Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients.
Migraine pathophysiology includes altered brainstem excitability, and recent neuromodulatory approaches aimed at controlling migraine episodes have targeted key brainstem relay and modulatory nuclei. In this study, we evaluated the impact of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel neuromodulatory intervention based on an existing transcutaneous vagus nerve stimulation approach, in the modulation of brainstem activity and connectivity in migraine patients. We applied 3T-functional magnetic resonance imaging with improved in-plane spatial resolution (2.62 × 2.62 mm) in episodic migraine (interictal) and age- and sex-matched healthy controls to evaluate brain response to RAVANS (gated to either inhalation or exhalation) and sham stimulation. We further investigated RAVANS modulation of tactile trigeminal sensory afference response in the brainstem using air-puff stimulation directed to the forehead during functional magnetic resonance imaging. Compared with sham and inhalatory-gated RAVANS (iRAVANS), exhalatory-gated RAVANS (eRAVANS) activated an ipsilateral pontomedullary region consistent with nucleus tractus solitarii (NTS). During eRAVANS, NTS connectivity was increased to anterior insula and anterior midcingulate cortex, compared with both sham and iRAVANS, in migraine patients. Increased connectivity was inversely correlated with relative time to the next migraine attack, suggesting clinical relevance to this change in connectivity. Poststimulation effects were also noted immediately after eRAVANS, as we found increased activation in putative pontine serotonergic (ie, nucleus raphe centralis) and noradrenergic (ie, locus coeruleus) nuclei in response to trigeminal sensory afference. Regulation of activity and connectivity of brainstem and cortical regions involved in serotonergic and noradrenergic regulation and pain modulation may constitute an underlying mechanism supporting beneficial clinical outcomes for eRAVANS applied for episodic migraine.


FSY1, a horizontally transferred gene in the Saccharomyces cerevisiae EC1118 wine yeast strain, encodes a high-affinity fructose/H+ symporter.
Transport of glucose and fructose in the yeast Saccharomyces cerevisiae plays a crucial role in controlling the rate of wine fermentation. In S. cerevisiae, hexoses are transported by facilitated diffusion via hexose carriers (Hxt), which prefer glucose to fructose. However, utilization of fructose by wine yeast is critically important at the end of fermentation. Here, we report the characterization of a fructose transporter recently identified by sequencing the genome of the commercial wine yeast strain EC1118 and found in many other wine yeasts. This transporter is designated Fsy1p because of its homology with the Saccharomyces pastorianus fructose/H(+) symporter Fsy1p. A strain obtained by transformation of the V5 hxt1-7Δ mutant with FSY1 grew well on fructose, but to a much lesser extent on glucose as the sole carbon source. Sugar uptake and symport experiments showed that FSY1 encodes a proton-coupled symporter with high affinity for fructose (K(m) 0.24±0.04mM). Using real-time RT-PCR, we also investigated the expression pattern of FSY1 in EC1118 growing on various carbon sources. FSY1 was repressed by high concentrations of glucose or fructose and was highly expressed on ethanol as the sole carbon source. The characteristics of this transporter indicate that its acquisition could confer a significant advantage to S. cerevisiae during the wine fermentation process. This transporter is a good example of acquisition of a new function in yeast by horizontal gene transfer.


In vivo blockade of ovarian sympathetic activity by Neosaxitoxin prevents polycystic ovary in rats.
A high sympathetic tone is observed in the development and maintenance of the polycystic ovary (PCO) phenotype in rats. Neosaxitoxin (NeoSTX) specifically blocks neuronal voltage-dependent Na+ channels, and we studied the capacity of NeoSTX administered into the ovary to block sympathetic nerves and PCO phenotype that is induced by estradiol valerate (EV). The toxin was administered with a minipump inserted into the bursal cavity using two protocols: (1) the same day as EV administration and (2) 30 days after EV to block the final step of cyst development and maintenance of the condition. We studied the estrous cycling activity, follicular morphology, steroid plasma levels, and norepinephrine concentration. NeoSTX administered together with EV decreased NA intraovarian levels that were induced by EV, increased the number of corpora lutea, decreased the number of follicular cyst found after EV administration, and decreased the previously increased testosterone plasma levels induced by the PCO phenotype. Estrous cycling activity also recovered. NeoSTX applied after 30 days of EV administration showed near recovery of ovary function, suggesting that there is a specific window in which follicular development could be protected from cystic development. In addition, plasma testosterone levels decreased while those of progesterone increased. Our data strongly suggest that chronic inhibition of sympathetic nerves by a locally applied long-lasting toxin is a new tool to manage the polycystic phenotype in the rat and could be applied to other mammals depending on sympathetic nerve activity.


Impact of anion shape on Li+ solvation and on transport properties for lithium-air batteries: a molecular dynamics study.
Lithium-air batteries have emerged as an interesting alternative for advanced energy storage devices. The complexity of such systems imposes great challenges. One of them resides in the selection of the lithium salt/solvent pair. Many electrolyte properties affect the operation of the batteries. Among these, the transport properties and structural features have a special place. Via molecular dynamics simulations, we have calculated solution viscosity, ionic diffusivities and conductivities, as well as structural information, for two different salts in dimethyl sulfoxide (DMSO): lithium hexafluorophosphate - LiPF6, and lithium pyrrolide - LiPyr, at different temperatures and salt molalities. We show that, despite similar ionic transport properties, Li+ solvation in the different salts is significantly different. Therefore, solutions with different solvation properties, which impact the overall battery performance, might present analogous ionic dynamics.


Association between Fruit and Vegetable Intakes and Mental Health in the Australian Diabetes Obesity and Lifestyle Cohort.
Increasing prevalence of mental health disorders within the Australian population is a serious public health issue. Adequate intake of fruits and vegetables (FV), dietary fibre (DF) and resistant starch (RS) is associated with better mental and physical health. Few longitudinal studies exist exploring the temporal relationship. Using a validated food frequency questionnaire, we examined baseline FV intakes of 5845 Australian adults from the AusDiab study and estimated food group-derived DF and RS using data from the literature. Perceived mental health was assessed at baseline and 5 year follow up using SF-36 mental component summary scores (MCS). We conducted baseline cross-sectional analysis and prospective analysis of baseline dietary intake with perceived mental health at 5 years. Higher baseline FV and FV-derived DF and RS intakes were associated with better 5 year MCS (p < 0.001). A higher FV intake (754 g/d vs. 251 g/d, Q4 vs. Q1) at baseline had 41% lower odds (OR = 0.59: 95% CI 0.46-0.75) of MCS below population average (<47) at 5 year follow up. Findings were similar for FV-derived DF and RS. An inverse association was observed with discretionary food-derived DF and RS. This demonstrates the association between higher intakes of FV and FV-derived DF and RS with better 5 year mental health outcomes. Further RCTs are necessary to understand mechanisms that underlie this association including elucidation of causal effects.


Learning curves in health professions education.
Learning curves, which graphically show the relationship between learning effort and achievement, are common in published education research but are not often used in day-to-day educational activities. The purpose of this article is to describe the generation and analysis of learning curves and their applicability to health professions education. The authors argue that the time is right for a closer look at using learning curves-given their desirable properties-to inform both self-directed instruction by individuals and education management by instructors.A typical learning curve is made up of a measure of learning (y-axis), a measure of effort (x-axis), and a mathematical linking function. At the individual level, learning curves make manifest a single person's progress towards competence including his/her rate of learning, the inflection point where learning becomes more effortful, and the remaining distance to mastery attainment. At the group level, overlaid learning curves show the full variation of a group of learners' paths through a given learning domain. Specifically, they make overt the difference between time-based and competency-based approaches to instruction. Additionally, instructors can use learning curve information to more accurately target educational resources to those who most require them.The learning curve approach requires a fine-grained collection of data that will not be possible in all educational settings; however, the increased use of an assessment paradigm that explicitly includes effort and its link to individual achievement could result in increased learner engagement and more effective instructional design.


Impaired nutritive skeletal muscle blood flow in patients with chronic renal failure.
1. The possibility that abnormalities of skeletal muscle may limit the exercise tolerance of patients with chronic renal failure was investigated in patients undergoing regular haemodialysis. 2. Blood flow to the calf, a vascular bed consisting predominantly of skeletal muscle, was measured in six patients before and after exercise and compared with values obtained from 12 control subjects. 3. The patients were limited on exertion and had an abnormal response of calf blood flow to bicycle exercise. Resting calf blood flow was similar in patients and control subjects, but the mean increase in calf blood flow in response to submaximal exercise was 0.55 (SEM 0.12) ml min-1 100 ml-1 in the patients and 1.43 (SEM 0.17) ml min-1 100 ml-1 in the control subjects. The increase after symptom-limited maximal exercise was 1.50 (SEM 0.80) ml min-1 100 ml-1 in the patients and 4.20 (SEM 0.40) ml min-1 100 ml-1 in the control subjects. 4. Skeletal muscle biopsies from eight haemodialysis patients were studied by histochemistry and electron microscopy. 5. Oxidative enzyme activity was increased and there were large subsarcolemmal aggregates of structurally normal mitochondria. Necrotic capillaries were observed as empty basement membrane tubes containing fragments of degenerating endothelium. 6. The changes were compatible with a response to a chronic reduction in skeletal muscle blood flow.


International normalized ratio and Model for End-stage Liver Disease score predict short-term outcome in cirrhotic patients after the resolution of hepatic encephalopathy.
In patients with cirrhosis, hepatic encephalopathy (HE) indicates a poor prognosis despite the use of artificial liver and liver transplantation, presenting as frequent hospitalizations and increased mortality rate. To determine predictors of early readmission and mid-term mortality in cirrhotic patients discharged after the resolution of HE. From January to February 2018, 213 patients were enrolled in this observational study assessing all the successive patients with cirrhosis discharged from Department of Gastroenterology and Department of Infectious and Liver Diseases, Second Affiliated Hospital of Chongqing Medical University after the resolution of HE. The patients were followed for 6 mo. For each subject, demographic, clinical, and laboratory variables were assessed at the time of diagnosis of HE, during hospital stay, at discharge, and during follow-up. The primary endpoints were incidence of early readmission and mid-term mortality. During follow-up, 65 (31%) patients experienced an early readmission. International normalized ratio (INR) [odds ratio (OR) = 2.40; P = 0.003) at discharge independently predicted early readmission. The incidence of early readmission was significantly higher in patients with an INR > 1.62 at discharge than in those with an INR ≤ 1.62 (44% vs 19%; P < 0.001). Model for End-stage Liver Disease (MELD) score (OR = 1.11; P = 0.048) at discharge proved to be an independent predictor of early readmission caused by HE. Hemoglobin (OR = 0.97; P = 0.005) at discharge proved to be an independent predictor of non-early readmission. During 6 months of follow-up, 34 (16%) patients died. Artificial liver use (hazard ratio = 6.67; P = 0.021) during the first hospitalization independently predicted mid-term mortality. INR could be applied to identify fragile cirrhotic patients, MELD score could be used to predict early relapse of HE, and anemia is a potential target for preventing early readmission.


