in adult stem cells and changes in their expression levels during differentiation. All known P2 receptors have been investigated, and a variety of P2X and P2Y receptor subtypes were detected in MSCs. Studies investigating intracellular calcium levels on receptor stimulation demonstrated that the found P2 receptors are metabolically active. Interestingly, up- or downregulation of several P2 receptor subtypes at gene and protein level was observed during adipogenic and osteogenic differentiation, and the effect on differentiation was directly influenced by both the application of agonists/antagonists and apyrase-induced nucleotide cleavage. Here, we show for the first time that the combination of several P2 receptors plays a role in the differentiation of adult stem cells. The expression pattern of the P2 receptors, as well as their fate in differentiation, varies in stem cells of mesenchymal origin if compared with stem cells of ectomesenchymal origin. The subtypes P2X6, P2Y4, and P2Y14 seem to be pivotal regulators in MSC commitment, as they are regulated in both adipogenic and osteogenic differentiation of adipose tissue-derived stem cells and DFCs. These findings provide new insights into the differentiation processes and might reveal novel options to influence stem cell fate in future applications.


Christmas and New Year as risk factors for death.
This paper poses three questions: (1) Does mortality from natural causes spike around Christmas and New Year? (2) If so, does this spike exist for all major disease groups or only specialized groups? (3) If twin holiday spikes exist, need this imply that Christmas and New Year are risk factors for death? To answer these questions, we used all official U.S. death certificates, 1979-2004 (n = 57,451,944) in various hospital settings to examine daily mortality levels around Christmas and New Year. We measured the Christmas increase by comparing observed deaths with expected deaths in the week starting on Christmas. The New Year increase was measured similarly. The expected number of deaths was determined by locally weighted regression, given the null hypothesis that mortality is affected by seasons and trend but not by holidays. On Christmas and New Year, mortality from natural causes spikes in dead-on-arrival (DOA) and emergency department (ED) settings. There are more DOA/ED deaths on 12/25, 12/26, and 1/1 than on any other day. In contrast, deaths in non-DOA/ED settings display no holiday spikes. For DOA/ED settings, there are holiday spikes for each of the top five disease groups (circulatory diseases; neoplasms; respiratory diseases; endocrine/nutritional/metabolic diseases; digestive diseases). For all settings combined, there are holiday spikes for most major disease groups and for all demographic groups, except children. In the two weeks starting with Christmas, there is an excess of 42,325 deaths from natural causes above and beyond the normal winter increase. Christmas and New Year appear to be risk factors for deaths from many diseases. We tested nine possible explanations for these risk factors, but further research is needed.


American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise.
The purpose of this Position Stand is to provide guidance to professionals who counsel and prescribe individualized exercise to apparently healthy adults of all ages. These recommendations also may apply to adults with certain chronic diseases or disabilities, when appropriately evaluated and advised by a health professional. This document supersedes the 1998 American College of Sports Medicine (ACSM) Position Stand, "The Recommended Quantity and Quality of Exercise for Developing and Maintaining Cardiorespiratory and Muscular Fitness, and Flexibility in Healthy Adults." The scientific evidence demonstrating the beneficial effects of exercise is indisputable, and the benefits of exercise far outweigh the risks in most adults. A program of regular exercise that includes cardiorespiratory, resistance, flexibility, and neuromotor exercise training beyond activities of daily living to improve and maintain physical fitness and health is essential for most adults. The ACSM recommends that most adults engage in moderate-intensity cardiorespiratory exercise training for ≥30 min·d on ≥5 d·wk for a total of ≥150 min·wk, vigorous-intensity cardiorespiratory exercise training for ≥20 min·d on ≥3 d·wk (≥75 min·wk), or a combination of moderate- and vigorous-intensity exercise to achieve a total energy expenditure of ≥500-1000 MET·min·wk. On 2-3 d·wk, adults should also perform resistance exercises for each of the major muscle groups, and neuromotor exercise involving balance, agility, and coordination. Crucial to maintaining joint range of movement, completing a series of flexibility exercises for each the major muscle-tendon groups (a total of 60 s per exercise) on ≥2 d·wk is recommended. The exercise program should be modified according to an individual's habitual physical activity, physical function, health status, exercise responses, and stated goals. Adults who are unable or unwilling to meet the exercise targets outlined here still can benefit from engaging in amounts of exercise less than recommended. In addition to exercising regularly, there are health benefits in concurrently reducing total time engaged in sedentary pursuits and also by interspersing frequent, short bouts of standing and physical activity between periods of sedentary activity, even in physically active adults. Behaviorally based exercise interventions, the use of behavior change strategies, supervision by an experienced fitness instructor, and exercise that is pleasant and enjoyable can improve adoption and adherence to prescribed exercise programs. Educating adults about and screening for signs and symptoms of CHD and gradual progression of exercise intensity and volume may reduce the risks of exercise. Consultations with a medical professional and diagnostic exercise testing for CHD are useful when clinically indicated but are not recommended for universal screening to enhance the safety of exercise.


