The experiences of districts in implementing a national incentive programme to promote safe delivery in Nepal.
Nepal's Safe Delivery Incentive Programme (SDIP) was introduced nationwide in 2005 with the intention of increasing utilisation of professional care at childbirth. It provided cash to women giving birth in a health facility and an incentive to the health provider for each delivery attended, either at home or in the facility. We explored early implementation of the programme at the district-level to understand the factors that have contributed to its low uptake. We conducted in ten study districts a series of key informant interviews and focus group discussions with staff from health facilities and the district health office and other stakeholders involved in implementation. Manual content analysis was used to categorise data under emerging themes. Problems at the central level imposed severe constraints on the ability of district-level actors to implement the programme. These included bureaucratic delays in the disbursement of funds, difficulties in communicating the policy, both to implementers and the wider public and the complexity of the programme's design. However, some district implementers were able to cope with these problems, providing reasons for why uptake of the programme varied considerably between districts. Actions appeared to be influenced by the pressure to meet local needs, as well individual perceptions and acceptance of the programme. The experience also sheds light on some of the adverse effects of the programme on the wider health system. The success of conditional cash transfer programmes in Latin America has led to a wave of enthusiasm for their adoption in other parts of the world. However, context matters and proponents of similar programmes in south Asia should give due attention to the challenges to implementation when capacity is weak and health services inadequate.


Molecular evidence from ascidians for the evolutionary origin of vertebrate cranial sensory placodes.
Cranial sensory placodes are specialised areas of the head ectoderm of vertebrate embryos that contribute to the formation of the cranial sense organs and associated ganglia. Placodes are often considered a vertebrate innovation, and their evolution has been hypothesised as one key adaptation underlying the evolution of active predation by primitive vertebrates. Here, we review recent molecular evidence pertinent to understanding the evolutionary origin of placodes. The development of vertebrate placodes is regulated by numerous genes, including members of the Pax, Six, Eya, Fox, Phox, Neurogenin and Pou gene families. In the sea squirt Ciona intestinalis (a basal chordate and close relative of the vertebrates), orthologues of these genes are deployed in the development of the oral and atrial siphons, structures used for filter feeding by the sessile adult. Our interpretation of these findings is that vertebrate placodes and sea squirt siphon primordia have evolved from the same patches of specialised ectoderm present in the common ancestor of the chordates.


Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis.
Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are critical agents used to halt the progression from multidrug-resistant tuberculosis to extensively resistant disease; however, fluoroquinolone resistance is emerging and new ways to bypass resistance are required. To better explain known differences in fluoroquinolone action, the crystal structures of the WT Mtb DNA gyrase cleavage core and a fluoroquinolone-sensitized mutant were determined in complex with DNA and five fluoroquinolones. The structures, ranging from 2.4- to 2.6-Å resolution, show that the intrinsically low susceptibility of Mtb to fluoroquinolones correlates with a reduction in contacts to the water shell of an associated magnesium ion, which bridges fluoroquinolone-gyrase interactions. Surprisingly, the structural data revealed few differences in fluoroquinolone-enzyme contacts from drugs that have very different activities against Mtb. By contrast, a stability assay using purified components showed a clear relationship between ternary complex reversibility and inhibitory activities reported with cultured cells. Collectively, our data indicate that the stability of fluoroquinolone/DNA interactions is a major determinant of fluoroquinolone activity and that moieties that have been appended to the C7 position of different quinolone scaffolds do not take advantage of specific contacts that might be made with the enzyme. These concepts point to new approaches for developing quinolone-class compounds that have increased potency against Mtb and the ability to overcome resistance.


Tight association of DNA polymerase alpha with granular structures in the nuclear matrix of chick embryo cell: immunocytochemical detection with monoclonal antibody against DNA polymerase alpha.
Immunofluorescent methods using a monoclonal antibody against chick DNA polymerase alpha and a rabbit antibody against chick DNA polymerase beta demonstrated that both DNA polymerases alpha and beta are present mainly in nuclei of cultured chick embryo cells. Fluorescence produced by anti-DNA polymerase alpha was more intense in the small granules than in other parts of the nucleus but, fluorescence produced by anti-DNA polymerase beta was distributed evenly in the nucleus. Cells first were treated with Nonidet P-40, followed by treatment with 50 micrograms/ml pancreatic DNase and 2 M NaCl in order to prepare the nuclear matrix. Fluorescence produced by anti-DNA polymerase alpha was still detectable in the granules after these treatments, but most of the fluorescence produced by anti-DNA polymerase beta disappeared. Our results indicate that a part of DNA polymerase alpha is tightly bound to a special structure present in the nuclear matrix which presumably is the DNA replication machinery.


Outcomes following cataract surgery in choroideremia.
PurposeTo present a case series of cataract surgery outcomes in choroideremia eyes with an emphasis on the safety of this common operation in advanced stages of the disease.MethodsA single centre retrospective interventional case series comprising six patients with varying degrees of visual loss secondary to choroideremia underwent cataract surgery at a single tertiary eye hospital. Pre- and post-operative best-corrected Snellen visual acuity, spectral domain optical coherence tomography (SD-OCT), and slit lamp examination were performed together with fundus autofluorescence (FAF) and colour fundus photographs.The prevalence of intra- or post-operative complications, post-operative visual outcome, and change in central macular thickness were recorded.ResultsThe pre-operative best-corrected Snellen visual acuity in the operated eyes ranged from 6/12 (20/40) to PL. All but one patient had either an objective or a subjective improvement in visual acuity. There was no evidence of retinal phototoxicity or post-operative cystoid macular oedema (CMO). Three patients developed early capsular fibrosis.ConclusionsAlthough the residual functioning retina in choroideremia patients may be potentially vulnerable, this report finds no evidence of iatrogenic vision loss after uncomplicated cataract surgery. This suggests that cataract surgery may be performed safely in choroideremia patients, although a guarded prognosis for visual improvement should be emphasized in the informed consent.


Evaluation context impacts neuropsychological performance of OEF/OIF veterans with reported combat-related concussion.
Although soldiers of Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) encounter combat-related concussion at an unprecedented rate, relatively few studies have examined how evaluation context, insufficient effort, and concussion history impact neuropsychological performances in the years following injury. The current study explores these issues in a sample of 119 U.S. veterans (OEF/OIF forensic concussion, n = 24; non-OEF/OIF forensic concussion, n = 20; OEF/OIF research concussion, n = 38; OEF/OIF research without concussion, n = 37). The OEF/OIF forensic concussion group exhibited significantly higher rates of insufficient effort relative to the OEF/OIF research concussion group, but a comparable rate of insufficient effort relative to the non-OEF/OIF forensic concussion group. After controlling for effort, the research concussion and the research non-concussion groups demonstrated comparable neuropsychological performance. Results highlight the importance of effort assessment among OEF/OIF and other veterans with concussion history, particularly in forensic contexts.


Effect of cancer surgery complexity on short-term outcomes, risk predictions, and hospital comparisons.
Concern exists that oncologic surgical complexity is not adequately captured by the primary procedure code alone. Our objectives were to characterize the association between secondary procedures and 30-day outcomes, evaluate the effect of surgical complexity on risk predictions, and assess the influence of surgical complexity on hospital-quality comparisons. Patients who underwent colon, rectal, or pancreatic resection for cancer (2007-2011) were identified from the American College of Surgeons NSQIP. Complexity was assessed by creating categorical complexity variables using secondary procedure codes and using total work relative value units. Regression methods were used to evaluate surgical complexity and hospital-quality comparisons. Patients had at least one secondary procedure documented in 48.0% of colon, 55.5% of rectal, and 63.1% of pancreatic cases. Surgical complexity variables were associated with worse outcomes across nearly all complications assessed. For example, serious morbidity was increased after an index colon resection with a synchronous liver resection (odds ratio = 1.39; 95% CI, 1.10-1.76) and a pancreatic resection with vascular reconstruction (odds ratio = 1.21; 95% CI, 1.01-1.45). Based on discrimination improvement indices and the likelihood ratio test, model-based predictions were enhanced with the addition of secondary surgical complexity variables, as well as total work relative value units, for nearly all procedures and outcomes assessed. Models that included total work relative value units had similar or marginally better discrimination compared with models with secondary procedure categories. Hospital performance did not change substantially after complexity adjustment. Surgical complexity adjustment is feasible and improves risk estimation of 30-day postoperative outcomes for colon, rectal, and pancreatic resections for cancer. Oncology-specific risk-adjustment models should include complexity adjustment using secondary procedure codes.