Giant Fecaloma Causing Small Bowel Obstruction: Case Report and Review of the Literature.
Fecaloma is a mass of hardened feces being impacted mostly in rectum and sigmoid. The most common sites of the fecaloma is the sigmoid colon and the rectum. There are several causes of fecaloma and have been described in association with Hirschsprung's disease, psychiatric patients, Chagas disease, both inflammatory and neoplastic, and in patients suffering with chronic constipation. Up to now several cases of giant fecaloma has been reported in the literature most of them presenting with megacolon or urinary retention. We herein report a case of giant fecaloma leading to bowel obstruction who was successfully treated by surgery. A 30-yrar-old man presented with sign and symptoms of acute bowel obstruction. He underwent exploratory laparotomy and enterotomy. He was found to have a giant fecaloma causing bowel obstruction in the jejunum. He was discharged after the operation with good condition. Jejunal fecaloma is extremely rare condition.


The clinical significance of diffusion-weighted MR imaging in stroke and TIA patients.
Diffusion-weighted magnetic resonance imaging (DWI) is an advanced imaging technique that allows non-invasive evaluation of water diffusibility in brain tissue. The following report focuses on the clinical significance of DWI in stroke and TIA patients (1) TIA patients demonstrate DWI lesions at a rate of 1 in 6 to 2 in 3. Symptom duration, speech or motor symptoms and aetiology seem to correlate with the rate of DWI positivity. (2) In stroke patients, the DWI detection rate of ischaemic lesions is >95%. Small lesion size and location in the brainstem increase the risk of false-negative DW-images. A negative DW-image in a patient with stroke-like symptoms should stimulate the search for an alternative diagnosis. However, one half of such patients can be expected to have ischaemic stroke as the best final diagnosis. (3) Infarct age determination based on DWI characteristics is not possible in the first few hours. However, the combined interpretation of DWI-images and apparent diffusion coefficient (ADC) maps enables the distinction of infarcts ?5 day old from infarcts >10 days old. On average in DW-images alone, the hyperintense signal disappears after two months. Normalisation can occur as early as one month and as late as four and a half months. (4) DWI lesion size is a prognostic marker of stroke outcome. However, in a mixed stroke population, outcome prediction by DWI cannot replace clinical outcome scores. (5) The mismatch concept hypothesises that DWI lesions reflect irreversibly infarcted tissue that is surrounded by an area of reduced perfusion. The larger the perfusion-diffusion mismatch the more tissue is potentially salvageable, e.g., by early reperfusion. Although this concept is appealing, more recent data have shown that DWI lesions are not necessarily irreversibly damaged tissue and that perfusion abnormalities tend to overestimate the ischaemic penumbra. More recently, the mismatch between clinical stroke severity as measured with the NIH-stroke Scale Score (NIHSSS) and the volume of DWI lesions has been introduced. (6) In posterior circulation stroke, DWI lesion detection rate is significantly lower than in anterior circulation stroke. (7) DWI features provide important information about stroke aetiology. Multiple DWI lesions in more than one circulation suggest cardioembolism. However, this assignment should be restricted to DWI lesions showing the same appearance on ADC-maps. In patients with lacunar syndromes, every fourth to sixth patient can be expected to have >1 DWI lesion, indicating an embolic mechanism. Thus, DWI findings may be clinically useful to tailor the aetiological work-up, which may result in early implementation of specific treatment for secondary stroke prevention. (8) DWI may detect clinically silent ischaemic lesions after carotid interventions. A systematic review reported the rate of new DWI lesions as being significantly higher in carotid stenting patients (37%) compared to carotid endarterectomy patients (10%). As caveats, all studies included were non randomized trials. In addition, the clinical significance of these lesions is unclear. Studies, comparing the risk of silent ischaemia in carotid stenting versus endarterectomy patients and evaluating the value of DWI as surrogate marker in a randomised, prospective setting are currently under way. DWI provides clinically useful information and has the means to improve the quality of diagnosis, treatment, and outcome prediction in stroke and TIA patients.


Domestic violence in patients visiting general practitioners--prevalence, phenomenology, and association with psychopathology.
It has been suggested that domestic violence is not only highly prevalent and associated with significant morbidity, but that it is also overlooked by medical practitioners. Despite this, few studies have focused on domestic violence in the South African setting, so that there is a paucity of data here on its prevalence, phenomenology, and associated psychopathology. Sixteen general practitioners from the South African Sentinel Practitioner Research Network (SASPREN) screened all their female patients aged 18 years or older for a 3-month period (N = 1,050). A sociodemographic questionnaire was completed, and symptoms of post-traumatic stress disorder (PTSD) and major depression were assessed, both in subjects with a history of domestic violence and in a control group without such a history. 21.5% of patients reported a history of domestic violence at screening. Patients and controls did not differ significantly in terms of age or race. However, patients with a history of domestic violence were significantly more likely to be married, not to have begun a high-school education, and to be working outside the home. Both PTSD and major depression were significantly more common in patients with a history of domestic violence (35.3% and 48.2%, respectively) than in controls (2.6% and 11.4%, respectively). Compared with other patients reporting domestic violence, those with either PTSD or major depression were subjected to more violence and were more likely to report a suicide attempt. In a large, diverse population of adult female patients presenting to a range of general practitioners in South Africa, there was a high prevalence of reported domestic violence. A significant association was found between domestic violence and both PTSD and major depression, with these diagnoses indicative of increased severity of abuse and increased morbidity. Routine screening by medical practitioners of all female patients for a history of domestic violence seems warranted, and patients with a history of domestic violence should be assessed for PTSD and depression.


Exploring Household-level Risk Factors for Self-reported Prevalence of Allergic Diseases Among Low-income Households in Seoul, Korea.
Indoor risk factors for allergic diseases in low-income households in Korea have been characterized only partially. We evaluated the prevalences of atopic dermatitis, asthma, and allergic rhinitis in Seoul, Korea, to identify key housing and behavioral risk factors of low-income households. Statistical analysis of the prevalence of these diseases and various risk factors was conducted using data from a 2010 Ministry of Environment household survey. Logistic regression models were generated using data from 511 low-income household apartments in districts of Seoul. In general, housing factors such as renovation history (P<0.1) and crowding status (P<0.01) were associated with allergic rhinitis, whereas behavioral factors such as frequency of indoor ventilation (P<0.05) and cleaning (P<0.1) were inversely correlated with atopic dermatitis. Indoor smoking was a major trigger of asthma and atopic dermatitis in low-income households (P<0.05). The presence of mold and water leakage in houses were the most important risk factors for all three diseases (P<0.05). Various risk factors play a role in triggering allergic diseases among low-income households in Seoul, and health or environmental programs mitigating allergic diseases should be tailored to address appropriate housing or behavioral factors in target populations.


Evidence from Opportunity's Microscopic Imager for water on Meridiani Planum.
The Microscopic Imager on the Opportunity rover analyzed textures of soils and rocks at Meridiani Planum at a scale of 31 micrometers per pixel. The uppermost millimeter of some soils is weakly cemented, whereas other soils show little evidence of cohesion. Rock outcrops are laminated on a millimeter scale; image mosaics of cross-stratification suggest that some sediments were deposited by flowing water. Vugs in some outcrop faces are probably molds formed by dissolution of relatively soluble minerals during diagenesis. Microscopic images support the hypothesis that hematite-rich spherules observed in outcrops and soils also formed diagenetically as concretions.


Multiple N-methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity: pharmacological and conformational studies.
Multiple N-methylation is a novel technology to improve bioavailability of peptides and increase receptor subtype selectivity. This technique has been applied here to the superpotent but nonselective cyclic peptide MT-II. A library of all possible 31 backbone N-methylated derivatives has been synthesized and tested for binding and activation at melanocortin receptor subtypes 1, 3, 4, and 5. It turned out that selectivity is improved with every introduced N-methyl group, resulting in several N-methylated selective and potent agonists for the hMC1R. The most potent of these derivatives is N-methylated on four out of five amide bonds in the cyclic structure. Its solution structure indicates a strongly preferred backbone conformation that resembles other alpha-MSH analogs but possesses much less flexibility and in addition distinct differences in the spatial arrangement of individual amino acid side chains.


Genetic diversity and identification of human infection by amplification of the chlamydial 60-kilodalton cysteine-rich outer membrane protein gene.
The 60-kDa cysteine-rich outer membrane protein genes of Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia trachomatis have very different 5' ends, but two areas flanking this variable region show absolute sequence conservation. This observation permitted differentiation of the three species of Chlamydia by the polymerase chain reaction (PCR), forming the basis of a diagnostic test for chlamydial infections. The PCR product containing the variable region of the respective 60-kDa CrP genes was also subjected to restriction endonuclease digestion, enabling differentiation of individual type strains of C. psittaci. Differentiation was possible between lymphogranuloma venereum and trachoma isolates of C. trachomatis. The PCR-based diagnostic test was successful with all strains of chlamydiae studied. The PCR primers showed high specificity and did not produce any product with common bacterial pathogens that may share the same sites of infection.


