Palliative and end-of-life care in prisons: a content analysis of the literature.
The growing numbers of terminally ill and dying in prison has high economic and moral costs as global correctional systems and the society at large. However, to date little is known about the extent to which palliative and end-of-life care is infused within global prison health care systems. The purpose of this paper is to fill a gap in the literature by reviewing and critically appraising the methods and major findings of the international peer-reviewed literature on palliative and end-of-life care in prison, identify the common elements of promising palliative and end-of-life services in prison, and what factors facilitate or create barrier to implementation. A content analysis was conducted of the existing peer-reviewed literature on palliative and end-of-life care in prison. English-language articles were located through a comprehensive search of peer-reviewed journals, such as Academic Search Premier Literature databases using differing combinations of key word search terms, "prison," "palliative care," and "end-of-life care." A total of 49 studies published between 1991 and 2013 met criteria for sample inclusion. Deductive and inductive analysis techniques were used to generate frequency counts and common themes related to the methods and major findings. The majority (n=39) of studies were published between 2001-2013 in the USA (n=40) and the UK (n=7). Most were about US prison hospice programs (n=16) or barriers to providing palliative and end of life care in prisons (n=10). The results of the inductive analysis identified common elements of promising practices, which included the use of peer volunteers, multi-disciplinary teams, staff training, and partnerships with community hospices. Obstacles identified for infusing palliative and end-of-life care in prison included ethical dilemmas based on custody vs care, mistrust between staff and prisoners, safety concerns, concern over prisoners' potential misuse of pain medication, and institutional, staff, and public apathy toward terminally ill prisoners and their human rights to health in the form of compassionate and palliative care, including the use of compassionate release laws. Implications for future research that foster human rights and public awareness of the economic and moral costs of housing the sick and dying in prisons. More research is needed to document human rights violations as well as best practices and evidence-based practices in palliative and end-of-life care in prisons. Future studies should incorporate data from the terminally ill in prison, peer supports, and family members. Future studies also should employ more rigorous research designs to evaluate human rights violations, staff and public attitudes, laws and policies, and best practices. Quantitative studies that use experimental designs, longitudinal data, and multiple informants are needed. Qualitative data would allow for thick descriptions of key stakeholders experiences, especially of the facilitators and barriers for implementing policy reform efforts and palliative care in prisons. Practical implications - This review provides a foundation on which to build on about what is known thus far about the human right to health, especially parole policy reform and infusing palliative and end-of-life care for the terminally ill and dying in prisons. This information can be used to develop or improve a new generation research, practice, policy, and advocacy efforts for that target terminally ill and dying in prison and their families and communities. There are significant social implications to this review. From a human rights perspective, the right to freedom from torture and cruel and unusual punishment is a fundamental human right along with prisoners' rights for an appropriate level of health care. These rights should be guaranteed regardless of the nature of their crime or whether they are in a prison placement. The information provided in this review can be used to educate and possible transform individual's and society's views toward the terminally ill and dying who are involved in the criminal justice system. This paper extends the extant literature by using both quantitative and qualitative analysis methods to organize, summarize, and critically analyze the international literature on palliative care and end of life care in prison. This review is designed to increase awareness among the international community of the pain and suffering of the terminally ill in prison and the facilitators and barriers to providing them compassionate care while in custody.


Cannabis Use Is an Independent Predictor for Acute Myocardial Infarction Related Hospitalization in Younger Population.
This study aimed to evaluate the risk of various substances in young acute myocardial infarction (AMI) inpatients and analyze patient demographics and hospital outcomes for significant substance use risk factors. We conducted a retrospective analysis of the Nationwide Inpatient Sample data (2010-2014). Patients (aged 15-22 years) with a primary diagnosis for AMI (N = 1,694) were compared with non-AMI (N = 9,465,255) inpatients for odds ratio (OR) of substance use by logistic regression model, adjusted for demographics, medical risk factors, and comorbid substance use. Tobacco (28.4%) and cannabis (14.9%) use were most prevalent in AMI inpatients. Cocaine (OR = 3.9), amphetamine (OR = 2.3), and cannabis (OR = 1.3) users were at higher risk of AMI hospitalizations. Higher proportion of cannabis users (14.7%) had major severity of illness at admission and higher mean total charge ($53,608) compared with that seen in cocaine and amphetamine users. Angioplasty was used more in cannabis users (19.4%) than others. The in-hospital mortalities were 2.7% and 2% in overall AMI cohort and cannabis users, respectively, and none in cocaine and amphetamine users. Our study demonstrates a higher prevalence and significant odds of AMI inpatients with cannabis use, along with the potential cost burdens because of severe morbidity and higher use of treatment modalities. Physicians need to familiarize themselves with rising use of cannabis and other substances in adolescent and younger population and the typical presentations of cannabis-induced myocardial infarction.


Cortical bone cyst following a greenstick radial fracture.
There are only a few reports of well defined cystic lesions of the peripheral skeleton following fracture. In children, these lesions are mostly small cortical defects affecting the distal radial metaphysis after a greenstick or torus fracture. A cyst is reported complicating a greenstick fracture, together with a brief review of published reports confirming that these are asymptomatic lesions which can be managed conservatively without further investigation.


Transplantation of benthic species to mitigate impacts of coastal development in Jamaica.
Maintaining regional competitiveness and economic viability for Port Bustamante - Kingston Harbour, Jamaica, required improved accessibility to "Post Panamax" (too large to pass through the Panama Canal) container vessels. Removal of the northern portion of the shallow coral reef at Rackham's Cay, which was partially obstructing the western end of the east ship channel, was proposed. This aesthetically valuable reef was used by local fishermen and comprises part of the declared Palisadoes - Port Royal Protected Area. The proposal to transplant certain of the benthic species was advanced to mitigate loss of viable reef components. Between December 2001 and February 2002, sixty thousand items, consisting of reef building massive and branching corals; gorgonians; urchins (Diadema and Tripneustes spp.) and Thalassia meristems were relocated. During dredging, sedimentation rates from suspended solids in the water column were 0.003 g/cm(2)/day at the control site and 0.008 g/cm(2)/day at the dredge site. Coral cover in the relocation area increased from 15% to 20% while bare substrate decreased from 27% to 21%. This paper documents the mitigation required; some factors controlling the ecology of Rackham's Cay reef, the methodology of the relocation process; and the level of post-dredging survivorship of relocated corals. Political and economic realities of some proposed developments often override ecological considerations. Transplantation of important marine benthic species although time consuming, technically challenging, and expensive, may be one way for developers and ecologists to achieve sometimes disparate goals. This project cost US$1.7 million. The "items" moved were neither unique nor endemic and remain vulnerable to natural and anthropogenic impacts. This project increased public awareness and interest regarding the ecological and economic importance of reef ecosystems. It is anticipated that future coastal and inland developments will benefit from the lessons taught by these mitigative interventions.


Living Donor Liver Re-Transplantation for Recurrent Hepatoblastoma in the Liver Graft following Complete Eradication of Peritoneal Metastases under Indocyanine Green Fluorescence Imaging.
The curability of chemotherapy-resistant hepatoblastoma (HB) largely depends on the achievement of radical surgical resection. Navigation techniques utilizing indocyanine green (ICG) are a powerful tool for detecting small metastatic lesions. We herein report a patient who underwent a second living donor liver transplantation (LDLTx) for multiple recurrent HBs in the liver graft following metastasectomy for peritoneal dissemination with ICG navigation. The patient initially presented with ruptured HB at 6 years of age and underwent 3 liver resections followed by the first LDLTx with multiple sessions of chemotherapy at 11 years of age. His alpha-fetoprotein (AFP) level increased above the normal limit, and metastases were noted in the transplanted liver and peritoneum four years after the first LDLTx. The patient underwent metastasectomy of the peritoneally disseminated HBs with ICG navigation followed by the second LDLTx for multiple metastases in the transplanted liver. The patient has been recurrence-free with a normal AFP for 30 months since the second LDLTx. To our knowledge, this report is the first successful case of re-LDLTx for recurrent HBs. Re-LDLTx for recurrent HB can be performed in highly select patients, and ICG navigation is a powerful surgical tool for achieving tumor clearance.


Structure and organization of the human thrombospondin 3 gene (THBS3).
The promoter/5' flank sequence, cDNA sequence, and exon/intron structures of the human thrombospondin 3 (THBS3) gene have been determined. THBS3 cDNA clones were obtained by PCR amplification of human fetal lung cDNA using THBS3-specific primers. Analysis of cDNA and genomic sequences showed the THBS3 gene to be composed of 23 exons, 1 more than the number of exons in the previously characterized mouse TSP3 gene. The additional exon results from the division of mouse exon F into exons F1 and F2. The cDNA encodes a polypeptide of 956 amino acids that is highly acidic, with a clustering of acidic side chains in the third quarter of the polypeptide. This region corresponds to seven type III (Ca(2+)-binding) repeats, a feature shared with other thrombospondins. In addition to these type III repeats, four type II (EGF-like) repeats and NH2- and COOH-terminal domains are present in thrombospondin 3. The THBS3 and mouse TSP3 genes differ in intron sizes, but exon sequences and sizes and positions of insertion of introns are conserved to a high degree. The structural organization of the THBS3 gene is of interest because of its close proximity to that of metaxin, with which it shares a common promoter sequence, and to the gene encoding glucocerebrosidase, a deficiency in which causes Gaucher disease.


