Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome.
LDL receptor (LDLR)-null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome, have vascular calcification (VC) worsened by chronic kidney disease (CKD) and ameliorated by bone morphogenetic protein-7 (BMP-7), an efficacious agent in treating animal models of renal osteodystrophy. Here, LDLR-/- high-fat-fed mice without CKD were shown to have significant reductions in bone formation rates, associated with increased VC and hyperphosphatemia. Superimposing CKD resulted in a low turnover osteodystrophy, whereas VC worsened and hyperphosphatemia persisted. BMP-7 treatment corrected the hyperphosphatemia, corrected the osteodystrophy, and prevented VC, compatible with skeletal phosphate deposition leading to reduced plasma phosphate and removal of a major stimulus to VC. A pathologic link between abnormal bone mineralization and VC through the serum phosphorus was supported by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in this model of the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to low bone turnover rates, producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through deposition of phosphate and increased bone formation.


Phylogenomic Relationships of Diploids and the Origins of Allotetraploids in Dactylorhiza (Orchidaceae).
Disentangling phylogenetic relationships proves challenging for groups that have evolved recently, especially if there is ongoing reticulation. Although they are in most cases immediately isolated from diploid relatives, sets of sibling allopolyploids often hybridize with each other, thereby increasing the complexity of an already challenging situation. Dactylorhiza (Orchidaceae: Orchidinae) is a genus much affected by allopolyploid speciation and reticulate phylogenetic relationships. Here, we use genetic variation at tens of thousands of genomic positions to unravel the convoluted evolutionary history of Dactylorhiza. We first investigate circumscription and relationships of diploid species in the genus using coalescent and maximum likelihood methods, and then group 16 allotetraploids by maximum affiliation to their putative parental diploids, implementing a method based on genotype likelihoods. The direction of hybrid crosses is inferred for each allotetraploid using information from maternally inherited plastid RADseq loci. Starting from age estimates of parental taxa, the relative ages of these allotetraploid entities are inferred by quantifying their genetic similarity to the diploids and numbers of private alleles compared with sibling allotetraploids. Whereas northwestern Europe is dominated by young allotetraploids of postglacial origins, comparatively older allotetraploids are distributed further south, where climatic conditions remained relatively stable during the Pleistocene glaciations. Our bioinformatics approach should prove effective for the study of other naturally occurring, nonmodel, polyploid plant complexes.


The consequences of gene flow for local adaptation and differentiation: a two-locus two-deme model.
We consider a population subdivided into two demes connected by migration in which selection acts in opposite direction. We explore the effects of recombination and migration on the maintenance of multilocus polymorphism, on local adaptation, and on differentiation by employing a deterministic model with genic selection on two linked diallelic loci (i.e., no dominance or epistasis). For the following cases, we characterize explicitly the possible equilibrium configurations: weak, strong, highly asymmetric, and super-symmetric migration, no or weak recombination, and independent or strongly recombining loci. For independent loci (linkage equilibrium) and for completely linked loci, we derive the possible bifurcation patterns as functions of the total migration rate, assuming all other parameters are fixed but arbitrary. For these and other cases, we determine analytically the maximum migration rate below which a stable fully polymorphic equilibrium exists. In this case, differentiation and local adaptation are maintained. Their degree is quantified by a new multilocus version of [Formula: see text] and by the migration load, respectively. In addition, we investigate the invasion conditions of locally beneficial mutants and show that linkage to a locus that is already in migration-selection balance facilitates invasion. Hence, loci of much smaller effect can invade than predicted by one-locus theory if linkage is sufficiently tight. We study how this minimum amount of linkage admitting invasion depends on the migration pattern. This suggests the emergence of clusters of locally beneficial mutations, which may form 'genomic islands of divergence'. Finally, the influence of linkage and two-way migration on the effective migration rate at a linked neutral locus is explored. Numerical work complements our analytical results.


Role of sleep duration and sleep-related problems in the metabolic syndrome among children and adolescents.
There is increasing recognition that sleep is a risk factor for metabolic syndrome (MetS). The aim of the present study was to analyze the relationship between self-reported sleep duration, sleep-related problems and the presence of MetS in children and adolescents from Bogotá, D.C., Colombia. This is a cross-sectional analysis from the FUPRECOL study (2014-15). Participants included 2779 (54.2% girls) youth from Bogota (Colombia). MetS was defined as the presence of ≥3 of the metabolic abnormalities (hyperglycemia, hypertriglyceridemia, low high-density lipoprotein cholesterol [HDL-c], hypertension, and increased waist circumference) according to the criteria of de Ferranti/Magge and colleges. Self-reported sleep duration and sleep-related problems were assessed with the BEARS questionnaire. Logistic regression analysis showed that boys who meet recommended duration of sleep had a decreased risk of elevated blood glucose levels (Odds Ratio [OR] = 0.71, 95%CI [0.40-0.94]; p = 0.031) compared to boys who have short-long sleep duration. Also, compared to young without sleep problems, excessive sleepiness during the day was related to low HDL-c levels in boys (OR = 1.36, 95%CI [1.02-1.83]; p = 0.036) and high triglyceride levels in girls (OR = 1.28, 95%CI [1.01-1.63]; p = 0.045). Girls with irregular sleep patterns had decreased HDL-c levels (OR = 0.71, 95%CI [0.55-0.91]; p = 0.009). Recommended sleep duration was associated with a decreased risk of elevated fasting glucose levels in boys, and sleep problems was related to lower HDL-c in girls and higher triglyceride levels in boys. These findings suggested the clinical importance of improving sleep hygiene to reduce metabolic risk factors in children and adolescents.


Boron stress activates the general amino acid control mechanism and inhibits protein synthesis.
Boron is an essential micronutrient for plants, and it is beneficial for animals. However, at high concentrations boron is toxic to cells although the mechanism of this toxicity is not known. Atr1 has recently been identified as a boron efflux pump whose expression is upregulated in response to boron treatment. Here, we found that the expression of ATR1 is associated with expression of genes involved in amino acid biosynthesis. These mechanisms are strictly controlled by the transcription factor Gcn4 in response to boron treatment. Further analyses have shown that boron impaired protein synthesis by promoting phosphorylation of eIF2α in a Gcn2 kinase dependent manner. The uncharged tRNA binding domain (HisRS) of Gcn2 is necessary for the phosphorylation of eIF2α in the presence of boron. We postulate that boron exerts its toxic effect through activation of the general amino acid control system and inhibition of protein synthesis. Since the general amino acid control pathway is conserved among eukaryotes, this mechanism of boron toxicity may be of general importance.


Effects of case management in community aged care on client and carer outcomes: a systematic review of randomized trials and comparative observational studies.
Case management has been applied in community aged care to meet frail older people's holistic needs and promote cost-effectiveness. This systematic review aims to evaluate the effects of case management in community aged care on client and carer outcomes. We searched Web of Science, Scopus, Medline, CINAHL (EBSCO) and PsycINFO (CSA) from inception to 2011 July. Inclusion criteria were: no restriction on date, English language, community-dwelling older people and/or carers, case management in community aged care, published in refereed journals, randomized control trials (RCTs) or comparative observational studies, examining client or carer outcomes. Quality of studies was assessed by using such indicators as quality control, randomization, comparability, follow-up rate, dropout, blinding assessors, and intention-to-treat analysis. Two reviewers independently screened potentially relevant studies, extracted information and assessed study quality. A narrative summary of findings were presented. Ten RCTs and five comparative observational studies were identified. One RCT was rated high quality. Client outcomes included mortality (7 studies), physical or cognitive functioning (6 studies), medical conditions (2 studies), behavioral problems (2 studies) , unmet service needs (3 studies), psychological health or well-being (7 studies) , and satisfaction with care (4 studies), while carer outcomes included stress or burden (6 studies), satisfaction with care (2 studies), psychological health or well-being (5 studies), and social consequences (such as social support and relationships with clients) (2 studies). Five of the seven studies reported that case management in community aged care interventions significantly improved psychological health or well-being in the intervention group, while all the three studies consistently reported fewer unmet service needs among the intervention participants. In contrast, available studies reported mixed results regarding client physical or cognitive functioning and carer stress or burden. There was also limited evidence indicating significant effects of the interventions on the other client and carer outcomes as described above. Available evidence showed that case management in community aged care can improve client psychological health or well-being and unmet service needs. Future studies should investigate what specific components of case management are crucial in improving clients and their carers' outcomes.


Transethnic meta-analysis of genomewide association studies.
The detection of loci contributing effects to complex human traits, and their subsequent fine-mapping for the location of causal variants, remains a considerable challenge for the genetics research community. Meta-analyses of genomewide association studies, primarily ascertained from European-descent populations, have made considerable advances in our understanding of complex trait genetics, although much of their heritability is still unexplained. With the increasing availability of genomewide association data from diverse populations, transethnic meta-analysis may offer an exciting opportunity to increase the power to detect novel complex trait loci and to improve the resolution of fine-mapping of causal variants by leveraging differences in local linkage disequilibrium structure between ethnic groups. However, we might also expect there to be substantial genetic heterogeneity between diverse populations, both in terms of the spectrum of causal variants and their allelic effects, which cannot easily be accommodated through traditional approaches to meta-analysis. In order to address this challenge, I propose novel transethnic meta-analysis methodology that takes account of the expected similarity in allelic effects between the most closely related populations, while allowing for heterogeneity between more diverse ethnic groups. This approach yields substantial improvements in performance, compared to fixed-effects meta-analysis, both in terms of power to detect association, and localization of the causal variant, over a range of models of heterogeneity between ethnic groups. Furthermore, when the similarity in allelic effects between populations is well captured by their relatedness, this approach has increased power and mapping resolution over random-effects meta-analysis.


