RIPK1 and PGAM5 Control Leishmania Replication through Distinct Mechanisms.
Leishmaniasis is an important parasitic disease found in the tropics and subtropics. Cutaneous and visceral leishmaniasis affect an estimated 1.5 million people worldwide. Despite its human health relevance, relatively little is known about the cell death pathways that control Leishmania replication in the host. Necroptosis is a recently identified form of cell death with potent antiviral effects. Receptor interacting protein kinase 1 (RIPK1) is a critical kinase that mediates necroptosis downstream of death receptors and TLRs. Heme, a product of hemoglobin catabolism during certain intracellular pathogen infections, is also a potent inducer of macrophage necroptosis. We found that human visceral leishmaniasis patients exhibit elevated serum levels of heme. Therefore, we examined the impact of heme and necroptosis on Leishmania replication. Indeed, heme potently inhibited Leishmania replication in bone marrow-derived macrophages. Moreover, we found that inhibition of RIPK1 kinase activity also enhanced parasite replication in the absence of heme. We further found that the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5), a putative downstream effector of RIPK1, was also required for inhibition of Leishmania replication. In mouse infection, both PGAM5 and RIPK1 kinase activity are required for IL-1β expression in response to Leishmania However, PGAM5, but not RIPK1 kinase activity, was directly responsible for Leishmania-induced IL-1β secretion and NO production in bone marrow-derived macrophages. Collectively, these results revealed that RIPK1 and PGAM5 function independently to exert optimal control of Leishmania replication in the host.


PDGF alpha-receptor mediated cellular responses are not dependent on Src family kinases in endothelial cells.
Two novel autophosphorylation sites in the juxtamembrane region of the PDGF alpha-receptor, Tyr-572 and Tyr-574, were identified. A Y572/574F mutant PDGF (alpha)-receptor was generated and stably expressed in porcine aortic endothelial cells. In contrast to the wild-type receptor, the mutant receptor was unable to associate with or activate Src family tyrosine kinases. Tyrosine phosphorylated synthetic peptides representing the juxtamembrane sequence of the receptor dose-dependently inhibited the binding of Src family tyrosine kinases to the autophosphorylated PDGF alpha-receptor. The mutant receptor showed similar PDGF-induced kinase activity and ability to mediate mitogenicity, actin reorganization and chemotaxis as the wild-type receptor. Thus activation of Src family kinases by the PDGF alpha-receptor is not essential for PDGF-induced mitogenicity or actin reorganization.


Dimensions of racism and their impact on partner selection among men of colour who have sex with men: understanding pathways to sexual risk.
While many studies have established the relationship between experiences of racism and sexual risk among men of colour who have sex with men, the pathways by which this occurs are underdeveloped. To address this gap, we must better investigate the lived realities of racism in the gay community. In this study, we had the unique opportunity to examine experiences of racism among African American, Asian/Pacific Islander and Latino men who have sex with men living in Los Angeles through focus groups and individual in-depth interviews. We found three themes of racism: exclusion from West Hollywood and the mainstream gay community, sexual rejection based on race/ethnicity and sexual stereotypes. There were differences across the three racial groups in the experiences of each theme, however. We then considered how racism impacted partner selection and found that race played a salient role in determining power differentials within mixed-race partnerships. Finally, we discussed several future areas for research that can better establish pathways between racism and sexual risk.


B-cell epitopes of canine parvovirus: distribution on the primary structure and exposure on the viral surface.
Ten antigenic sites on canine parvovirus (CPV) were mapped with a complete set of overlapping nonapeptides of the capsid proteins VP1 and VP2: five of these sites were recognized by sera from CPV-infected dogs, three were recognized by a rabbit anti-CPV antiserum, and two were recognized by murine monoclonal anti-CPV antibodies. A region covering the first 21 amino-terminal amino acid residues of VP2 was recognized by three sera from infected dogs, one neutralizing rabbit antiserum, and one neutralizing murine monoclonal antibody. Immunoabsorption experiments with full virions indicated that at least 6 of the 10 antigenic sites are located on the surface. Of these six, three sites occur in the amino terminus of VP2. When superimposed on the three-dimensional structure of canine parvovirus (J. Tsao, M. S. Chapman, M. Agbandje, W. Keller, K. Smith, H. Wu, M. Luo, T. J. Smith, M. G. Rossmann, R. W. Compans, and C. R. Parrish, Science 251:1456-1464, 1991), the other three epitopes are located on two loops of VP2 which form the highly exposed "spike" around the threefold-symmetry axis of the virus. Thus, these regions (amino terminus and loops 1 and 3) are of interest as major target sites for induction of neutralizing antibodies.


A neural extracellular matrix-based method for in vitro hippocampal neuron culture and dopaminergic differentiation of neural stem cells.
The ability to recreate an optimal cellular microenvironment is critical to understand neuronal behavior and functionality in vitro. An organized neural extracellular matrix (nECM) promotes neural cell adhesion, proliferation and differentiation. Here, we expanded previous observations on the ability of nECM to support in vitro neuronal differentiation, with the following goals: (i) to recreate complex neuronal networks of embryonic rat hippocampal cells, and (ii) to achieve improved levels of dopaminergic differentiation of subventricular zone (SVZ) neural progenitor cells. Hippocampal cells from E18 rat embryos were seeded on PLL- and nECM-coated substrates. Neurosphere cultures were prepared from the SVZ of P4-P7 rat pups, and differentiation of neurospheres assayed on PLL- and nECM-coated substrates. When seeded on nECM-coated substrates, both hippocampal cells and SVZ progenitor cells showed neural expression patterns that were similar to their poly-L-lysine-seeded counterparts. However, nECM-based cultures of both hippocampal neurons and SVZ progenitor cells could be maintained for longer times as compared to poly-L-lysine-based cultures. As a result, nECM-based cultures gave rise to a more branched neurite arborization of hippocampal neurons. Interestingly, the prolonged differentiation time of SVZ progenitor cells in nECM allowed us to obtain a purer population of dopaminergic neurons. We conclude that nECM-based coating is an efficient substrate to culture neural cells at different stages of differentiation. In addition, neural ECM-coated substrates increased neuronal survival and neuronal differentiation efficiency as compared to cationic polymers such as poly-L-lysine.


The use of patient-reported outcome measures to guide referral for hip and knee arthroplasty.
To calculate how the likelihood of obtaining measurable benefit from hip or knee arthroplasty varies with preoperative patient-reported scores. Existing UK data from 222,933 knee and 209,760 hip arthroplasty patients were used to model an individual's probability of gaining meaningful improvement after surgery based on their preoperative Oxford Knee or Hip Score (OKS/OHS). A clinically meaningful improvement after arthroplasty was defined as ≥ 8 point improvement in OHS, and ≥ 7 in OKS. The upper preoperative score threshold, above which patients are unlikely to achieve any meaningful improvement from surgery, is 41 for knees and 40 for hips. At lower scores, the probability of improvement increased towards a maximum of 88% (knee) and 95% for (hips). By our definition of meaningful improvement, patients with preoperative scores above 41 (OKS) and 40 (OHS) should not be routinely referred to secondary care for possible arthroplasty. Using lower thresholds would incrementally increase the probability of meaningful benefit for those referred but will exclude some patients with potential to benefit. The findings are useful to support the complex shared decision-making process in primary care for referral to secondary care; and in secondary care for experienced clinicians counselling patients considering knee or hip arthroplasty, but should not be used in isolation. Cite this article: Bone Joint J 2020;102-B(7):941-949.


[Uroliths of dogs in Switzerland from 2003 to 2009].
Information on composition of uroliths collected between 2003 and 2009 from dogs in Switzerland and epidemiologic data of affected dogs are summarised in this paper. Of 490 stones analysed 44% were composed of calcium oxalate, 330% of struvite, 80% of silica, 7% of urate, 3% of cystine, 3% were mixed stones and 1% each were calcium phosphate and xanthine stones. Compared to other dogs, Norwich Terriers, Norfolk Terriers, Miniature Schnauzers, Miniature Pinscher and Yorkshire Terriers had a significantly increased risk to suffer from calcium oxalate stones, Dalmatians and Continental Bulldogs from urate stones and English Bulldogs from cystine stones. No breed had an increased risk of struvite or silica stones. Stones composed of silica were more prevalent in Switzerland compared to other countries and were more common in the eastern part than in the western part of Switzerland. This study shows that there are differences in occurrence and prevalence of uroliths between Switzerland and surveys of other countries.


Comparative evaluation of angiogenesis assessment with anti-factor-VIII and anti-CD31 immunostaining in non-small cell lung cancer.
Anti-Factor VIII vessel immunostaining has been widely used in the detection of angiogenesis in non-small cell lung cancer and other tumors. Several new antibodies have shown a higher sensitivity, and anti-CD31 has recently been proposed to be the standard for microvessel study. In the present study, we comparatively evaluated the two antibodies in 134 cases of early operable non-small cell lung cancer. The F8/86 (anti-Factor VIII-associated antigen) and JC70 (anti-CD31) MoAbs were used in paraffin-embedded material. Eye appraisal of vascular grade (VG) and microvessel score (MS) was performed by three experienced pathologists. Different cutoff points were used for the analysis of VG and MS correlation with nodal involvement, overall survival, and thymidine phosphorylase expression. Intra- and interobserver variability was minimal for both antibodies. MS and VG were significantly correlated with each other. However, 54 and 22% of cases with high anti-CD31 VG or high MS, respectively, had low vascularization on anti-Factor VIII assessment. Anti-CD31 scoring was significantly associated with nodal involvement and overall survival for all cutoff points considered, which was not verified for anti-Factor VIII staining. VG was the most significant indicator of nodal involvement and survival for both antibodies. Tumors with high VG by anti-CD31 but low or medium VG by anti-Factor VIII behaved as tumors of high neoangiogenesis, defining a poor prognosis (P = 0.005) despite the failure of anti-factor VIII antibody to highlight intense neoangiogenesis. Anti-CD31 MS significantly associated with thymidine phosphorylase overexpression (P = 0.01), whereas no correlation was found for anti-Factor VIII counting. It was concluded that anti-CD31 microvessel immunostaining has several advantages over anti-Factor VIII, being a more sensitive method for highlighting small, immature microvessels or single endothelial cells. This could be of importance in revealing possible correlation of tumor angiogenesis with metastatic behavior, prognosis, or angiogenic factor overexpression. Vascular grading was the best method for neovascularization assessment, efficiently defining groups of tumors with aggressive clinical course.