A validation of the use of names to screen for risk of chronic hepatitis B in Victoria, Australia, 2001 to 2010.
The burden of chronic hepatitis B (CHB) is increasing in Australia, particularly in those born in the Asia-Pacific region, and nearly half are undiagnosed. Primary care clinicians have a key role in diagnosing CHB, however identification of patients at risk is hindered by lack of awareness and limited information on country of birth in patient records. This study evaluates the potential of a validated list of names associated with Asian country of birth as a screening tool to predict risk of CHB, by comparing it with surveillance records for all people diagnosed with CHB or salmonellosis in Victoria from 2001 to 2010, and analysed using standard screening tools. Name list match was associated with CHB notification, with over 60% of cases having one name matching the list (sensitivity), and nearly one third matching both given name and surname; less than 15% and 2% of salmonellosis notifications matched for one name and both names, respectively (false positives). These results show that more than half of notified cases of CHB would have been identified by this name list, and that it could be used in support of initiatives to improve diagnosis of patients with diseases associated with country of birth when limited information is available.


Autosomal dominant retinitis pigmentosa in a large family: a clinical and molecular genetic study.
To characterize the pedigree, visual function phenotype, and responsible mutation in a large family with autosomal dominant retinitis pigmentosa. Pedigree data were obtained by personal interviews and corroborated with community records. One hundred twenty-eight members of the family were examined clinically, and a subset of 12 affected subjects was further studied with dark- and light-adapted static perimetry and electroretinography. The coding region of the rhodopsin gene was polymerase chain reaction (PCR) amplified and resolved by denaturing gradient gel electrophoresis. Genomic DNA samples from nine affected and five unaffected family members were analyzed by PCR amplification and restriction enzyme digestion. A 14-generation pedigree was identified in which retinitis pigmentosa (RP) was inherited in an autosomal dominant fashion. Affected individuals reported early night blindness and showed vessel attenuation and bone spicule-like pigmentary changes. In these individuals, the rod electroretinogram (ERG) was not detectable, and the cone ERG was reduced in amplitude and delayed in timing. With dark-adapted perimetry, rod function could be detected in only one young patient, and it was markedly abnormal. Light-adapted perimetry indicated that cone sensitivity could be relatively well preserved in the central field, but it was diminished in the periphery even in the most mildly affected subjects. A valine345-to-leucine mutation was identified in the rhodopsin gene and shown to cosegregate in the heterozygous condition with the disease. The natural history of RP in this family begins with a loss of rod function, progresses to involve the cone system, and leads eventually to a severe loss of visual function. The invariance of valine345 in all functional vertebrate visual pigments sequenced to date, and the unusually conservative nature of the valine345-to-leucine mutation suggests that the carboxy terminus of rhodopsin is involved in a highly specific interaction with one or more rod proteins.


Topological analysis of large-scale biomedical terminology structures.
To characterize global structural features of large-scale biomedical terminologies using currently emerging statistical approaches. Given rapid growth of terminologies, this research was designed to address scalability. We selected 16 terminologies covering a variety of domains from the UMLS Metathesaurus, a collection of terminological systems. Each was modeled as a network in which nodes were atomic concepts and links were relationships asserted by the source vocabulary. For comparison against each terminology we created three random networks of equivalent size and density. Average node degree, node degree distribution, clustering coefficient, average path length. Eight of 16 terminologies exhibited the small-world characteristics of a short average path length and strong local clustering. An overlapping subset of nine exhibited a power law distribution in node degrees, indicative of a scale-free architecture. We attribute these features to specific design constraints. Constraints on node connectivity, common in more synthetic classification systems, localize the effects of changes and deletions. In contrast, small-world and scale-free features, common in comprehensive medical terminologies, promote flexible navigation and less restrictive organic-like growth. While thought of as synthetic, grid-like structures, some controlled terminologies are structurally indistinguishable from natural language networks. This paradoxical result suggests that terminology structure is shaped not only by formal logic-based semantics, but by rules analogous to those that govern social networks and biological systems. Graph theoretic modeling shows early promise as a framework for describing terminology structure. Deeper understanding of these techniques may inform the development of scalable terminologies and ontologies.


Use of cardiac magnetic resonance to detect changes in metabolism in heart failure.
The heart has a massive adenosine triphosphate (ATP) requirement, produced from the oxidation of metabolic substrates such as fat and glucose. Magnetic resonance spectroscopy offers a unique opportunity to probe this biochemistry: 31Phosphorus spectroscopy can demonstrate the production of ATP and quantify levels of the transport molecule phosphocreatine while 13Carbon spectroscopy can demonstrate the metabolic fates of glucose in real time. These techniques allow the metabolic deficits in heart failure to be interrogated and can be a potential future clinical tool.


Measuring spatial variation in secondary production and food quality using a common consumer approach in Lake Erie.
Lake Erie is a large lake straddling the border of the USA and Canada that has become increasingly eutrophic in recent years. Eutrophication is particularly focused in the shallow western basin. The western basin of Lake Erie is hydrodynamically similar to a large estuary, with riverine inputs from the Detroit and Maumee Rivers mixing together and creating gradients in chemical and physical conditions. This study was driven by two questions: (1) How does secondary production and food quality for consumers vary across this large mixing zone? and (2) Are there correlations between cyanobacterial abundance and secondary production or food quality for consumers? Measuring spatial and temporal variation in secondary production and food quality is difficult for a variety of logistical reasons, so here a common consumer approach was used. In a common consumer approach, individuals of a single species are raised under similar conditions until placed in the field across environmental gradients of interest. After some period of exposure, the response of that common consumer is measured to provide an index of spatial variation in conditions. Here, a freshwater mussel (Lampsilis siliquoidea) was deployed at 32 locations that spanned habitat types and a gradient in cyanobacterial abundance in the western basin of Lake Erie to measure spatial variation in growth (an index of secondary production) and fatty acid (FA) content (an index of food quality). We found secondary production was highest within the Maumee river mouth and lowest in the open waters of the lake. Mussel tissues in the Maumee river mouth also included more eicosapentaenoic and docosapentaenoic fatty acids (EPA and DPA, respectively), but fewer bacterial FAs, suggesting more algae at the base of the food web in the Maumee river mouth compared to open lake sites. The satellite-derived estimate of cyanobacterial abundance was not correlated to secondary production, but was positively related to EPA and DPA content in the mussels, suggesting more of these important FAs in locations with more cyanobacteria. These results suggest that growth of secondary consumers and the availability of important fatty acids in the western basin are centered on the Maumee river mouth.


Anatomic analysis of blood vessels in germinal matrix, cerebral cortex, and white matter in developing infants.
The germinal matrix (GM) located in the thick subependymal cell layer of the thalamostriate groove is a major site of cerebral hemorrhage in premature infants. Comparing the morphology of vasculature among GM, gray and white matter of the brain may help in understanding the pathogenesis of GM hemorrhage and also of periventricular leukomalacia. The objective of the present study was to determine the morphology of blood vessels in the GM, gray matter, and white matter and to examine maturational changes in the morphology of these vessels as a function of gestational age. We measured vessel density, percentage of blood vessel area, mean surface area, length, breadth, perimeter, radius, and shape of blood vessels in coronal sections of the GM, gray matter, and white matter in postmortem human brain samples for 17 fetuses and premature infants of gestational age 16-40 wk and 2 adults. We performed immunohistochemical staining using anti-laminin primary antibody, confocal microscopy to acquire images, and analysis using Metamorph version 6.1. Vessel density and the percentage of blood vessel area increased as a function of gestational age in the GM, gray matter, and white matter (p < 0.001 each). The blood vessel density and the percentage of blood vessel area were largest in the GM followed by gray matter and then white matter in all of the gestational age categories (p < 0.001 for all comparisons). Increased vascularity of the GM compared with gray and white matter may play a role in GM hemorrhage, whereas a relatively low vascularity of white matter may increase the propensity for the occurrence of periventricular leukomalacia in premature infants


Cord Blood Cells Responses to IL2, IL7 and IL15 Cytokines for mTOR Expression.
Purpose: Mammalian target of rapamycin (mTOR)is important in hematopoiesis and affect cell growth,differentiation and survival. Although previous studies were identified the effect of cytokines on the mononuclear cells development however the cytokines effect on mTOR in cord blood mononuclear cells was unclear. The aim of this study was to evaluate mTOR expression in cord blood mononuclear and cord blood stem cells (CD34+ cells) in culture conditions for lymphoid cell development. Methods: Isolation of The mononuclear cells (MNCs) from umbilical cord blood were done with use of Ficollpaque density gradient. We evaluated cultured cord blood mononuclear and CD34+ cells in presece of IL2, IL7 and IL15 at distinct time points during 21 days by using flow cytometry. In this study, we presented the role of IL2, IL7 and IL15 on the expression of mTOR in cord blood cells. Results: mTOR expression were increased in peresence of IL2, IL7 and IL15 in day 14 and afterword reduced. However in persence of IL2 and IL15 expression of mTOR significantly reduced. mTOR expression in CD34+ cells decreased significantly from day7 to day 21 in culture. Conclusion: cytokines play important role in mTOR expression during hematopoiesis and development of cord blood mononuclear cells.


Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells.
Up to 80% of human cancers, in particular solid tumors, contain cells with abnormal chromosomal numbers, or aneuploidy, which is often linked with marked chromosomal instability. Whereas in some tumors the aneuploidy occurs by missegregation of one or a few chromosomes, aneuploidy can also arise during proliferation of inherently unstable tetraploid cells generated by whole genome doubling from diploid cells. Recent findings from cancer genome sequencing projects suggest that nearly 40% of tumors underwent whole genome doubling at some point of tumorigenesis, yet its contribution to cancer phenotypes and benefits for malignant growth remain unclear. Here, we investigated the consequences of a whole genome doubling in both cancerous and non-transformed p53 positive human cells. SNP array analysis and multicolor karyotyping revealed that induced whole-genome doubling led to variable aneuploidy. We found that chromosomal instability (CIN) is a frequent, but not a default outcome of whole genome doubling. The CIN phenotypes were accompanied by increased tolerance to mitotic errors that was mediated by suppression of the p53 signaling. Additionally, the expression of pro-apoptotic factors, such as iASPP and cIAP2, was downregulated. Furthermore, we found that whole genome doubling promotes resistance to a broad spectrum of chemotherapeutic drugs and stimulates anchorage-independent growth even in non-transformed p53-positive human cells. Taken together, whole genome doubling provides multifaceted benefits for malignant growth. Our findings provide new insight why genome-doubling promotes tumorigenesis and correlates with poor survival in cancer.