Patient safety incidents during overnight polysomnography: a five-year observational cohort study.
Attended polysomnography (PSG) is a common procedure and is regarded as relatively safe. There have been few systematic evaluations of adverse events occurring during PSG. An understanding of the frequency and type of the adverse events during PSG should inform risk mitigation plans and the development of guidelines for sleep center accreditation. We aimed to identify, tabulate, and classify all adverse events that occurred during overnight PSG conducted at an accredited sleep center over a five-year period. All adverse events occurring from Jan 1, 2005, to Dec 31, 2010, at the Center for Sleep Medicine, Mayo Clinic, were identified. Information was collated from calls made to emergency responders, to the adverse event reporting system, and events forwarded to the medical director. A total of 36,141 PSGs were performed over the study duration. Fifty-eight adverse events occurred during the study period (1 event/623 PSGs). Most adverse events were cardiac in nature (17/58; 29.3%), a majority involving acute chest pain. Falls were the next most common (20.6%), followed by neurologic (8.6%), pulmonary (3.4%), and psychiatric (3.4%) events. The rest were classified as miscellaneous. There were no patient deaths during PSGs. The majority of patients experiencing an adverse event were transported to the emergency room (37/58; 63.79%). Of these, 15/37 (40.54%) were admitted to the hospital, and 3 required an ICU bed. Adverse events during a PSG were relatively uncommon. Previous emphasis on cardiac arrhythmias may be overstated, as chest pain and patient falls were commonest and resulted in hospitalization more often.


Guidance or Compliance: What Makes an Ethical Behavior Analyst?
In 2016, the Behavior Analyst Certification Board (BACB) made effective a new, revised ethical code for behavior analysts, the Professional and Ethical Compliance Code for Behavior Analysts, replacing the code that had been in effect since 2001. In this revised code, the certification board has shifted the language of the code from that of a set of guidelines to that of a set of enforceable rules. This important shift has not been well discussed in the field. This article explores the potential implications and possible consequences of such a shift and describes other ways that ethical behavior has been approached historically. The authors then propose an ethical decision-making process that might provide a better area of focus for the field of behavior analysis in seeking to develop the highest levels of ethical behavior in its professionals and provide a case example using that process to resolve an ethical dilemma.


Investigation into the effects of mosapride on motility of Guinea pig stomach, ileum, and colon.
Mosapride citrate (Mosapride) is a new prokinetic agent that enhances the gastrointestinal (GI) motility by stimulation of 5-HT4 receptors. This agent stimulates acetylcholine release from enteric cholinergic neurons in the GI wall. It was reported in several studies that mosapride selectively enhanced the upper, but not lower, GI motor activity. However, in these studies other 5-HT4 receptor agonists exerted stimulating effects on the motility of the colon. Moreover, it is well known that the receptors of 5-HT4 are also located in the colon. The purpose of this study was to estimate the effect of mosapride on the motility of the stomach, ileum and colon in the guinea pig and to investigate whether or not mosapride influenced the colonic motility. Mosapride significantly increased the amplitude of the contraction waves in the guinea pig stomach by electrical stimulation. In addition, it significantly increased the number of peaks, the area under the curve and the propagation velocity of the peristaltic contraction of the guinea pig ileum in a concentration dependent fashion. Mosapride also significantly shortened the transit time of the guinea pig colon. Accordingly, we concluded that mosapride exerted prokinetic effect on the entire GI tract of the guinea pig. Based on the possibility of similar results in humans, we suggest the potential use of mosapride for lower GI motor disorders such as constipation and upper GI motor disorders such as gastroesophageal reflex disease or gastroparesis.


Selection of reliable reference genes in Caenorhabditis elegans for analysis of nanotoxicity.
Despite rapid development and application of a wide range of manufactured metal oxide nanoparticles (NPs), the understanding of potential risks of using NPs is less completed, especially at the molecular level. The nematode Caenorhabditis elegans (C.elegans) has been emerging as an environmental model to study the molecular mechanism of environmental contaminations, using standard genetic tools such as the real-time quantitative PCR (RT-qPCR). The most important factor that may affect the accuracy of RT-qPCR is to choose appropriate genes for normalization. In this study, we selected 13 reference gene candidates (act-1, cdc-42, pmp-3, eif-3.C, actin, act-2, csq-1, Y45F10D.4, tba-1, mdh-1, ama-1, F35G12.2, and rbd-1) to test their expression stability under different doses of nano-copper oxide (CuO 0, 1, 10, and 50 µg/mL) using RT-qPCR. Four algorithms, geNorm, NormFinder, BestKeeper, and the comparative ΔCt method, were employed to evaluate these 13 candidates expressions. As a result, tba-1, Y45F10D.4 and pmp-3 were the most reliable, which may be used as reference genes in future study of nanoparticle-induced genetic response using C.elegans.


Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index: A Secondary Analysis of a Randomized Clinical Trial and Observational Study.
Obesity is associated with an increased risk of breast cancer, including the estrogen receptor (ER)-positive subtype in postmenopausal women. Whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown. To investigate the association between body fat and breast cancer risk in women with normal BMI. This ad hoc secondary analysis of the Women's Health Initiative (WHI) clinical trial and observational study cohorts was restricted to postmenopausal participants with a BMI ranging from 18.5 to 24.9. Women aged 50 to 79 years were enrolled from October 1, 1993, through December 31, 1998. Of these, 3460 participants underwent body fat measurement with dual-energy x-ray absorptiometry (DXA) at 3 US designated centers with follow-up. At a median follow-up of 16 years (range, 9-20 years), 182 incident breast cancers had been ascertained, and 146 were ER positive. Follow-up was complete on September 30, 2016, and data from October 1, 1993, through September 30, 2016, was analyzed August 2, 2017, through August 21, 2018. Body fat levels were measured at baseline and years 1, 3, 6, and 9 using DXA. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analyte levels were measured in subsets of participants. Among the 3460 women included in the analysis (mean [SD] age, 63.6 [7.6] years), multivariable-adjusted hazard ratios for the risk of invasive breast cancer were 1.89 (95% CI, 1.21-2.95) for the highest quartile of whole-body fat and 1.88 (95% CI, 1.18-2.98) for the highest quartile of trunk fat mass. The corresponding adjusted hazard ratios for ER-positive breast cancer were 2.21 (95% CI, 1.23-3.67) and 1.98 (95% CI, 1.18-3.31), respectively. Similar positive associations were observed for serial DXA measurements in time-dependent covariate analyses. Circulating levels of insulin, C-reactive protein, interleukin 6, leptin, and triglycerides were higher, whereas levels of high-density lipoprotein cholesterol and sex hormone-binding globulin were lower in those in the uppermost vs lowest quartiles of trunk fat mass. In postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women. ClinicalTrials.gov identifier: NCT00000611.


Antimicrobial resistance and virulence determinants in European Salmonella genomic island 1-positive Salmonella enterica isolates from different origins.
Salmonella genomic island 1 (SGI1) contains a multidrug resistance region conferring the ampicillin-chloramphenicol-streptomycin-sulfamethoxazole-tetracycline resistance phenotype encoded by bla(PSE-1), floR, aadA2, sul1, and tet(G). Its increasing spread via interbacterial transfer and the emergence of new variants are important public health concerns. We investigated the molecular properties of SGI1-carrying Salmonella enterica serovars selected from a European strain collection. A total of 38 strains belonging to S. enterica serovar Agona, S. enterica serovar Albany, S. enterica serovar Derby, S. enterica serovar Kentucky, S. enterica serovar Newport, S. enterica serovar Paratyphi B dT+, and S. enterica serovar Typhimurium, isolated between 2002 and 2006 in eight European countries from humans, animals, and food, were subjected to antimicrobial susceptibility testing, molecular typing methods (XbaI pulsed-field gel electrophoresis [PFGE], plasmid analysis, and multilocus variable-number tandem-repeat analysis [MLVA]), as well as detection of resistance and virulence determinants (PCR/sequencing and DNA microarray analysis). Typing experiments revealed wide heterogeneity inside the strain collection and even within serovars. PFGE analysis distinguished a total of 26 different patterns. In contrast, the characterization of the phenotypic and genotypic antimicrobial resistance revealed serovar-specific features. Apart from the classical SGI1 organization found in 61% of the strains, seven different variants were identified with antimicrobial resistance properties associated with SGI1-A (S. Derby), SGI1-C (S. Derby), SGI1-F (S. Albany), SGI1-L (S. Newport), SGI1-K (S. Kentucky), SGI1-M (S. Typhimurium), and, eventually, a novel variant similar to SGI1-C with additional gentamicin resistance encoded by aadB. Only minor serovar-specific differences among virulence patterns were detected. In conclusion, the SGI1 carriers exhibited pathogenetic backgrounds comparable to the ones published for susceptible isolates. However, because of their multidrug resistance, they may be more relevant in clinical settings.


Exploring techniques for encoding spoken instructions in working memory: a comparison of verbal rehearsal, motor imagery, self-enactment and action observation.
Encoding and recalling spoken instructions is subject to working memory capacity limits. Previous research suggests action-based encoding facilitates instruction recall, but has not directly compared benefits across different types of action-based techniques. The current study addressed this in two experiments with young adults. In Experiment 1, participants listened to instructional sequences containing four action-object pairs, and encoded these instructions using either a motor imagery or verbal rehearsal technique, followed by recall via oral repetition or enactment. Memory for instructions was better when participants used a motor imagery technique during encoding, and when recalling the instructions by enactment. The advantage of using a motor imagery technique was present in both verbal and enacted recall. In Experiment 2, participants encoded spoken instructions whilst implementing one of four techniques (verbal rehearsal, motor imagery, observation of others' actions or self-enactment), and then recalled the instructions by oral repetition or enactment. For both verbal and enacted recall, memory for instructions was least accurate in the rehearsal condition, while the other encoding conditions did not differ from each other. These novel findings indicate similar benefits of imagining, observation and execution of actions in encoding spoken instructions, and enrich current understanding of action-based benefits in working memory.