Comparison of somatostatin receptor expression in human gliomas and medulloblastomas.
The expression of the five somatostatin receptor subtypes, sst1-5 was compared on tissue containing glial tumours (glioblastomas or oligodendrogliomas), medulloblastomas, and on normal human cortex. By semiquantitative reverse transcription coupled to polymerase chain reaction, the receptor expression profiles were high in cortex and in tissue containing oligodendrogliomas. It was moderate in medulloblastomas. Tissue containing glioblastomas displayed lower expression of somatostatin receptor subtypes, sst1 and sst3 being mostly expressed. By 125I-Tyr0DTrp8 somatostatin-14 or 125I-Leu8DTrp22 Tyr25 somatostatin-28 autoradiography combined with synaptophysin immunohistochemistry, it was possible to differentiate between isolated tumoral cell component infiltrating the cerebral parenchyma (cortex or white matter) and tumoral tissue (without residual parenchyma) in glioblastomas or oligodendrogliomas. Glial tumoral tissue per se presented few somatostatin receptors. By contrast, medulloblastoma tumoral cells exhibited numerous octreotide sensitive somatostatin receptors. sst2 immunocytochemistry demonstrated immunostaining of neuronal cells and neuropile; sst2 and sst3 immunostaining was identified on glioblastoma proliferating vessels endothelial cells and on medulloblastomas tumoral cells. Faint sst2 immunostaining among glial tumoral cells was due to microglia, while glioma cells did not significantly stain. In summary, medulloblastoma tumoral cells express sst2/sst3 receptors at a high level while glioma cells do not. In gliomas, sst expression is restricted to endothelial cells on proliferating vessels (displaying both sst2 and sst3 receptors), including parenchyma and reactive microglia (only sst2). The differential expression of sst2/sst3 receptors on gliomas and medulloblastomas has implications for the therapy of these tumours.


Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease.
BCR-ABL is proposed to impair cell-cycle control by disabling p27, a tumor suppressor that inhibits cyclin-dependent kinases. We show that in cell lines p27 expression is inversely correlated with expression of SKP2, the F-box protein of SCF(SKP2) (SKP1/Cul1/F-box), the E3 ubiquitin ligase that promotes proteasomal degradation of p27. Inhibition of BCR-ABL kinase causes G(1) arrest, down-regulation of SKP2, and accumulation of p27. Ectopic expression of wild-type SKP2, but not a mutant unable to recognize p27, partially rescues cell-cycle progression. A similar regulation pattern is seen in cell lines transformed by FLT3-ITD, JAK2(V617F), and TEL-PDGFRbeta, suggesting that the SKP2/p27 conduit may be a universal target for leukemogenic tyrosine kinases. Mice that received transplants of BCR-ABL-infected SKP2(-/-) marrow developed a myeloproliferative syndrome but survival was significantly prolonged compared with recipients of BCR-ABL-expressing SKP2(+/+) marrow. SKP2(-/-) leukemic cells demonstrated higher levels of nuclear p27 than SKP2(+/+) counterparts, suggesting that the attenuation of leukemogenesis depends on increased p27 expression. Our data identify SKP2 as a crucial mediator of BCR-ABL-induced leukemogenesis and provide the first in vivo evidence that SKP2 promotes oncogenesis. Hence, stabilization of p27 by inhibiting its recognition by SCF(SKP2) may be therapeutically useful.


Cardiac Magnetic Resonance T1-Mapping of the Myocardium: Technical Background and Clinical Relevance.
Myocardial T1-mapping has become feasible over the past decade as emerging technological magnetic resonance imaging advances enable increasingly rapid and reliable acquisition techniques. A variety of T1-mapping sequences are in development, with most allowing for the acquisition of a single-slice T1-map in a single breath-hold. The development of these protocols has spurred investigation into a wide range of potential clinical uses, including the characterization of cardiomyopathies. Although native T1-mapping provides superior tissue characterization, postcontrast T1-mapping is still indispensable for extracellular volume quantification. Ongoing and future studies should investigate the reliability, reproducibility, accuracy, and precision of available techniques and establish disease-specific reference values for T1-mapping-based parameters.


Monocyte subset distribution in patients with stable atherosclerosis and elevated levels of lipoprotein(a).
Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100-containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16-), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 ± 3.8% vs 5.2 ± 3.0%; P = .026), whereas CM (82.6 ± 6.5% vs 82.0 ± 6.8%; P = .73) and NCM (10.5 ± 5.3 vs 12.8 ± 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease.


Quantitative autonomic testing in the management of botulism.
Even with mild neurological signs, patients with botulism frequently complain of autonomic symptoms. This study aimed at the evaluation of sudomotor and cardiovascular reflex functions by quantitative autonomic testing (QAT), which may identify patients with autonomic involvement but otherwise benign clinical presentation. Five patients with food-borne botulism were subjected to a structured questionnaire on autonomic symptoms, cardiac and neurological examination, and QAT after a median of 2 weeks (baseline) and 12 weeks (follow-up) post intoxication. For calculation of haemodynamic and cardiovascular autonomic parameters, we used the Task Force((R)) Monitor (Version 2.1, CNSystems, Graz, Austria). Cardiovagal function was assessed by Ewing's test battery. Autonomic complaints were more pronounced than neurological symptoms. Baseline tests revealed widely abnormal sudomotor function and marked impairment of heart rate variation and blood pressure response to standing. Prominent features of cardiovascular failure were high resting heart rate, supine hypertension, orthostatic hypotension, and impaired baroreflex function. Three patients reported inability to keep up with their routine amount of physical work. Based on the baseline QAT results, these three patients were instructed to engage in physical activity but avoid physical strain until there was considerable improvement. On follow-up, fatigue was the most frequent residual complaint, sympathetic skin responses were present, and cardiovascular QAT results were significantly improved and did not differ from those of ten control subjects. QAT identified autonomic involvement in botulism patients with otherwise benign neurological presentation. Comprehensive evaluation of autonomic failure may provide useful information for the management of botulism.


Addressing the caries dilemma: detection and intervention with a disclosing agent.
This study was undertaken after a joint symposium (in March 1993) of the operative section of the American Association for Dental Research and the cariology and diagnostic groups of the International Association for Dental Research called for investigation into new diagnostic modalities to determine and standardize criteria for reliable caries detection. As the incidence, prevalence, and progression rate of caries decline in Western countries, concern grows about the technical and clinical development involved in teaching dental students to diagnose the status and stage of carious lesions reliably. In this in vitro study, the disclosing agent Cari-D-Tech (Gresco Product Inc., Stafford, TX) was tested to validate its efficacy based on histologic specificity as its mode of detecting infected dentin. Extracted human teeth with clinical caries were sectioned into representative paired samples to create two groups. After dental excavation, with or without use of the disclosing agent, the teeth were coded to identify the method of removing caries. The coded samples were prepared to provide histologic specimens. Results showed that all infected dentin was removed, demonstrating the efficacy of this disclosing agent.


The experience of altered states of consciousness in shamanic ritual: the role of pre-existing beliefs and affective factors.
Much attention has been paid recently to the role of anomalous experiences in the aetiology of certain types of psychopathology, e.g. in the formation of delusions. We examine, instead, the top-down influence of pre-existing beliefs and affective factors in shaping an individual's characterisation of anomalous sensory experiences. Specifically we investigated the effects of paranormal beliefs and alexithymia in determining the intensity and quality of an altered state of consciousness (ASC). Fifty five participants took part in a sweat lodge ceremony, a traditional shamanic ritual which was unfamiliar to them. Participants reported significant alterations in their state of consciousness, quantified using the 'APZ' questionnaire, a standardized measure of ASC experience. Participants endorsing paranormal beliefs compatible with shamanic mythology, and those showing difficulty identifying feelings scored higher on positive dimensions of ASC experience. Our findings demonstrate that variation in an individual's characterisation of anomalous experiences is nuanced by pre-existing beliefs and affective factors.