Chronic one-kidney hypertension in rabbits. II. Evidence for a new factor.
The arterial pressure of rabbits with chronic one-kidney hypertension can be lowered to normotensive levels by direct immunization with preparations made from the cortex of hog kidneys. Hypertensive rabbits that are immunized with large amounts of renin may develop high plasma antirenin titers without affecting their blood pressure. Removal of renin by chromatography on columns of immobilized antirenin yields preparations with little or no renin. Such preparations may be effective in lowering blood pressure although they do not elicit the formation of plasma antirenin and the rabbits remain sensitive to challenging doses of rabbit renin. The evidence suggests that an unknown substance is responsible for the development of a cross-reacting antibody that neutralizes an unknown factor that is essential for the maintence of an elevated blood pressure level in rabbits with chronic one-kidney hypertension.


The molecular properties and applications of Anthozoa fluorescent proteins and chromoproteins.
The green fluorescent protein (GFP) from the jellyfish Aequorea victoria and its fluorescent homologs from Anthozoa corals have become invaluable tools for in vivo imaging of cells and tissues. Despite spectral and chromophore diversity, about 100 cloned members of the GFP-like protein family possess common structural, biochemical and photophysical features. Anthozoa GFP-like proteins are available in colors and properties unlike those of A. victoria GFP variants and thus provide powerful new fluorophores for molecular labeling and intracellular detection. Although Anthozoa GFP-like proteins provide some advantages over GFP, they also have certain drawbacks, such as obligate oligomerization and slow or incomplete fluorescence maturation. In the past few years, effective approaches for eliminating some of these limitations have been described. In addition, several Anthozoa GFP-like proteins have been developed into novel imaging agents, such as monomeric red and dimeric far-red fluorescent proteins, fluorescent timers and photoconvertible fluorescent labels. Future studies on the structure of this diverse set of proteins will further enhance their use in animal tissues and as intracellular biosensors.


Effect of feeding genetically modified Bt MON810 maize to ∼40-day-old pigs for 110 days on growth and health indicators.
A total of 72 male weaned pigs were used in a 110-day study to investigate the effect of feeding genetically modified (GM) Bt MON810 maize on selected growth and health indicators. It was hypothesised that in pigs fed Bt maize, growth and health are not impacted compared with pigs fed isogenic maize-based diets. Following a 12-day basal period, pigs (10.7 ± 1.9 kg body weight (BW); ∼40 days old) were blocked by weight and ancestry and randomly assigned to treatments: (1) non-GM maize diet for 110 days (non-GM), (2) GM maize diet for 110 days (GM), (3) non-GM maize diet for 30 days followed by GM maize diet up to day 110 (non-GM/GM) and (4) GM maize diet for 30 days followed by non-GM maize diet up to day 110 (GM/non-GM). BW and daily feed intake were recorded on days 0, 30, 60 and 110 (n = 15). Body composition was determined by dual energy X-ray absorptiometry (n = 10) on day 80. Following slaughter on day 110, organs and intestines were weighed and sampled for histological analysis and urine was collected for biochemical analysis (n = 10). Serum biochemistry analysis was performed on days 0, 30, 60, 100 and 110. Growth performance and serum biochemistry were analysed as repeated measures with time and treatment as main factors. The slice option of SAS was used to determine treatment differences at individual time points. There was no effect of feeding GM maize on overall growth, body composition, organ and intestinal weight and histology or serum biochemistry on days 60 and 100 and on urine biochemistry on day 110. A treatment × time interaction was observed for serum urea (SU; P < 0.05), creatinine (SC; P < 0.05) and aspartate aminotransferase (AST; P < 0.05). On day 30, SU was lower for the non-GM/GM treatment compared with the non-GM, GM and GM/non-GM treatments (P < 0.05). On day 110, SC was higher for the non-GM/GM and GM/non-GM treatments compared with non-GM and GM treatments (P < 0.05). Overall, serum total protein was lower for the GM/non-GM treatment compared with the non-GM/GM treatment (P < 0.05). The magnitude of change observed in some serum biochemical parameters did not indicate organ dysfunction and the changes were not accompanied by histological lesions. Long-term feeding of GM maize to pigs did not adversely affect growth or the selected health indicators investigated.


Ischemic mitral valve prolapse.
Ischemic mitral prolapse (IMP) is a pathologic entity encountered in about one-third among the patients undergoing surgery for ischemic mitral regurgitation (IMR). IMP is generally the result of a papillary muscle injury consequent to myocardial, but the recent literature is progressively unveiling a more complex pathogenesis. The mechanisms underlying its development regards the impairment of one or more components of the mitral apparatus, which comprises the annulus, the chordae tendineae, the papillary muscle and the left ventricular wall. IMP is not only a disorder of valvular function, but also entails coexistent aspects of a geometric disturbance of the mitral valve configuration and of the left ventricular function and dimension and a correct understanding of all these aspects is crucial to guide and tailor the correct therapeutic strategy to be adopted. Localization of prolapse, anatomic features of the prolapsed leaflets and the subvalvular apparatus should be carefully evaluated as also constituting the major determinants defining patient's outcomes. This review will summarize our current understanding of the pathophysiology and clinical evidence on IMP with a particular focus on the surgical treatment.


Equilibrium distribution from distributed computing (simulations of protein folding).
Multiple independent molecular dynamics (MD) simulations are often carried out starting from a single protein structure or a set of conformations that do not correspond to a thermodynamic ensemble. Therefore, a significant statistical bias is usually present in the Markov state model generated by simply combining the whole MD sampling into a network whose nodes and links are clusters of snapshots and transitions between them, respectively. Here, we introduce a depth-first search algorithm to extract from the whole conformation space network the largest ergodic component, i.e., the subset of nodes of the network whose transition matrix corresponds to an ergodic Markov chain. For multiple short MD simulations of a globular protein (as in distributed computing), the steady state, i.e., stationary distribution determined using the largest ergodic component, yields more accurate free energy profiles and mean first passage times than the original network or the ergodic network obtained by imposing detailed balance by means of symmetrization of the transition counts.


Atypical pattern of lung involvement in pacemaker endocarditis.
Pacemaker endocarditis has a high rate of morbidity and mortality and is associated with substantial health-care cost. To maximize the effectiveness of treatment, diagnosis of pacemaker endocarditis should be made as early as possible. Medical treatment alone is not successful, and the removal of the entire artificial pacing system is often required. We present a case of a female patient with a permanent transvenous pacemaker, recurring episodes of fever and chills, general malaise, and a computed tomography image of a solitary tumor-like lesion indicating pneumonia. The symptoms subsided with empirical antibiotics but without improvement in the radiologic images. A wedge resection of the lesion by thoracotomy was performed, revealing a necrotic lung lesion compatible with pulmonary infarct. Transesophageal echocardiography showed a mass that was adherent to the pacemaker lead. The therapeutic approach consisted of surgical removal of the complete pacing system along with long-term antibiotic therapy and implantation of a new device with an epicardial lead. Serial follow-up echocardiograms for a 1-y period did not show any recurrence, and the subsequent course was uneventful.


Safety and effectiveness of stereotactic laser ablation for epileptogenic cerebral cavernous malformations.
Magnetic resonance (MR) thermography-guided laser interstitial thermal therapy, or stereotactic laser ablation (SLA), is a minimally invasive alternative to open surgery for focal epilepsy caused by cerebral cavernous malformations (CCMs). We examined the safety and effectiveness of SLA of epileptogenic CCMs. We retrospectively analyzed 19 consecutive patients who presented with focal seizures associated with a CCM. Each patient underwent SLA of the CCM and adjacent cortex followed by standard clinical and imaging follow-up. All but one patient had chronic medically refractory epilepsy (median duration 8 years, range 0.5-52 years). Lesions were located in the temporal (13), frontal (five), and parietal (one) lobes. CCMs induced magnetic susceptibility artifacts during thermometry, but perilesional cortex was easily visualized. Fourteen of 17 patients (82%) with >12 months of follow-up achieved Engel class I outcomes, of which 10 (59%) were Engel class IA. Two patients who were not seizure-free from SLA alone became so following intracranial electrode-guided open resection. Delayed postsurgical imaging validated CCM involution (median 83% volume reduction) and ablation of surrounding cortex. Histopathologic examination of one previously ablated CCM following open surgery confirmed obliteration. SLA caused no detectable hemorrhages. Two symptomatic neurologic deficits (visual and motor) were predictable, and neither was permanently disabling. In a consecutive retrospective series, MR thermography-guided SLA was an effective alternative to open surgery for epileptogenic CCM. The approach was free of hemorrhagic complications, and clinically significant neurologic deficits were predictable. SLA presents no barrier to subsequent open surgery when needed.


Interactive point-based rendering of higher-order tetrahedral data.
Computational simulations frequently generate solutions defined over very large tetrahedral volume meshes containing many millions of elements. Furthermore, such solutions may often be expressed using non-linear basis functions. Certain solution techniques, such as discontinuous Galerkin methods, may even produce non-conforming meshes. Such data is difficult to visualize interactively, as it is far too large to fit in memory and many common data reduction techniques, such as mesh simplification, cannot be applied to non-conforming meshes. We introduce a point-based visualization system for interactive rendering of large, potentially non-conforming, tetrahedral meshes. We propose methods for adaptively sampling points from non-linear solution data and for decimating points at run time to fit GPU memory limits. Because these are streaming processes, memory consumption is independent of the input size. We also present an order-independent point rendering method that can efficiently render volumes on the order of 20 million tetrahedra at interactive rates.