Unilateral microphthalmia or anophthalmia in eight pythons (Pythonidae).
To provide morphological descriptions of microphthalmia or anophthalmia in eight pythons using microcomputerized tomography (μCT), magnetic resonance imaging (MRI), and histopathology. Seven Burmese pythons (Python bivittatus) and one ball python (P. regius) with clinically normal right eyes and an abnormal or missing left eye. At the time of euthanasia, four of the eight snakes underwent necropsy. Hereafter, the heads of two Burmese pythons and one ball python were examined using μCT, and another Burmese python was subjected to MRI. Following these procedures, the heads of these four pythons along with the heads of an additional three Burmese pythons were prepared for histology. All eight snakes had left ocular openings seen as dermal invaginations between 0.2 and 2.0 mm in diameter. They also had varying degrees of malformations of the orbital bones and a limited presence of nervous, glandular, and muscle tissue in the posterior orbit. Two individuals had small but identifiable eyes. Furthermore, remnants of the pigmented embryonic framework of the hyaloid vessels were found in the anophthalmic snakes. Necropsies revealed no other macroscopic anomalies. Eight pythons with unilateral left-sided microphthalmia or anophthalmia had one normal eye and a left orbit with malformed or incompletely developed ocular structures along with remnants of fetal structures. These cases lend further information to a condition that is often seen in snakes, but infrequently described.


Neuropathology of thiamine deficiency disorders.
The Wernicke-Korsakoff syndrome (WKS) is the most frequently encountered manifestation of thiamine deficiency in Western society. It is commonly seen in alcoholic patients, but may also occur in patients with impaired nutrition from other causes, such as those with gastrointestinal disease or AIDS. The pathology is restricted to the central nervous system and is characterised by neuronal loss, gliosis and vascular damage in regions surrounding the third and fourth ventricles and the cerebral aqueduct. In addition to WKS, thiamine deficiency may also result in beriberi, a cardiac and peripheral nervous system disease, and it has been implicated in the pathogenesis of cerebellar degeneration and peripheral neuropathy. Thus thiamine deficiency results in significant nervous system pathology and vigilance should be maintained in the diagnosis and treatment of this readily preventable cause of disease.


A biologically plausible model of thickening of arterial intima under shear.
A biologically plausible model of the early thickening of the arterial intima has been developed to interpret experimental data relating hemodynamic shear to human intimal morphology. The model included many processes known or commonly believed to take place in the vascular intima, including: smooth muscle cell migration, proliferation, metabolism, and expression of extracellular matrix; lipoprotein kinetics and binding; and monocyte chemotaxis, conversion to macrophage, and foam cell formation. Certain of these processes were allowed to be shear-dependent. The best fit to the data was obtained when smooth muscle cell accumulation was more rapid, and extracellular matrix expression proceeded more slowly where the fluid shear was relatively high and unidirectional. This result is consistent with the earlier inference that competing shear-dependent processes take place in the wall; it is also consistent with the notion that intimal thickening might be part of an adaptive mechanism by which the artery maintains a favorable shear environment.


Pd(II)-mediated assembly of porphyrin channels in bilayer membranes.
A membrane-spanning bis(meso-3-pyridyl) porphyrin 1 has been synthesized, embedded in EYPC vesicles, and upon Pd(II) addition has been shown to form ionophores that allow the passage of anionic 5/6-carboxyfluorescein through membranes. The geometric matching of bis(meso-3-pyridyl) porphyrin 1 and trans-Pd(II) was designed to give a cyclic porphyrin trimer [PdCl(2)(1)](3). However, solution-phase studies showed that PdCl(2)(PhCN)(2) cross linked 1 into linear oligomers at porphyrin concentrations above 10 mM, although the formation of cyclic species was inferred from studies at concentrations below 2 μM. Fluorescence titrations showed that embedding porphyrin 1 in bilayers greatly reduced its affinity for Pd(II), but the combination of porphyrin 1 and Pd(II) gave an ionophoric species that increased the rate of 5/6-carboxyfluorescein (5/6-CF) transit through the phospholipid bilayer 12-fold. A maximum in the 5/6-CF release rate was observed at a Pd(II) concentration of 4 μM, and the application of a solution-phase binding model to the membrane phase showed that this peak in ionophoric activity corresponded to the greatest extent of porphyrin oligomerization. Further studies suggested these Pd(II)/porphyrin oligomers transported 5/6-CF via a channel mechanism.


Motherhood during residency training: challenges and strategies.
To determine what factors enable or impede women in a Canadian family medicine residency program from combining motherhood with residency training. To determine how policies can support these women, given that in recent decades the number of female family medicine residents has increased. Qualitative study using in-person interviews. McMaster University Family Medicine Residency Program. Twenty-one of 27 family medicine residents taking maternity leave between 1994 and 1999. Semistructured interviews. The research team reviewed transcripts of audiotaped interviews for emerging themes; consensus was reached on content and meaning. NVIVO software was used for data analysis. Long hours, unpredictable work demands, guilt because absences from work increase workload for colleagues, and residents' high expectations of themselves cause pregnant residents severe stress. This stress continues upon return to work; finding adequate child care is an added stress. Residents report receiving less support from colleagues and supervisors upon return to work; they associate this with no longer being visibly pregnant. Physically demanding training rotations put additional strain on pregnant residents and those newly returned to work. Flexibility in scheduling rotations can help accommodate needs at home. Providing breaks, privacy, and refrigerators at work can help maintain breastfeeding. Allowing residents to remain involved in academic and clinical work during maternity leave helps maintain clinical skills, build new knowledge, and promote peer support. Pregnancy during residency training is common and becoming more common. Training programs can successfully enhance the experience of motherhood during residency by providing flexibility at work to facilitate a healthy balance among the competing demands of family, work, and student life.


Centralized cytogenetic analysis of pediatric acute leukemia: results of an Italian collaborative experience.
Cytogenetic analysis of acute leukemia yields important information which has been demonstrated to be correlated to patient survival. A reference laboratory was created in order to perform karyotype analysis on all cases of acute leukemia enrolled in the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica) protocols. From January 1990 to December 1995, 1115 samples of children with ALL or AML were sent in for cytogenetic analysis. The results of cell cultures were screened in the Reference Laboratory and then the fixed metaphases were sent to one of the six cytogenetic laboratories for analysis. The leukemic karyotypes of 556 patients were successfully analyzed. An abnormal clone was detected in 49% of cases of ALL and in 66% of AML. In ALL the most frequent abnormality was 9p rearrangement. Other recurrent abnormalities were t(9;22), t(4;11) and t(1;19). In AML t(8;21), t(15;17) and 11q23 rearrangement were the most frequent structural abnormalities. These findings are similar to the results obtained in other multicenter studies using a similar approach. Our data confirm the feasibility of performing cytogenetic analysis in a centralized laboratory on mailed samples of bone marrow and/or peripheral blood; this is very important considering that cytogenetic analysis of neoplastic tissue requires a special laboratory and expert staff.


[Counterfeit pharmaceuticals in Peru].
To determine the quantity of counterfeit pharmaceutical drugs found by the National Quality Control Center (Centro Nacional de Control de Calidad (CNCC), Instituto Nacional de Salud, Peru) during the period from 2005&2008, and the types and properties of these drugs. A form was created to amass the relevant data collected directly from CNCC reports. The reports underwent a review and analysis process, and where counterfeiting was confirmed, it was categorized by type into one of four groups. The percentage of counterfeit drugs relative to the total drugs evaluated was: 3.0% in 2005, 5.0% in 2006, 7.3% in 2007, and 9.2% in 2008. The main groups of counterfeit drugs, classified according to the World Health Organization Anatomical Therapeutic Chemical Classification System, were: alimentary tract and metabolism, 34.5% (29.1%-39.8%); antiinfectives for systemic use, 21.1% (16.5%-25.7%); nervous system, 17.1% (12.8%-21.3%); and musculo-skeletal system, 15.4% (11.3%-19.5%). The most common type of forgery occurred in cases where the drug contained the correct amount of active ingredients, but the manufacturer was one other than the one indicated (62.4% of the total counterfeit drugs); and medications that did not contain any active ingredient (22.4%). Of the counterfeit drugs, 61.0% (56.0%-67.0%) were national brands and 39.0%, (33.0%-44.0%) were imported. The pharmaceutical formulations with the highest rate of forgery were tablets, 66.0% (60.0%-71.0%); injectables, 19.0% (14.0%-23.0%); and capsules 7.0% (4.0%-10.0%). From 2005-2008, drug counterfeiting had an average annual variation of 45%. Drug counterfeiting was shown to be most prevalent among national brands - as opposed to imported medications - although the types and formulations of the fake drugs attest to a certain level of sophistication employed in the forgery process. The counterfeiting of life-saving drugs, such as antimicrobials, signifies a serious public health threat.


Thermodynamics of metal ion binding. 2. Metal ion binding by carbonic anhydrase variants.
The ability to construct molecular motifs with predictable properties in aqueous solution requires an extensive knowledge of the relationships between structure and energetics. The design of metal binding motifs is currently an area of intense interest in the bioorganic community. To date synthetic motifs designed to bind metal ions lack the remarkable affinities observed in biological systems. To better understand the structural basis of metal ion affinity, we report here the thermodynamics of binding of divalent zinc ions to wild-type and mutant carbonic anhydrases and the interpretation of these parameters in terms of structure. Mutations were made both to the direct His ligand at position 94 and to indirect, or second-shell, ligands Gln-92, Glu-117, and Thr-199. The thermodynamics of ligand binding by several mutant proteins is complicated by the development of a second zinc binding site on mutation; such effects must be considered carefully in the interpretation of thermodynamic data. In all instances modification of the protein produces a complex series of changes in both the enthalpy and entropy of ligand binding. In most cases these effects are most readily rationalized in terms of ligand and protein desolvation, rather than in terms of changes in the direct interactions of ligand and protein. Alteration of second-shell ligands, thought to function primarily by orienting the direct ligands, produces profoundly different effects on the enthalpy of binding, depending on the nature of the residue. These results suggest a range of activities for these ligands, contributing both enthalpic and entropic effects to the overall thermodynamics of binding. Together, our results demonstrate the importance of understanding relationships between structure and hydration in the construction of novel ligands and biological polymers.