A subset of topologically associating domains fold into mesoscale core-periphery networks.
Mammalian genomes are folded into a hierarchy of compartments, topologically associating domains (TADs), subTADs, and long-range looping interactions. The higher-order folding patterns of chromatin contacts within TADs and how they localize to disease-associated single nucleotide variants (daSNVs) remains an open area of investigation. Here, we analyze high-resolution Hi-C data with graph theory to understand possible mesoscale network architecture within chromatin domains. We identify a subset of TADs exhibiting strong core-periphery mesoscale structure in embryonic stem cells, neural progenitor cells, and cortical neurons. Hyper-connected core nodes co-localize with genomic segments engaged in multiple looping interactions and enriched for occupancy of the architectural protein CCCTC binding protein (CTCF). CTCF knockdown and in silico deletion of CTCF-bound core nodes disrupts core-periphery structure, whereas in silico mutation of cell type-specific enhancer or gene nodes has a negligible effect. Importantly, neuropsychiatric daSNVs are significantly more likely to localize with TADs folded into core-periphery networks compared to domains devoid of such structure. Together, our results reveal that a subset of TADs encompasses looping interactions connected into a core-periphery mesoscale network. We hypothesize that daSNVs in the periphery of genome folding networks might preserve global nuclear architecture but cause local topological and functional disruptions contributing to human disease. By contrast, daSNVs co-localized with hyper-connected core nodes might cause severe topological and functional disruptions. Overall, these findings shed new light into the mesoscale network structure of fine scale genome folding within chromatin domains and its link to common genetic variants in human disease.


Modulation of hormone-sensitive lipase and protein kinase A-mediated lipolysis by perilipin A in an adenoviral reconstituted system.
Perilipin (Peri) A is a phosphoprotein located at the surface of intracellular lipid droplets in adipocytes. Activation of cyclic AMP-dependent protein kinase (PKA) results in the phosphorylation of Peri A and hormone-sensitive lipase (HSL), the predominant lipase in adipocytes, with concurrent stimulation of adipocyte lipolysis. To investigate the relative contributions of Peri A and HSL in basal and PKA-mediated lipolysis, we utilized NIH 3T3 fibroblasts lacking Peri A and HSL but stably overexpressing acyl-CoA synthetase 1 (ACS1) and fatty acid transport protein 1 (FATP1). When incubated with exogenous fatty acids, ACS1/FATP1 cells accumulated 5 times more triacylglycerol (TG) as compared with NIH 3T3 fibroblasts. Adenoviral-mediated expression of Peri A in ACS1/FATP1 cells enhanced TG accumulation and inhibited lipolysis, whereas expression of HSL fused to green fluorescent protein (GFPHSL) reduced TG accumulation and enhanced lipolysis. Forskolin treatment induced Peri A hyperphosphorylation and abrogated the inhibitory effect of Peri A on lipolysis. Expression of a mutated Peri A Delta 3 (Ser to Ala substitutions at PKA consensus sites Ser-81, Ser-222, and Ser-276) reduced Peri A hyperphosphorylation and blocked constitutive and forskolin-stimulated lipolysis. Thus, perilipin expression and phosphorylation state are critical regulators of lipid storage and hydrolysis in ACS1/FATP1 cells.


Lactoferrin in Gingival Crevicular Fluid and Peripheral Blood during Experimental Gingivitis.
Lactoferrin (LF) is an iron binding protein and stored in the specific granules of granulocytes. It is released by degranulation following granulocyte activation. A positive correlation was previously reported between periodontitis and LF titers of gingival crevicular fluid (GCF) and blood. The purpose of this study was to examine alterations of GCF and blood levels of LF (LF-GCF and LF-BL, respectively), employing the experimental gingivitis model. Twelve systemically healthy volunteers, aged 19-21, were selected. Pre-experimental phase of hygiene was followed by a 14-day experimental gingivitis phase in which subjects refrained from all oral hygiene procedures. After that subjects resumed optimal plaque control for 21 days of recovery period. At days 0 (baseline), 14 and 35 gingival crevicular fluid (GCF) and blood samples were collected and plaque index (PI), gingival index (GI), bleeding on probing (BOP) and probing pocket depth scores were recorded. LF levels were measured with commercial enzyme-linked immunosorbent assay (ELISA) kit. PI, GI, BOP and LF-GCF increased significantly after 14 days of experimental gingivitis period and decreased significantly after reinstitution of oral hygiene measures (P<.05). LF-BL appeared to follow the same pattern. Significant negative correlation was detected between the level of LF-BL and BOP at day 14 (P<.05), whereas significant positive correlation was noticed between LF-BL and clinical scores PI, GI and BOP at day 35 (P<.05). LF-BL followed the same pattern with LF-GCF and clinical scores during the experimental gingivitis and recovery periods, although alterations of the LF-BL appeared statistically insignificant.


Investigation of conjugated metabolites of 4-hydroxyandrost-4-ene-3,17-dione in patient urine by liquid chromatography-atmospheric pressure ionization mass spectrometry.
Metabolism of the anticancer drug 4-hydroxyandrost-4-ene,3,17-dione (4OHA) was studied in cancer patients by HPLC-MS-MS. 40HA was administered orally to a breast cancer patient. The drug was extensively metabolized and was excreted in the urine as the 4OHA-glucuronide, 3 alpha-hydroxy-5 beta-androstan-4,17-dione (3 alpha OHA)-sulfate (or 4-hydroxytestosterone-sulfate) and 3 alpha,17-dihydroxy-5 beta-androstan-4-one (3,17-OHA)-sulfate conjugates in the 4 hr posttreatment sample. Other metabolites include 4OHA-sulfate, 3 alpha OHA-glucuronide, and 3,17-OHA-monoglucuronide. When 4OHA was given to the prostatic cancer patients intramuscularly, different metabolites were observed as compared with the female studies. The most noticeable difference is the absence of 4OHA-sulfate in both 24 and 48 hr posttreatment urine samples. The drug was eliminated mainly as 4OHA-glucuronide, 3 alpha OHA-sulfate, and 3,17-OHA-monosulfate. Other metabolites that have been detected include 3 alpha OHA-glucuronide, 3,17-OHA-glucuronide, 3,17-OHA-disulfate, and an unknown metabolite. The variation observed in metabolism could be attributed to a different route of drug administration (oral and intramuscular) and sex difference among the patients. This study describes the utilization of HPLC-MS-MS for monitoring the 4OHA conjugates and provides the first evidence of the presence of 4OHA-sulfate and its analogs in patient urinary extracts.


Electrocardiographic QT interval and mortality: a meta-analysis.
Extremely abnormal prolongation of the electrocardiographic QT interval is associated with malignant ventricular arrhythmias and sudden cardiac death. However, the implications of variations in QT-interval length within normal limits for mortality in the general population are still unclear. We performed a meta-analysis to investigate the relation of QT interval with mortality endpoints. Inverse-variance weighted random-effects models were used to summarize the relative risks across studies. Twenty-three observational studies were included. The pooled relative risk estimates comparing the highest with the lowest categories of QT-interval length were 1.35 (95% confidence interval = 1.24-1.46) for total mortality, 1.51 (1.29-1.78) for cardiovascular mortality, 1.71 (1.36-2.15) for coronary heart disease mortality, and 1.44 (1.01-2.04) for sudden cardiac death. A 50 milliseconds increase in QT interval was associated with a relative risk of 1.20 (1.15-1.26) for total mortality, 1.29 (1.15-1.46) for cardiovascular mortality, 1.49 (1.25-1.76) for coronary heart disease mortality, and 1.24 (0.97-1.60) for sudden cardiac death. We found consistent associations between prolonged QT interval and increased risk of total, cardiovascular, coronary, and sudden cardiac death. QT-interval length is a determinant of mortality in the general population.


Kynurenine 3-monooxygenase is implicated in antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions.
l-Tryptophan (TRP) is metabolized via serotonin and kynurenine pathways (KP). Several studies have demonstrated that abnormality of both pathways is involved in the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the KP, has been suggested to play major roles in physiological and pathological events mediated by bioactive kynurenine metabolites. In this study, we investigated the role of KMO in the emotional and cognitive functions by using KMO knockout (KO) mice. We measured contents of TRP and monoamines and their metabolites in the serum and hippocampus of KMO KO mice. Further, we investigated whether antidepressants improved the depressive-like behaviors in KMO KO mice. KMO KO mice showed depressive-like behaviors such as decreased sucrose preference and increased immobility in the forced swimming test and high anxiety by decreased time spent in the center area of open field. But, there was no difference in spontaneous alternation in Y-maze test, counts of rearing or locomotor activity. Higher contents of TRP metabolites such as kynurenine (KYN), kynurenic acid (KA), anthranilic acid (AA), and 3-hydroxykynurenine (3-HK) in the serum and hippocampus and decreased serotonin turnover and higher content of normetanephrine (NM) in the hippocampus were observed in the KMO KO mice. Although both antidepressant attenuated increase of immobility, sertraline but not imipramine improved decrease of sucrose preference in the KMO KO mice. These findings suggested that KMO KO mice show antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions via abnormality of kynurenine metabolism with good validities as MDD model.


7-Carboxy-7-deazaguanine Synthase: A Radical S-Adenosyl-l-methionine Enzyme with Polar Tendencies.
Radical S-adenosyl-l-methionine (SAM) enzymes are widely distributed and catalyze diverse reactions. SAM binds to the unique iron atom of a site-differentiated [4Fe-4S] cluster and is reductively cleaved to generate a 5'-deoxyadenosyl radical, which initiates turnover. 7-Carboxy-7-deazaguanine (CDG) synthase (QueE) catalyzes a key step in the biosynthesis of 7-deazapurine containing natural products. 6-Carboxypterin (6-CP), an oxidized analogue of the natural substrate 6-carboxy-5,6,7,8-tetrahydropterin (CPH4), is shown to be an alternate substrate for CDG synthase. Under reducing conditions that would promote the reductive cleavage of SAM, 6-CP is turned over to 6-deoxyadenosylpterin (6-dAP), presumably by radical addition of the 5'-deoxyadenosine followed by oxidative decarboxylation to the product. By contrast, in the absence of the strong reductant, dithionite, the carboxylate of 6-CP is esterified to generate 6-carboxypterin-5'-deoxyadenosyl ester (6-CP-dAdo ester). Structural studies with 6-CP and SAM also reveal electron density consistent with the ester product being formed in crystallo. The differential reactivity of 6-CP under reducing and nonreducing conditions highlights the ability of radical SAM enzymes to carry out both polar and radical transformations in the same active site.