On accurate simulations of thin-film solar cells with a thick glass superstrate.
The optical response of periodically nanotextured layer stacks with dimensions comparable to the wavelength of the incident light can be computed with rigorous Maxwell solvers, such as the finite element method (FEM). Experimentally, such layer stacks are often prepared on glass superstrates with a thickness, which is orders of magnitude larger than the wavelength. For many applications, light in these thick superstrates can be treated incoherently. The front side of thick superstrate is located far away from the computational domain of the Maxwell solvers. Nonetheless, it has to be considered in order to achieve accurate results. In this contribution, we discuss how solutions of rigorous Maxwell solvers can be corrected for flat front sides of the superstrates with an incoherent a posteriori approach. We test these corrections for hexagonal sinusoidal nanotextured silica-silicon interfaces, which are applied in certain silicon thin-film solar cells. These corrections are determined via a scattering matrix, which contains the full scattering information of the periodically nanotextured structure. A comparison with experimental data reveals that higher-order corrections can predict the measured reflectivity of the samples much better than an often-applied zeroth-order correction.


Neonatal short bowel syndrome as a model of intestinal failure: physiological background for enteral feeding.
Intestinal failure (IF) is a well identified clinical condition, which is characterised by the reduction of functional gut capacity below the minimum needed for adequate digestion and absorption of nutrients for normal growth in children. Short bowel syndrome (SBS) is the leading cause of IF in neonates, infants and young children usually as a result of extensive intestinal resection during the neonatal period. Simultaneously maintaining optimal nutritional status and achieving intestinal adaptation is a clinical challenge in short bowel patients. Both growth and development of the child as well as gut adaptation should be considered synergistically as primary outcome parameters. Enteral nutrition (EN) can be introduced orally and/or by tube feeding (TF). Several controversies over nutritional treatment of children with SBS related intestinal failure remain. As reported from different centres around the world, most practices are more "experienced based" rather than "evidence based". This is partly due to the small number of patients with this condition. This review (based on a consensus) discusses the physiological principles and nutritional management, including the type of diet and route of delivery. Perspectives in optimizing intestinal adaptation and reducing the consequences of small intestinal bacterial overgrowth are also discussed.


Efficacy of co-administration of albendazole and diethylcarbamazine against geohelminthiases: a study from South India.
The efficacy of single-dose combination drug therapy with diethylcarbamazine (DEC) plus albendazole (ALB), and single-drug therapy with DEC alone against geohelminths was compared as part of a mass drug administration (MDA) for elimination of filariasis. This study was conducted in two blocks of Villupuram District of Tamil Nadu State, India, covering a population of 321 000 including about 100 000 children 1-15 years of age. Prevalence and intensity of geohelminth infection were determined by the Kato-Katz technique immediately before and 3 weeks after the MDA. A pre-treatment cross-sectional survey was undertaken in 18 statistically selected villages out of 204 villages, including 646 school children. About 60% were infected with one or more geohelminths. The overall prevalence rates were 53.9%, 12.4% and 5.7% for Ascaris lumbricoides, hookworms and Trichuris trichiura, respectively. Combination therapy (DEC + ALB) produced a cure rate of 74.3% and an egg reduction rate of 97.3% for geohelminths, which were higher than the corresponding rates (30.4% and 79.0%) observed in the single drug therapy arm with DEC alone. The odds of cure with combination therapy were significantly higher for roundworm (5.3 times) and hookworms (3.5 times), then odds of cure with DEC alone. Both therapies were equally effective against trichuriasis, recording cure rates >77% and egg reduction rates >83%. In combination therapy, 53.5% of the children noticed expulsion of worms after MDA, while in single drug therapy only 20.9% did. Our study indicated that MDA of combination therapy was operationally feasible at the community level, and it may secure higher community compliance because of its perceived benefits and enhanced efficacy against geohelminths than single-drug therapy.


Platelet ultrastructure and secretion in acute ischemic stroke.
We used transmission electron microscopy to count the organelles (dense bodies, alpha granules, and mitochondria) contained within platelets from 11 acute ischemic stroke patients and 12 healthy controls. We randomly selected for evaluation 25 platelet profiles in ultrathin sections cut from three separate blocks. Compared with those from controls, platelets from stroke patients contained significantly fewer alpha granules (p less than 0.001) and mitochondria (p less than 0.02) and showed a trend toward fewer dense bodies. Supportive of our previous studies, the amount of adenosine triphosphate secreted following stimulation by collagen also tended to be greater in platelets from stroke patients. These observations support the presence of increased platelet secretion associated with acute cerebral infarction and raise the possibility that platelet secretion may be of separate importance to the mechanical occlusion of blood vessels by platelet aggregates in the pathogenesis of cerebral infarction.


An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quantified by comparative analysis centered on the clinical candidate F14512.
Combined computational-experimental analyses explain and quantify the spermine-vectorized F14512's boosted potency as a topoII poison. We found that an optimized polyamine moiety boosts drug binding to the topoII/DNA cleavage complex, rather than to the DNA alone. These results provide new structural bases and key reference data for designing new human topoII poisons.


A metagenomic approach to characterize temperate bacteriophage populations from Cystic Fibrosis and non-Cystic Fibrosis bronchiectasis patients.
Pseudomonas aeruginosa (Pa), normally a soil commensal, is an important opportunistic pathogen in Cystic Fibrosis (CF) and non-Cystic Fibrosis Bronchiectasis (nCFBR). Persistent infection correlates with accelerated decline in lung function and early mortality. The horizontal transfer of DNA by temperate bacteriophages can add gene function and selective advantages to their bacterial host within the constrained environment of the lower lung. In this study, we chemically induce temperate bacteriophages from clonal cultures of Pa and identify their mixed viral communities employing metagenomic approaches. We compared 92 temperate phage metagenomes stratified from these clinical backgrounds (47 CF and 45 nCFBR Pa isolates) using MG-RAST and GeneWise2. KEGG analysis shows the complexity of temperate phage accessory gene carriage increases with duration and severity of the disease. Furthermore, we identify the presence of Ig-like motifs within phage structural genes linked to bacterial adhesion and carbohydrate binding including Big_2, He_Pig, and Fn3. This study provides the first clinical support to the proposed bacteriophage adherence to mucus (BAM) model and the evolution of phages interacting at these mucosal surfaces over time.


Effects of plant-mediated differences in host quality on the development of two related endoparasitoids with different host-utilization strategies.
Among parasitoids that develop inside the bodies of feeding, growing hosts (so-called 'koinobiont' endoparasitoids), two strategies have evolved to dispose of host resources. The larvae of one group consumes most host tissues before pupation, whereas in the other the parasitoid larvae consume only host hemolymph and fat body and at maturity emerge through the host cuticle to pupate externally. Here we compared development and survival (to adult emergence) of two related larval endoparasitoids (Braconidae: Microgastrinae) of the diamondback moth, Plutella xylostella. Larvae of Dolichogenidea sicaria are tissue feeders whereas larvae of Cotesia vestalis are hemolymph feeders. Here, development of P. xylostella and the two parasitoids was compared on three populations (one cultivar [Cyrus], two wild, [Winspit and Kimmeridge]) of cabbage that have been shown to vary in direct defense and hence quality. Survival of P. xylostella and C. vestalis (to adult eclosion) did not vary with cabbage population, but did so in D. sicaria, where survival was lower when reared on the wild populations than on the cultivar. Furthermore, adult herbivore mass was significantly higher and development was significantly shorter in moths reared on the cultivar. The tissue-feeing D. sicaria was larger but took longer to develop than the hemolymph-feeder C. vestalis. The performance of both parasitoids was better on the cabbage cultivar than on the wild populations, although the effects were less apparent than in the host. Our results show that (1) differences in plant quality are diffused up the food chain, and (2) the effects of host quality are reflected on the development of both parasitoids.


Real-time neurochemical measurement of dynamic metabolic events during cardiac arrest and resuscitation in a porcine model.
This work describes a fully-integrated portable microfluidic analysis system for real-time monitoring of dynamic changes in glucose and lactate occurring in the brain as a result of cardiac arrest and resuscitation. Brain metabolites are sampled using FDA-approved microdialysis probes and coupled to a high-temporal resolution 3D printed microfluidic chip housing glucose and lactate biosensors. The microfluidic biosensors are integrated with a wireless 2-channel potentiostat forming a compact analysis system that is ideal for use in a crowded operating theatre. Data are transmitted to a custom-written app running on a tablet for real-time visualisation of metabolic trends. In a proof-of-concept porcine model of cardiac arrest, the integrated analysis system proved reliable in a challenging environment resembling a clinical setting; noise levels were found to be comparable with those seen in the lab and were not affected by major clinical interventions such as defibrillation of the heart. Using this system, we were able, for the first time, to measure changes in brain glucose and lactate levels caused by cardiac arrest and resuscitation; the system was sensitive to clinical interventions such as infusion of adrenaline. Trends suggest that cardiopulmonary resuscitation alone does not meet the high energy demands of the brain as metabolite levels only return to their values preceding cardiac arrest upon return of spontaneous circulation.