DUX4 differentially regulates transcriptomes of human rhabdomyosarcoma and mouse C2C12 cells.
Facioscapulohumeral muscular dystrophy (FSHD) is linked to the deletion of the D4Z4 arrays at chromosome 4q35. Recent studies suggested that aberrant expression of double homeobox 4 (DUX4) from the last D4Z4 repeat causes FSHD. The aim of this study is to determine transcriptomic responses to ectopically expressed DUX4 in human and mouse cells of muscle lineage. We expression profiled human rhabdomyosarcoma (RD) cells and mouse C2C12 cells transfected with expression vectors of DUX4 using the Affymetrix Human Genome U133 Plus 2.0 Arrays and Mouse Genome 430 2.0 Arrays, respectively. A total of 2267 and 150 transcripts were identified to be differentially expressed in the RD and C2C12 cells, respectively. Amongst the transcripts differentially expressed in the RD cells, MYOD and MYOG (2 fold, p<0.05), and six MYOD downstream targets were up-regulated in RD but not C2C12 cells. Furthermore, 13 transcripts involved in germline function were dramatically induced only in the RD cells expressing DUX4. The top 3 IPA canonical pathways affected by DUX4 were different between the RD (inflammation, BMP signaling and NRF-2 mediated oxidative stress) and the C2C12 cells (p53 signaling, cell cycle regulation and cellular energy metabolism). Amongst the 40 transcripts shared by the RD and C2C12 cells, UTS2 was significantly induced by 76 fold and 224 fold in the RD and C2C12 cells, respectively. The differential expression of MYOD, MYOG and UTS2 were validated using real-time quantitative RT-PCR. We further validated the differentially expressed genes in immortalized FSHD myoblasts and showed up-regulation of MYOD, MYOG, ZSCAN4 and UTS2. The results suggest that DUX4 regulates overlapped and distinct groups of genes and pathways in human and mouse cells as evident by the selective up-regulation of genes involved in myogenesis and gametogenesis in human RD and immortalized cells as well as the different molecular pathways identified in the cells.


Preoperative tyrosine kinase inhibition as an adjunct to debulking nephrectomy.
Since the introduction of tyrosine kinase inhibitors (TKI), treatment of metastatic renal cell carcinoma (RCC) has undergone dramatic changes. However, the use of TKI therapy in adjunctive settings remains to be defined. We present a single-institution experience of patients who received preoperative TKI before nephrectomy for metastatic or unresectable disease. The records of 9 patients with locally advanced or metastatic RCC treated with TKI therapy before nephrectomy at the University of North Carolina were reviewed. All procedures and radiographic images were performed at 1 institution. The cases were surveyed for the effect of TKI on tumor burden and surgical approach and timing. The patients received systemic therapy with either sorafenib or sunitinib before proceeding to nephrectomy on clinical trials for metastatic disease or as the standard of care. The surgery was well tolerated by all patients, without an apparent effect from TKI therapy on the surgical technique or complications. Responses were observed in the primary tumor, as well as in the metastatic sites. Neoadjuvant TKI therapy can induce responses in the primary tumor and has the potential advantage of cytoreduction when administered before nephrectomy for RCC. This setting also potentially provides an opportunity to evaluate the TKI responsiveness of patients with metastatic disease. However, prospective trials evaluating adjunctive surgical approaches to locally advanced and metastatic RCC are needed to determine the significant benefits of TKI therapy and to define the optimal agent, timing of therapy, and disease stage to derive benefit for preoperative therapy.


[Long-term use of narcotics in pain therapy].
From 1. 1. 1976 to 30. 6. 1987, a total of 25,611 prescriptions for narcotics were obtained from pharmacies by 4131 persons living in a town of 250,000 inhabitants in the Federal Republic of Germany. 2412 patients (58.4%) had been prescribed narcotics on only one occasion, 3178 patients (76.9%) over a limited period of six months, presumably for acute pain. Only 520 patients (12.6%) received, over a period of at least six months, five or more narcotic prescriptions per six months. Reasons for the latter prescriptions were malignant tumours in 273 (6.6%) and chronic pain due to benign diseases in 144 (3.5%). In 21 patients (0.5%) the narcotic dosage had risen over two years, presumably because of the development of tolerance. 19 patients had been on narcotics for at least eight years, without their doctor diagnosing addiction. The data suggest that, in prescribing narcotics for patients with incurable disease, the risk of addiction should play no role.


Prevalence and clinical significance of koala retrovirus in two South Australian koala (Phascolarctos cinereus) populations.
Koala retrovirus (KoRV-A) is 100 % prevalent in northern Australian (Queensland and New South Wales) koala populations, where KoRV-B has been associated with Chlamydia pecorum disease and the development of lymphosarcoma. In southern populations (Victoria and South Australia), KoRV-A is less prevalent and KoRV-B has not been detected in Victoria, while the current prevalence in South Australian populations is unknown but is thought to be low. This study aimed to determine (i) the prevalence of KoRV in the two largest South Australian koala populations [Kangaroo Island (KI) and Mount Lofty Ranges (MLR)], (ii) KoRV subtype and (iii) if an association between KoRV and C. pecorum exists. Wild koalas were sampled in KI ( n =170) between 2014 and 2017 and in MLR ( n =75) in 2016. Clinical examinations were performed, with blood collected for KoRV detection and typing by PCR. KoRV prevalence was 42.4 % [72/170, 95 % confidence interval (CI): 34.9-49.8 %] in KI and 65.3 % (49/75, 95 % CI: 54.6-76.1 %) in MLR. Only KoRV-A, and not KoRV-B, was detected in both populations. In MLR, there was no statistical association between KoRV and C. pecorum infection (P =0.740), or KoRV and C. pecorum disease status ( P=0.274), although KoRV-infected koalas were more likely to present with overt C. pecorum disease than subclinical infection (odds ratio: 3.15, 95 % CI: 0.91-5.39). KoRV-A is a prevalent pathogen in wild South Australian koala populations. Future studies should continue to investigate KoRV and C. pecorum associations, as the relationship is likely to be complex and to differ between the northern and southern populations.


Simvastatin in traumatic brain injury: effect on brain edema mechanisms.
Traumatic brain injury causes deleterious brain edema, leading to high mortality and morbidity. Brain edema exacerbates neurologic deficits and may be attributable to the breakdown of endothelial cell junction protein, leukocyte infiltration, and matrix metalloproteinase activation. These all contribute to loss of blood-brain barrier integrity. The pleiotropic effects of statins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, may inhibit posttraumatic brain edema. We therefore investigated the effect of acute simvastatin on neurologic deficits, cerebral edema, and its origins. Randomized laboratory animal study. University-affiliated research laboratory. Male Sprague-Dawley rats. Rats were subjected to lateral fluid percussion traumatic brain injury. Our preliminary dose-effect study indicated that 37.5 mg/kg simvastatin, administered orally 1 hr and 6 hrs after traumatic brain injury, has the greatest anti-edematous effect. This dose was used to study its effects on brain edema and on its mechanisms. We first assessed the effects of simvastatin 24 hrs after traumatic brain injury on brain edema, brain claudin-5 expression, and the vascular endothelial-cadherin (pTyr731)/total vascular endothelial-cadherin ratio, matrix metalloproteinase-9 activity, intercellular adhesion molecule-1 expression, and polymorphonuclear neutrophil infiltration. We also evaluated blood-brain barrier permeability by measuring Evans blue and fluorescein sodium salt extravasation into the cerebral parenchyma. We then investigated whether simvastatin reduces neurologic deficits, edema, and blood-brain barrier permeability earlier than 24 hrs; these effects were evaluated 6 hrs after traumatic brain injury. The anti-edematous effect of simvastatin 24 hrs after traumatic brain injury was associated with increased claudin-5 and decreased intercellular adhesion molecule-1, polymorphonuclear neutrophil infiltration, and blood-brain barrier permeability, with no effect on matrix metalloproteinase-9 activity or vascular endothelial-cadherin phosphorylation. Earlier, 6-hrs after traumatic brain injury, simvastatin reduced neurologic deficits, cerebral edema, and blood-brain barrier permeability. Simvastatin could be a new therapy for reducing posttraumatic edema by preventing damage to tight junctions and neutrophil infiltration into the parenchyma, thus preserving blood-brain barrier integrity.


Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality.
The proliferation of counterfeit and poor-quality drugs is a major public health problem; especially in developing countries lacking adequate resources to effectively monitor their prevalence. Simple and affordable field methods provide a practical means of rapidly monitoring drug quality in circumstances where more advanced techniques are not available. Therefore, we have evaluated refractometry, colorimetry and a technique combining both processes as simple and accurate field assays to rapidly test the quality of the commonly available antimalarial drugs; artesunate, chloroquine, quinine, and sulfadoxine. Method bias, sensitivity, specificity and accuracy relative to high-performance liquid chromatographic (HPLC) analysis of drugs collected in the Lao PDR were assessed for each technique. The HPLC method for each drug was evaluated in terms of assay variability and accuracy. The accuracy of the combined method ranged from 0.96 to 1.00 for artesunate tablets, chloroquine injectables, quinine capsules, and sulfadoxine tablets while the accuracy was 0.78 for enterically coated chloroquine tablets. These techniques provide a generally accurate, yet simple and affordable means to assess drug quality in resource-poor settings.


Maternal near miss in low-resource areas.
To describe the Global Network Near-Miss Maternal Mortality System and its application in seven sites. In a population-based study, pregnant women eligible for enrollment in the Maternal and Newborn Health Registry at seven sites (Democratic Republic of the Congo; Guatemala; Belagavi and Nagpur, India; Kenya; Pakistan; and Zambia) between January 2014 and April 2016 were screened to identify those likely to have a near-miss event. The WHO maternal near-miss criteria were modified for low-resource settings. The ratio of near-miss events to maternal deaths was calculated. Among 122 707 women screened, 18 307 (15.0%) had a potential near-miss event, of whom 4866 (26.6%; 4.0% of all women) had a near-miss maternal event. The overall maternal mortality ratio was 155 per 100 000 live births. The ratio of near-miss events to maternal deaths was 26 to 1. The most common factors involved in near-miss cases were the hematologic/coagulation system, infection, and cardiovascular system. By using the Global Network Near-Miss Maternal Mortality System, large numbers of women were screened for near-miss events, including those delivering at home or a low-level maternity clinic. The 4.0% incidence of near-miss maternal mortality is similar to previously reported data. The ratio of 26 near-miss cases to 1 maternal death suggests that near miss might evaluate the impact of interventions more efficiently than maternal mortality.


Abatement of Polychoro-1,3-butadienes in Aqueous Solution by Ozone, UV Photolysis, and Advanced Oxidation Processes (O3/H2O2 and UV/H2O2).
The abatement of 9 polychloro-1,3-butadienes (CBDs) in aqueous solution by ozone, UV-C(254 nm) photolysis, and the corresponding advanced oxidation processes (AOPs) (i.e., O3/H2O2 and UV/H2O2) was investigated. The following parameters were determined for 9 CBDs: second-order rate constants for the reactions of CBDs with ozone (kO3) (<0.1-7.9 × 103 M-1 s-1) or with hydroxyl radicals (k•OH) (0.9 × 109 - 6.5 × 109 M-1 s-1), photon fluence-based rate constants (k') (210-2730 m2 einstein-1), and quantum yields (Φ) (0.03-0.95 mol einstein-1). During ozonation of CBDs in a natural groundwater, appreciable abatements (>50% at specific ozone doses of 0.5 gO3/gDOC to ∼100% at ≥1.0 gO3/gDOC) were achieved for tetra-CBDs followed by (Z)-1,1,2,3,4-penta-CBD and hexa-CBD. This is consistent with the magnitude of the determined kO3 and k•OH. The formation of bromate, a potentially carcinogenic ozonation byproduct, could be significantly reduced by addition of H2O2. For a typical UV disinfection dose (400 J/m2), various extents of phototransformations (10-90%) could be achieved. However, the efficient formation of photoisomers from CBDs with E/Z configuration must be taken into account because of their potential residual toxicity. Under UV-C(254 nm) photolysis conditions, no significant effect of H2O2 addition on CBDs abatement was observed due to an efficient direct phototransformation of CBDs.


GABA and the GABAA receptor.
The neurotransmitter gamma-aminobutyric acid (GABA) inhibits the activity of signal-receiving neurons by interacting with the GABAA receptor on these cells. The GABAA receptor is a channel-forming protein that allows the passage of chloride ions into the cells. Excessive GABAA activation may play a role in mediating the sedative effects of alcohol and other sedating and anesthetic agents. For example, alcohol enhances the GABAA-mediated chloride flow into cells and may thereby enhance neuronal inhibition. Alcohol's effects on the GABAA-receptor function likely involve other molecules (e.g., other neurotransmitters and proteins that add phosphate groups to the receptor [i.e., protein kinases]). Several experimental approaches also have suggested that changes in GABAA-receptor function contribute to the tolerance to and dependence on alcohol. Finally, individual differences in the GABA system may play a role in determining a person's susceptibility to developing alcohol dependence.


Sleep quality in borderline personality disorder: a cross-sectional study.
In this study, relationships between sleep quality and borderline personality disorder were examined using 2 self-report measures. Using a cross-sectional design in a sample of convenience of internal medicine outpatients, we surveyed men and women (N=76), aged 18 years or older, who were seeking nonemergent medical care during the period January 2009 to September 2009. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and borderline personality was assessed with 2 measures: the borderline personality scale of the Personality Diagnostic Questionnaire-4 (PDQ-4) and the Self-Harm Inventory (SHI). The global PSQI score was statistically significantly associated with scores on the PDQ-4 (P < .01), the SHI (P < .01), and the combination PDQ-4 and SHI (P < .01). With regard to the components of the PSQI, subjective sleep quality (P < .05), sleep duration (P < .05), and daytime dysfunction (P < .01) were all statistically significantly associated with scores on the PDQ-4, and sleep latency was statistically significantly associated with the combined PDQ-4 and SHI (P < .05). Individuals with borderline personality symptomatology demonstrate a poorer overall quality of sleep than those without these symptoms.


[Intoxications with synthetic cannabinoids].
Synthetic Cannabinoid Receptor Agonists (SCRAs) are a group of New Psychoactive Substances. They are used recreationally to mimic the effects of THC in cannabis. However, THC is a partial agonist of the CB1-receptor and SCRAs are full agonists. Because of this specificity and potency serious adverse events may occur among which psychological, cardiovascular, and gastro-intestinal symptoms. Because of the low incidence in the Netherlands clinical information on SCRA intoxications is limited, making diagnosis and treatment difficult. In this clinical lesson, two cases of SCRA intoxications are described followed by treatment recommendations.


The potential usage of caffeic acid phenethyl ester (CAPE) against chemotherapy-induced and radiotherapy-induced toxicity.
Protection of the patients against the side effects of chemotherapy and radiotherapy regimens has attracted increasing interest of clinicians and practitioners. Caffeic acid phenethyl ester (CAPE), which is extracted from the propolis of honeybee hives as an active component, specifically inhibits nuclear factor κB at micromolar concentrations and show ability to stop 5-lipoxygenase-catalysed oxygenation of linoleic acid and arachidonic acid. CAPE has antiinflammatory, antiproliferative, antioxidant, cytostatic, antiviral, antibacterial, antifungal and antineoplastic properties. The purpose of this review is to summarize in vivo and in vitro usage of CAPE to prevent the chemotherapy-induced and radiotherapy-induced damages and side effects in experimental animals and to develop a new approach for the potential usage of CAPE in clinical trial as a protective agent during chemotherapy and radiotherapy regimens.


Comprehensive decongestive therapy in postmastectomy lymphedema: an Indian perspective.
Lymphedema following breast cancer treatment is one of the most morbid conditions affecting breast cancer survivors. Currently, no therapy completely cures this condition. Comprehensive Decongestive Therapy (CDT), a novel physiotherapeutic method offers promising results in managing this condition. This therapy is being widely used in the West. Till date, there are no studies evaluating the effectiveness and feasibility of this therapy in the east. The therapeutic responses of 25 patients with postmastectomy lymphedema were analyzed prospectively in this study. Each patient received an intensive phase of therapy for eight days from trained physiotherapists, which included manual lymphatic drainage, multi layered compression bandaging, exercises, and skin care. Instruction in self management techniques were given to the patients on completion of intensive therapy. The patients were followed up for three months. Changes in the volume of the edematous limb were assessed with a geometric approximation derived from serial circumference measurements of the limb and by water displacement volumetry. Changes in skin and sub cutis thickness were assessed using high frequency ultrasound. The reduction in limb volume observed after therapy was 32.3% and 42% of the excess, by measurement and volumetry, respectively. The maximum reduction was obtained after the intensive phase. The reduction in skin and subcutis thickness of the edematous limb followed the same pattern as volume reduction. Patients could maintain the reduction obtained by strictly following the protocols of the maintenance phase. CDT combined with long-term self management is effective in treating post mastectomy lymphedema. The tropical climate is a major factor limiting the regular use of bandages by the patients.