Apical negative pressure irrigation versus syringe irrigation: a systematic review of cleaning and disinfection of the root canal system.
The aim of this study was to systematically review and critically analyse the published data on the treatment outcome (primary outcome) and on the cleaning and disinfection of root canals (secondary outcomes) achieved by negative pressure irrigation as compared to syringe irrigation. An electronic search was conducted in EMBASE, LILACS, PubMed, SciELO, Scopus and Web of Knowledge using both free-text keywords and controlled vocabulary. Additional studies were sought through hand searching of endodontic journals and of the relevant chapters of endodontic textbooks. No language restriction was imposed. The retrieved studies were screened by two reviewers according to predefined criteria. Included studies were critically appraised and the extracted data were arranged in tables. The electronic search and hand search retrieved 489 titles. One clinical study and 14 in vitro studies were finally included in the review; none of these studies assessed treatment outcome, four studies assessed the antimicrobial effect, seven studies evaluated the removal of pulp tissue remnants, and four studies investigated the removal of hard tissue debris or both hard tissue debris and pulp tissue remnants. Poor standardization and description of the protocols was evident. Inconclusive results were reported about the cleaning and disinfection accomplished by the two irrigation methods. Negative pressure irrigation was more effective under certain conditions when compared to suboptimal syringe irrigation; however, the variability of the protocols hindered quantitative synthesis. There is insufficient evidence to claim general superiority of any one of these methods. The level of the available evidence is low, and the conclusions should be interpreted with caution.


Evaluation of orally administered famciclovir in cats experimentally infected with feline herpesvirus type-1.
To evaluate orally administered famciclovir for treatment of cats with experimentally induced disease attributable to feline herpesvirus type-1 (FHV-1). 16 nonvaccinated specific-pathogen-free cats. Cats were treated orally with famciclovir (90 mg/kg; n = 10) or a similar volume of lactose (400 mg; 6) 3 times/d for 21 days. Cats were inoculated with FHV-1 and administered the first treatment dose on day 0. Disease score; weight; results of urinalysis, serum biochemical analysis, and CBC; histologic conjunctivitis score; herpetic DNA shedding; goblet cell density; anti-FHV-1 antibody concentration; and plasma penciclovir concentration were measured. On days 4 to 18 following inoculation, disease scores were lower in famciclovir-treated cats than in lactose-treated cats. Lactose-treated cats decreased in weight during the first 7 days after inoculation, but famciclovir-treated cats increased in weight throughout the study. Percentage change in weight was greater in famciclovir-treated cats on days 7 and 14 than in lactose-treated cats. Serum globulin concentration was lower on days 3 through 9, conjunctivitis histologic score was lower on day 14, herpetic DNA was shed less frequently throughout the study, goblet cell density was greater on day 21, and circulating anti-FHV-1 antibody concentration at study end was lower in famciclovir-treated cats, compared with these measurements in lactose-treated cats. Approximate peak plasma penciclovir concentration was 2.0 μg/mL. Famciclovir administration improved outcomes for systemic, ophthalmic, clinicopathologic, virologic, and histologic variables in cats experimentally infected with FHV-1. Adjunctive topical mucinomimetic and antimicrobial treatments may also be necessary.


Differential trafficking and timed localization of two chitin synthase proteins, Chs2p and Chs3p.
The deposition of the polysaccharide chitin in the Saccharomyces cerevisiae cell wall is temporally and spatially regulated. Chitin synthase III (Chs3p) synthesizes a ring of chitin at the onset of bud emergence, marking the base of the incipient bud. At the end of mitosis, chitin synthase II (Chs2p) deposits a disk of chitin in the mother-bud neck, forming the primary division septum. Using indirect immunofluorescence microscopy, we have found that these two integral membrane proteins localize to the mother-bud neck at distinct times during the cell cycle. Chs2p is found at the neck at the end of mitosis, whereas Chs3p localizes to a ring on the surface of cells about to undergo bud emergence and in the mother-bud neck of small-budded cells. Cell synchronization and pulse-chase experiments suggest that the timing of Chs2p localization results from cell cycle-specific synthesis coupled to rapid degradation. Chs2p degradation depends on the vacuolar protease encoded by PEP4, indicating that Chs2p is destroyed in the vacuole. Temperature-sensitive mutations that block either the late secretory pathway (sec1-1) or the internalization step of endocytosis (end4-1) also prevent Chs2p degradation. In contrast, Chs3p is synthesized constitutively and is metabolically stable, indicating that Chs2p and Chs3p are subject to different modes of regulation. Differential centrifugation experiments show that a significant proportion of Chs3p resides in an internal compartment that may correspond to a vesicular species called the chitosome (Leal-Morales, C.A., C.E. Bracker, and S. Bartnicki-Garcia. 1988, Proc. Natl. Acad. Sci. USA. 85:8516-8520; Flores Martinez, A., and J. Schwencke. 1988. Biochim. Biophys. Acta. 946:328-336). Fractionation of membranes prepared from mutants defective in internalization (end3-1 and end4-1) indicate that the Chs3p-containing vesicles are endocytically derived. Collectively, these data suggest that the trafficking of Chs2p and Chs3p diverges after endocytosis; Chs3p is not delivered to the vacuole, but instead may be recycled.


Effects of Monascus-fermented rice extract on malignant cell-associated neovascularization and intravasation determined using the chicken embryo chorioallantoic membrane model.
The traditional Chinese medicine, Hong-Qu, also called red mold rice in the United States and Europe, is used for treating blood stasis, a disorder related to hyperlipidemia and atherosclerosis. In addition to improving metabolic syndrome, extracts from Monascus-fermented rice inhibit the proliferation of various cancer cells in vitro and in vivo. The objective was to examine the effect of red mold rice ethanol extract (RMRE) on angiogenesis, invasion, and metastasis during tumor progression. RMRE significantly inhibited the proliferation of SW480 and SW620 human colorectal carcinoma cells in a dose- and time-dependent manner by using the MTT assay. A capillary-like network morphology was observed after the addition of 20 ng/mL vascular endothelial growth factor or SW620 culture-conditional medium, which was not seen after RMRE treatment. Moreover, spontaneous intravasation into Matrigel grafts of SW620 cells from the upper to the lower layers in the chick embryo chorioallantoic membrane (CAM) model was detected by the polymerase chain reaction (PCR) amplification of human Alu genomic DNA from the lower CAMs in the RMRE-untreated group. Neovascularization increased to 75.3% +/- 11.6% by SW620 cells onplant with Matrigel grafts in the CAM model. However, RMRE significantly reduced CAM neovascularization in a dose-dependent manner. Finally, RMRE effectively decreased the activity of matrix metalloproteinase (MMP)-7 as determined by reverse transcription PCR (RT-PCR), Western blotting, and casein zymography assays. In summary, Monascus-fermented products exert a potent effect on tumor growth and activation, suggesting that they may serve as supplementary agents in adjuvant cancer therapy.


The Smart-Insole Dataset: Gait Analysis Using Wearable Sensors with a Focus on Elderly and Parkinson's Patients.
Gait analysis is crucial for the detection and management of various neurological and musculoskeletal disorders. The identification of gait events is valuable for enhancing gait analysis, developing accurate monitoring systems, and evaluating treatments for pathological gait. The aim of this work is to introduce the Smart-Insole Dataset to be used for the development and evaluation of computational methods focusing on gait analysis. Towards this objective, temporal and spatial characteristics of gait have been estimated as the first insight of pathology. The Smart-Insole dataset includes data derived from pressure sensor insoles, while 29 participants (healthy adults, elderly, Parkinson's disease patients) performed two different sets of tests: The Walk Straight and Turn test, and a modified version of the Timed Up and Go test. A neurologist specialized in movement disorders evaluated the performance of the participants by rating four items of the MDS-Unified Parkinson's Disease Rating Scale. The annotation of the dataset was performed by a team of experienced computer scientists, manually and using a gait event detection algorithm. The results evidence the discrimination between the different groups, and the verification of established assumptions regarding gait characteristics of the elderly and patients suffering from Parkinson's disease.


Indirect C-H azidation of heterocycles via copper-catalyzed regioselective fragmentation of unsymmetrical λ3-iodanes.
A C-H bond of electron-rich heterocycles is transformed into a C-N bond in a reaction sequence comprising the formation of heteroaryl(phenyl)iodonium azides and their in situ regioselective fragmentation to heteroaryl azides. A Cu(I) catalyst ensures complete regiocontrol in the fragmentation step and catalyzes the subsequent 1,3-dipolar cycloaddition of the formed azido heterocycles with acetylenes. The heteroaryl azides can also be conveniently reduced to heteroarylamines by aqueous ammonium sulfide. The overall C-H to C-N transformation is a mild and operationally simple one-pot sequential multistep process.


Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins.
Cell adhesion molecules play a significant role in cancer progression and metastasis. Cell-cell interactions of cancer cells with endothelium determine the metastatic spread. In addition, direct tumor cell interactions with platelets, leukocytes, and soluble components significantly contribute to cancer cell adhesion, extravasation, and the establishment of metastatic lesions. Clinical evidence indicates that heparin, commonly used for treatment of thromboembolic events in cancer patients, is beneficial for their survival. Preclinical studies confirm that heparin possesses antimetastatic activities that lead to attenuation of metastasis in various animal models. Heparin contains several biological activities that may affect several steps in metastatic cascade. Here we focus on the role of cellular adhesion receptors in the metastatic cascade and discuss evidence for heparin as an inhibitor of cell adhesion. While P- and L-selectin facilitation of cellular contacts during hematogenous metastasis is being accepted as a potential target of heparin, here we propose that heparin may also interfere with integrin activity and thereby affect cancer progression. This review summarizes recent findings about potential mechanisms of tumor cell interactions in the vasculature and antimetastatic activities of heparin.


Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment.
Low-density lipoprotein (LDL) cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy. A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10,001 ("Treating to New Targets") and 8888 ("Incremental Decrease in End Points through Aggressive Lipid Lowering") patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol was lost. In a model that contained non-HDL cholesterol and apolipoprotein B, neither was significant owing to collinearity. Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters. In patients receiving statin therapy, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol. Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships. These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy. Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I, it seems premature to consider the ratio variables as clinically useful.


Individualized nutritional recommendations: do we have the measurements needed to assess risk and make dietary recommendations?
Is the information currently available to adjust nutritional recommendations and develop individualized nutrition? No. There is not even the information needed for setting dietary recommendations with confidence now at the group level. Will it be available soon? The answer to this question depends on the drive and will of the nutritional community, the success in recruiting funding to the area, the education of nutritionists and the spawning of great ideas and approaches. The emerging tools of genomics, proteomics and metabolomics are enabling the in-depth study of relationships between diet, genetics and metabolism. The advent of technologies can be compared with the discovery of the microscope and the new dimensions of scientific visualization enabled by that discovery. Nutritionists stand at the crest of new waves of data that can be generated, and new methods for their digestion will be required. To date, the study of dietary requirements has been based largely on a black box approach. Subjects are supplemented or depleted and clinical outcomes are observed. Few recommendations are based on metabolic outcomes. Metabolomics and nutrigenomics promise tools with which recommendations can be refined to meet individual requirements and the potential of individualized nutrition can be explored. As yet, these tools are not being widely applied in nutritional research and are rarely being applied by nutritionists. The result is often interesting research that is frequently nutritionally flawed, resulting in inappropriate conclusions. Nutritional education is needed to put nutritionists at the forefront of the development of applications for these technologies, creating a generation of nutrigenomicists. A new generation of nutritionists should be working interdisciplinarily with geneticists, molecular biologists and bioinformaticians in the development of research strategies. The present paper reviews the current status of nutrigenomic research, the current controversies and limitations, and developments needed to advance nutrigenomics and explore fully the promise of individualized nutritional recommendations.


A method to extract image noise level from patient images in CT.
Image quality in computed tomography (CT) is usually not quantified in real time from patient scans. Rather, phantom scans are employed to measure the contrast, noise, and spatial resolution properties of a given system. This approach, however, is not ideal because many factors are difficult to represent using phantoms like variations in patient size, composition, and position within the gantry. Several methods for measuring the noise found within patient scans have been proposed. All of these methods rely on segmenting out relatively uniform regions within the patient in order to differentiate between morphological variations and pixel differences due to photon noise. In order to avoid this segmentation step, we propose to analyze the noise signal in the air surrounding the patient. We will demonstrate that the air signal surrounding the patient acts as a surrogate for the noise within the contours of the patient. Our work builds off the global noise index (GNI) method. In the GNI method, adjacent axial CT image slices are subtracted to remove the majority of the morphological variations in the data. Remaining morphological variations are removed with an edge-finding algorithm. Then the image is divided up into small regions of interest (ROI) and the pixel standard deviation is computed for each ROI. Only those ROIs not containing bone or air are then used to make a histogram of the standard deviation within the image. The mode of this histogram is referred to as the GNI. We refer to this as the traditional GNI (tradGNI). Our modification to this workflow is to apply this metric to just the air signal surrounding the patient. We evaluate the correlation between using the air signal and the in-phantom metric value for titration over: dose level, image slice thickness, kernel sharpness, iterative reconstruction level, model based iterative reconstruction, reconstruction field of view, and reconstruction interval. 373 patient abdomen pelvis exams were collected and the air based noise estimation metrics applied. Liver standard deviation values were measured on 40 of the patients and correlated with air GNI calculations. Our results show excellent linear correlation (R2 > 0.99) between the tradGNI being applied inside and outside of a phantom object. Our results are also shown to still be predictive of the noise under all scan parameters studied, including iterative and model based reconstruction. Fits of tradGNI versus dose level exhibited the expected square root dependence. Air based GNI metrics were predictive of human patient noise level and also correlated with manual liver standard deviation measurement (R2 = 0.73). Our results demonstrate the signal in the air surrounding an imaging object can accurately be used as a surrogate for the image noise within the object. Our method should enable faster and more robust patient specific image quality assessment due to the lack of the need to segment noise from morphological variations within a patient.


Factors affecting quantitative analysis in laser desorption/laser ionization mass spectrometry.
Microprobe laser desorption/laser ionization mass spectrometry (microL(2)MS) is a sensitive and selective technique that has proven useful in the qualitative and semiquantitative detection of trace organic compounds, particularly polycyclic aromatic hydrocarbons (PAHs). Recent efforts have focused on developing microL(2)MS as a quantitative method, often by measuring the ratio of signal strength of an analyte to an internal standard. Here, we present evidence of factors that affect these ratios and thus create uncertainty and irreproducibility in quantification. The power and wavelength of the desorption laser, the delay time between the desorption and ionization steps, the power of the ionization laser, and the ionization laser alignment are all shown to change PAH ratios, in some cases by up to a factor of 24. Although changes in the desorption laser parameters and the delay time cause the largest effects, the ionization laser power and alignment are the most difficult parameters to control and thus provide the most practical limitations for quantitative microL(2)MS. Variation in ratios is seen in both synthetic poly(vinyl chloride) membranes and in "real-life" samples of Murchison meteorite powder. Ratios between similar PAHs vary less than those between PAHs that differ greatly in mass and structure. This finding indicates that multiple internal standards may be needed for quantification of samples containing diverse PAHs.


Examining rare and low-frequency genetic variants previously associated with lone or familial forms of atrial fibrillation in an electronic medical record system: a cautionary note.
Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and familial atrial fibrillation (AF) using linkage and segregation analysis, functional characterization, and rarity in public databases. Here, we used a cohort of 20 204 patients of European or African ancestry with electronic medical records and exome chip data to compare the frequency of AF among carriers and noncarriers of these rare variants. The exome chip included 19 of 115 rare variants, in 9 genes, previously associated with lone or familial AF. Using validated algorithms querying a combination of clinical notes, structured billing codes, ECG reports, and procedure codes, we identified 1056 AF cases (>18 years) and 19 148 non-AF controls (>50 years) with available genotype data on the Illumina HumanExome BeadChip v.1.0 in the Vanderbilt electronic medical record-linked DNA repository, BioVU. Known correlations between AF and common variants at 4q25 were replicated. None of the 19 variants previously associated with AF were over-represented among AF cases (P>0.1 for all), and the frequency of variant carriers among non-AF controls was >0.1% for 14 of 19. Repeat analyses using non-AF controls aged >60 (n=14 904), >70 (n=9670), and >80 (n=4729) years did not influence these findings. Rare variants previously implicated in lone or familial forms of AF present on the exome chip are detected at low frequencies in a general population but are not associated with AF. These findings emphasize the need for caution when ascribing variants as pathogenic or causative.


Genetic architecture of skewed X inactivation in the laboratory mouse.
X chromosome inactivation (XCI) is the mammalian mechanism of dosage compensation that balances X-linked gene expression between the sexes. Early during female development, each cell of the embryo proper independently inactivates one of its two parental X-chromosomes. In mice, the choice of which X chromosome is inactivated is affected by the genotype of a cis-acting locus, the X-chromosome controlling element (Xce). Xce has been localized to a 1.9 Mb interval within the X-inactivation center (Xic), yet its molecular identity and mechanism of action remain unknown. We combined genotype and sequence data for mouse stocks with detailed phenotyping of ten inbred strains and with the development of a statistical model that incorporates phenotyping data from multiple sources to disentangle sources of XCI phenotypic variance in natural female populations on X inactivation. We have reduced the Xce candidate 10-fold to a 176 kb region located approximately 500 kb proximal to Xist. We propose that structural variation in this interval explains the presence of multiple functional Xce alleles in the genus Mus. We have identified a new allele, Xce(e) present in Mus musculus and a possible sixth functional allele in Mus spicilegus. We have also confirmed a parent-of-origin effect on X inactivation choice and provide evidence that maternal inheritance magnifies the skewing associated with strong Xce alleles. Based on the phylogenetic analysis of 155 laboratory strains and wild mice we conclude that Xce(a) is either a derived allele that arose concurrently with the domestication of fancy mice but prior the derivation of most classical inbred strains or a rare allele in the wild. Furthermore, we have found that despite the presence of multiple haplotypes in the wild Mus musculus domesticus has only one functional Xce allele, Xce(b). Lastly, we conclude that each mouse taxa examined has a different functional Xce allele.