Ten-year helium anomaly prior to the 2014 Mt Ontake eruption.
Mt Ontake in central Japan suddenly erupted on 27(th) September 2014, killing 57 people with 6 still missing. It was a hydro-volcanic eruption and new magmatic material was not detected. There were no precursor signals such as seismicity and edifice inflation. It is difficult to predict hydro-volcanic eruptions because they are local phenomena that only affect a limited area surrounding the explosive vent. Here we report a long-term helium anomaly measured in hot springs close to the central cone. Helium-3 is the most sensitive tracer of magmatic volatiles. We have conducted spatial surveys around the volcano at once per few years since November 1981. The (3)He/(4)He ratios of the closest site to the cone stayed constant until June 2000 and increased significantly from June 2003 to November 2014, while those of distant sites showed no valuable change. These observations suggest a recent re-activation of Mt Ontake and that helium-3 enhancement may have been a precursor of the 2014 eruption. We show that the eruption was ultimately caused by the increased input of magmatic volatiles over a ten-year period which resulted in the slow pressurization of the volcanic conduit leading to the hydro-volcanic event in September 2014.


White matter changes in dementia: role of impaired drainage of interstitial fluid.
White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease.


Human Antimicrobial Peptides in Bodily Fluids: Current Knowledge and Therapeutic Perspectives in the Postantibiotic Era.
Antimicrobial peptides (AMPs) are an integral part of the innate immune defense mechanism of many organisms. Due to the alarming increase of resistance to antimicrobial therapeutics, a growing interest in alternative antimicrobial agents has led to the exploitation of AMPs, both synthetic and isolated from natural sources. Thus, many peptide-based drugs have been the focus of increasing attention by many researchers not only in identifying novel AMPs, but in defining mechanisms of antimicrobial peptide activity as well. Herein, we review the available strategies for the identification of AMPs in human body fluids and their mechanism(s) of action. In addition, an overview of the distribution of AMPs across different human body fluids is provided, as well as its relation with microorganisms and infectious conditions.


Genetic and biochemical evidence that gastrulation defects in Pofut2 mutants result from defects in ADAMTS9 secretion.
Protein O-fucosyltransferase 2 (POFUT2) adds O-linked fucose to Thrombospondin Type 1 Repeats (TSR) in 49 potential target proteins. Nearly half the POFUT2 targets belong to the A Disintegrin and Metalloprotease with ThromboSpondin type-1 motifs (ADAMTS) or ADAMTS-like family of proteins. Both the mouse Pofut2 RST434 gene trap allele and the Adamts9 knockout were reported to result in early embryonic lethality, suggesting that defects in Pofut2 mutant embryos could result from loss of O-fucosylation on ADAMTS9. To address this question, we compared the Pofut2 and Adamts9 knockout phenotypes and used Cre-mediated deletion of Pofut2 and Adamts9 to dissect the tissue-specific role of O-fucosylated ADAMTS9 during gastrulation. Disruption of Pofut2 using the knockout (LoxP) or gene trap (RST434) allele, as well as deletion of Adamts9, resulted in disorganized epithelia (epiblast, extraembryonic ectoderm, and visceral endoderm) and blocked mesoderm formation during gastrulation. The similarity between Pofut2 and Adamts9 mutants suggested that disruption of ADAMTS9 function could be responsible for the gastrulation defects observed in Pofut2 mutants. Consistent with this prediction, CRISPR/Cas9 knockout of POFUT2 in HEK293T cells blocked secretion of ADAMTS9. We determined that Adamts9 was dynamically expressed during mouse gastrulation by trophoblast giant cells, parietal endoderm, the most proximal visceral endoderm adjacent to the ectoplacental cone, extraembryonic mesoderm, and anterior primitive streak. Conditional deletion of either Pofut2 or Adamts9 in the epiblast rescues the gastrulation defects, and identified a new role for O-fucosylated ADAMTS9 during morphogenesis of the amnion and axial mesendoderm. Combined, these results suggested that loss of ADAMTS9 function in the extra embryonic tissue is responsible for gastrulation defects in the Pofut2 knockout. We hypothesize that loss of ADAMTS9 function in the most proximal visceral endoderm leads to slippage of the visceral endoderm and altered characteristics of the extraembryonic ectoderm. Consequently, loss of input from the extraembryonic ectoderm and/or compression of the epiblast by Reichert's membrane blocks gastrulation. In the future, the Pofut2 and Adamts9 knockouts will be valuable tools for understanding how local changes in the properties of the extracellular matrix influence the organization of tissues during mammalian development.


Contextualizing the effects of yoga therapy on diabetes management: a review of the social determinants of physical activity.
This article provides a review of literature both to identify the effects of yoga-based therapy on the management of type 2 diabetes mellitus and to examine the social context of physical activity. Findings from the review indicate that yoga has a positive short-term effect on multiple diabetes-related outcomes; however, long-term effects of yoga therapy on diabetes management remain unclear. The context of the social environment, including interpersonal relationships, community characteristics, and discrimination, influences the adoption and maintenance of health behaviors such as physical activity, including yoga practice. Further research is necessary to determine the extent of this influence.


Experience-based learning: a model linking the processes and outcomes of medical students' workplace learning.
To develop a model linking the processes and outcomes of workplace learning. We synthesised a model from grounded theory analysis of group discussions before and after experimental strengthening of medical students' workplace learning. The research was conducted within a problem-based clinical curriculum with little early workplace experience, involving 24 junior and 12 senior medical students. To reach their ultimate goal of helping patients, medical students must develop 2 qualities. One is practical competence; the other is a state of mind that includes confidence, motivation and a sense of professional identity. These 2 qualities reinforce one another. The core process of clinical workplace learning involves 'participation in practice', which evolves along a spectrum from passive observation to performance. Practitioners help students participate by being both supportive and challenging. The presentation of clear learning objectives and continuous periods of attachment that are as personal to the student(s) and practitioner(s) as possible promote workplace learning. The core condition for clinical workplace learning is 'supported participation', the various outcomes of which are mutually reinforcing and also reinforce students' ability to participate in further practice. This synthesis has 2 important implications for contemporary medical education: any reduction in medical students' participation in clinical practice that results from the patient safety agenda and expanded numbers of medical students is likely to have an adverse effect on learning, and the construct of 'self-directed learning', which our respondents too often found synonymous with 'lack of support', should be applied with very great caution to medical students' learning in clinical workplaces.


Single-cell pluripotency regulatory networks.
Pluripotent stem cells (PSCs) are a popular model system for investigating development, tissue regeneration, and repair. Although much is known about the molecular mechanisms that regulate the balance between self-renewal and lineage commitment in PSCs, the spatiotemporal integration of responsive signaling pathways with core transcriptional regulatory networks are complex and only partially understood. Moreover, measurements made on populations of cells reveal only average properties of the underlying regulatory networks, obscuring their fine detail. Here, we discuss the reconstruction of regulatory networks in individual cells using novel single-cell transcriptomics and proteomics, in order to expand our understanding of the molecular basis of pluripotency, including the role of cell-cell variability within PSC populations, and ways in which networks may be controlled in order to reliably manipulate cell behavior.


US physician practices versus Canadians: spending nearly four times as much money interacting with payers.
Physician practices, especially the small practices with just one or two physicians that are common in the United States, incur substantial costs in time and labor interacting with multiple insurance plans about claims, coverage, and billing for patient care and prescription drugs. We surveyed physicians and administrators in the province of Ontario, Canada, about time spent interacting with payers and compared the results with a national companion survey in the United States. We estimated physician practices in Ontario spent $22,205 per physician per year interacting with Canada's single-payer agency--just 27 percent of the $82,975 per physician per year spent in the United States. US nursing staff, including medical assistants, spent 20.6 hours per physician per week interacting with health plans--nearly ten times that of their Ontario counterparts. If US physicians had administrative costs similar to those of Ontario physicians, the total savings would be approximately $27.6 billion per year. The results support the opinion shared by many US health care leaders interviewed for this study that interactions between physician practices and health plans could be performed much more efficiently.


Purification and characterization of a factor stimulating DNA polymerase alpha activity from mouse FM3A cells.
A protein factor which stimulates DNA polymerase alpha activity on heat-denatured DNA has been purified from mouse FM3A cells. The final preparation had a specific activity of 43,000 units/mg protein and lacked detectable DNA polymerase, RNA polymerase, DNA-dependent- and independent ATPase, exo- and endodeoxyribonuclease and phosphatase activities. The stimulating factor sedimented at 2.9S in a glycerol gradient. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the glycerol gradient fraction revealed the presence of a major band of 36,000 daltons, the amount of which corresponded well with the level of stimulating activity. The stimulation by the factor was specific for heat-denatured DNA, and a little or no stimulation was observed with native DNA, ribo- and deoxyribohomopolymers and single stranded circular DNA. Alkaline sucrose gradient sedimentation analysis of the reaction products revealed that newly synthesized DNA was covalently linked to the termini of heat-denatured DNA. The average chain length of the elongated span determined by the digestion with micrococcal nuclease and phosphodiesterase II, did not differ between in the presence and absence of the stimulating factor, suggesting that the stimulation by the factor was due to the increase in the initiation frequency of DNA synthesis from the 3'-hydroxyl terminus of heat-denatured DNA.