The term 'non-radiographic axial spondyloarthritis' is much more important to classify than to diagnose patients with axial spondyloarthritis.
The term axial spondyloarthritis (axSpA) now is used frequently to describe patients with predominantly axial symptoms who fit into the spectrum of a well-recognised rheumatic disease that continues to be known as ankylosing spondylitis (AS). The 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria, developed to identify patients with early or atypical disease which could not be classified by the 1984 modified New York (mNY) criteria for AS, have led to a differentiation between non-radiographic axial spondyloarthritis (nr-axSpA) and radiographic axSpA, which is largely synonymous with AS. The main reason to distinguish between these ends of the spectrum of axSpA was that tumor necrosis factor (TNF) inhibitors (TNFi) approved for AS could obtain additional labelling for nr-axSpA and be used to treat all patients manifesting clinical features of axSpA. These two terms are distinguished by the degree of 'radiographic sacroiliitis' assessed by conventional radiography, according to the 1984 mNY criteria for AS. Since this differentiation has been shown to be not very reliable, we argue that the terms nr-axSpA and AS should only be used for classification of patients with axSpA and not as separate diagnoses. Therefore, we propose that only the term axSpA be used to diagnose patients, unless there is a meaningful medical reason to differentiate nr-axSpA from AS. The available data justify performing randomised controlled trials designed to obtain regulatory approval for therapeutic agents in patients across the entire spectrum of axSpA.


Notch1 engagement by Delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells.
Notch signaling regulates B and T lymphocyte development and T cell effector class decision. In this work, we tested whether Notch activity affects mature B cell activation and differentiation to antibody-secreting cells (ASC). We show increased frequency of ASC in cultures of splenic B cells activated with LPS or anti-CD40 when provided exogenous Notch ligand Delta-like-1 (Dll1). Our results indicate that Notch-Dll1 interaction releases a default pathway that otherwise inhibits Ig secretion upon B cell activation. Thus, Dll1 enhanced spontaneous Ig secretion by naturally activated marginal zone B and B1 cells and reversed the inhibition of ASC differentiation mediated by B cell receptor crosslinking during LPS. Moreover, suppression of Notch signaling in B cell expression of either a dominant-negative mutant form of Mastermind-like 1 or a null mutation of Notch1 not only prevented Dll1-mediated enhancement of ASC differentiation but also reduced dramatically LPS-induced Ig secretion. Finally, we show that Dll1 and Jagged-1 are differentially expressed in discrete areas of the spleen, and that the effect of Notch engagement on Ig secretion is ligand-specific. These results indicate that Notch ligands participate in the definition of the mature B cell microenvironment that influences their terminal differentiation.


Evaluating the anti-fertility potential of α-chlorohydrin on testis and spermatozoa in the adult male wild Indian house rat (Rattus rattus).
To examine the effects of α-chlorohydrin on testis and cauda epididymis in the male house rat (Rattus rattus), 24 adult male rats were segregated into two groups. Group I rats were force-fed daily by intragastric intubation with α-chlorohydrin at a single dose of 1.0 mg/100 g body weight/d for 5, 15, and 45 days. Another group was fed with distilled water, which served as the control. The treated male rats were paired with 24 adult proestrus female rats for 5 days after the last oral treatment and fertility was tested. At the end of the experiments, all of the male rats were weighed and killed by cervical dislocation. The right testes were removed, weighed, and processed for ultrastructural changes of spermatozoa from the cauda epididymis and testis under scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The seminiferous tubular area, nuclear diameter of the Sertoli and Leydig cells, percentage of spermatogonia, primary spermatocytes, secondary spermatocytes, spermatids, spermatozoa, and Sertoli cells in each group were compared morphometrically. Our results showed that the percentages of primary spermatocytes steadily increased from 5 to 15 days, but primary and secondary spermatocytes decreased significantly at 45 days. There was a steady decline in the percentages of spermatozoa and spermatids at all fixation intervals in the treated animals, but the percentages of spermatogonia and Sertoli cells increased significantly at 15 and 45 days. Seminiferous tubular areas, nuclear diameter of Leydig and Sertoli cells, and fertility rates were reduced after 45 days of treatment. SEM and TEM studies revealed severe morphological abnormalities in the spermatozoa, including deglutination of the acrosomal part, loss of head capsules, and fragmentation of tail fibrils. There was an enhanced anti-fertility effect and a lower number of implantation sites in the rats treated for 5 days. Our results validate α-chlorohydrin as a successful anti-fertility agent that prevents spermatogenesis.


Integration of 64-detector lower extremity CT angiography into whole-body trauma imaging: feasibility and early experience.
To evaluate the image quality and clinical utility of a polytrauma computed tomographic (CT) protocol that integrates lower extremity CT angiography into multiphasic whole-body trauma CT by utilizing 64-detector CT and a single contrast material bolus. This retrospective study was institutional review board approved and HIPAA compliant. Informed consent was waived. All patients who underwent CT angiography of the lower extremities integrated with multiphasic torso CT for trauma between May 2005 and September 2009 were included. Two hundred eighty-four patients met the inclusion criteria. The mechanism of trauma was blunt injury in 228 (80.3%) of 284 patients and penetrating in 56 (19.7%) of 284 patients. CT angiography encompassed the joints proximal and distal to the injured region, with scan delay fixed at 25 seconds. Two radiologists retrospectively reviewed all the extremity CT angiograms, noting the presence of vascular injury, and measured the attenuation in the lower extremity arteries. Arterial attenuation, in Hounsfield units, was measured at multiple vascular divisions, and CT angiographic results were compared with clinical outcome, and if available, repeat lower extremity CT angiographic, conventional angiographic, or surgical findings. Sensitivity and specificity with 95% confidence intervals were calculated. Sixty-three arterial injuries were identified in 44 (15.5%) of 284 patients as follows: occlusion (n = 37), narrowing (n = 9), active extravasation (n = 14), pseudoaneurysm (n= 2), and arteriovenous fistula (n = 1). Three patients underwent conventional angiography after CT angiography. Seven patients underwent surgical therapy with all CT angiographic findings confirmed. There were no injuries subsequently identified in the subgroup with a negative result at CT angiography. Of the 864 vascular divisions in which attenuation was measured, 69 (8%) of 864 had a mean attenuation less than 150 HU. Integration of lower extremity CT angiography into multiphasic whole-body trauma imaging is feasible, helps detect clinically relevant vascular injuries, and results in diagnostic image quality in the majority of patients.


Research in focus.
This section presents a brief review of articles on dental implants considered of special interest for the reader, in order to encourage the development of research, the interest for data analysis and the attention to scientific publications. Your comments are welcome. Please contact Dr Michele Nieri at email@example.com.


Social phobia and interpretation of social events.
It has been suggested that social phobia may be characterized by two interpretation biases. First, a tendency to interpret ambiguous social events in a negative fashion. Second, a tendency to interpret unambiguous but mildly negative social events in a catastrophic fashion. To assess this possibility, patients with generalized social phobia, equally anxious patients with another anxiety disorder, and non-patient controls were presented with ambiguous scenarios depicting social and non-social events, and with unambiguous scenarios depicting mildly negative social events. Interpretations were assessed by participants' answers to open-ended questions and by their rankings and belief ratings for experimenter-provided, alternative explanations. Compared to both control groups, patients with generalized social phobia were more likely to interpret ambiguous social events in a negative fashion and to catastrophize in response to unambiguous, mildly negative social events.


Fast and efficient direct formation of size-controlled nanostructures of coordination polymers based on copper(i)-iodine bearing functional pyridine terminal ligands.
We report on the direct formation of 1D nanostructures of two coordination polymers based on copper(i)-iodine double chains decorated with ethyl isonicotinate or 2-amino-5-nitropyridine as terminal ligands. The use of different reaction conditions, e.g. energy of the formation process, solvents, and/or concentration of reactants, has allowed the control of the size of the fibres and ribbons directly formed in this process going from micron- to submicron- up to nano-size. We show experiments that direct the formation of materials kinetically versus thermodynamically controlled, adjusting simple experimental parameters. Finally, a morphological study on the Cu(i)-iodine bearing 2-amino-5-nitropyridine nanofibres has confirmed their reversible molecular recognition ability towards acetic acid vapours.