Effects of androgenic-anabolic steroids in athletes.
Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone testosterone. They can exert strong effects on the human body that may be beneficial for athletic performance. A review of the literature revealed that most laboratory studies did not investigate the actual doses of AAS currently abused in the field. Therefore, those studies may not reflect the actual (adverse) effects of steroids. The available scientific literature describes that short-term administration of these drugs by athletes can increase strength and bodyweight. Strength gains of about 5-20% of the initial strength and increments of 2-5 kg bodyweight, that may be attributed to an increase of the lean body mass, have been observed. A reduction of fat mass does not seem to occur. Although AAS administration may affect erythropoiesis and blood haemoglobin concentrations, no effect on endurance performance was observed. Little data about the effects of AAS on metabolic responses during exercise training and recovery are available and, therefore, do not allow firm conclusions. The main untoward effects of short- and long-term AAS abuse that male athletes most often self-report are an increase in sexual drive, the occurrence of acne vulgaris, increased body hair and increment of aggressive behaviour. AAS administration will disturb the regular endogenous production of testosterone and gonadotrophins that may persist for months after drug withdrawal. Cardiovascular risk factors may undergo deleterious alterations, including elevation of blood pressure and depression of serum high-density lipoprotein (HDL)-, HDL2- and HDL3-cholesterol levels. In echocardiographic studies in male athletes, AAS did not seem to affect cardiac structure and function, although in animal studies these drugs have been observed to exert hazardous effects on heart structure and function. In studies of athletes, AAS were not found to damage the liver. Psyche and behaviour seem to be strongly affected by AAS. Generally, AAS seem to induce increments of aggression and hostility. Mood disturbances (e.g. depression, [hypo-]mania, psychotic features) are likely to be dose and drug dependent. AAS dependence or withdrawal effects (such as depression) seem to occur only in a small number of AAS users. Dissatisfaction with the body and low self-esteem may lead to the so-called 'reverse anorexia syndrome' that predisposes to the start of AAS use. Many other adverse effects have been associated with AAS misuse, including disturbance of endocrine and immune function, alterations of sebaceous system and skin, changes of haemostatic system and urogenital tract. One has to keep in mind that the scientific data may underestimate the actual untoward effects because of the relatively low doses administered in those studies, since they do not approximate doses used by illicit steroid users. The mechanism of action of AAS may differ between compounds because of variations in the steroid molecule and affinity to androgen receptors. Several pathways of action have been recognised. The enzyme 5-alpha-reductase seems to play an important role by converting AAS into dihydrotestosterone (androstanolone) that acts in the cell nucleus of target organs, such as male accessory glands, skin and prostate. Other mechanisms comprises mediation by the enzyme aromatase that converts AAS in female sex hormones (estradiol and estrone), antagonistic action to estrogens and a competitive antagonism to the glucocorticoid receptors. Furthermore, AAS stimulate erythropoietin synthesis and red cell production as well as bone formation but counteract bone breakdown. The effects on the cardiovascular system are proposed to be mediated by the occurrence of AAS-induced atherosclerosis (due to unfavourable influence on serum lipids and lipoproteins), thrombosis, vasospasm or direct injury to vessel walls, or may be ascribed to a combination of the different mechanisms. AAS-induced increment of muscle tissue can be attributed to hypertrophy and the formation of new muscle fibres, in which key roles are played by satellite cell number and ultrastructure, androgen receptors and myonuclei.