Association of Migraine With Incident Hypertension After Menopause: A Longitudinal Cohort Study.
Migraine has been identified as a potential risk factor for hypertension in prospective studies. In women, migraine prevalence decreases after menopause, but no studies have determined whether migraine is associated with hypertension after menopause. This study sought to determine whether history of migraine was associated with an increased risk of hypertension among menopausal women. We assessed associations between migraine and hypertension in a longitudinal cohort study of 56,202 menopausal women participating in the French E3N cohort, with follow-up beginning in 1993. We included women who did not have hypertension or cardiovascular disease at the time of menopause. Migraine was classified as ever or never at each questionnaire cycle. Cox proportional hazards models were used to investigate relations between migraine and hypertension, controlling for potential confounding. A secondary analysis with baseline in 2011 considered aura status, grouping participants reporting migraine as migraine with aura, migraine without aura, or unknown migraine type. During 826,419 person-years, 12,501 cases of incident hypertension were identified, including 3,100 among women with migraine and 9,401 among women without migraine. Migraine was associated with an increased risk of hypertension in menopausal women (hazard ratio [HR]migraine 1.29 [95% confidence interval 1.24, 1.35]) and was consistent in post hoc sensitivity analyses, such as when controlling for common migraine medications. Associations between migraine and hypertension were similar whether or not women reported aura (HRmigraine aura 1.54 [1.04, 2.30], HRmigraine no aura 1.32 [0.87, 2.02], p heterogeneity 0.60). Associations were slightly stronger among ever users of menopausal hormone therapy (HRmigraine 1.34 [1.27, 1.41]) than among never users (HRmigraine 1.19 [1.11, 1.28]). Migraine was associated with an increased risk of hypertension among menopausal women. In secondary analysis, we did not observe a significant difference between migraine with aura and migraine without aura.


Intrasequence GFP in class I MHC molecules, a rigid probe for fluorescence anisotropy measurements of the membrane environment.
Fluorescence anisotropy measurements can elucidate the microenvironment of a membrane protein in terms of its rotational diffusion, interactions, and proximity to other proteins. However, use of this approach requires a fluorescent probe that is rigidly attached to the protein of interest. Here we describe the use of one such probe, a green fluorescent protein (GFP) expressed and rigidly held within the amino acid sequence of a major histocompatibility complex (MHC) class I molecule, H2L(d). We contrast the anisotropy of this GFP-tagged MHC molecule, H2L(d)GFPout, with that of an H2L(d) that was GFP-tagged at its C-terminus, H2L(d)GFPin. Both molecules fold properly, reach the cell surface, and are recognized by specific antibodies and T-cell receptors. We found that polarized fluorescence images of H2L(d)GFPout in plasma membrane blebs show intensity variations that depend on the relative orientation of the polarizers and the membrane normal, thus demonstrating that the GFP is oriented with respect to the membrane. These variations were not seen for H2L(d)GFPin. Before transport to the membrane surface, MHC class I associates with the transporter associated with antigen processing complex in the endoplasmic reticulum. The intensity-dependent steady-state anisotropy in the ER of H2L(d)GFPout was consistent with FRET homotransfer, which indicates that a significant fraction of these molecules were clustered. After MCMV-peptide loading, which supplies antigenic peptide to the MHC class I releasing it from the antigen processing complex, the anisotropy of H2L(d)GFPout was independent of intensity, suggesting that the MHC proteins were no longer clustered. These results demonstrate the feasibility and usefulness of a GFP moiety rigidly attached to the protein of interest as a probe for molecular motion and proximity in cell membranes.


Universal Method for Large-Scale Synthesis of Layered Transition Metal Dichalcogenides.
The layered transition metal dichalcogenides are currently amongst the most intensively investigated materials. These compounds constitute a broad family of materials, with characteristic layered structures, covering both semiconductors and metallic materials. The great attention arises from the possibility to exfoliate these materials down to single layers with many unique properties, such as thickness dependent band-gap energy, and the possibility of tuning transport properties by phase transitions. The research in the field of transition metal dichalcogenides is also motivated by their high electrocatalytic activity towards several industrially important reactions, such as the hydrogen evolution reaction, as well as many other applications in nano- and optoelectronics. Although these materials are studied intensively, their availability is extremely limited and only disulfides of molybdenum and tungsten are broadly commercially available. Here an optimized procedure for simple direct synthesis of transition metal dichalcogenides using powder metals and elemental chalcogens is reported. The optimized thermal treatment allowed the synthesis scaling of the sulfides, selenides and tellurides of 4th, 5th, 6th, and 7th group of layered-structure dichalcogenides. The synthesized transition metal dichalcogenides were single phase. The phase purity, structure, and morphology were investigated in detail by electron microscopy and EDS, X-ray diffraction, and Raman spectroscopy.


Acetaminophen Adducts Detected in Serum of Pediatric Patients With Acute Liver Failure.
Previous studies in patients with acute liver failure identified acetaminophen (APAP) protein adducts in the serum of 12% and 19% of children and adults, respectively, with acute liver failure of indeterminate etiology. This article details the testing of APAP adducts in a subset (n = 393) of patients with varied diagnoses in the Pediatric Acute Liver Failure Study Group (PALFSG). Serum samples were available from 393 participants included in the PALFSG registry. Adduct measurement was performed using validated methods. Participants were grouped by diagnostic category as known APAP overdose, known other diagnosis, and indeterminate etiology. Demographic and clinical characteristics and participant outcomes were compared by adduct status (positive or negative) within each group. APAP adduct testing was positive in 86% of participants with known APAP overdose, 6% with other known diagnoses, and 11% with an indeterminate cause of liver failure. Adduct-positive participants were noted to have marked elevation of serum alanine aminotransferase and aspartate aminotransferase coupled with total serum bilirubin that was significantly lower than adduct-negative patients. In the indeterminate group, adduct-positive patients had different outcomes than adduct-negative patients (P = 0.03); spontaneous survival was 16 of 21 (76%) in adduct-positive patients versus 75 of 169 (44%) in adduct-negative patients. Prognosis did not vary by adduct status in patients with known diagnoses. Furthermore, study is needed to understand the relation of APAP exposure, as determined by the presence of APAP adducts, to the clinical phenotype and outcomes of children with acute liver failure.


Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis.
Laboratory testing for the identification of heritable thrombophilia in high-risk patient groups have become common practice; however, indiscriminate testing of all patients is unjustified. The objective of this study was to evaluate the cost-effectiveness of universal and selective history-based thrombophilia screening relative to no screening, from the perspective of the UK National Health Service, in women prior to prescribing combined oral contraceptives and hormone replacement therapy, women during pregnancy and patients prior to major orthopaedic surgery. A decision analysis model was developed, and data from meta-analysis, the literature and two Delphi studies were incorporated in the model. Incremental cost-effectiveness ratios (ICERs) for screening compared with no screening was calculated for each patient group. Of all the patient groups evaluated, universal screening of women prior to prescribing hormone replacement therapy was the most cost-effective (ICER 6824 pounds). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER 202,402 pounds). Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism was more cost-effective than universal screening in all the patient groups evaluated.


Muscle Atrophy Marker Expression Differs between Rotary Cell Culture System and Animal Studies.
Muscular atrophy, defined as the loss of muscle tissue, is a serious issue for immobilized patients on Earth and for humans during spaceflight, where microgravity prevents normal muscle loading. In vitro modeling is an important step in understanding atrophy mechanisms and testing countermeasures before animal trials. The most ideal environment for modeling must be empirically determined to best mimic known responses in vivo. To simulate microgravity conditions, murine C2C12 myoblasts were cultured in a rotary cell culture system (RCCS). Alginate encapsulation was compared against polystyrene microcarrier beads as a substrate for culturing these adherent muscle cells. Changes after culture under simulated microgravity were characterized by assessing mRNA expression of MuRF1, MAFbx, Caspase 3, Akt2, mTOR, Ankrd1, and Foxo3. Protein concentration of myosin heavy chain 4 (Myh4) was used as a differentiation marker. Cell morphology and substrate structure were evaluated with brightfield and fluorescent imaging. Differentiated C2C12 cells encapsulated in alginate had a significant increase in MuRF1 only following simulated microgravity culture and were morphologically dissimilar to normal cultured muscle tissue. On the other hand, C2C12 cells cultured on polystyrene microcarriers had significantly increased expression of MuRF1, Caspase 3, and Foxo3 and easily identifiable multinucleated myotubes. The extent of differentiation was higher in simulated microgravity and protein synthesis more active with increased Myh4, Akt2, and mTOR. The in vitro microcarrier model described herein significantly increases expression of several of the same atrophy markers as in vivo models. However, unlike animal models, MAFbx and Ankrd1 were not significantly increased and the fold change in MuRF1 and Foxo3 was lower than expected. Using a standard commercially available RCCS, the substrates and culture methods described only partially model changes in mRNAs associated with atrophy in vivo.


Amplitude-phase retrieval attack free cryptosystem based on direct attack to phase-truncated Fourier-transform-based encryption using a random amplitude mask.
We propose a simple amplitude-phase retrieval attack free cryptosystem based on direct attack to phase-truncated Fourier-transform-based encryption using a random amplitude mask (RAM). The RAM that is not saved during the encryption provides extremely high security for the two private keys, and no iterative calculations are involved in the nonlinear encryption process. Lack of enough constraints makes the specific attack based on iterative amplitude-phase retrieval algorithms unusable. Numerical simulation results are given for testing the validity and security of the proposed approach.