An overview of the objectives of and the approaches to propensity score analyses.
The assessment of treatment effects from observational studies may be biased with patients not randomly allocated to the experimental or control group. One way to overcome this conceptual shortcoming in the design of such studies is the use of propensity scores to adjust for differences of the characteristics between patients treated with experimental and control interventions. The propensity score is defined as the probability that a patient received the experimental intervention conditional on pre-treatment characteristics at baseline. Here, we review how propensity scores are estimated and how they can help in adjusting the treatment effect for baseline imbalances. We further discuss how to evaluate adequate overlap of baseline characteristics between patient groups, provide guidelines for variable selection and model building in modelling the propensity score, and review different methods of propensity score adjustments. We conclude that propensity analyses may help in evaluating the comparability of patients in observational studies, and may account for more potential confounding factors than conventional covariate adjustment approaches. However, bias due to unmeasured confounding cannot be corrected for.


Cerebellar involvement in autism and ADHD.
The cerebellum has long been known for its importance in motor learning and coordination. However, increasing evidence supports a role for the cerebellum in cognition and emotion. Consistent with a role in cognitive functions, the cerebellum has emerged as one of the key brain regions affected in nonmotor disorders, including autism spectrum disorder and attention deficit-hyperactivity disorder. Here, we discuss behavioral, postmortem, genetic, and neuroimaging studies in humans in order to understand the cerebellar contributions to the pathogenesis of both disorders. We also review relevant animal model findings.


In vivo anticlastogenic effect of silymarin from milk thistle Silybum marianum L.
Silymarin, extracted from the seeds of Silybum marianum L. (Milk thistle), is traditionally used for treating various illnesses such as diabetes, cancer, inflammation, hepatitis, liver cirrhosis, and renal problems. Acute cytotoxicity and genotoxicity studies have been reported with ambiguous outcomes; however, its relevant anticlastogenic potential is not yet evaluated. This study was aimed to evaluate in vivo subacute anticlastogenic properties of silymarin to validate its use as a medicinal agent. Silymarin was isolated from seeds of milk thistle. Various genotoxicity bioassays of silymarin were performed using mice. First, the bone marrow cell proliferation was estimated by calculating mitotic index. Second, the chromosomal abnormalities in mice bone marrow cells were studied. Third, micronucleated polychromatic erythrocytes (MPE) test and in vivo activation of sister chromatid exchanges (SCEs) were carried out in mice bone marrow cells. Finally, primary spermatocytes were analyzed to estimate genotoxic effect of silymarin on germ cells. We found that silymarin is capable of inducing a significant increase (P ≤ 0.05) in cell proliferation of bone marrow cells. There is no increase in chromosomal aberrations following silymarin treatments. Results clearly showed that it significantly (P ≤ 0.05) decreased the MPE. Likewise, it was found to be a negative inducer of SCEs. It decreased in total abnormal metaphase, SCEs, MPE, and aberrant diakinesis. The results demonstrated that silymarin has a strong anticlastogenic activity upon mice genome in somatic and germ cells, indicating its safe use as a medicinal substance. Furthermore, it is not only safe but also has protective effect from clastogens.


Polyphenols: skin photoprotection and inhibition of photocarcinogenesis.
Polyphenols are a large family of naturally occurring plant products and are widely distributed in plant foods, such as, fruits, vegetables, nuts, flowers, bark and seeds, etc. These polyphenols contribute to the beneficial health effects of dietary products. Clinical and epidemiological studies suggest that exposure of the skin to environmental factors/pollutants, such as solar ultraviolet (UV) radiation induce harmful effects and leads to various skin diseases including the risk of melanoma and non-melanoma skin cancers. The incidence of non-melanoma skin cancer, comprising of squamous cell carcinoma and basal cell carcinoma, is a significant public health concern world-wide. Exposure of the skin to solar UV radiation results in inflammation, oxidative stress, DNA damage, dysregulation of cellular signaling pathways and immunosuppression thereby resulting in skin cancer. The regular intake of natural plant products, especially polyphenols, which are widely present in fruits, vegetables, dry legumes and beverages have gained considerable attention as protective agents against the adverse effects of UV radiation. In this article, we first discussed the impact of polyphenols on human health based on their structure-activity relationship and bioavailability. We then discussed in detail the photoprotective effects of some selected polyphenols on UV-induced skin inflammation, proliferation, immunosuppression, DNA damage and dysregulation of important cellular signaling pathways and their implications in skin cancer management. The selected polyphenols include: green tea polyphenols, pomegranate fruit extract, grape seed proanthocyanidins, resveratrol, silymarin, genistein and delphinidin. The new information on the mechanisms of action of these polyphenols supports their potential use in skin photoprotection and prevention of photocarcinogenesis in humans.


Antimicrobial susceptibility of pathogens isolated from surgical site infections in Japan: Comparison of data from nationwide surveillance studies conducted in 2010 and 2014-2015.
A nationwide survey was conducted in Japan from 2014 to 2015 to investigate the antimicrobial susceptibility of pathogens isolated from surgical site infections (SSI). The resulting data were compared with that obtained in an earlier survey, conducted in 2010. Seven main organisms were collected, and 883 isolates were studied. A significant reduction in methicillin resistance was observed among Staphylococcus aureus isolates, dropping from 72.5% in 2010 to 53.8% in 2014-2015 (p < 0.001). MRSA isolates with a vancomycin minimum inhibitory concentration (MIC) of 2 μg/mL accounted for 1.2% of all MRSA isolates, which was significantly lower than in 2010 (9.7%, p = 0.029). Of the Escherichia coli isolates, 23.0% produced an extended spectrum β-lactamase (ESBL) in the 2014-2015 survey, which was a significant increase from 9.5% in 2010 (p = 0.011). The geometric mean MICs for ESBL-producing isolates were 0.07 μg/mL for meropenem, 9.51 μg/mL for tazobactam/piperacillin, 0.15 μg/mL for flomoxef, and 1.56 μg/mL for gentamycin. There was a significant increase in the isolation rate of non-fragilis Bacteroides among Bacteroides fragilis group species between the two study periods (35.2% vs. 53.1%, p = 0.007). More than 90% of isolates belonging to the B. fragilis group remained susceptible to tazobactam/piperacillin, meropenem, and metronidazole. In contrast, lower levels of susceptibility were observed for cefmetazole (49.6%), moxifloxacin (61.9%), and clindamycin (46.9%). Non-fragilis Bacteroides isolates had lower rates of antibiotic susceptibility compared with B. fragilis. Overall, the surveillance data clarified trends in antimicrobial susceptibility for organisms commonly associated with SSI.


A comparison of fruits, vegetables, sugar-sweetened beverages, and desserts in the packed lunches of elementary school children.
An estimated 40% of children bring a packed lunch to school. These lunches are not required to meet nutrition standards. The aim of this study was to compare differences in the nutritional quality of elementary packed lunches by the presence or absence of sugar-sweetened beverages (SSB), desserts, and fruits and vegetables (FVs). Observational data for prekindergarten and kindergarten packed lunches were collected from three schools in rural Virginia for 5 consecutive school days and analyzed for macro- and micronutrients and by the presence or absence of food and beverage items. Of the 561 packed lunch observations collected, 41.7% contained no FV, 41.2% contained an SSB, and 61.1% contained a dessert. The nutrient profile of packed lunches with at least one fruit or vegetable had significantly higher levels of carbohydrate, fiber, sugar, vitamin A, and vitamin C. Packed lunches containing an SSB had significantly higher levels of sugar and vitamin C and significantly lower levels of protein, fiber, vitamin A, calcium, and iron. Packed lunches containing a dessert had significantly higher levels of energy, carbohydrate, fat, saturated fat, sodium, sugar, vitamin C, and iron and significantly lower levels of vitamin A. Additional research is needed to fully understand parent and child motivations for packing lunches and the decision processes that influence the inclusion of food items. The development of packed lunch interventions, encouragement of National School Lunch Program participation, or enactment of school policies to increase the nutritional value of packed lunches is warranted.