The impact on mothers of bringing up a child with intellectual disabilities: a cross-cultural study.
Most research into the impact on mothers of having a child with an intellectual disability has been done in Western cultures. These mothers are at increased risk of stress, along with poorer health and weakened family relationships. Nurses are well placed to support these mothers. (1) To describe across three different cultures-Irish, Taiwanese and Jordanian-the inter-relationships among three indicators of maternal well-being. (2) To identify the coping strategies of mothers and the professional and informal supports available to them. (3) To identify the variables that have a negative impact on maternal well-being and possible moderating influences on them. A survey approach with three groups of self-selected mothers. The characteristics of the child determined the inclusion criteria; namely aged 5-18 years with a diagnosis of intellectual disability of such severity that the children attended special schools or centres. In each country, the special services within particular geographical areas were approached and all families known to them were given the opportunity to participate. In all 206 mothers agreed to participate. Mothers were interviewed individually at home or in the day centre attended by their child. They completed various rating scales of known reliability and validity. In addition they described in their own words, the impact the child had on their lives and how they coped. In all three countries, mothers experienced poor mental health, increased levels of child-related stress and poorer family functioning which the qualitative data further illuminated. Their child's behaviour problems were a major factor in this. The impacts on mothers' well-being were not alleviated by access to professional supports or use of coping strategies. Health professionals need to adopt family-centred approaches that embrace the support needs of mothers. Similar strategies would apply across all cultures although they must be responsive to individual need.


16S ribosomal DNA sequence analysis distinguishes biotypes of Streptococcus bovis: Streptococcus bovis Biotype II/2 is a separate genospecies and the predominant clinical isolate in adult males.
We characterized 22 human clinical strains of Streptococcus bovis by genotypic (16S rRNA gene sequence analysis [MicroSeq]; Applied Biosystems, Foster City, Calif.) and phenotypic (API 20 Strep and Rapid ID32 Strep systems (bioMerieux Vitek, Hazelton, Mo.) methods. The strains, isolated from blood, cerebrospinal fluid (CSF), and urine, formed two distinct 16S ribosomal DNA sequence clusters. Three strains which were associated with endocarditis urinary tract infection (UTI), and sepsis clustered with the S. bovis type strain ATCC 33317 (cluster 1); other closely related type strains were S. equinus and S. infantarius. Nineteen strains clustered at a distance of about 2.5% dissimilarity to the S. bovis type strain (cluster 2) and were associated with central nervous system (CNS) disease in addition to endocarditis, UTI, and sepsis. All strains were distinct from S. gallolyticus. Within cluster 2, a single strain grouped with ATCC strain 43143 (cluster 2a) and may be phenotypically distinct. All the other strains formed a second subgroup (cluster 2b) that was biochemically similar to S. bovis biotype II/2 (mannitol negative and beta galactosidase, alpha galactosidase, beta glucuronidase, and trehalose positive). The API 20 Strep system identified isolates of cluster 2b as S. bovis biotype II/2, those of cluster 1 as S. bovis biotype II/1, and that of cluster 2a as S. bovis biotype I. There was an excellent correlation of biotype and genotype: S. bovis biotype II/2 isolates form a separate genospecies distinct from the S. bovis, S. gallolyticus, and S. infantarius type strains and are the most common isolates in adult males.


Contralateral prophylactic mastectomy and survival: report from the National Cancer Data Base, 1998-2002.
The use of contralateral prophylactic mastectomy (CPM) has been increasing despite questionable survival benefit. We examined the effect of CPM on survival using the National Cancer Data Base. We examined overall survival on 219,983 mastectomy patients diagnosed with unilateral AJCC Stage 1-III invasive breast cancer between 1998 and 2002 of which 14,994 (7 %) underwent CPM at the time of their index mastectomy. Median follow up time was 5 years. Neoadjuvant and locally advanced breast cancers were excluded. Approximately 4 % underwent CPM in 1998 compared to 9.4 % in 2002, an ~125 % increase. CPM patients were significantly younger than non-CPM patients, on managed care plans, and were treated at high volume centers. The unadjusted hazard ratio (HR) of death was 0.55 (95 % CI 0.52-0.57) for CPM compared to unilateral mastectomy. In a multivariable Cox model adjusting for age, race, stage, grade, histology, insurance, facility characteristics, use of adjuvant hormonal, chemotherapy, and radiotherapy, and year of diagnosis, the adjusted HR was 0.88 (95 % CI 0.83-0.93; p < 0.001) which translated into an absolute 5-year benefit of 2 %. There was a differential effect of CPM by stage and age: HR = 0.88 (95 % CI 0.82-0.94; p < 0.001) in women younger than 70 with stage I/II, and HR = 0.95 (95 % CI 0.88-1.04; p = 0.28) in women with stage III or older than age 69 which translated into an absolute 5-year benefit of 1.3 %. Utilization of hormonal therapy or chemotherapy had no effect on the HR. After adjusting for confounding, the overall survival benefit for CPM is minimal at best.


'Creative Ferment': abortion and reproductive agency in Bessie Head's Personal Choices trilogy.
Using original archival research from Amazwi South African Museum of Literature, this article examines representations of abortion in three novels by Bessie Head: When Rain Clouds Gather (1968), Maru (1971) and A Question of Power (1973). I argue that Bessie Head documents both changing attitudes to terminations of pregnancy and dramatic environmental, medical, and sociopolitical developments during southern Africa's liberation struggles. Furthermore, her fictional writing queers materialism and its traditionally gender-dichotomous origins, presenting an understanding of development which exceeds temporal or national boundaries. Her treatment of human reproduction in both tangible and figurative terms disrupts teleological definitions of exile: separation and loss, rendered through literal and metaphorical abortions, are seen as inherently vital processes for gaining agency in post/colonial southern Africa. Instead of using discourse from contemporary debates about freedom and choice, which are often polarised, I use the term 'reproductive agency' to refer to a continuum of ethical presentness, rooted in considering women's desires. My literary analysis explicitly concentrates on Head's biological imagery of growth and separation and how this ruptures repronormative discourse underpinning colonial expansion in southern Africa. I refer to Head's ethical outlook as a critical form of humanism. My understanding of critical humanism differs from humanism proper in that it relies on queer associations: both queerness as strangeness, and queerness as resistance to categorisation (much like Head's critiques of essentialist national identities). Adapting new materialist theories with postcolonial scholarship, I coin the term 'queer vitality' to argue that abortion involves both tragedy and desire, and that southern African feminist fiction functions as postcolonial theory when the concept of reproductive agency is understood to encompass both individual and collective desires. In Head's words, in her creative worlds, abortion does not signal the ending of a life, but rather a plethora of new possibilities.


Feasibility of adjustment of insulin dose by insulin-requiring type II diabetic patients.
Type II (non-insulin-dependent) diabetes accounts for most of the diabetes morbidity and expense, yet no systematic study of the effects of intensification of treatment by such patients who require insulin treatment has been conducted. Therefore, patients were recruited from our diabetes clinics, and by random assignment, experimental and control groups were created (n = 26 and 27, respectively) that were not different at 0 mo regarding 20 demographic, physiological, and treatment variables. Experimental patients practiced an algorithm for adjustment of insulin dosage based on daily prebreakfast capillary blood glucose (CBG) measurements and any symptomatic hypoglycemia. At 2-, 4-, and 6-mo visits, records of CBG measurements were available to the physicians (n = 7), who changed insulin dosages of both groups ad libitum. Feasibility of the experimental treatment is evidenced by study completion by 87% of enrollers, monitoring on 88% of days, accuracy of CBG recording (recorded as percentage of memory meter value, 100.8), weight gain not exceeding that of control subjects, practice of treatment algorithm to effect changes in insulin dosage, modest increase in frequency of mild insulin reactions, and a decrease of glycosylated hemoglobin into the normal range.


Masking by inaudible sounds and the linearity of temporal summation.
Many natural sounds, including speech and animal vocalizations, involve rapid sequences that vary in spectrum and amplitude. Each sound within a sequence has the potential to affect the audibility of subsequent sounds in a process known as forward masking. Little is known about the neural mechanisms underlying forward masking, particularly in more realistic situations in which multiple sounds follow each other in rapid succession. A parsimonious hypothesis is that the effects of consecutive sounds combine linearly, so that the total masking effect is a simple sum of the contributions from the individual maskers. The experiment reported here tests a counterintuitive prediction of this linear-summation hypothesis, namely that a sound that itself is inaudible should, under certain circumstances, affect the audibility of subsequent sounds. The results show that, when two forward maskers are combined, the second of the two maskers can continue to produce substantial masking, even when it is completely masked by the first masker. Thus, inaudible sounds can affect the perception of subsequent sounds. A model incorporating instantaneous compression (reflecting the nonlinear response of the basilar membrane in the cochlea), followed by linear summation of the effects of the maskers, provides a good account of the data. Despite the presence of multiple sources of nonlinearity in the auditory system, masking effects by sequential sounds combine in a manner that is well captured by a time-invariant linear system.