Systematic Medical Appraisal, Referral and Treatment (SMART) Mental Health Programme for providing innovative mental health care in rural communities in India.
India has few mental health professionals to treat the large number of people suffering from mental disorders. Rural areas are particularly disadvantaged due to lack of trained health workers. Ways to improve care could be by training village health workers in basic mental health care, and by using innovative methods of service delivery. The ongoing Systematic Medical Appraisal, Referral and Treatment Mental Health Programme will assess the acceptability, feasibility and preliminary effectiveness of a task-shifting mobile-based intervention using mixed methods, in rural Andhra Pradesh, India. The key components of the study are an anti-stigma campaign followed by a mobile-based mental health services intervention. The study will be done across two sites in rural areas, with intervention periods of 1 year and 3 months, respectively. The programme uses a mobile-based clinical decision support tool to be used by non-physician health workers and primary care physicians to screen, diagnose and manage individuals suffering from depression, suicidal risk and emotional stress. The key aim of the study will be to assess any changes in mental health services use among those screened positive following the intervention. A number of other outcomes will also be assessed using mixed methods, specifically focussed on reduction of stigma, increase in mental health awareness and other process indicators. This project addresses a number of objectives as outlined in the Mental Health Action Plan of World Health Organization and India's National Mental Health Programme and Policy. If successful, the next phase will involve design and conduct of a cluster randomised controlled trial.


EQUILIBRIA IN PRECIPITIN REACTIONS : THE COEXISTENCE OF A SINGLE FREE ANTIGEN AND ITS ANTIBODY IN THE SAME SERUM.
1. In these studies several phases of the predpitm reactions were investigated by the use of purified proteins as antigens. These preparations were edestin from hemp-seed and crystalline ovalbumin from fresh eggs. The ovalbumin, isolated by the method of Hopkins and Pinkus,.was apparently as pure as is obtainable by chemical means. This albumin, however, produced moderately severe anaphylactic reactions in animals sensitized with ovoglobulin. Anaphylactic tests of the individuality of a protein cannot be any longer regarded as the criterion of the purity of the substance as an antigen. Wells and Osborne have shown that proteins of considerable chemical difference may have a common antigenic group which causes mutual anaphylactic reactions in animals sensitized to these proteins. In particular, as egg globulin is a mixture of proteins, one of which is undoubtedly egg albumin, anaphylaxis produced by injections of albumin into animals sensitized to the so called globulin offers no evidence for or against the purity of the albumin. The character of the curves shown in Text-fig. 1 confirms the assumption, based upon chemical data, that crystalline egg albumin is a single protein. 2. With edestin and crystalline egg albumin as antigens phases in the precipitin reaction were found in which these substances and their specific precipitins could be demonstrated to be coexistent but ununited in the same serum. 3. When edestin or crystalline egg albumin is injected into a rabbit immunized thereto, the antigen may be found in the circulating blood during 48 hours after its injection, while at the same time the animal maintains a high titer of free precipitin in its blood. 4. When the pure protein antigen is mixed in proper proportions with the serum of a specifically immunized rabbit and the resulting precipitate removed by centrifugation, the supernatant fluid contains both antigen and antibody. 5. The serum drawn from a rabbit during the period in which free antigen and antibody are coexistent in the circulation undergoes slow spontaneous precipitation when kept in sterile tubes in the ice box. The curve of this reaction is reproduced as Text-fig. 1. The relationships of the parabola indicate that the interaction of antigen and antibody takes place according to a definite law. When sufficient quantitative data are obtained to allow an analysis of this curve, the formulas for this reaction will undoubtedly throw light upon the chemical or physical nature of the process. 6. The protective action of the solution of egg albumin as a third colloid preventing precipitation in a reaction between human serum and its antibody was readily demonstrated. This observation and the constancy of the long prozone in precipitin test with egg albumin are in accord with the protective action of ovalbumin upon colloidal gold.


Childhood cow's milk allergy and the risk of multiple sclerosis: a population based study.
Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis (MS) and vitamin D is hypothesised to contribute to disease susceptibility. Cow's milk allergy (CMA) is a common childhood allergy arising from an immune system imbalance and can also lead to vitamin D deficiency due to dairy food avoidance. Here, we investigated whether or not CMA influences the subsequent risk to develop MS in a population-based cohort. We identified 6638 MS index cases and 2509 spousal controls with CMA information from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Frequency of CMA was compared between index cases and controls. No significant differences were found. Childhood CMA thus does not appear to be a risk factor for MS.


History of the establishment of the Preterm Birth international collaborative (PREBIC).
The primary aim of PREBIC is to assess the underlying mechanisms and developing strategies for preterm birth (PTB) prevention. We used concept mapping and logic models to track goals. This paper reviews our progress over 13 years using working group activities, research developments, guest speakers, and publications. Using interactions between genetics, environment, and behaviors we identified complex interactions between biological systems. PREBIC determined that epidemiology and biomarkers should be an initial focus. In 2005, we initiated presentations by young investigators, yearly satellite meetings, working groups including nutrition and inflammation, assessment of clinical trials, and accepted an invitation by the WHO to begin yearly meetings in Geneva. PREBIC used epidemiology to identify PTB factors and complex pathways. Candidate genes are associated with the environment, behavior (stress), obesity, inflammation and insulin resistance. Epigenetic changes and production of proteins can be used as biomarkers to define risk. Subsequently, we found risk factors for PTB that were also associated with the risk of cardiovascular disease (CVD) of the mother. Tanz et al. (2017) found that a history of PTB is independently predictive of CVD later in life and suggested that a modest proportion of PTB-CVD association was accounted by CVD risk factors, many of which have been identified in this paper. Our findings support a relationship between genes, environment, behaviors and risk of CVD in women. The next several years must assess which factors are modifiable early in life and before pregnancy to prevent PTB.


Carbon pricing and planetary boundaries.
Human activities are threatening to push the Earth system beyond its planetary boundaries, risking catastrophic and irreversible global environmental change. Action is urgently needed, yet well-intentioned policies designed to reduce pressure on a single boundary can lead, through economic linkages, to aggravation of other pressures. In particular, the potential policy spillovers from an increase in the global carbon price onto other critical Earth system processes has received little attention to date. To this end, we explore the global environmental effects of pricing carbon, beyond its effect on carbon emissions. We find that the case for carbon pricing globally becomes even stronger in a multi-boundary world, since it can ameliorate many other planetary pressures. It does however exacerbate certain planetary pressures, largely by stimulating additional biofuel production. When carbon pricing is allied with a biofuel policy, however, it can alleviate all planetary pressures.


The ATPase domain of ISWI is an autonomous nucleosome remodeling machine.
ISWI slides nucleosomes along DNA, enabling the structural changes of chromatin required for the regulated use of eukaryotic genomes. Prominent mechanistic models imply cooperation of the ISWI ATPase domain with a C-terminal DNA-binding function residing in the HAND-SANT-SLIDE (HSS) domain. Contrary to these models, we show by quantitative biochemical means that all fundamental aspects of nucleosome remodeling are contained within the compact ATPase module of Drosophila ISWI. This domain can independently associate with DNA and nucleosomes, which in turn activate ATP turnover by inducing a conformational change in the enzyme, and it can autonomously reposition nucleosomes. The role of the HSS domain is to increase the affinity and specificity for nucleosomes. Nucleosome-remodeling enzymes may thus have evolved directly from ancestral helicase-type motors, and peripheral domains have furnished regulatory capabilities that bias the remodeling reaction toward different structural outcomes.


Methodological guide to adopting new aesthetic surgical innovations.
Aesthetic surgery is known for its prolific introduction of new techniques, devices, and products. The implementation of any aesthetic innovation, however, may inadvertently expose patients to potential complications and adverse events. How do we decide whether a new technique or technology is superior-in both safety and effectiveness-compared with prevailing interventions? In this paper, we present some basic steps anchored in evidence-based surgery that aesthetic surgeons need to pursue in the adoption of a new technique, technology, or product. These steps include: (1) gaining familiarity with and understanding the levels of evidence; (2) performing an effective literature search; (3) formulating a critical appraisal of an article; (4) making the decision to adopt or reject; (5) recognizing the need for continued assessment; (6) acknowledging the need for education and credentialing; and (7) translation of the gathered knowledge. We hope that this paper will foster critical thinking and reduce the reliance on "photographic evidence" in aesthetic surgery literature.


Rebuilding marine life.
Sustainable Development Goal 14 of the United Nations aims to "conserve and sustainably use the oceans, seas and marine resources for sustainable development". Achieving this goal will require rebuilding the marine life-support systems that deliver the many benefits that society receives from a healthy ocean. Here we document the recovery of marine populations, habitats and ecosystems following past conservation interventions. Recovery rates across studies suggest that substantial recovery of the abundance, structure and function of marine life could be achieved by 2050, if major pressures-including climate change-are mitigated. Rebuilding marine life represents a doable Grand Challenge for humanity, an ethical obligation and a smart economic objective to achieve a sustainable future.


Incidence of nonvertebral fractures in relation to time on treatment and bone density in glucocorticoid-treated patients: a retrospective approach.
The effects of duration of treatment and bone mineral density (BMD) on nonvertebral fracture in 560 glucocorticoid users were examined by using baseline and retrospective data from 2 parallel studies assessing the efficacy and safety of alendronate therapy. Baseline spine and hip BMD were significantly (P < 0.01) lower with increased time spent receiving glucocorticoids. Forty-three patients (7.7%) had experienced at least 1 nonvertebral fracture after starting glucocorticoid treatment. The hazard function for nonvertebral fracture occurrence increased significantly (P < 0.01) with time spent receiving glucocorticoids: fracture incidence per 1,000 person-years on glucocorticoids was 18 (< 5 years), 31 (5-10 years), and 35 (> 10 years). Patients with a history of nonvertebral fractures after starting glucocorticoid treatment had significantly lower lumbar spine (P < 0.01) and hip (< 0.01) BMD value than those without fractures. This retrospective analysis suggests that a BMD measurement of spine and hip may identify risk for nonvertebral fractures in a heterogeneous population of glucocorticoid users.