Evidence for the assembly of a bacterial tripartite multidrug pump with a stoichiometry of 3:6:3.
The multiple transferable resistance (mTR) pump from Neisseria gonorrhoeae MtrCDE multidrug pump is assembled from the inner and outer membrane proteins MtrD and MtrE and the periplasmic membrane fusion protein MtrC. Previously we established that while there is a weak interaction of MtrD and MtrE, MtrC binds with relatively high affinity to both MtrD and MtrE. MtrD conferred antibiotic resistance only when it was expressed with MtrE and MtrC, suggesting that these proteins form a functional tripartite complex in which MtrC bridges MtrD and MtrE. Furthermore, we demonstrated that MtrC interacts with an intraprotomer groove on the surface of MtrE, inducing channel opening. However, a second groove is apparent at the interface of the MtrE subunits, which might also be capable of engaging MtrC. We have now established that MtrC can be cross-linked to cysteines placed in this interprotomer groove and that mutation of residues in the groove impair the ability of the pump to confer antibiotic resistance by locking MtrE in the closed channel conformation. Moreover, MtrE K390C forms an intermolecular disulfide bond with MtrC E149C locking MtrE in the open channel conformation, suggesting that a functional salt bridge forms between these residues during the transition from closed to open channel conformations. MtrC forms dimers that assemble into hexamers, and electron microscopy studies of single particles revealed that these hexamers are arranged into ring-like structures with an internal aperture sufficiently large to accommodate the MtrE trimer. Cross-linking of single cysteine mutants of MtrC to stabilize the dimer interface in the presence of MtrE, trapped an MtrC-MtrE complex with a molecular mass consistent with a stoichiometry of 3:6 (MtrE(3)MtrC(6)), suggesting that dimers of MtrC interact with MtrE, presumably by binding to the two grooves. As both MtrE and MtrD are trimeric, our studies suggest that the functional pump is assembled with a stoichiometry of 3:6:3.


Workgroup report: public health strategies for reducing aflatoxin exposure in developing countries.
Consecutive outbreaks of acute aflatoxicosis in Kenya in 2004 and 2005 caused > 150 deaths. In response, the Centers for Disease Control and Prevention and the World Health Organization convened a workgroup of international experts and health officials in Geneva, Switzerland, in July 2005. After discussions concerning what is known about aflatoxins, the workgroup identified gaps in current knowledge about acute and chronic human health effects of aflatoxins, surveillance and food monitoring, analytic methods, and the efficacy of intervention strategies. The workgroup also identified public health strategies that could be integrated with current agricultural approaches to resolve gaps in current knowledge and ultimately reduce morbidity and mortality associated with the consumption of aflatoxin-contaminated food in the developing world. Four issues that warrant immediate attention were identified: a) quantify the human health impacts and the burden of disease due to aflatoxin exposure; b) compile an inventory, evaluate the efficacy, and disseminate results of ongoing intervention strategies; c) develop and augment the disease surveillance, food monitoring, laboratory, and public health response capacity of affected regions; and d) develop a response protocol that can be used in the event of an outbreak of acute aflatoxicosis. This report expands on the workgroup's discussions concerning aflatoxin in developing countries and summarizes the findings.


Evolving perspectives on the etiology and pathogenesis of acne vulgaris.
As the pathophysiology of acne is complex and multifactorial, the continued influx of new basic science and clinical information requires careful analysis before drawing conclusions about what truly contributes to the development and progression of this chronic disease. Our objective is to review the latest evidence and highlight a number of important perspectives on the pathophysiology of acne. An improved understanding of acne pathogenesis should lead to more rational therapy and a better understanding of the role of P acnes opens new perspectives for the development of new treatments and management. Further research may be directed at targeting receptors, adhesion molecules, cytokines, chemokines or other pro-inflammatory targets implicated in the activation of immune detection and response (i.e., toll-like receptors [TLRs], protease-activated receptors [PARs]) that appear to contribute to the pathophysiology of acne. Therapeutic options that reduce the need for topical and/or oral antibiotic therapy for acne are welcome as bacterial resistance to antibiotics is a clinically relevant concern both in the United States and globally.


Evaluation of the tobacco heating system 2.2. Part 9: Application of systems pharmacology to identify exposure response markers in peripheral blood of smokers switching to THS2.2.
As part of current harm reduction strategies, candidate modified risk tobacco products (MRTP) are developed to offer adult smokers who want to continue using tobacco product an alternative to cigarettes while potentially reducing individual risk and population harm compared to smoking cigarettes. One of these candidate MRTPs is the Tobacco Heating System (THS) 2.2 which does not burn tobacco, but instead heats it, thus producing significantly reduced levels of harmful and potentially harmful constituents (HPHC) compared with combustible cigarettes (CC). A controlled, parallel group, open-label clinical study was conducted with subjects randomized to three monitored groups: (1) switching from CCs to THS2.2; (2) continuous use of non-menthol CC brand (CC arm); or (3) smoking abstinence (SA arm) for five days. Exposure response was assessed by measuring biomarkers of exposure to selected HPHCs. To complement the classical exposure response measurements, we have used the previously reported whole blood derived gene signature that can distinguish current smokers from either non-smokers or former smokers with high specificity and sensitivity. We tested the small signature consisting of only 11 genes on the blood transcriptome of subjects enrolled in the clinical study and showed a reduced exposure response in subjects that either stopped smoking or switched to a candidate MRTP, the THS2.2, compared with subjects who continued smoking their regular tobacco product.


Inhibition of Multidrug Resistance Proteins by MK 571 Enhances Bladder, Prostate, and Urethra Relaxation through cAMP or cGMP Accumulation.
The biologic effect of cAMP and cGMP is terminated by phosphodiesterases and multidrug resistance proteins MRP4 and MRP5, which pump cyclic nucleotides out of the cell. Therefore, this study aimed to characterize the role of MRP inhibitor, MK 571 (3-[[[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propanoic acid), in the bladder, prostate, and urethra of male mice by means of functional assays, protein expression, and cyclic nucleotide quantification. The cumulative addition of MK 571 (1-30 µM) produced only small relaxation responses (approximately 25%) in all studied tissues. In the bladder, isoprenaline/fenoterol and forskolin concentration-dependently relaxed and MK 571 (20 µM) increased the maximal response values by 37% and 24%, respectively. When MK 571 was coincubated with fenoterol or forskolin, intracellular levels of cAMP and protein expression of phospho-vasodilator-stimulated phosphoprotein (p-VASP) Ser157 were significantly greater compared with bladders stimulated with fenoterol or forskolin alone. In the prostate and urethra, sodium nitroprusside concentration-dependently relaxed and MK 571 (20 µM) significantly increased relaxation responses by 70% and 56%, respectively, accompanied by greater intracellular levels of cGMP and protein expression of p-VASP Ser239 in the prostate. Tadalafil and BAY 41-2272 (5-cyclopropyl-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinamine) also relaxed the prostate and urethra, respectively, and MK 571 markedly enhanced this response. The stable analog of cGMP (8-Br-cGMP) induced concentration-dependent relaxation responses in the prostate and urethra, and MK 571 significantly increased the relaxation response. In conclusion, to our knowledge, this is the first study to show that efflux transporters are physiologically active in the bladder, prostate, and urethra to control intracellular levels of cAMP or cGMP.


Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome.
The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite beta-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients. We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543+/-65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with beta-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P<0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc <500 ms predicted very low risk. The percentage of patients with >5 CEs declined from 55% to 8% (P<0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (P=0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite beta-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.


Viral etiology of severe pneumonia among Kenyan infants and children.
Pneumonia is the leading cause of childhood death in sub-Saharan Africa. Comparative estimates of the contribution of causative pathogens to the burden of disease are essential for targeted vaccine development. To determine the viral etiology of severe pneumonia among infants and children at a rural Kenyan hospital using comprehensive and sensitive molecular diagnostic techniques. Prospective observational and case-control study during 2007 in a rural Kenyan district hospital. Participants were children aged 1 day to 12 years, residing in a systematically enumerated catchment area, and who either were admitted to Kilifi District Hospital meeting World Health Organization clinical criteria for severe pneumonia or very severe pneumonia; (2) presented with mild upper respiratory tract infection but were not admitted; or (3) were well infants and children attending for immunization. The presence of respiratory viruses and the odds ratio for admission with severe disease. Of 922 eligible admitted patients, 759 were sampled (82% [median age, 9 months]). One or more respiratory viruses were detected in 425 of the 759 sampled (56% [95% confidence interval {CI}, 52%-60%]). Respiratory syncytial virus (RSV) was detected in 260 participants (34% [95% CI, 31%-38%]) and other respiratory viruses were detected in 219 participants (29%; 95% CI, 26%-32%), the most common being Human coronavirus 229E (n = 51 [6.7%]), influenza type A (n = 44 [5.8%]), Parainfluenza type 3 (n = 29 [3.8%]), Human adenovirus (n = 29 [3.8%]), and Human metapneumovirus (n = 23 [3.0%]). Compared with well control participants, detection of RSV was associated with severe disease (5% [corrected] in control participants; adjusted odds ratio, 6.11 [95% CI, 1.65-22.6]) while collectively, other respiratory viruses were not associated with severe disease (23% in control participants; adjusted odds ratio, 1.27 [95% CI, 0.64-2.52]). In a sample of Kenyan infants and children admitted with severe pneumonia to a rural hospital, RSV was the predominant viral pathogen.


Systems genetics of hepatocellular damage in vivo and in vitro: identification of a critical network on chromosome 11 in mouse.
Quantitative trait locus (QTL) mapping is a powerful method to find modifier loci that influence disease risk and progression without prior knowledge of underlying genetic mechanisms. The aim of this study is to identify gene loci that contribute to individual differences in liver fibrosis following chronic liver damage. For this purpose, we carried out a mapping study across a panel of 21 BXD recombinant inbred strains using primary hepatocytes challenged with transforming growth factor (TGF)-β for 48 h. We identified a 6 Mb interval on chromosome 11 that is a major modifier of TGF-β-induced hepatocyte injury. Corresponding in vivo genetic analysis of fibrosis after chronic hepatotoxic injury by carbon tetrachloride (CCl4 ip for 6 wk) highlighted the same locus. Expression QTL (eQTL) analysis in liver tissues in the BXD family identified six polymorphisms in this region that are associated with strong cis eQTLs and that correlate well with gene expression in liver after both 6 wk CCl4 treatment and acute ethanol damage of the liver. Within this interval we rank two genes containing coding sequence variants as strong candidates that may modulate the severity of liver fibrosis: 1) the extracellular proteinase inhibitor gene Expi (also known as Wdnm1 or Wfdc18) and 2) musashi RNA-binding protein 2 (Msi2). The powerful combination of experimental, genetics, and bioinformatics methods, as well as combined in vitro and in vivo approaches can be used to define QTLs, genes, and even candidate sequence variants linked to hepatotoxicity and fibrosis.