The effect of anaesthesia of the airway in dog and man: a study of respiratory reflexes, sensations and lung mechanics.
1. The effect of breathing an anaesthetic aerosol of 5% bupivacaine hydrochloride has been assessed in dog and man. 2. In the dog, the cough reflex was abolished and the Hering-Breuer inflation reflex severely impaired or abolished; breathing became slower and deeper; no pathological changes were found in the lungs of these dogs. 3. In man, no untoward effects resulted from a 10 min period of aerosol inhalation; there were no systematic effects on airway resistance or lung volumes and the cough reflex in response to either tactile or chemical (citric acid aerosol) stimulation was invariably abolished. The Hering-Breuer inflation reflex was impaired, but this was not associated with any change in resting ventilation. The Ve/CO2 response was enhanced after aerosol anaesthesia; subjects felt an exaggerated dyspnoea. The aerosol anaesthesia abolished the afferent pathway of a reflexly elicited bronchoconstriction in one subject. There was no effect on the ability to hold the breath, or on the quality of the associated sensation. 4. Control aerosols of sodium chloride solution or phosphate buffer produced no effects. Control experiments with intravenous infusions of bupivacaine proved that none of the effects could have been produced by systemic effects of the absorbed anaesthetic. 5. Plasma concentrations of bupivacaine in man did not exceed a recognized toxic level. The experiments demonstrate a safe reversible anaesthesia of the airways in man lasting for a period of 10-20 min.


Efficacy of various protein-based coating on enhancing the shelf life of fresh eggs during storage.
The effectiveness of various coatings (whey protein isolate [WPI], whey protein concentrate [WPC], zein, and shellac) on functional properties, interior quality, and eggshell breaking strength of fresh eggs were evaluated during storage at 24 °: C for 6 weeks. Coatings and storage time had significant effects on Haugh unit, yolk index, albumen pH, dry matter (DMA), relative whipping capacity (RWC), and albumen viscosity. Uncoated eggs had higher albumen pH (9.56) and weight loss, and lower albumen viscosity (5.73), Haugh unit (HU), and yolk index (YI) during storage. Among the coated eggs, the shellac and zein coated eggs had the highest value of albumen viscosity (27.26 to 26.90), HU (74.10 to 73.61), and YI (44.84 to 44.63) after storage. Shellac (1.44%) was more effective in preventing weight loss than WPC (4.59%), WPI (4.60%), and zein (2.13%) coatings. Uncoated eggs had the higest value (6.71%) of weight lost. All coatings increased shell strength (5.18 to 5.73 for top and 3.58 to 4.71 for bottom) significantly (P < 0.05) compared to the uncoated eggs (4.70 for top and 3.15 for bottom). The functional properties such as albumen DMA (14.50 to 16.66 and 18.97 for uncoated) and albumen RWC (841 to 891 and 475 for uncoated) of fresh eggs can be preserved during storage when they are coated. The shellac and zein coatings were more effective for maintaining the internal quality of fresh eggs during storage. Fourier transform near infrared (FT-NIR) in the 800 to 2500 nm reflection spectra were used to quantify the contents of the fresh eggs at the end of storage. Eggs coated with shellac or zein displayed a higher absorbance at 970 and 1,197 nm respectively (OH vibration of water) compared with those coated with WPI or WPC and the uncoated group at the end of storage. The coatings improved functional properties and also shell strength and could be a viable alternative technology for maintaining the internal quality of eggs during long-term storage. This study highlights the promising use of various coatings to both enhance the functional properties and to reduce the breakage of eggs.


Antidiuretic hormone release in the bovine: values at rest, and evidence for sex differences under stressful conditions including severe hemorrhage.
This study investigates antidiuretic hormone (ADH) plasma concentration in bulls and heifers at rest, after transportation stress, trauma and massive hyper-acute hemorrhage at slaughter, with special attention to differences between sexes. We also quantified ADH concentration in the ADH-producing hypothalamic area. The study was carried out on animals at the abattoir, exploiting the routinely procedure of slaughtering to obtain the experimental stressful conditions. The control group was represented by a group of animals matched for breed, age and gender. ADH plasma values suggest that transportation stress has little or no effect in heifers in contrast to bulls. In both sexes ADH release increases after open head trauma due to stunning prior to slaughter. Hemorrhagic hyper-acute stress caused by bleeding induces a rapid hundredfold rise of ADH plasma concentration that becomes diergic (physiologically different between sexes), with males showing far higher values. Females show a higher ADH concentration in the hypothalamus. This study points out a difference in ADH output between bulls and heifers under conditions of severe hemorrhagic stress, as produced by severing of the neck vessels at slaughtering. Extreme stress unmasks endocrine differences in bovine ADH release that may be relevant only during specific circumstances, such as fighting.


Improving child health care through federal policy: an emerging opportunity.
Policymakers considering the 2009 reauthorization of the State Children's Health Insurance Program (SCHIP) have an opportunity to strengthen federal provisions to promote primary, preventive, and developmental child health care. Several pieces of legislation introduced in 2007 focused on aspects of child health quality, but none placed a specific emphasis on primary care. This issue brief describes three legislative proposals and additional quality provisions related specifically to primary care to consider for incorporation into federal law. These provisions include: 1) establishing a core set of primary child health service outcomes for tracking within Medicaid and SCHIP; 2) creating a structure within the Centers for Medicare and Medicaid Services that focuses on strengthening primary, preventive, and developmental child health services; 3) supporting additional research on child health quality and outcomes in primary care; and 4) providing incentives to states to promote evidence-based practices in children's primary health care


Strengthening the Practice of Exercise and Sport-Science Research.
Exercise and sport sciences continue to grow as a collective set of disciplines investigating a broad array of basic and applied research questions. Despite the progress, there is room for improvement. A number of problems pertaining to reliability and validity of research practices hinder advancement and the potential impact of the field. These problems include inadequate validation of surrogate outcomes, too few longitudinal and replication studies, limited reporting of null or trivial results, and insufficient scientific transparency. The purpose of this review is to discuss these problems as they pertain to exercise and sport sciences based on their treatment in other disciplines, namely psychology and medicine, and to propose a number of solutions and recommendations.


Effects of population structure on within-group variation in the Jirels of Nepal.
The impact of population structure on phenotypic differentiation is most frequently considered in terms of between-subdivision variation. However, the demographic and social structures of a population also induce changes in within-group variation. We analyze the intragenerational dynamics of within-group variation for the Jirels, a tribal population of eastern Nepal. In the analyses we utilized age- and sex-corrected cranial measures (head length, head breadth, bizygomatic diameter, minimum frontal diameter, and head circumference) available for 526 adults (ages 15-54 years). We used a multivariate measure of variance, the standardized generalized variance, to assess levels of within-village variability, quantifying the sampling variance for this statistic by using a jackknife methodology. To generate null expectations of within-group variation, we used permutation procedures, which permit robust testing of significance without distributional assumptions. We also compared the within-birthplace variation in adults to the observed within-residence variation to examine migration effects. Contrary to expectation, some villages with high rates of in-migration have less variability than those with few migrants. When differences between the sexes at birth are controlled for, females in some villages exhibit greater variance than males, reflecting known differences in sex-specific dispersal.


A non-enzymatic microsurgical dissection technique of mouse embryonic tissues for gene expression profiling applications.
With the increased use of gene expression profiling to identify molecular regulators of cellular and developmental mechanisms, developmental biologists face a new challenge in dissecting tissues without cross-contamination or change in RNA profile, and with intact RNA integrity. We have developed a technique that overcomes these problems. We took the dissection of rudimentary mouse embryonic mammary glands as an example, as these structures are particularly difficult to separate from their contiguous ectoderm and strongly adhering mesenchyme. Contrary to conventional enzymatic tissue-separation methods, we blocked transcriptional activity prior to dissection and protected RNA from degradation during dissection, by the use of RNAlater. While RNAlater dehydrates specimens so severely that it interferes with visibility and clean dissection of organs or tissues, we established rehydration conditions that in fact facilitated tissue separation and shortened dissection time to about 10 minutes. The extracted RNA had an excellent quality, rendering it perfectly suitable for transcriptional profiling. Visual inspection of separated tissues and tissue specific gene expression analysis by microarray and RT-PCR confirmed that the tissues were separated with minimal or no cross-contamination. We show that this dissection method can be applied to a broad variety of organs, and that the tissue is still amenable to protein detection. In conclusion, this is a rapid, cheap and effective non-enzymatic tissue separation method which greatly facilitates the exploration of molecular mechanisms in organ formation.


Three-year results from a preclinical implantation study of a long-term resorbable surgical mesh with time-dependent mechanical characteristics.
The purpose of this study was to evaluate the biocompatibility, local tissue effects and performance of a synthetic long-term resorbable test mesh (TIGR(®) Matrix Surgical Mesh) compared to a non-resorbable polypropylene control mesh following implantation in a sheep model. Full-thickness abdominal wall defects were created in 14 sheep and subsequently repaired using test or control meshes. Sacrifices were made at 4, 9, 15, 24 and 36 months and results in terms of macroscopic observations, histology and collagen analysis are described for 4, 9, 15, 24 and 36 months. The overall biocompatibility was good, and equivalent in the test and control meshes while the resorbable mesh was characterized by a collagen deposition more similar to native connective tissue and an increased thickness of the integrating tissue. The control polypropylene mesh provoked a typical chronic inflammation persistent over the 36-month study period. As the resorbable test mesh gradually degraded it was replaced by a newly formed collagen matrix with an increasing ratio of collagen type I/III, indicating a continuous remodeling of the collagen towards a strong connective tissue. After 36 months, the test mesh was fully resorbed and only microscopic implant residues could be found in the tissue. This study suggests that the concept of a long-term resorbable mesh with time-dependent mechanical characteristics offers new possibilities for soft tissue repair and reinforcement.