Local gene therapy with CTLA4-immunoglobulin fusion protein in experimental allergic encephalomyelitis.
It has been reported previously that the induction phase of experimental allergic encephalomyelitis (EAE) is highly sensitive to systemic blockade of stimulation via MHC class II molecules and co-stimulation via the CD28:CD80/CD86 pathways. In contrast, the effector phases of EAE were relatively unaffected by similar treatments using MHC class II antigen (Ag)-specific mAb and cytotoxic T lymphocyte antigen (CTLA)4-Ig fusion proteins in some studies. This has been attributed to different sensitivities of effector cell function or the poor penetrance of inhibitory proteins into the central nervous system (CNS). To examine this question further, MHC class II Ag-specific mAb and CTLA4-Ig were delivered directly into the CNS following EAE induction, and both were found to inhibit disease. While it was found that systemic administration of mouse CTLA4-Ig could also inhibit the progression of effector immune responses when administered shortly before or during clinical disease, these were significantly more active when delivered directly into the CNS, which probably involved an action on both CD28 ligands, CD80 and CD86. Although mouse CTLA4-human Ig was therapeutically less efficient than mouse CTLA4-mouse Ig protein, probably due to the enhanced immunogenicity and lower functional activity, gene delivery of CTLA4-human Ig into the CNS using a non-replicating adenoviral vector was more effective than a single injection of CTLA4-human Ig protein. Gene delivery significantly ameliorated the development of EAE, without necessarily inhibiting unrelated peripheral immune responsiveness. Local gene delivery of CTLA4-Ig may thus be an important target for immunotherapy of human autoimmune conditions such as multiple sclerosis.


The effect of cytokine profiles on the viral response to re-treatment in antiviral-experienced patients with chronic hepatitis C virus infection.
There have been few studies on the potential immunological factors associated with viral controls in antiviral-experienced patients on a second round of combination therapy. In this study, we evaluated the level of systemic cytokines and potential impact on combination therapy in both antiviral-naïve and -experienced patients chronically infected with hepatitis C virus. Longitudinal analysis of 27 cytokines and chemokines was performed using the multiplex Biorad 27 plex assay in 37 antiviral-naïve and 24 experienced chronically HCV-1b-infected patients during combination therapy with peginterferon-alfa and ribavirin. A group of healthy donors was included as the control (n=11). Fifty percent of antiviral-experienced chronically HCV-patients could achieve a delayed and slow virologic response after 48 weeks combination therapy, comparing with an early and fast virologic response in antiviral-naïve patients. A distinction of immune mediators profiling before and during antiviral therapy between antiviral-naïve and -experienced patients was identified, IL-4, IFN-γ and CCL-3 (MIP-1a) were significantly higher in naïve patients than those in experienced patients (P=0.005, 0.047 and 0.017, respectively) while G-CSF in naïve was lower than in experienced patients (P<0.05). Notably, higher Th1 type cytokine IFN-γ and lower Th2 type cytokine IL-4 at baseline and week 4 were associated with HCV clearance in naïve patients, and a similar trend appeared at week 12 in experienced patients. We found a successful second round therapy in antiviral-experienced patients appears to be associated with the host immune response. Dominant Th1-polar cytokines, especially IFN-γ, is a potential predictor of viral responsiveness.