Redistribution of regional blood flow after administration of saralasin in salt-depleted dogs.
1. Salt depletion was produced in five dogs by a low salt diet and daily administration of frusemide for 5 days; a control group of five dogs was placed on the same diet, to which 2.5 g of sodium chloride was added. 2. Saralasin infusion (0.5 microgram min-1 kg-1) reduced mean aortic blood pressure and total peripheral vascular resistance and increased cardiac output in salt-depleted dogs, but did not affect the heart rate and left ventricular dP/dt. 3. Saralasin infusion increased mean aortic blood pressure slightly in normal dogs; other systemic haemodynamic parameters did not change significantly. 4. Saralasin decreased hepatic arterial flow in both normal and salt-depleted dogs, but increased blood flow to left ventricle and kidneys only in salt-depleted dogs. 5. These results suggest that saralasin exerts a partial agonist effect in normal dogs to increase arterial blood pressure, but causes a depressor response during salt depletion because it reverses the vasoconstrictor effect of angiotensin II, particularly on the renal and coronary circulations.


Clinical practice guideline: acute otitis externa.
This guideline provides evidence-based recommendations to manage diffuse acute otitis externa (AOE), defined as generalized inflammation of the external ear canal, which may also involve the pinna or tympanic membrane. The primary purpose is to promote appropriate use of oral and topical antimicrobials and to highlight the need for adequate pain relief. In creating this guideline, the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) selected a development group representing the fields of otolaryngology-head and neck surgery, pediatrics, family medicine, infectious disease, internal medicine, emergency medicine, and medical informatics. The guideline was created with the use of an explicit, a priori, evidence-based protocol. The group made a strong recommendation that management of AOE should include an assessment of pain, and the clinician should recommend analgesic treatment based on the severity of pain. The group made recommendations that clinicians should: 1) distinguish diffuse AOE from other causes of otalgia, otorrhea, and inflammation of the ear canal; 2) assess the patient with diffuse AOE for factors that modify management (nonintact tympanic membrane, tympanostomy tube, diabetes, immunocompromised state, prior radiotherapy); and 3) use topical preparations for initial therapy of diffuse, uncomplicated AOE; systemic antimicrobial therapy should not be used unless there is extension outside of the ear canal or the presence of specific host factors that would indicate a need for systemic therapy. The group made additional recommendations that: 4) the choice of topical antimicrobial therapy of diffuse AOE should be based on efficacy, low incidence of adverse events, likelihood of adherence to therapy, and cost; 5) clinicians should inform patients how to administer topical drops, and when the ear canal is obstructed, delivery of topical preparations should be enhanced by aural toilet, placing a wick, or both; 6) when the patient has a tympanostomy tube or known perforation of the tympanic membrane, the clinician should prescribe a nonototoxic topical preparation; and 7) if the patient fails to respond to the initial therapeutic option within 48 to 72 hours, the clinician should reassess the patient to confirm the diagnosis of diffuse AOE and to exclude other causes of illness. And finally, the panel compiled a list of research needs based on limitations of the evidence reviewed. This clinical practice guideline is not intended as a sole source of guidance in evaluating patients with AOE. Rather, it is designed to assist clinicians by providing an evidence-based framework for decision-making strategies. It is not intended to replace clinical judgment or establish a protocol for all individuals with this condition and may not provide the only appropriate approach to the diagnosis and management of this problem. This is the first, explicit, evidence-based clinical practice guideline on acute otitis externa, and the first clinical practice guideline produced independently by the AAO-HNSF.


Three-dimensional polarization ray-tracing calculus II: retardance.
The concept of retardance is critically analyzed for ray paths through optical systems described by a three-by-three polarization ray-tracing matrix. Algorithms are presented to separate the effects of retardance from geometric transformations. The geometric transformation described by a "parallel transport matrix" characterizes nonpolarizing propagation through an optical system, and also provides a proper relationship between sets of local coordinates along the ray path. The proper retardance is calculated by removing this geometric transformation from the three-by-three polarization ray-tracing matrix. Two rays with different ray paths through an optical system can have the same polarization ray-tracing matrix but different retardances. The retardance and diattenuation of an aluminum-coated three fold-mirror system are analyzed as an example.


Experimental infection of rhesus monkeys with type D retrovirus.
The naturally occurring immunodeficiency syndrome of macaque monkeys is an important animal model for the acquired immunodeficiency syndrome in humans. A new type D retrovirus, distinct from Mason-Pfizer monkey virus, has been isolated from affected animals at the New England Regional Primate Research Center. We now report the results of experimental infection of macaques with retrovirus D/New England after 13 months of study. Inoculated macaques developed lymphadenopathy without follicular hyperplasia, profound neutropenia, and a transient decrease in peripheral blood lymphocyte blastogenic responsiveness. Despite our varying the strain of virus, the manner in which the virus was grown, the size of the inoculum, and the age of the inoculated animals, infected macaques have not developed opportunistic infections or profound, prolonged loss of T cell function, key features of the macaque immunodeficiency syndrome. Therefore, experimental infection of naive macaques with D/New England has not reproduced the naturally occurring macaque immunodeficiency syndrome.


Dermatologic conditions in skin of color: part II. Disorders occurring predominately in skin of color.
Several skin conditions are more common in persons with skin of color, including dermatosis papulosa nigra, pseudofolliculitis barbae, acne keloidalis nuchae, and keloids. Dermatosis papulosa nigra is a common benign condition characterized by skin lesions that do not require treatment, although several options are available for removal to address cosmetic concerns. Pseudofolliculitis barbae occurs as a result of hair removal. Altering shaving techniques helps prevent lesions from recurring. In acne keloidalis nuchae, keloidal lesions are found on the occipital scalp and posterior neck. Early treatment with steroids, antibiotics, and retinoids prevents progression. A key part of the management of keloids is prevention. First-line medical therapy includes intralesional steroid injections. The distinct structure of the hair follicle in blacks results in hair care practices that can lead to common scalp disorders. For example, chemical relaxers decrease the strength of hair and may cause breakage. Better patient education, with early diagnosis and treatment, often leads to better outcomes.


Sexual practices and sexual satisfaction: a population based study of Chinese urban adults.
This study examined sexual satisfaction and its social and behavioral correlates among urbanites aged 20-64 in China, using data from a nationally representative sample of 1,194 women and 1,217 men with a spouse or other long-term sexual partner with whom they had sex during the last year. The results from structural equation models suggest a multiplex set of determinants of sexual satisfaction, including relationship characteristics, sexual knowledge and personal values, physical vitality, and environmental impediments. A large proportion of the effect of these background characteristics was mediated by frequent orgasms, varied sexual practices, and perceived partner affection. In particular, much of the effect of knowledge and beliefs was mediated through variety in sexual practices. While many of the observed patterns were shared among women and men, much of the effect of relationship characteristics was mediated through perceived partner affection for women. Men, in contrast, paid greater attention to his partner's physical attractiveness and to her extramarital sex. A sexual transition is well underway in urban China, even if more rapidly for men than for women. While knowledge and values are arguably more important in this transitional period, many antecedents of sexual well-being drawn from the literature on sexual behavior in developed Western countries are also applicable to urban China.


sigE facilitates the adaptation of Bordetella bronchiseptica to stress conditions and lethal infection in immunocompromised mice.
The cell envelope of a bacterial pathogen can be damaged by harsh conditions in the environment outside a host and by immune factors during infection. Cell envelope stress responses preserve the integrity of this essential compartment and are often required for virulence. Bordetella species are important respiratory pathogens that possess a large number of putative transcription factors. However, no cell envelope stress responses have been described in these species. Among the putative Bordetella transcription factors are a number of genes belonging to the extracytoplasmic function (ECF) group of alternative sigma factors, some of which are known to mediate cell envelope stress responses in other bacteria. Here we investigate the role of one such gene, sigE, in stress survival and pathogenesis of Bordetella bronchiseptica. We demonstrate that sigE encodes a functional sigma factor that mediates a cell envelope stress response. Mutants of B. bronchiseptica strain RB50 lacking sigE are more sensitive to high temperature, ethanol, and perturbation of the envelope by SDS-EDTA and certain β-lactam antibiotics. Using a series of immunocompromised mice deficient in different components of the innate and adaptive immune responses, we show that SigE plays an important role in evading the innate immune response during lethal infections of mice lacking B cells and T cells. SigE is not required, however, for colonization of the respiratory tract of immunocompetent mice. The sigE mutant is more efficiently phagocytosed and killed by peripheral blood polymorphonuclear leukocytes (PMNs) than RB50, and exhibits decreased cytotoxicity toward macrophages. These altered interactions with phagocytes could contribute to the defects observed during lethal infection. Much of the work on transcriptional regulation during infection in B. bronchiseptica has focused on the BvgAS two-component system. This study reveals that the SigE regulon also mediates a discrete subset of functions associated with virulence. SigE is the first cell envelope stress-sensing system to be described in the bordetellae. In addition to its role during lethal infection of mice deficient in adaptive immunity, our results indicate that SigE is likely to be important for survival in the face of stresses encountered in the environment between hosts.