Computational Study of Protein-Ligand Unbinding for Enzyme Engineering.
The computational prediction of unbinding rate constants is presently an emerging topic in drug design. However, the importance of predicting kinetic rates is not restricted to pharmaceutical applications. Many biotechnologically relevant enzymes have their efficiency limited by the binding of the substrates or the release of products. While aiming at improving the ability of our model enzyme haloalkane dehalogenase DhaA to degrade the persistent anthropogenic pollutant 1,2,3-trichloropropane (TCP), the DhaA31 mutant was discovered. This variant had a 32-fold improvement of the catalytic rate toward TCP, but the catalysis became rate-limited by the release of the 2,3-dichloropropan-1-ol (DCP) product from its buried active site. Here we present a computational study to estimate the unbinding rates of the products from DhaA and DhaA31. The metadynamics and adaptive sampling methods were used to predict the relative order of kinetic rates in the different systems, while the absolute values depended significantly on the conditions used (method, force field, and water model). Free energy calculations provided the energetic landscape of the unbinding process. A detailed analysis of the structural and energetic bottlenecks allowed the identification of the residues playing a key role during the release of DCP from DhaA31 via the main access tunnel. Some of these hot-spots could also be identified by the fast CaverDock tool for predicting the transport of ligands through tunnels. Targeting those hot-spots by mutagenesis should improve the unbinding rates of the DCP product and the overall catalytic efficiency with TCP.


Study protocol: a pragmatic randomised controlled trial of a 12-week physical activity and nutritional education program for overweight Aboriginal and Torres Strait Islander women.
Aboriginal and Torres Strait Islander women have a higher prevalence and incidence of obesity and type 2 diabetes than non-Indigenous Australian women. Physical inactivity is a key modifiable risk factor for obesity and evidence shows that even modest reductions in waist circumference (WC) have significant health benefits. Trialing physical activity programs in difficult-to-reach high risk groups, especially urban Indigenous Australians poses distinct implementation challenges. The trial objective is to evaluate the effectiveness of a structured 12-week physical activity group program with nutritional advice. The design is a pragmatic randomised controlled trial. This study protocol describes the implementation and evaluation of the program. Participants are randomised into either an intervention or waitlisted group. The waitlisted group have a 12 month waiting period before commencing the 12-week program. Participant data is collected at baseline, 12, 24 and 52 weeks. Participants are Aboriginal and Torres Strait Islander women, aged 18-64 years with a waist circumference greater than 80 centimetres residing in Adelaide. The primary outcome measure is WC change immediately post program from baseline. Secondary outcomes include short term and long term changes in WC, weight, blood pressure, fasting blood glucose, insulin, insulin resistance (calculated HOMA), haemoglobin A1C (HbA1C), triglycerides and C-reactive protein (CRP). Behavioural and psychosocial surveys are administered to assess physical activity, dietary intake and the participant's motivation, self-efficacy and perceived social support for physical activity. Qualitative interviews focusing on participants' motivation, enablers and barriers to healthy eating and physical activity will be undertaken. Implementation fidelity and participation are also assessed. The Aboriginal and Torres Strait Islander Women's Fitness Program (WFP) is designed to provide a rigorous physiological and client-based evaluation of a structured 12-week program aimed to increase metabolic fitness and reduce WC in this high risk population. Evaluation results aim to provide the support necessary to design programs that are accessible, affordable and effective at reducing WC, while also improving the metabolic profile of overweight Aboriginal and Torres Strait Islander women. Australian New Zealand Clinical Trials Registry ACTRN12610000224022.


Patterns of radioactivity in the eyes of rats after injection of iodinated prolactin.
The present study involves the intracardial injection of iodinated ovine prolactin into albino rats and the autoradiographic demonstration of patterns of isotopic incorporation into ocular tissues, including the retina, choroid coat and ciliary body. Control procedures include the utilization of competitive hormonal binding, a comparison of the radioactive pattern in eyes after the injection of iodinated beef serum albumen and an autoradiographic evaluation of the thyroid glands of all groups. The competitive uptake of iodinated prolactin into ocular tissues also was examined by liquid scintillation spectrometry. In normal rats, radioactivity was localized over the cells of the choroid coat and ciliary body of all groups receiving iodinated prolactin. The inner segments of the photoreceptors were radioactive in rats at 15 min after injection, but were unlabeled at only 5 min after injection.


Fetal intra-nigral ventral mesencephalon and kidney tissue bridge transplantation restores the nigrostriatal dopamine pathway in hemi-parkinsonian rats.
We have previously demonstrated that intranigral transplantation of fetal ventral mesencephalic (VM) tissue and nigrostriatal administration of glial cell line-derived neurotrophic factor (GDNF) restores striatal dopamine input in hemiparkinsonian rats. Since it has been found that GDNF is highly expressed in fetal kidney, we examined the possibility that fetal kidney tissue may provide trophic support, similar to GDNF, to an intranigral dopamine (DA) transplant and restore the nigrostriatal pathway. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Completeness of the lesion was evaluated by measuring amphetamine-induced rotation. One month after 6-OHDA lesioning, fetal VM cells were grafted into the lesioned nigral area followed by transplantation of fetal kidney tissue or vehicle along a pathway from nigra to striatum. Animals receiving these transplants showed a significant decrease both in amphetamine-induced rotation and in postural asymmetry 1 to 3 months after grafting. Immunocytochemical studies demonstrated tyrosine hydroxylase (TH) positive fiber tracts in the lesioned striatum. Control animals that received vehicle injection after the intranigral graft or no transplantation showed no alterations in amphetamine-induced turning and no TH-positive fibers in the lesioned striatum. These results indicate that combinations of fetal nigral and kidney transplants may restore the nigrostriatal DA pathway in Parkinsonian rats. As fetal kidney contains a variety of trophic proteins, it may provide a synergistic admixture to optimally promote DA fiber outgrowth.


Ascorbic acid, blood pressure, and the American diet.
A large controlled study supported by the NIH, the DASH study (Dietary Approaches to Stop Hypertension), demonstrated that a diet rich in fruits and vegetables can reduce blood pressure in persons with moderate elevation in blood pressure (BP). Fruits and vegetables are important sources of antioxidants such as vitamin C and carotenoids. We conducted a study in which we fed people a diet deficient in vitamin C for 30 days, followed for another 30 days by a diet adequate in vitamin C. Their blood levels of vitamin C and blood pressure (BP) were tracked. Plasma vitamin C was inversely related to diastolic blood pressure one month later (correlation = -0.48, P < 0.0001). Persons whose blood levels of vitamin C went down the furthest on depletion had the highest blood pressure one month later. Persons in the lowest one-fourth of the plasma vitamin C distribution had diastolic BP 7 mm Hg higher than did those in the upper one-fourth of the plasma ascorbic acid distribution. Multivariate control for age, body mass index, other plasma antioxidants, and dietary energy, calcium, fiber, sodium, and potassium did not reduce the plasma vitamin C effect. We believe that this indicates that the tissue stores of vitamin C may be important in regulating blood pressure. It is often thought that Americans' intake of vitamin C is ample, since the average intake is about 100 mg/day. However, this average level obscures the fact that substantial numbers of people actually have habitually low intake levels and low blood levels. African Americans tend to have low blood levels of vitamin C as well as the highest risk of hypertension. Low intake of antioxidant-rich fruits and vegetables may be one of the causes of hypertension.


Relationships Among C-Reactive Protein, Alanine Aminotransferase, and Metabolic Syndrome in Apparently Healthy Chinese Subjects.
Elevated levels of C-reactive protein (CRP) and alanine aminotransferase (ALT) are tightly associated with metabolic syndrome (MetS). However, it is unclear whether the combination of normal CRP and ALT increases probability of the presence of MetS. We enrolled 433 Chinese in health screening with both CRP and ALT in normal range. They were divided into four groups: both low (BL, both low baseline CRP and ALT), only high CRP (HCRP), only high ALT (HALT), and both high (BH, both high baseline CRP and ALT) in different genders. The receiver operating characteristic curve was used for comparing the sensitivity and assessing the cutoff point. The BH group had more numbers of MetS components than the BL group. Addition of CRP and ALT did not further increase the accuracy of predicting MetS with a sensitivity of 65.1% and a specificity of 59.1% in men, and a sensitivity of 77.8% and a specificity of 60.2% in women. The area under curve for ALT was greater than that for CRP (0.62 vs. 0.524 in men; 0.663 vs. 0.598 in women). After adjusting for age, ALT could significantly predict the incidental MetS in both genders; nevertheless, CRP failed to demonstrate prediction. The formula of probability of occurrence of MetS was established on CRP and ALT. Healthy subjects with high baseline ALT may be at risk of developing MetS, and early recognition and prevention are important for health providers. We concluded that local liver inflammation is significantly associated with the presence of MetS compared with systemic inflammation in health screening subjects.


Bactericidal effect of dentin primer containing antibacterial monomer methacryloyloxydodecylpyridinium bromide (MDPB) against bacteria in human carious dentin.
The aim of this study was to investigate the bactericidal effect of a dentin primer incorporating the antibacterial monomer 12-methacryloyloxydodecylpyridinium bromide (MDPB) against bacteria in human dentinal carious lesions. To evaluate the antibacterial activity of MDPB against anaerobes, the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) against obligate anaerobes and facultative anaerobic strains of lactobacilli were determined. Bacteria were recovered from carious dentin samples obtained from the teeth of patients, and the bactericidal activities of the experimental primer containing 5% MDPB and three commercially available primers were compared by counting the number of viable cells after contact with diluted solutions of each primer for 30 s. MDPB showed strong antibacterial activity against anaerobes, the MIC and MBC values ranging from 3.9 to 31.3 micrograms/ mL-1 and 15.6-125 micrograms/ mL-1, respectively. Experimental primer containing MDPB was the most bactericidal among the materials tested (ANOVA, Fisher's PLSD test, P < 0.05) and was able to kill the bacteria completely even when diluted 40 times, while the three commercial products exhibited little activity at 40 times dilution. These results indicate that incorporation of MDPB into dentin primer could be beneficial for eliminating the residual bacteria in cavities.


Phase relationship between normal human respiration and baroreflex responsiveness.
1. We studied the influences of phase of respiration and breathing frequency upon human sinus node responses to arterial baroreceptor stimulation. 2. Carotid baroreceptors were stimulated with brief (0.6 sec), moderate (30 mmHg) neck suction during early, mid, and late inspiration or expiratin at usual breathing rates, or, during early inspiration and expiration at breathing rates of 3, 6, 12, and 24 breaths/min. 3. Baroreceptor stimuli applied during early and mid inspiration and late expiration provoked only minor sinus node inhibition; stimuli begun during late inspiration and early expiration provoked maximum sinus node inhibition. 4. At breathing rates of 3, 6 and 12 breaths/min, expiratory baroreflex responses were significantly greater than inspiratory responses; at 24 breaths/min, however, inspiratory and expiratory baroreceptor stimuli produced comparable degrees of sinus node inhibition. 5. Our results delineate an important central biological rhythm in normal man: human baroreflex responsiveness oscillates continuously during normal, quiet respiration. The phase shift of baroreflex responsiveness on respiration suggests that this interaction cannot be ascribed simply to gating synchronous with central inspiratory neurone activity. Regularization of heart rate during rapid breathing is associated with loss of the differential inspiratory-expiratory baroreflex responsiveness which is present at usual breathing rates.