Resting GABA and glutamate concentrations do not predict visual gamma frequency or amplitude.
Gamma band oscillations arise in neuronal networks of interconnected GABAergic interneurons and excitatory pyramidal cells. A previous study found a correlation between visual gamma peak frequency, as measured with magnetoencephalography, and resting GABA levels, as measured with magnetic resonance spectroscopy (MRS), in 12 healthy volunteers. If true, this would allow studies in clinical populations testing modulation of this relationship, but this finding has not been replicated. We addressed this important question by measuring gamma oscillations and GABA, as well as glutamate, in 50 healthy volunteers. Visual gamma activity was evoked using an established gratings paradigm, and we applied a beamformer spatial filtering technique to extract source-reconstructed gamma peak frequency and amplitude from the occipital lobe. We determined gamma peak frequency and amplitude from the location with maximal activation and from the location of the MRS voxel to assess the relationship of GABA with gamma. Gamma peak frequency was estimated from the highest value of the raw spectra and by a Gaussian fit to the spectra. MRS data were acquired from occipital cortex. We did not replicate the previously found correlation between gamma peak frequency and GABA concentration. Calculation of a Bayes factor provided strong evidence in favor of the null hypothesis. We also did not find a correlation between gamma activity and glutamate or between gamma and the ratio of GABA/glutamate. Our results suggest that cortical gamma oscillations do not have a consistent, demonstrable relationship to excitatory/inhibitory network activity as proxied by MRS measurements of GABA and glutamate.


The social brain meets neuroimaging.
Recent neuroimaging studies in humans have indicated that individual differences in social network size correlate with amygdala volume and the volume of brain regions associated with theory of mind. A new article demonstrates that this is also true for monkeys. Taken together, these findings provide crucial support for the social brain hypothesis.


Neurobiology underlying fibromyalgia symptoms.
Fibromyalgia is characterized by chronic widespread pain, clinical symptoms that include cognitive and sleep disturbances, and other abnormalities such as increased sensitivity to painful stimuli, increased sensitivity to multiple sensory modalities, and altered pain modulatory mechanisms. Here we relate experimental findings of fibromyalgia symptoms to anatomical and functional brain changes. Neuroimaging studies show augmented sensory processing in pain-related areas, which, together with gray matter decreases and neurochemical abnormalities in areas related to pain modulation, supports the psychophysical evidence of altered pain perception and inhibition. Gray matter decreases in areas related to emotional decision making and working memory suggest that cognitive disturbances could be related to brain alterations. Altered levels of neurotransmitters involved in sleep regulation link disordered sleep to neurochemical abnormalities. Thus, current evidence supports the view that at least some fibromyalgia symptoms are associated with brain dysfunctions or alterations, giving the long-held "it is all in your head" view of the disorder a new meaning.


Evaluation of a Mindfulness-Based Stress Reduction (MBSR) program for caregivers of children with chronic conditions.
Given the demands of caring for chronically ill children, it is not surprising that caregivers often experience high levels of chronic stress. A Mindfulness-Based Stress Reduction (MBSR) program may offer relief to these caregivers by providing tools for self-care and heath promotion that otherwise may be lacking. MBSR classes were offered without restriction to parents of children attending various clinics at a large urban children's medical centre. Caregivers completed the Profile of Mood States (POMS) and Symptoms of Stress Inventory (SOSI) both before and after program participation. Forty-four caregivers participated in one of seven group MBSR sessions that were offered between August 2001 and February 2004. Most were mothers of children with special needs and various chronic conditions, who had been diagnosed an average of 7 years previous. Prior to the intervention, caregivers reported very high levels of stress and mood disturbance. These decreased substantially over the 8-week program, with an overall reduction in stress symptoms of 32% (p < .001), and in total mood disturbance of 56% (p < .001). This brief MBSR program for caregivers of chronically ill children was successful in significantly decreasing substantial stress symptoms and mood disturbance. Further studies would benefit from using more rigorous methodology and applying the program to other groups of chronically stressed caregivers.


Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors.
Hepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR-BI), CD81, claudin-1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species-specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100-fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2-specific antibodies indicative of major conformational changes of virus-resident E1/E2-complexes. Neutralization with CD81, SR-BI- and claudin-1-specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR-BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species-specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.