Clinically relevant differences between assays for von Willebrand factor activity.
Essentials It is unclear whether there are differences between von Willebrand factor (VWF) activity assays. We compared the four most used VWF activity assays in 661 von Willebrand disease (VWD) patients. All assays correlated excellently, but a discrepant classification was seen in 20% of patients. Differences between VWF activity assays have a large impact on the classification of VWD. SUMMARY: Background Measuring the ability of von Willebrand factor (VWF) to bind to platelets is crucial for the diagnosis and classification of von Willebrand disease (VWD). Several assays that measure this VWF activity using different principles are available, but the clinical relevance of different assay principles is unclear. Objective To compare the four most widely used VWF activity assays in a large VWD patient population. Methods We measured VWF:RCo (ristocetin to activate VWF + whole platelets), VWF:GPIbR (ristocetin + platelet glycoprotein Ib receptor [GPIb] fragments), VWF:GPIbM (gain-of-function GPIb fragments that bind VWF spontaneously without ristocetin) and VWF:Ab (monoclonal antibody directed against the GPIb binding epitope of VWF to mimic platelets) in 661 VWD patients from the nationwide 'Willebrand in the Netherlands' (WiN) Study. Results All assays correlated excellently (Pearson r > 0.9), but discrepant results led to a different classification for up to one-fifth of VWD patients. VWF:RCo was not sensitive enough to classify 18% of patients and misclassified half of genotypic 2B VWD patients, especially those with p.Arg1306Trp. VWF:GPIbR was more sensitive, accurately classified the vast majority of patients, and was unaffected by the p.Asp1472His variant that causes artificially low VWF:RCo. VWF:GPIbM was the most precise assay but misclassified over a quarter of genotypic 2A, 2B and 3 patients. VWF:Ab, often not considered an actual VWF activity assay, performed at least equally to the other assays with regard to accurate VWD classification. Conclusion Although the different VWF activity assays are often considered similar, differences between assays have a large impact on the classification of VWD.


Whole-genome analysis of pseudorabies virus gene expression by real-time quantitative RT-PCR assay.
Pseudorabies virus (PRV), a neurotropic herpesvirus of pigs, serves as an excellent model system with which to investigate the herpesvirus life cycle both in cultured cells and in vivo. Real-time RT-PCR is a very sensitive, accurate and reproducible technique that can be used to detect very small amounts of RNA molecules, and it can therefore be applied for analysis of the expression of herpesvirus genes from the very early period of infection. In this study, we have developed and applied a quantitative reverse transcriptase-based real-time PCR technique in order to profile transcription from the whole genome of PRV after lytic infection in porcine kidney cells. We calculated the relative expression ratios in a novel way, which allowed us to compare different PRV genes with respect to their expression dynamics, and to divide the PRV genes into distinct kinetic classes. This is the first publication on the whole-genome analysis of the gene expression of an alpha-herpesvirus by qRT2-PCR. We additionally established the kinetic properties of uncharacterized PRV genes and revised or confirmed data on PRV genes earlier examined by traditional methods such as Northern blot analysis. Our investigations revealed that genes with the same expression properties form clusters on the PRV genome: nested overlapping genes belong in the same kinetic class, while most convergent genes belong in different kinetic classes. Further, we detected inverse relationships as concerns the expressions of EP0 and IE180 mRNAs and their antisense partners. Most (if not all) PRV genes begin to be expressed from the onset of viral expression. No sharp boundary was found between the groups of early and late genes classified on the basis of their requirement for viral DNA synthesis. The expressions of the PRV genes were analyzed, categorized and compared by qRT2-PCR assay, with the average of the minimum cycle threshold used as a control for the calculation of a particular R value. In principle, this new calculation technique is applicable for the analysis of gene expression in all temporally changing genetic systems.


Heating and flooding: a unified approach for rapid generation of free energy surfaces.
We propose a general framework for the efficient sampling of conformational equilibria in complex systems and the generation of associated free energy hypersurfaces in terms of a set of collective variables. The method is a strategic synthesis of the adiabatic free energy dynamics approach, previously introduced by us and others, and existing schemes using Gaussian-based adaptive bias potentials to disfavor previously visited regions. In addition, we suggest sampling the thermodynamic force instead of the probability density to reconstruct the free energy hypersurface. All these elements are combined into a robust extended phase-space formalism that can be easily incorporated into existing molecular dynamics packages. The unified scheme is shown to outperform both metadynamics and adiabatic free energy dynamics in generating two-dimensional free energy surfaces for several example cases including the alanine dipeptide in the gas and aqueous phases and the met-enkephalin oligopeptide. In addition, the method can efficiently generate higher dimensional free energy landscapes, which we demonstrate by calculating a four-dimensional surface in the Ramachandran angles of the gas-phase alanine tripeptide.


Rapid increase in aggressive behavior precedes the decrease in brain aromatase activity during socially mediated sex change in Lythrypnus dalli.
In the bluebanded goby, Lythrypnus dalli, removal of the male from a social group results in a rapid behavioral response where one female becomes dominant and changes sex to male. In a previous study, within hours of male removal, aromatase activity in the brain (bAA) of dominant females was almost 50% lower than that of control females from a group in which the male had not been removed. For those females that displayed increased aggressive behavior after the male was removed, the larger the increase in aggressive behavior, the greater the reduction in bAA. To investigate whether decreased bAA leads to increased aggression, the present study used a more rapid time course of behavioral profiling and bAA assay, looking within minutes of male removal from the group. There were no significant differences in bAA between control females (large females from groups with the male still present), females that doubled their aggressive behavior by 10 or 20 min after male removal, or females that did not double their aggressive behavior within 30 min after male removal. Further, individual variation in bAA and aggressive behavior were not correlated in these fish. Whole brain decreases in aromatase activity thus appear to follow, rather than precede, rapid increases in aggressive behavior, which provides one potential mechanism underlying the rapid increase in androgens that follows aggressive interactions in many vertebrate species. For fish species that change sex from female to male, this increase in androgens could subsequently facilitate sex change.


Squaring the circle. Social and environmental implications of pre-pottery neolithic building technology at Tell Qarassa (South Syria).
We present the results of the microstratigraphic, phytolith and wood charcoal study of the remains of a 10.5 ka roof. The roof is part of a building excavated at Tell Qarassa (South Syria), assigned to the Pre-Pottery Neolithic B period (PPNB). The Pre-Pottery Neolithic (PPN) period in the Levant coincides with the emergence of farming. This fundamental change in subsistence strategy implied the shift from mobile to settled aggregated life, and from tents and huts to hard buildings. As settled life spread across the Levant, a generalised transition from round to square buildings occurred, that is a trademark of the PPNB period. The study of these buildings is fundamental for the understanding of the ever-stronger reciprocal socio-ecological relationship humans developed with the local environment since the introduction of sedentism and domestication. Descriptions of buildings in PPN archaeological contexts are usually restricted to the macroscopic observation of wooden elements (posts and beams) and mineral components (daub, plaster and stone elements). Reconstructions of microscopic and organic components are frequently based on ethnographic analogy. The direct study of macroscopic and microscopic, organic and mineral, building components performed at Tell Qarassa provides new insights on building conception, maintenance, use and destruction. These elements reflect new emerging paradigms in the relationship between Neolithic societies and the environment. A square building was possibly covered here with a radial roof, providing a glance into a topologic shift in the conception and understanding of volumes, from round-based to square-based geometries. Macroscopic and microscopic roof components indicate buildings were conceived for year-round residence rather than seasonal mobility. This implied performing maintenance and restoration of partially damaged buildings, as well as their adaptation to seasonal variability.


Serum and tissue autoantibodies to colonic epithelium in ulcerative colitis.
Sera and colonic tissue-bound immunoglobulin extracts from patients with ulcerative colitis and disease controls were examined immunohistochemically and by killer cell cytotoxicity assay for the presence of anticolonic epithelial autoantibodies. IgG yields in the tissue extracts from patients with colitis and control subjects were similar, and the extracts were uniformly autoantibody negative. Of 41 sera from patients with inflammatory bowel disease, 'classical' anticolon antibody was present in 41% and was commoner in patients with sclerosing cholangitis. Cytotoxic anticolon antibody was present in 20% overall and was strongly associated with disease activity; it did not correlate with the presence of 'classical' anticolon antibody. The heterogeneous and non-universal antiepithelial autoantibody response and the failure to detect tissue bound autoantibody in vivo argue against the hypothesis that humoral autoimmunity is of major importance in the pathogenesis of ulcerative colitis.


Principal component analysis of Mn(salen) catalysts.
The theoretical study of Mn(salen) catalysts has been traditionally performed under the assumption that Mn(acacen') (acacen' = 3,3'-(ethane-1,2-diylbis(azanylylidene))bis(prop-1-en-olate)) is an appropriate surrogate for the larger Mn(salen) complexes. In this work, the geometry and the electronic structure of several Mn(salen) and Mn(acacen') model complexes were studied using Density Functional Theory (DFT) at diverse levels of approximation, with the aim of understanding the effects of truncation, metal oxidation, axial coordination, substitution on the aromatic rings of the salen ligand and chirality of the diimine bridge, as well as the choice of the density functional and basis set. To achieve this goal, geometric and structural data, obtained from these calculations, were subjected to Principal Component Analysis (PCA) and PCA with orthogonal rotation of the components (rPCA). The results show the choice of basis set to be of paramount importance, accounting for up to 30% of the variance in the data, while the differences between salen and acacen' complexes account for about 9% of the variance in the data, and are mostly related to the conformation of the salen/acacen' ligand around the metal centre. Variations in the spin state and oxidation state of the metal centre also account for large fractions of the total variance (up to 10% and 9%, respectively). Other effects, such as the nature of the diimine bridge or the presence of an alkyl substituent in the 3,3 and 5,5 positions of the aldehyde moiety, were found to be less important in terms of explaining the variance within the data set. A matrix of discriminants was compiled using the loadings of the principal and rotated components that best performed in the classification of the entries in the data. The scores obtained from its application to the data set were used as independent variables for devising linear models of different properties, with satisfactory prediction capabilities.


A simple, modular synthesis of C4-substituted tryptophan derivatives.
The modular and versatile synthesis of C4-substituted tryptophan derivatives by direct functionalization of easily available N-acetyl 4-boronate tryptophan methyl ester via transition metal-catalyzed and metal-mediated cross coupling reactions is described. The versatility of the chemistry is highlighted by the gram-scale synthesis of 4-boronated N-acetyl-tryptophan methyl ester and the rapid synthesis of C4-aryl, C4-alkyl, C4-cyano, C4-trifluoromethyl, C4-azido, and C4-hydroxy tryptophan derivatives. The utility of our methodology is illustrated through the quick approach to the tricyclic azepino indole skeleton embedded in many natural products.


[Psoriasis in a female chimpanzee].
Psoriasis, a widespread genodermatosis in Homo sapiens, also appears in primates. We report on a female chimpanzee in Leipzig Zoo. After years of captivity the animal developed erythematosquamous, highly hyperkeratotic, lesions, some confluent, on the knees, elbows, back of the hands and feet and on the forearms and the seat, which showed histologically characteristic features of psoriasis. It may be that both previous infections and psychic stress resulting from social isolation had caused eruption of the disease. In the literature single cases of psoriasiform dermatoses have also been described in other species of monkeys and even in a springer spaniel. Nonetheless, the search for an animal model of psoriasis vulgaris is still going on.