Transcriptome genetics using second generation sequencing in a Caucasian population.
Gene expression is an important phenotype that informs about genetic and environmental effects on cellular state. Many studies have previously identified genetic variants for gene expression phenotypes using custom and commercially available microarrays. Second generation sequencing technologies are now providing unprecedented access to the fine structure of the transcriptome. We have sequenced the mRNA fraction of the transcriptome in 60 extended HapMap individuals of European descent and have combined these data with genetic variants from the HapMap3 project. We have quantified exon abundance based on read depth and have also developed methods to quantify whole transcript abundance. We have found that approximately 10 million reads of sequencing can provide access to the same dynamic range as arrays with better quantification of alternative and highly abundant transcripts. Correlation with SNPs (small nucleotide polymorphisms) leads to a larger discovery of eQTLs (expression quantitative trait loci) than with arrays. We also detect a substantial number of variants that influence the structure of mature transcripts indicating variants responsible for alternative splicing. Finally, measures of allele-specific expression allowed the identification of rare eQTLs and allelic differences in transcript structure. This analysis shows that high throughput sequencing technologies reveal new properties of genetic effects on the transcriptome and allow the exploration of genetic effects in cellular processes.


Participation and needs of children with developmental coordination disorder at home and in the community: Perceptions of children and parents.
The existing literature provides only a partial understanding of the viewpoints of elementary school-aged children with developmental coordination disorder (DCD) regarding their participation and needs. In order to plan and develop health and social services driven by a personalized approach, it is essential to further document their perceptions with those of their parents. The aim of the study was to explore the participation and needs of school-aged children with DCD at home and in the community, as perceived by children and parents. Participants were ten school-aged children with DCD, from 6 to 13 years old, and their parents, including one couple (n=11). Individual semi-structured interviews were conducted with each participant, except the couple who were interviewed together. Most children and all parents perceived some difficulties at home but few in the community. However, participation and needs varied for each child. Children rarely expressed the same expectations as their parents. While most children did not want more support, parents requested training on DCD. When planning health and social services for children with DCD, it is recommended to consult all stakeholders, including children, as well as offer indirect interventions, such as training and coaching for parents.


Neuroenhancing Substances Use, Exam Anxiety and Academic Performance in Bosnian-Herzegovinian First-Year University Students.
The aim of this study was to assess the relationship between the use of neuroenhancing substances, exam anxiety and academic performance among first-year Bosnian-Herzegovinian (BH) university students. In a cross-sectional study, an ad hoc questionnaire was delivered to a sample of BH first-year university students. The following data were collected: socio-demographic features, consumption of neuroenchancing substances, the Westside Test Anxiety Scale (WTAS) and academic performance. A total of 214 students were included. Consumption of lifestyle substances, coffee, energy drinks, nicotine, alcohol, and marijuana, for the purpose of neuroenhancement increased during the week before the exams. OTC cognitive enhancer use was reported by 31.0%, and of benzodiazepines by 1.5% of students. No psycostimulants were used. A high to extremely high exam WTAS score was reported in 38.3% students. The exam WTAS score was positively correlated with consumption of coffee (rho=0.31; P<0.001), energy drinks (rho=0.18; P=0.009), and nicotine (rho=0.22; P=0.001), and negatively correlated with last exam grade (rho=-0.33; P<0.001). The exam WTAS score was a significant independent predictor (OR=0.55; 95% CI 0.31 to 0.97, P=0.039) for self-assessed academic performance. Self-assessed academic performance was positively correlated with last exam grade (rho=0.15; P=0.043). Although first-year BH university students do not seem to use either prescription or illicit psycostimulants, the consumption of nicotine, alcohol, and marijuana is worrying. However, the consumption of these neuroenhancing substances seems not to be related to better self-assessed academic performance. Finally, exam anxiety seems to be a significant problem among BH first-year university students.


The effect of cantilevered bar length on strain around two implants supporting a mandibular overdenture.
The aim of this study was to evaluate the effect of cantilevered bar length on strain produced around two implants supporting a mandibular overdenture. Two root-form implants were placed bilaterally in the canine region of an edentulous acrylic resin mandibular cast and connected with a resilient bar/clip attachment. Four linear strain gauges were bonded to the acrylic resin at the mesial and distal surfaces of each implant. Each gauge was wired separately into a 1/4 Wheatstone bridge of a multichannel digital bridge amplifier. Strains were measured without cantilevered bar extensions (control group) and with the following lengths of cantilevered bars: 11 mm (group 1), 9 mm (group 2), and 7 mm (group 3). For each cantilevered bar length, strains were measured using clips placed on the cantilevers and attached to the overdenture (bar-clip contact) and without clips (bar-acrylic resin contact). Strain measurements were performed under central and unilateral loading using a loading device. The bar with cantilevers (either with or without clips) demonstrated a significant increase in strain compared to the bar without cantilevers. The 11-mm cantilever length generated the highest peri-implant strain values, while the 7-mm length recorded the lowest. For all cantilevered bar lengths, the strains significantly decreased with bar-clip contact compared to bar-acrylic resin contact. Under central loading, distal and mesial peri-implant strains were the highest and the lowest values, respectively, while under unilateral loading, the highest strain was recorded at distal sites of the loading side and the lowest was recorded at distal sites of the nonloading side. A positive correlation was found between the recorded strain and the cantilevered bar length. The 7-mm cantilevered bar with clips placed on the cantilevers was recommended when two implants were used to support mandibular overdentures, as it demonstrated the lowest magnitude of strains with no significant differences between peri-implant sites.


Visuo-vestibular interaction in the reconstruction of travelled trajectories.
We recently published a study of the reconstruction of passively travelled trajectories from optic flow. Perception was prone to illusions in a number of conditions, and was not always veridical in the others. Part of the illusionary reconstructed trajectories could be explained by assuming that subjects base their reconstruction on the ego-motion percept built during the stimulus' initial moments. In the current paper, we test this hypothesis using a novel paradigm: if the final reconstruction is governed by the initial percept, providing additional, extra-retinal information that modifies the initial percept should predictably alter the final reconstruction. The extra-retinal stimulus was tuned to supplement the information that was under-represented or ambiguous in the optic flow; the subjects were physically displaced or rotated at the onset of the visual stimulus. A highly asymmetric velocity profile (high acceleration, very low deceleration) was used. Subjects were required to guide an input device (in the form of a model vehicle; we measured position and orientation) along the perceived trajectory. We show for the first time that a vestibular stimulus of short duration can influence the perception of a much longer-lasting visual stimulus. Perception of the ego-motion translation component in the visual stimulus was improved by a linear physical displacement, perception of the ego-motion rotation component by a physical rotation. This led to a more veridical reconstruction in some conditions, but to a less veridical reconstruction in other conditions.


Fatigue and Quality of Life Outcomes of Palliative Care Consultation: A Prospective, Observational Study in a Tertiary Cancer Center.
Fatigue is one of the most common symptoms seen in patients with advanced cancer. It is known to influence the Quality of Life (QoL) of patients. This study examines the interrelationship of fatigue and QoL in patients with advanced cancer on palliative care. A prospective cohort study was conducted in the outpatient clinic of the Department of Palliative Medicine from January to June 2014. Patients with advanced cancer registered with hospital palliative care unit, meeting the inclusion criteria (Eastern Cooperative Oncology Group [ECOG] ≤3, Edmonton Symptom Assessment Scale [ESAS] fatigue score ≥1), and willing to participate in the study were assessed for symptom burden (ESAS) and QoL (European Organization for Research and Treatment of Cancer QoL Core 15-Palliative module [EORTC-QoL PAL15]). All study patients received standard palliative care consultation and management. They were followed up in person or telephonically within 15-30 days from the first consult for assessment of outcomes. Of a total of 500 cases assessed at baseline, 402 were available for follow-up (median age of 52 years; 51.6% male). On the EORTC-QoL PAL15 scale, overall QoL, emotional functioning, and constipation were found to be significantly associated with severity of fatigue at baseline (P < 0.05). Statistically significant improvement in fatigue score was observed (P < 0.001) at follow-up. Improvement in physical functioning and insomnia were significantly associated with better fatigue outcomes. Fatigue improved with the standard palliative care delivered at our specialty palliative care clinic. Certain clinical, biochemical factors and QoL aspects were associated with fatigue severity at baseline, improvement of which lead to lesser fatigue at follow-up.


A Course on Terror Medicine: Content and Evaluations.
The development of medical school courses on medical responses for disaster victims has been deemed largely inadequate. To address this gap, a 2-week elective course on Terror Medicine (a field related to Disaster and Emergency Medicine) has been designed for fourth year students at Rutgers New Jersey Medical School in Newark, New Jersey (USA). This elective is part of an overall curricular plan to broaden exposure to topics related to Terror Medicine throughout the undergraduate medical education. A course on Terror Medicine necessarily includes key aspects of Disaster and Emergency Medicine, though the converse is not the case. Courses on Disaster Medicine may not address features distinctively associated with a terror attack. Thus, a terror-related focus not only assures attention to this important subject but to accidental or naturally occurring incidents as well. The course, implemented in 2014, uses a variety of teaching modalities including lectures, videos, and tabletop and hands-on simulation exercises. The subject matter includes biological and chemical terrorism, disaster management, mechanisms of injury, and psychiatry. This report outlines the elective's goals and objectives, describes the course syllabus, and presents outcomes based on student evaluations of the initial iterations of the elective offering. All students rated the course as "excellent" or "very good." Evaluations included enthusiastic comments about the content, methods of instruction, and especially the value of the simulation exercises. Students also reported finding the course novel and engaging. An elective course on Terror Medicine, as described, is shown to be feasible and successful. The student participants found the content relevant to their education and the manner of instruction effective. This course may serve as a model for other medical schools contemplating the expansion or inclusion of Terror Medicine-related topics in their curriculum.