Society for Maternal-Fetal Medicine Special Statement: Surgical safety checklists for cesarean delivery.
The routine use of surgical safety checklists can reduce perioperative complications. Generic surgical safety checklists are insufficient for cesarean delivery because each cesarean delivery involves 2 patients (the mother and the fetus or newborn), each with separate care teams and health and safety considerations. To address the added complexity of care coordination and communication inherent in cesarean delivery, the Society for Maternal-Fetal Medicine presents sample standard surgical safety checklists for cesarean delivery that include elements of care for both the mother and newborn. In addition, we present an alternative checklist for time-critical emergency cesarean deliveries in which there is no time to safely perform the standard checklist and a sample preoperative checklist for use before moving the patient to the operating room. We also recommend steps for implementation of the checklists at individual facilities.


Targeting thyroid diseases with TSH receptor analogs.
The thyroid-stimulating hormone (TSH) receptor (TSHR) is a major regulator of thyroid function and growth, and is the key antigen in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Various effective treatment strategies are currently available for many of these clinical conditions such as antithyroid drugs or radioiodine therapy, but they are not devoid of side effects. In addition, treatment of complications of Graves' disease such as Graves' ophthalmopathy is often difficult and unsatisfactory using current methods. Recent advances in basic research on both in vitro and in vivo models have suggested that TSH analogs could be used for diagnosis and treatment of some of the thyroid diseases. The advent of high-throughput screening methods has resulted in a group of TSH analogs called small molecules, which have the potential to be developed as promising drugs. Small molecules are low molecular weight compounds with agonist, antagonist and, in some cases, inverse agonist activity on TSHR. This short review will focus on current advances in development of TSH analogs and their potential clinical applications. Rapid advances in this field may lead to the conduct of clinical trials of small molecules related to TSHR for the management of Graves' disease, thyroid cancer, and thyroid-related osteoporosis in the coming years.


Novelty detection using level set methods.
This paper presents a level set boundary description (LSBD) approach for novelty detection that treats the nonlinear boundary directly in the input space. The proposed approach consists of level set function (LSF) construction, boundary evolution, and termination of the training process. It employs kernel density estimation to construct the LSF of the initial boundary for the training data set. Then, a sign of the LSF-based algorithm is proposed to evolve the boundary and make it fit more tightly in the data distribution. The training process terminates when an expected fraction of rejected normal data is reached. The evolution process utilizes the signs of the LSF values at all training data points to decide whether to expand or shrink the boundary. Extensive experiments are conducted on benchmark data sets to evaluate the proposed LSBD method and compare it against four representative novelty detection methods. The experimental results demonstrate that the novelty detector modeled with the proposed LSBD can effectively detect anomalies.


Identification and referral of patients with progressive CKD: a national study.
It is unclear whether primary care physicians (PCPs) and nephrologists differ in their recognition of progressive chronic kidney disease (CKD), agree on diagnostic and referral strategies, and identify similar barriers to caring for patients. We conducted a national study of PCPs and nephrologists in the United States through a questionnaire describing a PCP caring for a patient with progressing CKD and questions to assess recognition of kidney dysfunction and approaches to diagnostic evaluation and referral. We identified participant and patient characteristics independently associated with CKD recognition and referral. We randomly identified a national sample of 304 physicians (126 nephrologists [39% response rate], 89 family physicians [28% response rate], and 89 general internists [28% response rate]). PCPs recognized CKD less (adjusted percentage, 59%; 95% confidence interval [CI], 47 to 69, family physicians; adjusted percentage, 78%; 95% CI, 67 to 86, general internists; adjusted percentage, 97%; 95% CI, 93 to 99, nephrologists; P < 0.01), differed from nephrologists in their recommendations for diagnostic testing, and recommended referral less (adjusted percentage, 76%; 95% CI, 65 to 84, family physicians; adjusted percentage, 81%; 95% CI, 70 to 89, general internists; adjusted percentage, 99%; 95% CI, 95 to 100, nephrologists; P < 0.01). PCPs differed from nephrologists in their expected intensity of specialists' involvement in care (16%, family physicians; 20%, general internists; 6%, nephrologists recommending nephrologist input monthly to every 6 months; P = 0.01). Lack of awareness of clinical practice guidelines and lack of clinical and administrative resources were identified as important barriers to care. PCPs recognize and recommend specialist care for progressive CKD less than nephrologists and differ in their clinical evaluations and expectations for referral. Improved dissemination of existing guidelines and targeted education in conjunction with efforts to build consensus among PCPs and nephrologists regarding their roles in the care of patients with CKD, including the collaborative development of clinical practice guidelines, could enhance patient care.


Orientation and disorientation: lessons from patients with epilepsy.
Orientation in time, space, and person is a fundamental cognitive faculty and the bedrock of neurological and psychiatric mental status examination. Nevertheless, research in orientation and disorientation is neglected in both cognitive science and neuropsychiatry. Specifically, it is still unclear whether disorientations in time, space, and person represent a failure of the same system or merely share a common nomenclature and whether these three domains of orientation depend on different psychological and neural systems. Here, we analyzed descriptions of patients with specific orientation failures associated with circumscribed cortical lesions, with a primary focus on epilepsy. The form of disorientation is analyzed according to its specific domain, the underlying neuropsychiatric disorder, and its anatomical correlate. Disorientations in the different domains are classified as self-referenced (incorrect self-localization) or nonself-referenced (incorrect localization or knowledge of other places, events, and people). Analysis of the cognitive and neural systems disturbed in these patients suggests that disorientation in one or several domains may be related to a failure in a specific brain mechanism localized mostly in the right hemisphere, partially overlapping with the default mode network (mostly the medial and lateral parietal, medial temporal, and lateral prefrontal cortices), which processes essential self-related cognitive faculties such as orientation.


Haemocytes collected from experimentally infected Pacific oysters, Crassostrea gigas: Detection of ostreid herpesvirus 1 DNA, RNA, and proteins in relation with inhibition of apoptosis.
Recent transcriptomic approaches focused on anti-viral immunity in molluscs lead to the assumption that the innate immune system, such as apoptosis, plays a crucial role against ostreid herpesvirus type 1 (OsHV-1), infecting Pacific cupped oyster, Crassostrea gigas. Apoptosis constitutes a major mechanism of anti-viral response by limiting viral spread and eliminating infected cells. In this way, an OsHV-1 challenge was performed and oysters were monitored at three times post injection to investigate viral infection and host response: 2h (early after viral injection in the adductor muscle), 24h (intermediate time), and 48h (just before first oyster mortality record). Virus infection, associated with high cumulative mortality rates (74% and 100%), was demonstrated in haemocytes by combining several detection techniques such as real-time PCR, real-time RT PCR, immunofluorescence assay, and transmission electron microscopy examination. High viral DNA amounts ranged from 5.46×104 to 3.68×105 DNA copies ng-1 of total DNA, were detected in dead oysters and an increase of viral transcripts was observed from 2, 24, and 48hpi for the five targeted OsHV-1 genes encoding three putative membrane proteins (ORFs 25, 41, and 72), a putative dUTPase (ORF 75), and a putative apoptosis inhibitor (ORF 87). Apoptosis was studied at molecular and cellular levels with an early marker (phosphatidyl-serine externalisation measured by flow cytometry and epifluorescence microscopy) and a later parameter (DNA fragmentation by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay (TUNEL)). The down-regulation of genes encoding proteins involved in the activation of the apoptotic pathway (TNF and caspase 3) and the up-regulation of genes encoding anti-apoptotic proteins (IAP-2, and Bcl-2) suggested an important anti-apoptosis phenomenon in haemocytes from OsHV-1 infected oysters at 24 and 48hpi. Additionally, more phosphatidyl-serines were externalized and more cells with DNA fragmentation were observed in haemocytes collected from artificial seawater injected oysters than in haemocytes collected from OsHV-1 infected oysters at 24 and 48hpi, suggesting an inhibition of the apoptotic process in presence of the virus. In conclusion, this study is the first to focus on C. gigas haemocytes, cells involved in the host immune defense, during an OsHV-1 challenge in controlled conditions by combining various and original approaches to investigate apoptosis at molecular and cellular levels.


What do parents perceive are the barriers and facilitators to accessing psychological treatment for mental health problems in children and adolescents? A systematic review of qualitative and quantitative studies.
A minority of children and adolescents with mental health problems access treatment. The reasons for poor rates of treatment access are not well understood. As parents are a key gatekeeper to treatment access, it is important to establish parents' views of barriers/facilitators to accessing treatment. The aims of this study are to synthesise findings from qualitative and quantitative studies that report parents' perceptions of barriers/facilitators to accessing treatment for mental health problems in children/adolescents. A systematic review and narrative synthesis were conducted. Forty-four studies were included in the review and were assessed in detail. Parental perceived barriers/facilitators relating to (1) systemic/structural issues; (2) views and attitudes towards services and treatment; (3) knowledge and understanding of mental health problems and the help-seeking process; and (4) family circumstances were identified. Findings highlight avenues for improving access to child mental health services, including increased provision that is free to service users and flexible to their needs, with opportunities to develop trusting, supportive relationships with professionals. Furthermore, interventions are required to improve parents' identification of mental health problems, reduce stigma for parents, and increase awareness of how to access services.


Azobenzene-based ruthenium(ii) catalysts for light-controlled hydrogen generation.
Eight new ruthenium(ii) half-sandwich complexes containing azobenzene-appended pyridine (1), bipyridine (2-5) and phosphine (6 and 7) ligands have been synthesized and fully characterized. UV-vis spectroscopic studies showed that the trans-to-cis photoisomerization was strongly inhibited upon coordination to the metal centre in azopyridine-derived ligands 1 and 2, but it remained efficient in azobenzene-appended bipyridine (3-5) and phosphine (6 and 7) ligands. The complexes were tested as precatalysts for photo-controlled hydrogen generation by hydrolytic decomposition of ammonia-borane (AB). In situ irradiation of the reaction mixtures of compounds [Ru(p-Cym)(6)Cl]Cl and [Ru(p-Cym)(7)Cl]Cl induced a clear change in the catalytic reaction rate, serving as a proof of concept for light-controlled hydrogen generation.