Decreased surface tension of water by hard-x-ray irradiation.
We discovered that intense irradiation by hard-x-ray strongly decreases the effects of natural surface tension of water in droplets and capillary tubes. The effect was revealed by direct experimental observations with phase contrast microradiology. A model based on ionization and surface charging explains this so far undetected phenomenon. The effect can impact the results of many experimental techniques based on x rays. This is an example of the largely unexplored effects that can be produced by extreme intense x-ray irradiation-an important issue due to current development of x-ray free-electron-lasers with unprecedented brilliance.


Transplantation of reversibly immortalized insulin-secreting human hepatocytes controls diabetes in pancreatectomized pigs.
Type 1 diabetes results from the destruction of insulin-producing pancreatic beta-cells by a beta-cell-specific autoimmune process. Although converting other cell types into insulin-producing cells may compensate for the loss of the beta-cell mass while evading beta-cell-specific T-cell responses, proof-of-principle of this approach in large animal models is lacking. This investigation was initiated to determine whether an insulin-producing human hepatocyte line can control diabetes when transplanted into totally pancreatectomized diabetic pigs. We established a reversibly immortalized human hepatocyte line, YOCK-13, by transferring a human telomerase reverse transcriptase cDNA and a drug-inducible Cre recombinase cassette, followed by cDNA for a modified insulin under the control of the L-type pyruvate kinase (L-PK) promoter. YOCK-13 cells produced small amounts of modified insulin and no detectable endogenous L-PK at low glucose concentrations, whereas they produced large amounts of both modified insulin and L-PK in response to high glucose concentrations. Xenotransplantation of YOCK-13 cells via the portal vein into immunosuppressed, totally pancreatectomized pigs decreased hyperglycemia and prolonged survival without adverse effects such as portal thrombosis, liver necrosis, pulmonary embolism, and tumor development. We suggest that this reversibly immortalized, insulin-secreting human hepatocyte line may overcome the shortage of donor pancreata for islet transplantation into patients with type 1 diabetes.


Statistical analysis, trial design and duration in Alzheimer's disease clinical trials: a review.
The social and economic burden of Alzheimer's disease (AD) and its increasing prevalence has led to much work on new treatment strategies and clinical trials. The search for surrogate markers of disease progression continues but traditional parallel group trial designs that use well-established, but often insensitive, clinical outcome measures predominate. We performed a systematic search across the Cochrane Library and PubMed abstracts published between January 2004 and August 2009. Information regarding the clinical trial methodology, outcome measures, intervention type and primary statistical analysis techniques was extracted and categorized, according to a standard protocol. We identified 149 papers describing results from clinical trials in AD containing sufficient detail for our purposes. The largest proportion (38%) presented results of trials based on tests of cognition as the primary outcome measure. The primary analysis in most papers (85%) was a univariate significance test of a single primary outcome measure. The majority of trials reported a comparison of baseline and end-point assessment over relatively short patient follow-up periods, using univariate statistical methods to compare differences between intervention and control groups in the primary analysis. There is considerable scope to introduce newer statistical methods and trial designs in treatment evaluations in AD.


Incidence and survival of chronic myelomonocytic leukemia in Girona (Spain): a population-based study, 1993-2007.
Chronic myelomonocytic leukemia is a very rare blood cancer observed mostly in the elderly. Here we report the incidence trends and survival of patients with chronic myelomonocytic leukemia over a 15-year period (1993-2007). Cases were provided by the population-based Girona Cancer Registry. The crude incidence rate was 0.72/100,000 inhabitants/year. No statistically significant increase in trends was detected over the 15 years. Median overall survival was 28 months although survival markedly decreased with advancing age. The 5-years observed and relative survivals were 20% and 29%, respectively. This is the first population-based study that reports the incidence and survival of chronic myelomonocytic leukemia in Spain.


Genetic characterization of local Criollo pig breeds from the Americas using microsatellite markers.
Little is known about local Criollo pig genetic resources and relationships among the various populations. In this paper, genetic diversity and relationships among 17 Criollo pig populations from 11 American countries were assessed with 24 microsatellite markers. Heterozygosities, F-statistics, and genetic distances were estimated, and multivariate, genetic structure and admixture analyses were performed. The overall means for genetic variability parameters based on the 24 microsatellite markers were the following: mean number of alleles per locus of 6.25 ± 2.3; effective number of alleles per locus of 3.33 ± 1.56; allelic richness per locus of 4.61 ± 1.37; expected and observed heterozygosity of 0.62 ± 0.04 and 0.57 ± 0.02, respectively; within-population inbreeding coefficient of 0.089; and proportion of genetic variability accounted for by differences among breeds of 0.11 ± 0.01. Genetic differences were not significantly associated with the geographical location to which breeds were assigned or their country of origin. Still, the NeighborNet dendrogram depicted the clustering by geographic origin of several South American breeds (Criollo Boliviano, Criollo of northeastern Argentina wet, and Criollo of northeastern Argentina dry), but some unexpected results were also observed, such as the grouping of breeds from countries as distant as El Salvador, Mexico, Ecuador, and Cuba. The results of genetic structure and admixture analyses indicated that the most likely number of ancestral populations was 11, and most breeds clustered separately when this was the number of predefined populations, with the exception of some closely related breeds that shared the same cluster and others that were admixed. These results indicate that Criollo pigs represent important reservoirs of pig genetic diversity useful for local development as well as for the pig industry.


A comparison of three estimators of the population-scaled recombination rate: accuracy and robustness.
We have performed simulations to assess the performance of three population genetics approximate-likelihood methods in estimating the population-scaled recombination rate from sequence data. We measured performance in two ways: accuracy when the sequence data were simulated according to the (simplistic) standard model underlying the methods and robustness to violations of many different aspects of the standard model. Although we found some differences between the methods, performance tended to be similar for all three methods. Despite the fact that the methods are not robust to violations of the underlying model, our simulations indicate that patterns of relative recombination rates should be inferred reasonably well even if the standard model does not hold. In addition, we assess various techniques for improving the performance of approximate-likelihood methods. In particular we find that the composite-likelihood method of Hudson (2001) can be improved by including log-likelihood contributions only for pairs of sites that are separated by some prespecified distance.


Acquired Vitelliform Lesions: correlation of clinical findings and multiple imaging analyses.
To correlate clinical observations with multimodal imaging analysis in acquired vitelliform lesions (AVLs) and to elucidate their nature, pathogenesis, and natural course. Clinical examination, color fundus photography, fluorescein angiography, near-infrared reflectance, fundus autofluorescence, and spectral-domain optical coherence tomography (SD-OCT) data were retrospectively reviewed for a consecutive series of 90 eyes of 67 patients with an AVL secondary to a variety of diagnoses. In all 90 eyes with AVLs, SD-OCT helped localize the clinically apparent yellowish material to the subretinal space above the retinal pigment epithelial (RPE) band. Only 19 eyes (21.1%) had SD-OCT evidence of subretinal fluid. All eyes exhibited abnormal hyperautofluorescence corresponding to the material seen clinically. In 18 of 72 eyes (25.0%) imaged simultaneously with SD-OCT and near-infrared reflectance imaging, near-infrared hyperreflectivity corresponding to presumed collections of pigment-laden macrophages and RPE cells was observed. Resolution of some AVLs appeared to coincide with progressive thinning of the outer nuclear layer, indicating a gradual loss of photoreceptors. Visual acuity at baseline was best predicted by the subfoveal integrity of the external limiting membrane (P = 0.001) and the inner segment/outer segment junction (P = 0.0002) on SD-OCT. Fluorescein angiography revealed a pattern often mimicking poorly defined (Type 1) choroidal neovascularization. Acquired vitelliform lesions occur in a variety of different clinical entities that share common features with multimodal imaging analyses. We propose that both dysfunctional RPE and loss of apposition between the photoreceptor tips and the RPE can interfere with the phagocytosis of shed outer segments. Both this material and pigment-laden macrophages and RPE cells appear to contribute to the yellowish appearance of AVLs. Ongoing photoreceptor loss may in some cases be associated with the spontaneous resolution of an AVL.


Contactless optical scanning of fingerprints with 180 degrees view.
Fingerprint recognition technology is an integral part of criminal investigations. It is the basis for the design of numerous security systems in both the private and public sectors. In a recent study emulating the fingerprinting procedure with widely used optical scanners, it was found that, on average, the distance between ridges decreases about 20% when a finger is positioned on a scanner. Using calibrated silicon pressure sensors, the authors scanned the distribution of pressure across a finger, pixel by pixel, and also generated maps of the average pressure distribution during fingerprinting. Controlled loading of a finger demonstrated that it is impossible to reproduce the same distribution of pressure across a given finger during repeated fingerprinting procedures. Based on this study, a novel method of scanning the fingerprint with more than a 180 degrees view was developed. Using a camera rotated around the finger, small slices of the entire image of the finger were acquired. Equal sized slices of the image were processed with a special program assembling a more than 180 degrees view of the finger. Comparison of two images of the same fingerprint, namely the registered and actual images, could be performed by a new algorithm based on the symmetry of the correlation function. The novel method is the first contactless optical scanning technique to view 180 degrees of a fingerprint without moving the finger. In a machine which is under design, it is expected that the full view of one finger would be acquired in about a second.


A multifaceted risk analysis of fathers' self-reported physical violence toward their children.
Existing research has shown that child maltreatment is carried out by both mothers and fathers. There is also an extensive body of literature analyzing reasons for mothers' violent behavior. Among fathers, reasons are less well studied, resulting in the lack of a comprehensive picture of paternal child abuse. In this study, 20 child-, parent-, and family-related factors have been included in a combined analysis to assess which of these may pose a risk for fathers' severe violent behavior toward their children. The study is based on merged data from Finland and Sweden, in which an anonymous survey was answered by parents, based on representative samples of parents with 0-12-year-old children. The merged data set included 679 fathers and analyses were carried out using logistic regression models. Six percent of the fathers had committed severe violent acts, that is, slapped, hit, punched, kicked, bit, hit/tried to hit their child with an object or shook (under 2-year-old) their child at least once during the 12 months preceding the survey. Corporal punishment experienced by the fathers when they were children, or used by the father as a method of discipline, strongly increased the likelihood of severe violent acts. The findings emphasize the importance of preventing all forms of corporal punishment in seeking to minimize the occurrence of severe physical violence by fathers toward their children. Aggr. Behav. 43:317-328, 2017. © 2016 Wiley Periodicals, Inc.