Clinical features of autoimmune hepatitis and comparison of two diagnostic criteria in Korea: a nationwide, multicenter study.
As a rare liver disease, little is known about autoimmune hepatitis (AIH). This study investigated the clinical features and compared two diagnostic criteria of AIH in Korea. A nationwide, multicenter, retrospective analysis was done of data of adult patients diagnosed with AIH from January 2005 to December 2009. The enrolled patients (n = 343; mean age, 52.8 years; range, 19-87 years; 12% male, 88% female) met diagnostic criteria of AIH according to the revised original criteria (n = 311) or the simplified criteria (n = 250). At diagnosis, 30.6% were asymptomatic, 22.7% were cirrhotic, and 4.3% displayed hepatic decompensation. The positive results for anti-nuclear antibody, smooth muscle antibody, and anti-liver/kidney microsomal antibody were 94.2%, 23.0%, and 2.9%, respectively. Definite AIH and probable AIH according to the revised original criteria were 24.8% and 65.3%, respectively, while those according to the simplified criteria were 34.4% and 38.5%, respectively. The diagnostic sensitivity and positive predictive value of simplified criteria in comparison with the revised original criteria were 69.9% and 86.4%, respectively. As an initial therapy, corticosteroid (37.7%) or corticosteroid with azathioprine (36.8%) was administered. Remission, incomplete response, and treatment failure were noted with 85.7%, 10.5%, and 3.9% of patients, respectively. Autoimmune hepatitis in Korea is mostly type I, showing a mean age of 53 years with comparable clinical features to other countries. The concordant rate of the two diagnostic criteria was rather low with modest sensitivity of the simplified criteria. Further studies on the validation of the diagnostic criteria are warranted.


Muscle activity and hand motion in veterinarians performing laparoscopic training tasks with a box trainer.
To evaluate muscle activity and hand motion in veterinarians performing a standard set of laparoscopic training tasks. 12 veterinarians with experience performing laparoscopic procedures. Participants were asked to perform peg transfer, coordination, precision cutting, and suturing tasks in a laparoscopic box trainer. Activity of the right biceps brachii, triceps brachii, forearm flexor, forearm extensor, and trapezius muscles was analyzed by means of surface electromyography. Right hand movements and wrist angle data were registered through the use of a data glove, and risk levels for the wrist joint were determined by use of a modified rapid upper limb assessment (RULA) method. One-way repeated-measures ANOVA with a Bonferroni post hoc test was performed to compare values between tasks. Activity in the biceps muscle did not differ significantly among the 4 tasks. Activity in the triceps, forearm flexor, and forearm extensor muscles was significantly higher during precision cutting than during the coordination task. Activity in the trapezius muscle was highest during the suturing task and did not differ significantly among the other 3 tasks. The RULA score was unacceptable (score, 3) for the coordination, peg transfer, and precision cutting tasks but was acceptable (score, 2) for the suturing task. Results indicated that the ergonomics of laparoscopic training depended on the tasks performed and the design of the instruments used. Precision cutting and suturing tasks were associated with the highest muscle activity. Acceptable wrist position, as determined with the RULA method, was found with the suturing task, which was performed with an axial-handled instrument.


Epigenome-Wide Association Study of Dietary Fiber Intake in African American Adolescents.
Low fiber intake is associated with increased risk for cardiovascular disease (CVD) and cancer. However, the underlying mechanisms are not well understood. Two hypotheses are tested: 1) dietary fiber would be associated with DNA methylation levels; 2) those DNA methylation changes would be associated with visceral adiposity and inflammation. Also the possibility that the associations between fiber and DNA methylation levels might be confounded with folic acid intake as sensitivity analysis are explored. An epigenome-wide association study is conducted using Illumina 450K Bead-Chip on leukocyte DNA in 284 African American adolescents. Linear regression is performed to identify differentially methylated CpG sites associated with fiber. The methylation levels of 3 CpG sites (cg15200711, cg19462022, and cg07035602) in LPCAT1 and RASA3 genes are associated with fiber (false discovery rate [FDR] < 0.05) after adjustment for covariates including folic acid. The methylation levels of cg07035602 and cg19462022 are also associated with visceral adiposity and inflammation. The data show that DNA methylation levels at LPCAT1 and RASA3 genes are associated with dietary fiber intake as well as with adiposity and inflammation. Future studies are warranted to determine whether epigenetic regulation may underlie the beneficial effects of fiber intake on adiposity and inflammation.


Comment on "Eigenfields and output beams of an unstable Bessel-Gauss resonator".
We comment on a recent paper by D. Ling et al. [Appl. Opt. 45, 4102 (2006)]. In that paper, the authors adopted the entire matrix formalism that we established in a previous work [J. Opt. Soc. Am. A 22, 1909 (2005)] for finding the eigenmodes of an unstable Bessel resonator. Nevertheless, the results are inaccurate mainly because (a) it was overlooked that light crosses through the axicon twice in a complete round trip and (b) the numerical method used to evaluate the diffraction integral equations cannot resolve the eigenvalues and eigenfields for the given resonator configuration.


Determinants of periodontal health in pregnant women and association with infants' anthropometric status: a prospective cohort study from Eastern Uganda.
Preterm-low birth weight delivery is a major cause of infant morbidity and mortality in sub Saharan Africa and has been linked to poor periodontal health during pregnancy. This study investigated predisposing and enabling factors as Determinants of oral health indicators in pregnancy as well as the association between periodontal problems at 7 months gestational age and the infants' anthropometric status. A community -based prospective cohort study was conducted in Mbale, Eastern Uganda between 2006 and 2008. Upon recruitment, 713 pregnant women completed interviews and a full mouth oral clinical examination using the CPITN (Community Periodontal Index of Treatment Need) and OHI-S (Simplified Oral Hygiene) indices. A total of 593 women were followed up with anthropometric assessments of their infants 3 weeks after delivery. Multiple logistic regression analyses were used to identify independent determinants of periodontal problems and use of dental services during pregnancy. Analysis of covariance (ANCOVA) was used to investigate the relationship between periodontal problems and the child's anthropometric status in terms of wasting, underweight and stunting. A total of 67.0% women presented with periodontal problems, 12.1% with poor oral hygiene, 29.8% with recent dental visit and 65.0% with periodontal symptoms. Of the infants, 2.0% were wasted, 6.9% were underweight and 10.0% were stunted. The odds ratio of having CPI > 0 increased with increased maternal age and single marital status, and was lower in primiparous women and those who used mosquito bed nets. Mean wasting scores discriminated between mothers with CPI = 0 and CPI > 0 as well as between mothers with good and poor OHI-S scores. Socio-demographic factors and information about oral health were associated with oral health indicators in pregnant women. Second, the height- for- age status at 3 weeks postpartum was worse in infants of mothers having periodontal problems and poor oral hygiene during pregnancy. Efforts to prevent oral diseases during pregnancy should be part of the local state and national health policy agenda in Uganda.


Associations between perceptions of evidence and adoption of H1N1 influenza infection prevention strategies among healthcare workers providing care to persons with spinal cord injury.
To examine associations between perceptions of evidence (research evidence, clinical expertise, patient preferences) and outcomes of a nationwide programme to implement H1N1 influenza prevention guidelines. Healthcare workers do not consistently adhere to recommended infection control practices and this may be associated with their perceptions of evidence sources. Cross-sectional mailed survey. A survey of healthcare workers was administered in August 2010 after implementation of H1N1 prevention guidelines. Outcomes of interest were ratings of adherence to H1N1 prevention guidelines. Respondents with complete data (N = 283) were included in analyses. Facility-level adherence to guidelines was associated with opinions of clinical experts. Healthcare workers who rated clinical expertise as aligning with recommendations also rated their facilities as being more adherent to guidelines. Perceptions of research evidence and patient preferences were not associated with facility adherence. Personal adherence was not associated with perceptions of evidence, except among those healthcare workers who rated both clinical experts and patients as unsupportive of guidelines; these practitioners were less likely to adhere to recommended personal hygiene practices. Efforts to implement guidelines might be most effective when capitalizing on the influence of clinical experts. To better explain variability in guideline adherence, inclusion of a broader array of variables is recommended for future studies.


Iodine soil dynamics and methods of measurement: a review.
Iodine is an essential micronutrient for human health: insufficient intake can have multiple effects on development and growth, affecting approximately 1.9 billion people worldwide. Previous reviews have focussed on iodine analysis in environmental and biological samples, however, no such review exists for the determination of iodine fractionation and speciation in soils. This article reviews the geodynamics of both stable 127I and the long-lived isotope 129I (t1/2 = 15.7 million years), alongside the analytical methods for determining iodine concentrations in soils, including consideration of sample preparation. The ability to measure total iodine concentration in soils has developed significantly from rudimentary spectrophotometric analysis methods to inductively coupled plasma mass spectrometry (ICP-MS). Analysis with ICP-MS has been reported as the best method for determining iodine concentrations in a range of environmental samples and soils due to developments in extraction procedures and sensitivity, with extremely good detection limits typically <μg L-1. The ability of ICP-MS to measure iodine and its capabilities to couple on-line separation tools has the significance to develop the understanding of iodine geodynamics. In addition, nuclear-related analysis and recent synchrotron light source analysis are discussed.