Fine-scale genetic correlates to condition and migration in a wild cervid.
The relationship between genetic variation and phenotypic traits is fundamental to the study and management of natural populations. Such relationships often are investigated by assessing correlations between phenotypic traits and heterozygosity or genetic differentiation. Using an extensive data set compiled from free-ranging mule deer (Odocoileus hemionus), we combined genetic and ecological data to (i) examine correlations between genetic differentiation and migration timing, (ii) screen for mitochondrial haplotypes associated with migration timing, and (iii) test whether nuclear heterozygosity was associated with condition. Migration was related to genetic differentiation (more closely related individuals migrated closer in time) and mitochondrial haplogroup. Body fat was related to heterozygosity at two nuclear loci (with antagonistic patterns), one of which is situated near a known fat metabolism gene in mammals. Despite being focused on a widespread panmictic species, these findings revealed a link between genetic variation and important phenotypes at a fine scale. We hypothesize that these correlations are either the result of mixing refugial lineages or differential mitochondrial haplotypes influencing energetics. The maintenance of phenotypic diversity will be critical to enable the potential tracking of changing climatic conditions, and these correlates highlight the need to consider evolutionary mechanisms in management, even in widely distributed panmictic species.


Telling the patient's story: using theatre training to improve case presentation skills.
A medical student's ability to present a case history is a critical skill that is difficult to teach. Case histories presented without theatrical engagement may fail to catch the attention of their intended recipients. More engaging presentations incorporate 'stage presence', eye contact, vocal inflection, interesting detail and succinct, well organised performances. They convey stories effectively without wasting time. To address the didactic challenge for instructing future doctors in how to 'act', the Mayo Medical School and The Mayo Clinic Center for Humanities in Medicine partnered with the Guthrie Theater to pilot the programme 'Telling the Patient's Story'. Guthrie teaching artists taught storytelling skills to medical students through improvisation, writing, movement and acting exercises. Mayo Clinic doctors participated and provided students with feedback on presentations and stories from their own experiences in patient care. The course's primary objective was to build students' confidence and expertise in storytelling. These skills were then applied to presenting cases and communicating with patients in a fresher, more engaging way. This paper outlines the instructional activities as aligned with course objectives. Progress was tracked by comparing pre-course and post-course surveys from the seven participating students. All agreed that the theatrical techniques were effective teaching methods. Moreover, this project can serve as an innovative model for how arts and humanities professionals can be incorporated for teaching and professional development initiatives at all levels of medical education.


A Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways.
Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity.


Metabolic syndrome and psychiatrists' choice of follow-up interventions in patients treated with atypical antipsychotics in Denmark and Sweden.
The aim of the present study was to obtain point prevalence estimates of the metabolic syndrome according to the NCEP III criteria in a sample of patients with schizophrenia spectrum disorders treated with atypical antipsychotic drugs in Denmark and Sweden, and to assess the psychiatrists' choice of recommendations for follow-up interventions based on the patients' laboratory results. This was a cross-sectional, observational multi-center study in Denmark and Sweden, in consecutively screened in- and outpatients with schizophrenia spectrum disorders and continuously treated for at least 3 months with atypical antipsychotic drugs. The metabolic syndrome as per medical history was present in 1% of 582 evaluable patients at baseline. After performing laboratory measurements and applying the NCEP III criteria, metabolic syndrome was confirmed in 43% of subjects. The high rate of metabolic syndrome did not elicit much decisive action on the part of the treating psychiatrists; the most frequent action taken was dietary and exercise advice (in 75% of subjects), while in 54% and 19% of subjects a laboratory follow-up and blood pressure follow-up were advised respectively. Change of antipsychotic medication was recommended in only 10% of patients, and in further 11% of patients, no action was taken. Observed metabolic syndrome prevalence rates were at least twice the rates observed in a normal, non-diabetic population. It appears that in this vulnerable population of patients with schizophrenia spectrum disorders, metabolic syndrome remains underdiagnosed and undertreated.


Regulating the Golgi apparatus by co-delivery of a COX-2 inhibitor and Brefeldin A for suppression of tumor metastasis.
Finding a cure for breast cancer currently remains a medical challenge in due to the failure of common treatment methods to inhibit invasion and metastasis of cancer cells, which eventually leads to recurrence of breast cancer. Many secreted proteins are overexpressed and play crucial roles in tumorigenesis and development. The Golgi apparatus is a key protein processing and secretion factory in which metastasis-associated proteins are modified, transported and secreted; thus, regulating the Golgi apparatus of tumor cells is a viable strategy to inhibit tumor metastasis. Herein, celecoxib (CLX) and Brefeldin A (BFA) were encapsulated into the biocompatible polymer PLGA-PEG to form nanoparticles that act on the Golgi apparatus to treat metastatic breast cancer; CLX is a specific COX-2 inhibitor which accumulates in the Golgi apparatus, and BFA is a protein transport inhibitor fusing the Golgi apparatus into endoplasmic reticulum. The optimized CLX and BFA co-loaded nanoparticles (CBNPs) possessed good physicochemical properties. CBNPs efficiently damaged the Golgi apparatus within 30 min and showed enhanced cytotoxicity of CLX and BFA toward murine metastatic breast cancer 4T1 cells. The migration and invasion abilities of the cells were dramatically suppressed by the CBNPs. Further, the expression and secretion of metastasis-associated proteins such as matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) were remarkably decreased. Our findings showed that co-delivering CLX and BFA to regulate the Golgi apparatus may be an efficient strategy to inhibit breast cancer growth and suppress tumor cell metastasis.


Altered expression of cell cycle and apoptotic proteins in chronic hepatitis C virus infection.
A disrupted cell cycle progression of hepatocytes was reported in chronic hepatitis C virus (HCV) infection, which can contribute significantly in the associated pathogenesis. The present study aimed to further elaborate these disruptions by evaluating the expression of key cell cycle and apoptotic proteins in chronic HCV infection with particular reference to genotype 3. Archival liver biopsy specimens of chronic HCV-infection (n = 46) and normal histology (n = 5) were analyzed by immunohistochemistry using antibodies against proliferation marker Mcm-2, G1 phase marker Cyclin D1, S phase marker Cyclin A, cell cycle regulators p21 (CDK inhibitor) and p53 (tumor suppressor protein), apoptotic protein Caspase-3 and anti-apoptotic protein Bcl-2. Elevated Mcm-2 expression was observed in hepatocytes in chronic HCV infection, indicating increased cell cycle entry. Cyclin D1 expression was higher than cyclin A, which suggests a slow progression through the G1 phase. Expression of cell cycle regulators p21 and p53 was elevated, with no concordance between their expressions. The Mcm-2 and p21 expressions were associated with the fibrosis stage (p = 0.0001 and 0.001 respectively) and that of p53 with the inflammation grade (p = 0.051). Apoptotic marker, Caspase-3, was mostly confined to sinusoidal lining cells with little expression in hepatocytes. Anti-apoptotic protein, Bcl-2, was negligible in hepatocytes and detected principally in infiltrating lymphocytes. Expression of all these proteins was unrelated to the HCV genotype and were detected only rarely in the hepatocytes of normal liver. The results showed an arrested cell cycle state in the hepatocytes of chronic HCV infection, regardless of any association with genotype 3. Cell cycle arrest is characterized by an increased expression of p21, in relation to fibrosis, and of p53 in relation to inflammation. Furthermore, expression of p21 was independent of the p53 expression and coincided with the reduced expression of apoptotic protein Caspase-3 in hepatocytes. The altered expression of these cell cycle proteins in hepatocytes is suggestive of an impaired cell cycle progression that could limit the regenerative response of the liver to ongoing injury, leading to the progression of disease.


Nodular pseudoangiomatous stromal hyperplasia of mammary stroma in a case showing rapid tumor growth.
Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon benign breast disease that presents as a localized breast mass. Breast tissue affected by PASH is characterized by a dense, collagenous proliferation of mammary stroma, forming interanastomosing capillary-like spaces. The importance of this benign lesion lies in distinguishing it from low grade angiosarcoma. We report a case of a 38-year-old woman who presented with a rapidly growing breast tumor. She visited our hospital with a complaint of a painless right breast mass. Physical examination revealed a 3.6 x 2.2 cm, oval, elastic-firm, well-defined and easily movable mass. Mammograms revealed no discrete mass or calcifications. Sonographic examination revealed a 3.5 x 2.5 x 2.2 cm, oval, well-defined and homogenous hypoechoic mass without a cyst. A fine-needle aspiration sample of the breast mass showed some clusters of epithelial cells with small papillary structures and many scattered stromal cells with naked nuclei. Based on these findings, a provisional diagnosis of fibroadenoma was made and the patient was followed up. One year after the first visit, the mass enlarged rapidly and a follow-up mammogram revealed an 8.2 x 5.5 cm circumscribed mass without calcifications. Given the history of rapid growth of the mass, tumor excision was performed. The excised tumor was well demarcated and had a smooth external surface. Histologic examination revealed normal breast ducts and lobules, and specific proliferative epithelial changes were not seen. The lobular and duct structure of the breast parenchyma were separated by an increased amount of stroma. The fibrous stroma contained numerous anastomosing slit-like spaces. Isolated spindle cells appeared intermittently at the margins of the spaces resembled endothelial cells. Immunohistochemical staining showed that endothelial cells lining true blood vessels were positive for Factor VIII-related antigen, but the spindle cells were negative for Factor VIII. Pseudoangiomatous stromal hyperplasia was diagnosed.