Coumarin-based luminescent ligand that forms helicates with dicationic metal ions.
The potentially hexadentate ligand L, which contains two terminal coumarin fluorophores, forms dinuclear double-stranded helicates with dicationic metal ions, giving species of the generic form [M(2)L(2)](4+). In solution the free ligand was fluorescent with emission attributed to the coumarin fluorophores (lambda(em) = 437 nm). The luminescent properties of the corresponding dimetallic helicates complexes were examined and revealed that the Zn(2+) complex demonstrates enhanced emission when compared to the parent ligand, whereas Co(2+), Cu(2+), Cd(2+) and Hg(2+) induce varying degrees of fluorescence quenching. In particular, comparative luminescence measurements at 77 K and room temperature showed that the quenching mechanism for [Cu(2)L(2)](4+) can be attributed to a photoinduced electron transfer. ESI-MS selectivity studies showed that in the presence of a mixture of metal dications no preference for any one metal ion was observed.


Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma.
To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL). In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity rate of <33% in cycle 1 and <33% of patients discontinuing before cycle 3 due to treatment-related adverse events (AEs). Part 3 (n = 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP. The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m2 The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21). Inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 22(19); 4807-16. ©2016 AACR.


Structural mimicry for vinculin activation by IpaA, a virulence factor of Shigella flexneri.
Invasion of epithelial cells by Shigella flexneri is characterized by cytoskeletal rearrangements of the host cell membrane, promoting internalization of the bacterium. The bacterial effector IpaA is injected into the epithelial cell by a type III secretion apparatus and recruits vinculin to regulate actin polymerization at the site of entry. We analysed the complex formed between a carboxy-terminal fragment of IpaA (IpaA(560-633)) and the vinculin D1 domain (VD1), both in crystals and in solution. We present evidence that IpaA(560-633) has two alpha-helical vinculin-binding sites that simultaneously bind two VD1 molecules. The interaction of IpaA(560-633) with VD1 is highly similar to the interaction of the endogenous, eukaryotic proteins talin and alpha-actinin with VD1, showing that Shigella uses a structural mimicry strategy to activate vinculin.


Comparative Effectiveness of Patient-Controlled Analgesia for Treating Acute Pain in the Emergency Department.
We assess the effectiveness of patient-controlled analgesia in the emergency department (ED). We hypothesized that decline in pain intensity from 30 to 120 minutes after initial intravenous opioid administration is greater in patients receiving morphine by patient-controlled analgesia compared with usual care and would differ by a clinically significant amount. This was a pragmatic randomized controlled trial of patient-controlled analgesia and usual care (opioid and dose at physician's discretion) in 4 EDs. Entry criteria included age 18 to 65 years and acute pain requiring intravenous opioids. The primary outcome was decline in numeric rating scale pain score 30 to 120 minutes postbaseline. Secondary outcomes included satisfaction, time to analgesia, adverse events, and patient-controlled analgesia pump-related problems. We used a mixed-effects linear model to compare rate of decline in pain (slope) between groups. A clinically significant difference between groups was defined as a difference in slopes equivalent to 1.3 numeric rating scale units. Six hundred thirty-six patients were enrolled. The rate of decline in pain from 30 to 120 minutes was greater for patients receiving patient-controlled analgesia than usual care (difference=1.0 numeric rating scale unit; 95% confidence interval [CI] 0.6 to 1.5; P<.001) but did not reach the threshold for clinical significance. More patients receiving patient-controlled analgesia were satisfied with pain management (difference=9.3%; 95% CI 3.3% to 15.1%). Median time to initial analgesia was 15 minutes longer for patient-controlled analgesia than usual care (95% CI 11.4 to 18.6 minutes). There were 7 adverse events in the patient-controlled analgesia group and 1 in the usual care group (difference=2.0%; 95% CI 0.04% to 3.9%), and 11 pump-programming errors. The findings of this study do not favor patient-controlled analgesia over usual ED care for acute pain management.


Bisacremines E-G, Three Polycyclic Dimeric Acremines Produced by Acremonium persicinum SC0105.
Three dimeric acremines, bisacremines E-G (1-3), with an unusual carbon skeleton were isolated from cultures of the soil-derived fungus Acremonium persicinum SC0105. Their structures were elucidated by spectroscopic analysis, X-ray diffraction, and ECD/TDDFT computations. Compound 3 exhibited inhibitory effects on the production of TNF-α, IL-6, and NO in LPS-stimulated macrophages. A biogenetic pathway with a [4 + 2] cycloaddition as the key reaction is proposed for 1-3.


The SKYNET data: demography and injury reporting in Swedish skydiving.
The Swedish Parachute Association (SFF) national registry of skydiving injuries is one of the few trauma databases available for research on sport parachuting. The usefulness of this compulsory reporting system may benefit from a description of its base population and an evaluation of its sensitivity and specificity. Cross-sectional analysis based on data collected through a web-based questionnaire (SKYNET), from all persons renewing a Swedish skydiving license 2008 (n=1049). Sensitivity was measured as the proportion of injury events fulfilling the reporting criterion (injury event requiring care of a physician) that were actually reported, by comparing the injury events reported to the SFF during the skydiving seasons 2006 and 2007 with the injury events retrospectively reported to the web-based questionnaire for the same time period. Specificity was measured as the proportion of false positives in relation to the defined reporting criterion for the same time period. Self-stated bone fractures, shoulder dislocations and cruciate ligament injuries were labeled as non-minor injuries. Factors affecting the likelihood of reporting were evaluated using logistic regression. The response rate was 100%. The overall sensitivity of the reporting system 2006/2007 was 0.37 (95% confidence interval (CI) 0.24-0.51). With self-stated non-minor injuries as the target for reporting, the sensitivity was 0.67 (95% CI 0.43-0.85). No significant effect on reporting was found for gender, age, license level, years in the sport, total number of jumps or club affiliation. The specificity was 0.91 (95% CI 0.83-0.95). Descriptive statistics of the Swedish skydiving population show several gender differences. The low sensitivity will yield false low incidence calculations, but as there is no evidence for differential underreporting, risk comparisons related to the candidate predictor variables appear reasonably valid. The false positive reporting warrants assortment of incoming data and a clarification of the reporting criteria. Attitudes to reporting may be of value to study, to understand the drivers and constraints for achieving a more complete notification of skydiving injuries.


Attitudes of college music students towards noise in youth culture.
The effectiveness of a hearing loss prevention program within a college may be dependent on attitudes among students majoring in music. The purpose of this study was to assess the attitudes of music majors toward noise and to compare them to students not majoring in music. Participants ( N = 467) filled out a questionnaire designed to assess attitudes toward noise in youth culture and attitudes toward influencing their sound environment. Results showed that students majoring in music have a healthier attitude toward sound compared to students not majoring in music. Findings also showed that music majors are more aware and attentive to noise in general, likely to perceive sound that may be risky to hearing as something negative, and are more likely to carry out behaviors to decrease personal exposure to loud sounds. Due to these differences, music majors may be more likely than other students to respond to and benefit from a hearing loss prevention program.


Endonasal management of sellar arachnoid cysts: simple cyst obliteration technique.
Symptomatic sellar arachnoid cysts (ACs) have typically been treated via the transsphenoidal route. After sellar cyst wall fenestration, some authors have advocated cyst wall resection and increasing communication between the AC and suprasellar subarachnoid space (SAS). This study is a report of the authors' experience using a simplified approach to reinforce a defective diaphragma sellae or unseen arachnoid diverticulum by deliberately not enlarging the AC-SAS communication and obliterating the cyst cavity with adipose tissue followed by skull base reconstruction. A retrospective analysis was conducted of patients who underwent an endonasal transsphenoidal obliteration of symptomatic ACs with a fat graft and skull base repair. Between July 1998 and September 2010, 8 patients with a sellar AC were identified (6 women and 2 men, mean age 57 years). Clinical presentation included headache, pituitary dysfunction, and visual dysfunction (4 patients each group). Maximal cyst diameter averaged 22 mm (range 15-32 mm). In all cases the sellar communication to the SAS was deliberately not enlarged. The endoscope was used for visualization in 8 of 9 procedures. Postoperatively, headache improved in all 4 patients, vision in all 4 patients, and partial resolution of endocrine dysfunction (hyperprolactinemia and/or recurrent hyponatremia) occurred in 3 (75%) of 4 patients. No new endocrinopathy, CSF leak, meningitis, or neurological deficits occurred. Two patients experienced cyst reaccumulation: 1 symptomatic recurrence was treated with reoperation at 43 months postsurgery, and 1 asymptomatic partial recurrence continued to be monitored at 29 months postsurgery. Sellar ACs can be effectively treated using endonasal fenestration and obliteration with fat with resultant reversal of presenting symptoms in the majority of patients. This simplified technique of AC cavity obliteration without enlarging communication to the SAS has a low risk of CSF leakage, and in most cases appears to effectively disrupt cyst progression, although longer follow-up is required to monitor for cyst recurrence.