Prospective evaluation of extracranial carotid stenosis: MR angiography with maximum-intensity projections and multiplanar reformation compared with conventional angiography.
The purpose of this prospective study was to compare MR angiography of the carotid artery from the aortic arch through the circle of Willis using maximum-intensity projection (MIP) and multiplanar reformation (MPR) images with intraarterial angiography in the depiction of extracranial carotid atherosclerosis. The carotid arteries in 20 patients were studied with MR and intraarterial angiography. MR angiography included two-dimensional (2D) time-of-flight (TOF) sequences from the aortic arch through the skull base and three-dimensional (3D) TOF sequences centered at the carotid bifurcation and multiple overlapping thin slab acquisition (MOTSA) from the skull base to above the circle of Willis. Targeted MIP images of the 2D and 3D TOF MR angiograms through each carotid bifurcation were obtained. Last, MPR images of the 3D TOF MR angiograms at the obliquity that showed the greatest stenosis were obtained. All studies were reviewed in a double-blinded fashion by two neuroradiologists. Caliper measurements of MR angiograms and intraarterial angiograms were made by using North American Symptomatic Carotid Endarterectomy Trial criteria. Global MIPs of the aortic arch and common carotid arteries from the 2D TOF MR angiograms and targeted MIPs of the intracranial carotid arteries from the MOTSA MR angiograms were compared with the intraarterial angiogram and graded as normal, mild, moderate, severely stenotic, or occluded. MPR of the 3D TOF MR angiograms was highly correlated with intraarterial angiograms for both observers 1 and 2 (0.94/p < .001, 0.96/p < .001 [Pearson correlation/p value]). No statistically significant difference between 3D TOF MPR and intraarterial angiography was seen with a paired t-test. With an alpha = 0.05 (5% probability of type 1 error), the power to detect a difference as small as +/- 5% stenosis between 3D TOF MPR and intraarterial angiogram was 80% for observer 1 and 90% for observer 2. Although both MIPs of the 2D and 3D TOF MR angiograms showed high Pearson correlation coefficients (0.83, 0.90) with intraarterial angiography, the paired t-test revealed a statistically significant difference in the estimation of carotid stenosis. Both observers thought the global MIPs of the 2D TOF MR angiogram allowed good to excellent visualization of the common carotid arteries. The aortic arch was seen in 70% of patients; most of the missed cases occurred early in our experience, when the 2D axial images were not placed sufficiently inferior to include the arch. No stenosis of the great vessel origins was seen in this study. All four stenoses of the intracranial internal carotid artery identified with intraarterial angiography were seen with the MOTSA MR angiogram but with a tendency to overestimate stenosis. Only one carotid siphon was thought to show severe stenosis on the MR angiogram. Intraarterial angiography showed a 50% stenosis. It is possible to image the entire carotid artery from the aortic arch through the circle of Willis with MR angiography in a clinically acceptable time. MPR of the 3D TOF MR angiogram reliably shows the percentage of carotid stenosis with no statistically significant difference compared with intraarterial angiography. The role of MR angiography in showing lesions in the circle of Willis or the aortic arch is promising, but the limited number of tandem lesions in this study makes it difficult to draw any conclusions.


Initial feasibility of a woman-focused intervention for pregnant african-american women.
African-American women who use crack are vulnerable to HIV because of the complex social circumstances in which they live. Drug-abuse treatment for these women during pregnancy may provide time for changing risk behaviors. This paper examines the initial 6-month feasibility of a women-focused HIV intervention, the Women's CoOp, adapted for pregnant women, relative to treatment-as-usual among 59 pregnant African-American women enrolled in drug-abuse treatment. At treatment entry, the women were largely homeless, unemployed, practicing unsafe sex, and involved in violence. Results indicated marked reductions in homelessness, use of cocaine and illegal drugs, involvement in physical violence, and an increase in knowledge of HIV from baseline to 6-month followup for both conditions. Findings suggest that the Women's CoOp intervention could be successfully adapted to treat this hard-to-reach population. Future studies should examine the efficacy of the pregnancy-adapted Women's CoOp for women not enrolled in drug-abuse treatment.


Development of a chimeric hemicellulase to enhance the xylose production and thermotolerance.
Xylan is an abundant plant cell wall polysaccharide and its reduction to xylose units for subsequent biotechnological applications requires a combination of distinct hemicellulases and auxiliary enzymes, mainly endo-xylanases and ß-xylosidases. In the present work, a bifunctional enzyme consisting of a GH11 endo-1,4-β-xylanase fused to a GH43 β-xylosidase, both from Bacillus subtilis, was designed taking into account the quaternary arrangement and accessibility to the substrate. The parental enzymes and the resulting chimera were successfully expressed in Escherichia coli, purified and characterized. Interestingly, the substrate cleavage rate was altered by the molecular fusion improving at least 3-fold the xylose production using specific substrates as beechwood xylan and hemicelluloses from pretreated biomass. Moreover, the chimeric enzyme showed higher thermotolerance with a positive shift of the optimum temperature from 35 to 50 °C for xylosidase activity. This improvement in the thermal stability was also observed by circular dichroism unfolding studies, which seems to be related to a gain of stability of the β-xylosidase domain. These results demonstrate the superior functional and stability properties of the chimeric enzyme in comparison to individual parental domains, suggesting the molecular fusion as a promising strategy for enhancing enzyme cocktails aiming at lignocellulose hydrolysis.


Accurate quantification of microorganisms in PCR-inhibiting environmental DNA extracts by a novel internal amplification control approach using Biotrove OpenArrays.
PCR-based detection assays are prone to inhibition by substances present in environmental samples, thereby potentially leading to inaccurate target quantification or false-negative results. Internal amplification controls (IACs) have been developed to help alleviate this problem but are generally applied in a single concentration, thereby yielding less-than-optimal results across the wide range of microbial gene target concentrations possible in environmental samples (J. Hoorfar, B. Malorny, A. Abdulmawjood, N. Cook, M. Wagner, and P. Fach, J. Clin. Microbiol. 42:1863-1868, 2004). Increasing the number of IACs for each quantitative PCR (qPCR) sample individually, however, typically reduces sensitivity and, more importantly, the reliability of quantification. Fortunately, current advances in high-throughput qPCR platforms offer the possibility of multiple reactions for a single sample simultaneously, thereby allowing the implementation of more than one IAC concentration per sample. Here, we describe the development of a novel IAC approach that is specifically designed for the state-of-the-art Biotrove OpenArray platform. Different IAC targets were applied at a range of concentrations, yielding a calibration IAC curve for each individual DNA sample. The developed IACs were optimized, tested, and validated by using more than 5,000 unique qPCR amplifications, allowing accurate quantification of microorganisms when applied to soil DNA extracts containing various levels of PCR-inhibiting compounds. To our knowledge, this is the first study using a suite of IACs at different target concentrations to monitor PCR inhibition across a wide target range, thereby allowing reliable and accurate quantification of microorganisms in PCR-inhibiting DNA extracts. The developed IAC is ideally suited for high-throughput screenings of, for example, ecological and agricultural samples on next-generation qPCR platforms.


Fatty acids in cardiovascular health and disease: a comprehensive update.
Research dating back to the 1950s reported an association between the consumption of saturated fatty acids (SFAs) and risk of coronary heart disease. Recent epidemiological evidence, however, challenges these findings. It is well accepted that the consumption of SFAs increases low-density lipoprotein cholesterol (LDL-C), whereas carbohydrates, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) do not. High-density lipoprotein (HDL)-C increases with SFA intake. Among individuals who are insulin resistant, a low-fat, high-carbohydrate diet typically has an adverse effect on lipid profiles (in addition to decreasing HDL-C, it also increases triglyceride and LDL particle concentrations). Consequently, a moderate fat diet in which unsaturated fatty acids replace SFAs and carbohydrates are not augmented is advised to lower LDL-C; compared with a low-fat diet, a moderate-fat diet will lower triglycerides and increase HDL-C. Now, there is some new evidence that is questioning the health benefits of even MUFAs and PUFAs. In addition, in a few recent studies investigators have also failed to demonstrate expected cardiovascular benefits of marine-derived omega-3 fatty acids. To clarify the clinical pros and cons of dietary fats, the National Lipid Association held a fatty acid symposium at the 2011 National Lipid Association Scientific Sessions. During these sessions, the science regarding the effects of different fatty acid classes on coronary heart disease risk was reviewed.


Association of Helicobacter pylori infection with the development of colorectal polyps and colorectal carcinoma.
Recent studies have suggested a possible association between Helicobacter pylori (HP) infection and colon neoplasia. HP infection causes hypergastrinemia, and gastrin increases colorectal mucosal proliferation, potentially leading to colorectal cancer. We investigated whether HP infection is associated with colon neoplasia. We conducted a cross-sectional, single-center study in which patients who underwent routine outpatient colonoscopy and were tested for HP infection on esophagogastroduodenoscopy from January 1, 2008 to November 1, 2009 were identified. Patient demographic data (gender and age) and information on colon polyp characteristics (size, number of polyps, location, morphology, and histology) were abstracted from retrospective chart review. Presence of adenoma/carcinoma was compared in the HP-positive cases and HP-negative controls. A total of 192 patients were included in the study, with 96 patients each in the HP-positive and -negative groups. The two groups did not differ significantly in gender, age, polyp size, number of polyps, polyp location, morphology, and histology. Adenomatous colon polyps were noted in 31% of the HP-positive cases and in 26% of the HP-negative controls (P = 0.52). Colon carcinoma was found in 6% of HP-positive and 2% of HP-negative patients (P = 0.28). The higher prevalence of adenomatous colon polyps/carcinoma in HP-positive patients compared to HP-negative patients was not statistically significant. Larger studies are needed to examine further the potential association between HP infection and colorectal adenoma/carcinoma.


Search for physics beyond the standard model in events with two leptons of same sign, missing transverse momentum, and jets in proton-proton collisions at s = 13 TeV.
A data sample of events from proton-proton collisions with two isolated same-sign leptons, missing transverse momentum, and jets is studied in a search for signatures of new physics phenomena by the CMS Collaboration at the LHC. The data correspond to an integrated luminosity of 35.9 fb - 1 , and a center-of-mass energy of 13 TeV . The properties of the events are consistent with expectations from standard model processes, and no excess yield is observed. Exclusion limits at 95% confidence level are set on cross sections for the pair production of gluinos, squarks, and same-sign top quarks, as well as top-quark associated production of a heavy scalar or pseudoscalar boson decaying to top quarks, and on the standard model production of events with four top quarks. The observed lower mass limits are as high as 1500 GeV for gluinos, 830 GeV for bottom squarks. The excluded mass range for heavy (pseudo)scalar bosons is 350-360 (350-410) GeV . Additionally, model-independent limits in several topological regions are provided, allowing for further interpretations of the results.