Association of green tea consumption with mortality from all-cause, cardiovascular disease and cancer in a Chinese cohort of 165,000 adult men.
Tea is the most ancient and popular beverage in the world, and its beneficial health effects has attracted tremendous attention worldwide. However, the prospective evidence relating green tea consumption to total and cause-specific mortality is still limited and inconclusive. We recruited 164,681 male participants free of pre-existing disease during 1990-1991, with green tea consumption and other covariates assessed by the standardized questionnaire and mortality follow up continued until 2006 (mean 11 years; total person-years: 1,961,791). Cox regression analyses were used to quantify the associations of green tea consumption with all-cause (n = 32,700), CVD (n = 11,839) and cancer (n = 7002) mortality, adjusting simultaneously for potential confounders. At baseline, 18 % reported regular consumption of green tea. Compared with non-green tea drinkers, regular drinkers had significantly lower all-cause mortality, with adjusted hazard ratios (HRs) being 0.94 (95 % CI 0.89, 0.99) for ≤5 g/day, 0.95 (0.91, 0.99) for 5-10 g/day and 0.89 (0.85, 0.93) for >10 g/day. For CVD mortality, the corresponding HRs were 0.93 (0.85, 1.01) 0.91 (0.85, 0.98) and 0.86 (0.79, 0.93), respectively, while for cancer they were 0.86 (0.78, 0.98), 0.92 (0.83, 1.00) and 0.79 (0.71, 0.88), respectively. The patterns of these associations varied by smoking, alcohol drinking and locality. This large prospective study shows that regular green tea consumption is associated with significantly reduced risk of death from all-cause, CVD and cancer among Chinese adults.


Concentrations and profiles of bisphenol A and other bisphenol analogues in foodstuffs from the United States and their implications for human exposure.
As the concern over the safety of bisphenol A (BPA) continues to grow, this compound is gradually being replaced, in industrial applications, with compounds such as bisphenol F (BPF) and bisphenol S (BPS). Occurrence of bisphenols, including BPA and BPS, has been reported in paper products and in environmental matrices. Information on the occurrence of bisphenols, other than BPA, in foodstuffs, however, is scarce. In this study, several bisphenol analogues, including BPA, BPF, and BPS, were analyzed in foodstuffs (N = 267) collected from Albany, NY, USA, using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Foodstuffs were divided into nine categories of beverages, dairy products, fats and oils, fish and seafood, cereals, meat and meat products, fruits, vegetables, and "others". Bisphenols were found in the majority (75%) of the food samples, and the total concentrations of bisphenols (ΣBPs: sum of eight bisphenols) were in the range of below the limit of quantification (LOQ) to 1130 ng/g fresh weight, with an overall mean value of 4.38 ng/g. The highest overall mean concentration of ΣBPs was found in the "others" category, which included condiments (preserved, ready-to-serve foods). A sample of mustard (dressing) and ginger, placed in the category of vegetables, contained the highest concentrations of 1130 ng/g for bisphenol F (BPF) and 237 ng/g for bisphenol P (BPP). Concentrations of BPs in beverages (mean = 0.341 ng/g) and fruits (0.698 ng/g) were low. The predominant bisphenol analogues found in foodstuffs were BPA and BPF, which accounted for 42 and 17% of the total BP concentrations, respectively. Canned foods contained higher concentrations of individual and total bisphenols in comparison to foods sold in glass, paper, or plastic containers. On the basis of measured concentrations and daily ingestion rates of foods, the daily dietary intakes of bisphenols (calculated from the mean concentration) were estimated to be 243, 142, 117, 63.6, and 58.6 ng/kg body weight (bw)/day for toddlers, infants, children, teenagers, and adults, respectively.


A 5-HT2C receptor promoter polymorphism (HTR2C - 759C/T) is associated with obesity in women, and with resistance to weight loss in heterozygotes.
The serotonin 5-HT(2C) receptor (HTR2C) helps regulate appetite and body weight. An HTR2C promoter polymorphism (-759C/T) has been associated with obesity and with weight gain in response to antipsychotic (neuroleptic) drugs. We studied this polymorphism in 120 obese women (BMI > or = 30) and 104 non-obese (BMI < or = 25) women. The C allele was commoner in the obese group (OR = 1.72 [95% CI, 1.13-2.64], P = 0.008). Ninety-five of the obese women participated in a randomized trial of psychological treatments for weight loss. Among these women, heterozygotes lost less weight during the trial than did homozygotes (6.8 vs. 9.7 kg; P = 0.047) and weighed more 6 months (90.1 vs. 83.6 kg; P = 0.006) and 12 months (91.8 vs. 84.6 kg; P = 0.009) later. Heterozygotes also had higher triglyceride levels than homozygotes. C/C subjects in the obesity trial did not differ from T/T subjects in terms of weight loss or triglycerides. In a separate RT-PCR study of 43 subjects, we found that HTR2C mRNA abundance in frontal cortex was unaffected by -759C/T status. Our data extend the evidence that HTR2C promoter variation may be a risk factor for obesity and, perhaps through heterosis, influences weight loss by obese women. Pharmacogenetic testing of HTR2C promoter variants may be valuable when evaluating anti-obesity drugs which act directly or indirectly on the receptor.