Mechanisms of resistance to antiangiogenesis therapy.
Angiogenesis, the formation of new blood vessels from existing vasculature, plays an essential role in tumour growth, invasion and metastasis. Vascular endothelial growth factor (VEGF) is one of the key factors responsible for its regulation. High expression of VEGF has been observed in many cancers, and is associated with worse survival. When antiangiogenic agents are used alone they typically initially cause reduction in blood flow or vascular permeability, in many types of cancer. In some cases tumour regression occurs, mainly in renal cancer. In combination with chemotherapy, progression-free survival is often prolonged, but overall survival is not. Many tumours fail to respond initially - de novo resistance. Others develop resistance over time, with progression after a few months of treatment. The mechanisms of resistance are not well understood. The theoretical benefits of VEGF inhibitors are more likely to be realised by understanding these mechanisms and modifying therapy accordingly. This article reviews current knowledge on resistance mechanisms and the therapeutic implications.


Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort.
The aim of this work was to investigate the mechanisms underlying the risk of type 2 diabetes associated with statin treatment in the population-based Metabolic Syndrome in Men (METSIM) cohort. A total of 8,749 non-diabetic participants, aged 45-73 years, were followed up for 5.9 years. New diabetes was diagnosed in 625 men by means of an OGTT, HbA1c ≥6.5% (48 mmol/mol) or glucose-lowering medication started during the follow-up. Insulin sensitivity and secretion were evaluated with OGTT-derived indices. Participants on statin treatment (N = 2,142) had a 46% increased risk of type 2 diabetes (adjusted HR 1.46 [95% CI 1.22, 1.74]). The risk was dose dependent for simvastatin and atorvastatin. Statin treatment significantly increased 2 h glucose (2hPG) and glucose AUC of an OGTT at follow-up, with a nominally significant increase in fasting plasma glucose (FPG). Insulin sensitivity was decreased by 24% and insulin secretion by 12% in individuals on statin treatment (at FPG and 2hPG <5.0 mmol/l) compared with individuals without statin treatment (p < 0.01). Decreases in insulin sensitivity and insulin secretion were dose dependent for simvastatin and atorvastatin. Statin treatment increased the risk of type 2 diabetes by 46%, attributable to decreases in insulin sensitivity and insulin secretion.


Health insurance coverage, medical expenditure and coping strategy: evidence from Taiwan.
The health insurance system in Taiwan is comprised of public health insurance and private health insurance. The public health insurance, called "universal national health insurance" (NHI), was first established in 1995 and amended in 2011. The goal of this study is to provide an updated description of several important aspects of health insurance in Taiwan. Of special interest are household insurance coverage, medical expenditures (both gross and out-of-pocket), and coping strategies. Data was collected via a phone call survey conducted in August and September of 2011. A household was the unit for survey and data analysis. A total of 2,424 households covering all major counties and cities in Taiwan were surveyed. The survey revealed that households with smaller sizes and higher incomes were more likely to have higher coverage of public and private health insurance. In addition, households with the presence of chronic diseases were more likely to have both types of insurance. Analysis of both gross and out-of-pocket medical expenditure was conducted. It was suggested that health insurance could not fully remove the financial burden caused by illness. The presence of chronic disease and inpatient treatment were significantly associated with higher gross and out-of-pocket medical expenditure. In addition, the presence of inpatient treatment was significantly associated with extremely high medical expenditure. Regional differences were also observed, with households in the northern, central, and southern regions having less gross medical expenditures than those on the offshore islands. Households with the presence of inpatient treatment were more likely to cope with medical expenditure using means other than salaries. Despite the considerable achievements of the health insurance system in Taiwan, there is still room for improvement. This study investigated coverage, cost, and coping strategies and may be informative to stakeholders of both basic and commercial health insurance.


Molecular cloning of human phosphomevalonate kinase and identification of a consensus peroxisomal targeting sequence.
Two overlapping cDNAs which encode human liver phosphomevalonate kinase (PMKase) were isolated. The human PMKase cDNAs predict a 191-amino acid protein with a molecular weight of 21,862, consistent with previous reports for mammalian PMKase (Mr = 21,000-22,500). Further verification of the clones was obtained by expression of PMKase activity in bacteria using a composite 1024-base pair cDNA clone. Northern blot analysis of several human tissues revealed a doublet of transcripts at approximately 1 kilobase (kb) in heart, liver, skeletal muscle, kidney, and pancreas and lower but detectable transcript levels in brain, placenta, and lung. Analysis of transcripts from human lymphoblasts subcultured in lipid-depleted sera (LDS) and LDS supplemented with lovastatin indicated that PMKase gene expression is subject to regulation by sterol at the level of transcription. Southern blotting indicated that PMKase is a single copy gene covering less than 15 kb in the human genome. The human PMKase amino acid sequence contains a consensus peroxisomal targeting sequence (PTS-1), Ser-Arg-Leu, at the C terminus of the protein. This is the first report of a cholesterol biosynthetic protein which contains a consensus PTS-1, providing further evidence for the concept that early cholesterol and nonsterol isoprenoid biosynthesis may occur in the peroxisome.


A diamond trilogy: superplumes, supercontinents, and supernovae
Diamond is a remarkable mineral and has been long recognized for its unusual physical and chemical properties: robust and widespread in industry, yet regally adorned. This diversity is even greater than formally appreciated because diamond is recognized as an extraordinary recorder of astrophysical and geodynamic events that extend from the far reaches of space to Earth's deep interior. Many diamonds are natural antiques that formed in presolar supernovae by carbon vapor deposition, in asteroidal impacts and meteorite craters by shock metamorphism, and in Earth's mantle 1 to 2 billion years after planetary accretion from fluids and melts. The carbon in diamond is primordial, but there are unexplained isotopic fractionations and uncertainties in heterogeneity.


Antibiotics for preventing recurrent sore throat.
Antibiotics are sometimes used to prevent recurrent sore throat, despite concern about resistance. However, there is conflicting primary evidence regarding their effectiveness. To assess the effects of antibiotics in patients with recurrent sore throat. The Cochrane Ear, Nose and Throat Disorders Group (CENTDG) Trials Search Co-ordinator searched the CENTDG Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 5); PubMed; EMBASE; CINAHL; Web of Science; Clinicaltrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 25 June 2015. Randomised controlled trials (RCTs) of antibiotics in adults and children suffering from pre-existing recurrent sore throat, defined as three or more sore throats in a year, examining the incidence of sore throat recurrence, with follow-up of at least 12 months post-antibiotic therapy. Two authors independently assessed trial quality and extracted data. Multiple attempts to contact the authors of one study yielded no response. We identified no trials that met the inclusion criteria for the review. We discarded the majority of the references retrieved from our search following screening of the title and abstract. We formally excluded four studies following review of the full-text report. There is insufficient evidence to determine the effectiveness of antibiotics for preventing recurrent sore throat. This finding must be balanced against the known adverse effects and cost of antibiotic therapy, when considering antibiotics for this purpose. There is a need for high quality RCTs that compare the effects of antibiotics versus placebo in adults and children with pre-existing recurrent sore throat on the following outcomes: incidence of sore throat recurrence, adverse effects, days off work and absence from school, and the incidence of complications. Future studies should be conducted and reported according to the CONSORT statement.


Envelope glycoproteins of human immunodeficiency virus type 1: profound influences on immune functions.
Infection by human immunodeficiency virus type 1 (HIV-1) leads to progressive destruction of the CD4+ T-cell subset, resulting in immune deficiency and AIDS. The specific binding of the viral external envelope glycoprotein of HIV-1, gp120, to the CD4 molecules initiates viral entry. In the past few years, several studies have indicated that the interaction of HIV-1 envelope glycoprotein with cells and molecules of the immune system leads to pleiotropic biological effects on immune functions, which include effects on differentiation of CD34+ lymphoid progenitor cells and thymocytes, aberrant activation and cytokine secretion patterns of mature T cells, induction of apoptosis, B-cell hyperactivity, inhibition of T-cell dependent B-cell differentiation, modulation of macrophage functions, interactions with components of complement, and effects on neuronal cells. The amino acid sequence homologies of the envelope glycoproteins with several cellular proteins have suggested that molecular mimicry may play a role in the pathogenesis of the disease. This review summarizes work done by several investigators demonstrating the profound biological effects of envelope glycoproteins of HIV-1 on immune system cells. Extensive studies have also been done on interactions of the viral envelope proteins with components of the immune system which may be important for eliciting a "protective immune response." Understanding the influences of HIV-1 envelope glycoproteins on the immune system may provide valuable insights into HIV-1 disease pathogenesis and carries implications for the trials of HIV-1 envelope protein vaccines and immunotherapeutics.


Quantitating error in blood flow measurements with radioactive microspheres.
Accurate determination of the reproducibility of measurements using the microsphere technique is important in assessing differences in blood flow to different organs or regions within organs, as well as changes in perfusion under various experimental conditions. The sources of error of the technique are briefly reviewed. In addition, we derived a method for combining quantifiable sources of error into a single estimate that was evaluated experimentally by simultaneously injecting eight or nine sets of microspheres (each with a different radionuclide label) into four anesthetized dogs. Each nuclide was used to calculate blood flow in 145-190 myocardial regions. We compared each flow determination (using a single nuclide label) with a weighted mean for the piece (based on the remaining nuclides). The difference was defined as "measured" error. In all, there were a total of 5,975 flow observations. We compared measured error with theoretical estimates based on the Poisson error of radioactive disintegration and microsphere entrapment, nuclide separation error, and reference flow error. We found that combined estimates based on these sources completely accounted for measured error in the relative distribution of microspheres. In addition, our estimates of the error in measuring absolute flows (which were established using microsphere reference samples) slightly, but significantly, underestimated measured error in absolute flow.