Preoperative testing before low-risk surgical procedures.
There is concern about increasing utilization of low-value health care services, including preoperative testing for low-risk surgical procedures. We investigated temporal trends, explanatory factors, and institutional and regional variation in the utilization of testing before low-risk procedures. For this retrospective cohort study, we accessed linked population-based administrative databases from Ontario, Canada. A cohort of 1 546 223 patients 18 years or older underwent a total of 2 224 070 low-risk procedures, including endoscopy and ophthalmologic surgery, from Apr. 1, 2008, to Mar. 31, 2013, at 137 institutions in 14 health regions. We used hierarchical logistic regression models to assess patient- and institution-level factors associated with electrocardiography (ECG), transthoracic echocardiography, cardiac stress test or chest radiography within 60 days before the procedure. Endoscopy, ophthalmologic surgery and other low-risk procedures accounted for 40.1%, 34.2% and 25.7% of procedures, respectively. ECG and chest radiography were conducted before 31.0% (95% confidence interval [CI] 30.9%-31.1%) and 10.8% (95% CI 10.8%-10.8%) of procedures, respectively, whereas the rates of preoperative echocardiography and stress testing were 2.9% (95% CI 2.9%-2.9%) and 2.1% (95% CI 2.1%-2.1%), respectively. Significant variation was present across institutions, with the frequency of preoperative ECG ranging from 3.4% to 88.8%. Receipt of preoperative ECG and radiography were associated with older age (among patients 66-75 years of age, for ECG, adjusted odds ratio [OR] 18.3, 95% CI 17.6-19.0; for radiography, adjusted OR 2.9, 95% CI 2.8-3.0), preoperative anesthesia consultation (for ECG, adjusted OR 8.7, 95% CI 8.5-8.8; for radiography, adjusted OR 2.2, 95% CI 2.1-2.2) and preoperative medical consultation (for ECG, adjusted OR 6.8, 95% CI 6.7-6.9; for radiography, adjusted OR 3.6, 95% CI 3.5-3.6). The median ORs for receipt of preoperative ECG and radiography were 2.3 and 1.6, respectively. Despite guideline recommendations to limit testing before low-risk surgical procedures, preoperative ECG and chest radiography were performed frequently. Significant variation across institutions remained after adjustment for patient- and institution-level factors.


Coping with the Challenges of COVID-19 Using the Sociotype Framework: A Rehearsal for the Next Pandemic.
The world, as a global village, is currently taking part in a real-time public health, medical, socio-cultural, and economic experiment on how best to combat the COVID-19 pandemic. Extraordinary times demand extraordinary measures. Depending on the time from the outbreak, strategies have ranged from minimal intervention to mitigation by quarantine for high-risk groups (elderly with chronic illnesses) to containment and lockdown. Adherence to such restrictions have depended on the individual and national psyche and culture. One can understand and forgive governments for being over-cautious, but not for being ill-prepared. It seems that Singapore after SARS (2003) and South Korea after MERS (2015) learnt from their experiences and have fared relatively well with minimal disruption to daily routines. Coping with the challenge of COVID-19 is an urgent global task. We use the Sociotype ecological framework to analyze different coping responses at three levels: Context (government and leadership, social context, health services, and media); Relationships; and the Individual. We describe the many negative outcomes (e.g. mortality [obviously], unemployment, economic damage, food insecurity, threat to democracy, claustrophobia) and the positive ones (e.g. new, remote teaching, working, and medical routines; social bonding and solidarity; redefining existential values and priorities) of this surreal situation, which is still evolving. We highlight the importance of humor in stress reduction. Regular and reliable communication to the public has to be improved, acknowledging incomplete data, and learning to deal with fake news, misinformation, and conspiracy theories. Excess mortality is the preferred statistic to follow and compare outcomes. When the health risks are over, the economic recovery responses will vary according to the financial state of countries. If world order is to be reshaped, then a massive economic aid plan should be launched by the rich countries-akin to the Marshall plan after the Second World War. It should be led preferably by the USA and China. The results of the tradeoffs between health and economic lockdowns will only become apparent in the months to come. The experiences and lessons learned from this emergency should be used as a rehearsal for the next epi-/pandemic, which will surely take place in the foreseeable future.


sck1, a high copy number suppressor of defects in the cAMP-dependent protein kinase pathway in fission yeast, encodes a protein homologous to the Saccharomyces cerevisiae SCH9 kinase.
Schizosaccharomyces pombe regulates intracellular cAMP levels, and thus cAMP-dependent protein kinase (PKA) activity, in response to changes in nutrient conditions. Mutations in any of eight git genes inhibit glucose repression of fbp1 transcription, alter the cell morphology, and cause a reduction in the growth rate. The eight git genes encode components of an adenylate cyclase activation pathway, adenylate cyclase itself, and the catalytic subunit of PKA. Three of these genes have been identified in other studies as regulators of meiosis. Here we show that the sck1 gene, cloned as a high copy number suppressor of a mutation in git3, is able to suppress the defects conferred by a mutation in any of these git genes. Sequence analysis suggests that sck1 encodes a protein most closely related to the Saccharomyces cerevisiae SCH9 protein kinase that had previously been identified as a high copy number suppressor of mutations in S. cerevisiae that reduce or eliminate PKA activity. Disruption of the sck1 gene causes a significant delay in exit from stationary phase when combined with a disruption of the pka1 (git6) gene encoding the catalytic subunit of PKA. However, the sck1 disruption by itself has little or no effect upon fbp1 transcription, meiosis, or exit from stationary phase, and does not enhance the constitutive fbp1 transcription observed in a pka1 mutant. Therefore, sck1 appears to function in a redundant fashion to pka1, but to varying degrees, in the pathways regulated by pka1.


Forensic mental health law reform in Japan: from criminal warehousing to broad-spectrum specialist services?
Since the 1980s Japan has undergone a number of mental health law reforms culminating in the 2005 forensic law. This added to its enactments on involuntary commitment, long-term aged care and substitute decision making, bringing Japan into focus as an industrialized state now possessed of a full package of civil and forensic provisions. This article seeks to demonstrate that the new forensic law cannot achieve its own stated goals without seeking to put into place financial and administrative supports aimed to integrate the myriad of patient populations that will be inevitably affected by the new forensic system. In order to avoid the widespread syndrome that has already been experienced internationally of warehousing mentally ill offenders in jails, it is critical that the Japanese government develop effective and culturally sensitive techniques for dealing with low risk populations through a diversionary process. Furthermore, although the legislation addresses serious crimes, it is imperative that policies be put into place to avoid directing young offenders, violent patients from the general hospital system, the developmentally handicapped, already convicted persons found in hospital settings and problematic cases in the correctional system, to the new forensic units established by the legislation. It is only though contemplating unintended outcomes of the legislation that the Japanese government will be able to avoid the ongoing stigmatization and prolonged institutionalization of mentally ill populations. Despite apparent cultural differences internationally vetted human rights requirements must be properly protected, not only in the forensic context, but throughout the mental health system at large. The coordination of services and the development of specialty training are necessary conditions for the realization of improved and humane conditions for mentally ill persons in Japan.


Adaptive phenotypic plasticity in the Midas cichlid fish pharyngeal jaw and its relevance in adaptive radiation.
Phenotypic evolution and its role in the diversification of organisms is a central topic in evolutionary biology. A neglected factor during the modern evolutionary synthesis, adaptive phenotypic plasticity, more recently attracted the attention of many evolutionary biologists and is now recognized as an important ingredient in both population persistence and diversification. The traits and directions in which an ancestral source population displays phenotypic plasticity might partly determine the trajectories in morphospace, which are accessible for an adaptive radiation, starting from the colonization of a novel environment. In the case of repeated colonizations of similar environments from the same source population this "flexible stem" hypothesis predicts similar phenotypes to arise in repeated subsequent radiations. The Midas Cichlid (Amphilophus spp.) in Nicaragua has radiated in parallel in several crater-lakes seeded by populations originating from the Nicaraguan Great Lakes. Here, we tested phenotypic plasticity in the pharyngeal jaw of Midas Cichlids. The pharyngeal jaw apparatus of cichlids, a second set of jaws functionally decoupled from the oral ones, is known to mediate ecological specialization and often differs strongly between sister-species. We performed a common garden experiment raising three groups of Midas cichlids on food differing in hardness and calcium content. Analyzing the lower pharyngeal jaw-bones we find significant differences between diet groups qualitatively resembling the differences found between specialized species. Observed differences in pharyngeal jaw expression between groups were attributable to the diet's mechanical resistance, whereas surplus calcium in the diet was not found to be of importance. The pharyngeal jaw apparatus of Midas Cichlids can be expressed plastically if stimulated mechanically during feeding. Since this trait is commonly differentiated--among other traits--between Midas Cichlid species, its plasticity might be an important factor in Midas Cichlid speciation. The prevalence of pharyngeal jaw differentiation across the Cichlidae further suggests that adaptive phenotypic plasticity in this trait could play an important role in cichlid speciation in general. We discuss several possibilities how the adaptive radiation of Midas Cichlids might have been influenced in this respect.


Selective focusing of catecholamines and weakly acidic compounds by capillary electrophoresis using a dynamic pH junction.
A systematic study of selective analyte focusing in a multisection electrolyte system by capillary electrophoresis (CE) is presented. It was found that a dynamic pH junction between sample and background electrolyte zones can be used to focus zwitterionic catecholamines and weakly acidic compounds without the use of special ampholytes. Differences in pH and concentration of complexing agents, such as borate, in the sample and background electrolyte zones were determined to cause focusing through changes in the local velocity of the analyte in two different segments of the capillary. Velocity-difference induced focusing (V-DIF) of analytes using a dynamic pH junction allowed the injection of large sample volumes and significantly improved the concentration sensitivity of CE. Under optimized conditions, the limit of detection for epinephrine was determined to be about 4 x 10(-8) M (the original sample) with conventional UV absorbance detection. Moreover, separation efficiencies greater than a million theoretical plates can be achieved by focusing such large sample volumes into narrow zones. Multisection electrolyte systems, which lead to the formation of a dynamic pH junction, can be tuned toward improving the concentration sensitivity of specific analytes if their chemical properties are known.