[Motor neuron heterogeneity and selective vulnerability in ALS].
Different and selective vulnerability among motor neuron subtypes are a fundamental, but unexplained, feature of amyotrophic lateral sclerosis (ALS): fast-fatigable (FF) motor neurons are the most vulnerable, and fast fatigue-resistant/slow (FR/S) motor neurons are relatively resistant. We identified that osteopontin (OPN) can serve as a marker of FR/S motor neurons, whereas matrix metalloproteinase-9 (MMP9) is expressed by FF motor neurons in mice. In SOD1G93A ALS model mice, as the disease progressed, OPN was secreted and accumulated as granular deposits in the extracellular matrix. We also detected OPN/MMP9 co-expressed motor neurons around the disease onset. These double positive motor neurons showed the expression of αvβ3 integrin (OPN receptor) and up-regulation of ER stress markers. We discovered that the double positive motor neurons are remodeled FR/S motor neurons, which compensated for FF motor neuron degeneration (the first wave of degeneration). Genetic ablation of OPN delayed the onset of disease, but later accelerated disease progression. This reflects two modes of OPN involvement in the pathogenesis of ALS: cell-autonomous and non-cell-autonomous effects on motor neuron vulnerability. Our study suggests that OPN expressed in FR/S motor neurons is involved in the second wave of motor neuron degeneration in ALS, and an OPN-αvβ3 integrin-MMP9 axis could be a potentially useful therapeutic target for ALS.


Ammonia excretion in Caenorhabditis elegans: mechanism and evidence of ammonia transport of the Rhesus protein CeRhr-1.
The soil-dwelling nematode Caenorhabditis elegans is a bacteriovorous animal, excreting the vast majority of its nitrogenous waste as ammonia (25.3±1.2 µmol gFW(-1) day(-1)) and very little urea (0.21±0.004 µmol gFW(-1) day(-1)). Although these roundworms have been used for decades as genetic model systems, very little is known about their strategy to eliminate the toxic waste product ammonia from their bodies into the environment. The current study provides evidence that ammonia is at least partially excreted via the hypodermis. Starvation reduced the ammonia excretion rates by more than half, whereas mRNA expression levels of the Rhesus protein CeRhr-2, V-type H(+)-ATPase (subunit A) and Na(+)/K(+)-ATPase (α-subunit) decreased correspondingly. Moreover, ammonia excretion rates were enhanced in media buffered to pH 5 and decreased at pH 9.5. Inhibitor experiments, combined with enzyme activity measurements and mRNA expression analyses, further suggested that the excretion mechanism involves the participation of the V-type H(+)-ATPase, carbonic anhydrase, Na(+)/K(+)-ATPase, and a functional microtubule network. These findings indicate that ammonia is excreted, not only by apical ammonia trapping, but also via vesicular transport and exocytosis. Exposure to 1 mmol l(-1) NH4Cl caused a 10-fold increase in body ammonia and a tripling of ammonia excretion rates. Gene expression levels of CeRhr-1 and CeRhr-2, V-ATPase and Na(+)/K(+)-ATPase also increased significantly in response to 1 mmol l(-1) NH4Cl. Importantly, a functional expression analysis showed, for the first time, ammonia transport capabilities for CeRhr-1 in a phylogenetically ancient invertebrate system, identifying these proteins as potential functional precursors to the vertebrate ammonia-transporting Rh-glycoproteins.


Consensus: varicella vaccination of healthy children--a challenge for Europe.
The seriousness of varicella-zoster virus (VZV) infection as a public health issue is becoming clearer as country-specific epidemiologic and pharmacoeconomic data become available. In Germany, for example, studies have shown that >5.5% of immunologically healthy individuals develop varicella-related complications such as bacterial superinfections, acute neurologic disorders, pneumonia, bronchitis and otitis media; whereas in Italy, 3.5 to 5% of childhood cases of varicella cause complications such as upper respiratory tract and cutaneous infections. Varicella vaccines are now available. These live attenuated Oka strain vaccines have been shown in extensive studies to be highly immunogenic and well-tolerated in immunocompetent and immunocompromised children, with seroconversion rates ranging from 94 to 100% and 53 to 100%, respectively. These vaccines are also highly effective against clinical disease. These considerations led to a reevaluation of varicella vaccination policies. A routine varicella vaccination program targeting healthy children has already been implemented in the US, and data produced are encouraging and valuable. Similar strategies have not yet been adopted across Europe. The European Working Group on Varicella (EuroVar) was formed in 1998 to address the issues surrounding varicella epidemiology in Europe. After a series of meetings, the EuroVar members prepared a consensus statement recommending routine varicella vaccination for all healthy children between 12 and 18 months and to all susceptible children before their 13th birthday, in addition to catch-up vaccination in older children and adults who have no reliable history of varicella and who are at high risk of transmission and exposure. However, such a policy is recommended only if a very high coverage rate can be achieved. This could be reached with a measles-mumps-rubella-varicella combined vaccine.


Best of both worlds: promise of combining brain stimulation and brain connectome.
Transcranial current brain stimulation (tCS) is becoming increasingly popular as a non-pharmacological non-invasive neuromodulatory method that alters cortical excitability by applying weak electrical currents to the scalp via a pair of electrodes. Most applications of this technique have focused on enhancing motor and learning skills, as well as a therapeutic agent in neurological and psychiatric disorders. In these applications, similarly to lesion studies, tCS was used to provide a causal link between a function or behavior and a specific brain region (e.g., primary motor cortex). Nonetheless, complex cognitive functions are known to rely on functionally connected multitude of brain regions with dynamically changing patterns of information flow rather than on isolated areas, which are most commonly targeted in typical tCS experiments. In this review article, we argue in favor of combining tCS method with other neuroimaging techniques (e.g., fMRI, EEG) and by employing state-of-the-art connectivity data analysis techniques (e.g., graph theory) to obtain a deeper understanding of the underlying spatiotemporal dynamics of functional connectivity patterns and cognitive performance. Finally, we discuss the possibilities of using these combined techniques to investigate the neural correlates of human creativity and to enhance creativity.


Ultrasound-guided injection for plantar fasciitis: A brief review.
Plantar fasciitis (PF) is a distressing condition experienced by many patients. Although self-limiting, it tends to become a chronic ailment if the precipitating factors are not addressed. One of the modality of treating PF is intra-lesional corticosteroid injection. This was done using palpation technique earlier but nowadays many specialists use ultrasound (US) imaging as a guide to give injection accurately instead of inadvertently damaging the plantar fascia or injecting into surrounding soft tissue, both of which can have serious implications. We did a literature search in Medline, Scopus, and Embase databases to find out articles describing US-guided corticosteroid injection for treating PF and whether guided injection was effective than injection given by palpation.


A rational biomimetic approach to structure defect generation in colloidal nanocrystals.
Controlling the morphology of nanocrystals (NCs) is of paramount importance for both fundamental studies and practical applications. The morphology of NCs is determined by the seed structure and the following facet growth. While means for directing facet formation in NC growth have been extensively studied, rational strategies for the production of NCs bearing structure defects in seeds have been much less explored. Here, we report mechanistic investigations of high density twin formation induced by specific peptides in platinum (Pt) NC growth, on the basis of which we derive principles that can serve as guidelines for the rational design of molecular surfactants to introduce high yield twinning in noble metal NC syntheses. Two synergistic factors are identified in producing twinned Pt NCs with the peptide: (1) the altered reduction kinetics and crystal growth pathway as a result of the complex formation between the histidine residue on the peptide and Pt ions, and (2) the preferential stabilization of {111} planes upon the formation of twinned seeds. We further apply the discovered principles to the design of small organic molecules bearing similar binding motifs as ligands/surfactants to create single and multiple twinned Pd and Rh NCs. Our studies demonstrate the rich information derived from biomimetic synthesis and the broad applicability of biomimetic principles to NC synthesis for diverse property tailoring.


A stereospecific carboxyl esterase from Bacillus coagulans hosting nonlipase activity within a lipase-like fold.
Microbial carboxylesterases are important biocatalysts that selectively hydrolyze an extensive range of esters. Here, we report the biochemical and structural characterization of an atypical carboxylesterase from Bacillus coagulans (BCE), endowed with high enantioselectivity toward different 1,2-O-isopropylideneglycerol (IPG or solketal) esters. BCE efficiently catalyzes the production of enantiopure (S)-IPG, a chiral building block for the synthesis of β-blockers, glycerophospholipids, and prostaglandins; efficient hydrolysis was observed up to 65 °C. To gain insight into the mechanistic bases of such enantioselectivity, we solved the crystal structures of BCE in apo- and glycerol-bound forms at resolutions of 1.9 and 1.8 Å, respectively. In silico docking studies on the BCE structure confirmed that IPG esters with small acyl chains (≤ C6) were easily accommodated in the active site pocket, indicating that small conformational changes are necessary to accept longer substrates. Furthermore, docking studies suggested that enantioselectivity may be due to an improved stabilization of the tetrahedral reaction intermediate for the S-enantiomer. Contrary to the above functional data implying nonlipolytic functions, BCE displays a lipase-like 3D structure that hosts a "lid" domain capping the main entrance to the active site. In lipases the lid mediates catalysis through interfacial activation, a process that we did not observe for BCE. Overall, we present the functional-structural properties of an atypical carboxyl esterase that has nonlipase-like functions, yet possesses a lipase-like 3D fold. Our data provide original enzymatic information in view of BCE applications as an inexpensive, efficient biocatalyst for the production of enantiopure (S)-IPG. Coordinates and structure factors have been deposited in the Protein Data Bank (www.rcsb.org) under accession numbers 5O7G (apo-BCE) and 5OLU (glycerol-bound BCE).