A morphometric, immunohistochemical, and in situ hybridization study of the dorsal raphe nucleus in major depression, bipolar disorder, schizophrenia, and suicide.
Several lines of evidence implicate 5-hydroxytryptamine (5-HT, serotonin) in the pathophysiology of mood disorders and suicide. However, it is unclear whether these conditions include morphological involvement of the dorsal raphe nucleus (DRN), the origin of most forebrain 5-HT innervation. We used morphometric, immunohistochemical, and molecular methods to compare the DRN in post-mortem tissue of 50 subjects (13 controls, 14 major depressive disorder [MDD], 13 bipolar disorder, 10 schizophrenia; 17 of the cases died by suicide). NeuN and PH8 antibodies were used to assess all neurons and serotonergic neurons respectively; 5-HT(1A) autoreceptor expression was investigated by regional and cellular in situ hybridization. Measurements were made at three rostrocaudal levels of the DRN. In MDD, the area of the DRN was decreased. In bipolar disorder, serotonergic neuronal size was decreased. Suicide was associated with an increased DRN area, and with a higher density but decreased size of serotonergic neurons. Total neuronal density and 5-HT(1A) receptor mRNA abundance were unaffected by diagnosis or suicide. No changes were seen in schizophrenia. The results show that mood disorders and suicide are associated with differential, limited morphological alterations of the DRN. The contrasting influences of MDD and suicide may explain some of the discrepancies between previous studies, since their design precluded detection of the effect.


Gamma knife surgery for idiopathic trigeminal neuralgia performed using a far-anterior cisternal target and a high dose of radiation.
Gamma knife surgery (GKS) has emerged as a suitable treatment of pharmacologically resistant idiopathic trigeminal neuralgia. The optimal radiation dose and target for this therapy, however, remain to be defined. The authors analyzed the results of GKS in which a high dose of radiation and a distal target was used, to determine the best parameters for this treatment. The authors evaluated results in 47 patients who were treated with this approach. All patients underwent clinical and magnetic resonance imaging examinations at 6 weeks, 6 months, and 1 year post-GKS. Fifteen potential prognostic factors associated with favorable pain control were studied. The mean follow-up period was 16 months (range 6-42 months). The initial pain relief was excellent (100% pain control) in 32 patients, good (90-99% pain control) in seven patients, fair (50-89% pain control) in three patients, and poor (< 50% pain control) in five patients. The actuarial curve of pain relief displayed a 59% rate of excellent pain control and a 71% excellent or good pain control at 42 months after radiosurgery. Radiosurgery-induced facial numbness was bothersome for two patients and mild for 18 patients. Three prognostic factors were found to be statistically significant factors for successful pain relief: a shorter distance between the target and the brainstem, a higher radiation dose delivered to the brainstem, and the development of a facial sensory disturbance after radiosurgery. To optimize pain control and minimize complications of this therapy, we recommend that the nerve be targeted at a distance of 5 to 8 mm from the brainstem.


Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy.
Continuous theta burst stimulation (cTBS) is a novel transcranial stimulation technique that causes significant inhibition of synaptic transmission for <or=1 h when applied over the primary motor cortex (M1) in humans. Here we use magnetic resonance spectroscopy to define mechanisms mediating this inhibition by noninvasively measuring local changes in the cortical concentrations of gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx). cTBS to the left M1 led to an increase in GABA compared with stimulation at a control site without significant change in Glx. This direct evidence for increased GABAergic interneuronal activity is framed in terms of a new hypothesis regarding mechanisms underlying cTBS.