The centromeric protein Sgo1 is required to sense lack of tension on mitotic chromosomes.
Chromosome alignment on the mitotic spindle is monitored by the spindle checkpoint. We identify Sgo1, a protein involved in meiotic chromosome cohesion, as a spindle checkpoint component. Budding yeast cells with mutations in SGO1 respond normally to microtubule depolymerization but not to lack of tension at the kinetochore, and they have difficulty attaching sister chromatids to opposite poles of the spindle. Sgo1 is thus required for sensing tension between sister chromatids during mitosis, and its degradation when they separate may prevent cell cycle arrest and chromosome loss in anaphase, a time when sister chromatids are no longer under tension.


Evolutionary trajectory of SARS-CoV-2 and emerging variants.
The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more recently, the independent evolution of multiple SARS-CoV-2 variants has generated renewed interest in virus evolution and cross-species transmission. While all known human coronaviruses (HCoVs) are speculated to have originated in animals, very little is known about their evolutionary history and factors that enable some CoVs to co-exist with humans as low pathogenic and endemic infections (HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1), while others, such as SARS-CoV, MERS-CoV and SARS-CoV-2 have evolved to cause severe disease. In this review, we highlight the origins of all known HCoVs and map positively selected for mutations within HCoV proteins to discuss the evolutionary trajectory of SARS-CoV-2. Furthermore, we discuss emerging mutations within SARS-CoV-2 and variants of concern (VOC), along with highlighting the demonstrated or speculated impact of these mutations on virus transmission, pathogenicity, and neutralization by natural or vaccine-mediated immunity.


Ambassadors of hope, research pioneers and agents of change-individuals' expectations and experiences of taking part in a randomised trial of an innovative health technology: longitudinal qualitative study.
While a growing body of research has explored why people take part in clinical trials, this research has not considered how people's understandings, motivations and agendas might influence their conduct during a trial. This is an important area of enquiry because it is now widely recognised that an intervention might lead to different clinical outcomes when delivered as part of a trial than when implemented in routine clinical practice; however, the reasons for this are not fully understood. We interviewed 24 individuals who took part in a trial of an innovative health technology under development for people with type 1 diabetes which automatically regulates blood glucose: the closed-loop system. Participants were interviewed following randomisation to a closed-loop and at trial closeout. Participants provided complex agendas for taking part in which altruistic and self-interested considerations were often inseparable. Many described belonging to a wider diabetes community and being beneficiaries of others' participation in research and how this had given rise to attendant citizenship obligations. Participants also shared the excitement and pride they experienced from contributing to research which situated them at the forefront of technological innovation and enabled them to present themselves to others, by virtue of their trial participation, as ambassadors of hope and research pioneers. Given their desire to support the progression of a potentially life-changing technology, and be part of that innovation, participants, at follow-up, described having made extra effort during the trial. Specifically, participants described having been more focused on their diabetes management to help create conditions in which the closed-loop could work most effectively to optimize their blood glucose control. Our findings contribute a new dimension to understandings of trial effects; specifically, we argue that, to aid interpretation of trial outcomes, participants' understandings and motivations for participation need to be considered. We highlight the potential pertinence of our findings in the contemporary era of bio-citizenship where, increasingly, people are driving research agendas and see themselves as co-producers of knowledge. We also recommend a new concept be introduced into the literature-'the altruselfish agenda'-to recognise potential inseparability of self-interested and altruistic motivations. ClinicalTrials.gov, NCT02523131 . Registered on 14 August 2015.


New insights into cathepsin D in mammary tissue development and remodeling.
Cathepsin D (CatD) is a lysosomal aspartyl endopeptidase originally considered a "house keeping enzyme" involved in the clearance of unwanted proteins. However, recent studies have revealed CatD's involvement in apoptosis and autophagy, thus signifying an important function in the proper development and maintenance of multi-cellular organs. In the mammary gland, matrix degradation and the remodeling process are orchestrated by proteolytic enzymes, but the role of CatD at distinct developmental stages has remained mostly unexplored. Based on our previous studies we sought to address the role of this endopeptidase in mammary gland development and remodeling. By employing a mouse model, we report a previously unidentified participation of CatD in different stages of mammary gland development. Our findings reveal that CatD undergoes distinct protein processing at different stages of mammary gland development, and this customized processing results in differential enzymatic activity (constitutive and low pH activatable) best fitting particular stage(s) of development. In addition, at the onset of involution the N-glycan structure of this endopeptidase switches from a mixed high mannose and hybrid structure to an almost exclusively high mannose type, but reverts back to the original N-glycan composition by day 4 of involution. Our findings illuminate (at least in part) the "raison d'être" for CatD's numerous and highly regulated proteolytic processing steps from the pro-form to the mature enzyme. In the mammary gland, specific cleavage product(s) perform specialized function(s) befitting each stage of remodeling. It is noteworthy that deregulated synthesis, secretion and glycosylation of CatD are hallmarks of cancer progression. Thus, identifying the role of CatD in a dynamic normal tissue undergoing highly regulated cycles of remodeling could provide valuable information illuminating the deregulation of CatD associated with cancer development and metastasis.


Stereoselective Inhibition of the hERG1 Potassium Channel.
A growing number of drugs have been shown to prolong cardiac repolarization, predisposing individuals to life-threatening ventricular arrhythmias known as Torsades de Pointes. Most of these drugs are known to interfere with the human ether à-gogo related gene 1 (hERG1) channel, whose current is one of the main determinants of action potential duration. Prolonged repolarization is reflected by lengthening of the QT interval of the electrocardiogram, as seen in the suitably named drug-induced long QT syndrome. Chirality (presence of an asymmetric atom) is a common feature of marketed drugs, which can therefore exist in at least two enantiomers with distinct three-dimensional structures and possibly distinct biological fates. Both the pharmacokinetic and pharmacodynamic properties can differ between enantiomers, as well as also between individuals who take the drug due to metabolic polymorphisms. Despite the large number of reports about drugs reducing the hERG1 current, potential stereoselective contributions have only been scarcely investigated. In this review, we present a non-exhaustive list of clinically important molecules which display chiral toxicity that may be related to hERG1-blocking properties. We particularly focus on methadone cardiotoxicity, which illustrates the importance of the stereoselective effect of drug chirality as well as individual variations resulting from pharmacogenetics. Furthermore, it seems likely that, during drug development, consideration of chirality in lead optimization and systematic assessment of the hERG1 current block with all enantiomers could contribute to the reduction of the risk of drug-induced LQTS.


A Novel Bacteriophage Exclusion (BREX) System Encoded by the pglX Gene in Lactobacillus casei Zhang.
The bacteriophage exclusion (BREX) system is a novel prokaryotic defense system against bacteriophages. To our knowledge, no study has systematically characterized the function of the BREX system in lactic acid bacteria. Lactobacillus casei Zhang is a probiotic bacterium originating from koumiss. By using single-molecule real-time sequencing, we previously identified N6-methyladenine (m6A) signatures in the genome of L. casei Zhang and a putative methyltransferase (MTase), namely, pglX This work further analyzed the genomic locus near the pglX gene and identified it as a component of the BREX system. To decipher the biological role of pglX, an L. casei Zhang pglX mutant (ΔpglX) was constructed. Interestingly, m6A methylation of the 5'-ACRCAG-3' motif was eliminated in the ΔpglX mutant. The wild-type and mutant strains exhibited no significant difference in morphology or growth performance in de Man-Rogosa-Sharpe (MRS) medium. A significantly higher plasmid acquisition capacity was observed for the ΔpglX mutant than for the wild type if the transformed plasmids contained pglX recognition sites (i.e., 5'-ACRCAG-3'). In contrast, no significant difference was observed in plasmid transformation efficiency between the two strains when plasmids lacking pglX recognition sites were tested. Moreover, the ΔpglX mutant had a lower capacity to retain the plasmids than the wild type, suggesting a decrease in genetic stability. Since the Rebase database predicted that the L. casei PglX protein was bifunctional, as both an MTase and a restriction endonuclease, the PglX protein was heterologously expressed and purified but failed to show restriction endonuclease activity. Taken together, the results show that the L. casei Zhang pglX gene is a functional adenine MTase that belongs to the BREX system.IMPORTANCELactobacillus casei Zhang is a probiotic that confers beneficial effects on the host, and it is thus increasingly used in the dairy industry. The possession of an effective bacterial immune system that can defend against invasion of phages and exogenous DNA is a desirable feature for industrial bacterial strains. The bacteriophage exclusion (BREX) system is a recently described phage resistance system in prokaryotes. This work confirmed the function of the BREX system in L. casei and that the methyltransferase (pglX) is an indispensable part of the system. Overall, our study characterizes a BREX system component gene in lactic acid bacteria.


Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer.
Metastatic bone cancer causes severe pain that is primarily treated with opioids. A model of bone cancer pain in which the progression of cancer pain and bone destruction is tightly controlled was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced, rather than diminished, spontaneous, and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or tumor burden in vivo but accelerated sarcoma-induced bone destruction and doubled the incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity and upregulated IL-1 beta within the femurs of sarcoma-treated mice suggesting enhancement of sarcoma-induced osteolysis. These results indicate that sustained morphine increases pain, osteolysis, bone loss, and spontaneous fracture, as well as markers of neuronal damage in DRG cells and expression of pro-inflammatory cytokines. Morphine treatment may result in "add-on" mechanisms of pain beyond those engaged by sarcoma alone. While it is not known whether the present findings in this model of osteolytic sarcoma will generalize to other cancers or opioids, the data suggest a need for increased understanding of neurobiological consequences of prolonged opioid exposure which may allow improvements in the use of opiates in the effective management of cancer pain.


Formation of fullerides and fullerene-based heterostructures.
Two potassium fulleride phases, metallic K(3)C(60) and nonmetallic K(6)C(60), are formed when potassium is incorporated into thin C(60) films under ultrahigh vacuum conditions. Phase separation is observed for intermediate stoichiometries. Results obtained for the C(60)-K(3)C(60) heterostructure demonstrate that it is stable against potassium migration from the K(3)C(60) phase. In contrast, the C(60)-K(6)C(60) interface is not stable and K(3)C(60) is formed.


Inhibition of arteriole alpha 2- but not alpha 1-adrenoceptor constriction by acidosis and hypoxia in vitro.
We have found that hypoxia and acidosis inhibit constriction by alpha 2D-adrenoceptors but not by alpha 1D-adrenoceptors on arterioles of rat skeletal muscle, facilitating local metabolic control of blood flow. When activated by full agonists like norepinephrine, this alpha 2D-constriction relies on Ca2+ influx through dihydropyridine-sensitive, voltage-operated Ca2+ channels (VOC), while alpha 1D-constriction does not. The purpose of the present study was to examine the dose sensitivity of this selective metabolic inhibition of alpha 2D-constriction and determine whether inhibition of VOCs is involved. Changes in lumen diameter of microcannulated arterioles isolated from rat skeletal muscle (107 +/- 3 microns control diam) were measured by videomicroscopy for bath-added agents. Decreases in pH (7.4-7.0) or PO2 (70 to 10 mmHg) caused graded inhibition of alpha 2D-adrenoceptor constriction (UK-14304 plus prazosin); the half-maximum inhibitory concentration for acidosis was 7.1 and for PO2 was 24 mmHg. alpha 1D-Adrenoceptor constriction by the respective full and partial alpha 1-agonists, phenylephrine (PE) and St-587 (both plus rauwolscine), was unaffected. Because St-587 but not PE constriction was dependent on VOC activation, the sensitivity of alpha 2D- but not alpha 1D-constriction to acidosis and hypoxia appeared to be independent of reliance on VOCs. This was examined directly; contractile sensitivity to KCl and the VOC agonist, SDZ-202-791, was unaffected by pH 7.0 or PO2 10 mmHg. These data suggest that alpha 2D-constriction is sensitive to inhibition by hypoxia and acidosis through a mechanism that does not involve direct blockade of dihydropyridine-sensitive Ca2+ channels.


Hypoparathyroidism in pregnancy.
Pregnancy and lactation are associated with remarkable changes in calcium homeostasis, resulting from pregnancy-induced alterations in the production, metabolism and excretion of calcium and calcitropic hormones. Therefore, the clinical course of disorders affecting the parathyroid glands during pregnancy and lactation is often atypical. As the symptoms experienced by patients with parathyroid disorders are not specific, their diagnosis during gestation and breastfeeding may be sometimes very difficult. If left untreated, parathyroid disorders may pose a significant risk to the mother and fetus associated with increased perinatal and maternal morbidity and mortality. Hypoparathyroidism is a disorder rarely observed during pregnancy, resulting in most cases from surgical thyroidectomy. In our article, we present the case of a 32-year-old female with primary hypoparathyroidism diagnosed for the first time during pregnancy. We describe in details the treatment strategies undertaken in this patient and their impact on the outcome of pregnancy and lactation.


Refractive errors in students from Middle Eastern backgrounds living and undertaking schooling in Australia.
Environmental factors associated with schooling systems in various countries have been implicated in the rising prevalence of myopia, making the comparison of prevalence of refractive errors in migrant populations of interest. This study aims to determine the prevalence of refractive errors in children of Middle Eastern descent, raised and living in urban Australia but actively maintaining strong ties to their ethnic culture, and to compare them with those in the Middle East where myopia prevalence is generally low. A total of 354 out of a possible 384 late primary/early secondary schoolchildren attending a private school attracting children of Middle Eastern background in Melbourne were assessed for refractive error and visual acuity. A Shin Nippon open-field NVision-K5001 autorefractor was used to carry out non-cycloplegic autorefraction while viewing a distant target. For statistical analyses students were divided into three age groups: 10-11 years (n = 93); 12-13 years (n = 158); and 14-15 years (n = 102). All children were bilingual and classified as of Middle Eastern (96.3 per cent) or Egyptian (3.7 per cent) origin. Ages ranged from 10 to 15 years, with a mean of 13.17 ± 0.8 (SEM) years. Mean spherical equivalent refraction (SER) for the right eye was +0.09 ± 0.07 D (SEM) with a range from -7.77 D to +5.85 D. The prevalence of myopia, defined as a spherical equivalent refraction 0.50 D or more of myopia, was 14.7 per cent. The prevalence of hyperopia, defined as a spherical equivalent refraction of +0.75 D or greater, was 16.4 per cent, while hyperopia of +1.50 D or greater was 5.4 per cent. A significant difference in SER was seen as a function of age; however, no significant gender difference was seen. This is the first study to report the prevalence of refractive errors for second-generation Australian schoolchildren coming from a predominantly Lebanese Middle Eastern Arabic background, who endeavour to maintain their ethnic ties. The relatively low prevalence of myopia is similar to that found for other metropolitan Australian school children but higher than that reported in the Middle East. These results suggest that lifestyle and educational practices may be a significant influence in the progression of myopic refractive errors.


Erythropoietin treatment in patients with chronic heart failure: a meta-analysis.
Anaemia is common in patients with chronic heart failure (HF), and erythropoiesis stimulating proteins (ESPs) are frequently used for its treatment. However, recent studies in patients with malignancies and renal failure have raised concerns about the safety of these agents. To determine whether treatment of anaemic patients with chronic HF with ESPs is associated with an effect on morbidity and mortality. A systematic literature search in Medline, the Cochrane Controlled Trials Register Database and ClinicalTrials.gov through July 2008 was performed. Randomised clinical trials comparing the effect of ESP treatment with placebo or usual care in anaemic patients with HF were included. Seven randomised controlled trials were identified that enrolled 650 patients, of whom 363 were treated with ESPs and 287 with placebo. ESP treatment had a significantly lower risk of HF hospitalisation (risk ratio (RR) = 0.59; 95% CI 0.41 to 0.86; p = 0.006).There was no significant difference in the mortality risk between the two groups (RR = 0.69; 95% CI 0.39 to 1.23; p = 0.21). No significant differences were observed in the occurrence of hypertension or venous thrombosis. In chronic HF, treatment with ESPs is not associated with a higher mortality rate or more adverse events, whereas a beneficial effect on HF hospitalisation is seen. These outcomes are in contrast with studies in cancer and kidney disease, and support a large phase III morbidity and mortality trial of anaemia correction in patients with chronic HF.


Human-induced changes in landscape configuration influence individual movement routines: lessons from a versatile, highly mobile species.
Landscape conversion by humans may have detrimental effects on animal populations inhabiting managed ecosystems, but human-altered areas may also provide suitable environments for tolerant species. We investigated the spatial ecology of a highly mobile nocturnal avian species-the red-necked nightjar (Caprimulgus ruficollis)-in two contrastingly managed areas in Southwestern Spain to provide management recommendations for species having multiple habitat requirements. Based on habitat use by radiotagged nightjars, we created maps of functional heterogeneity in both areas so that the movements of breeding individuals could be modeled using least-cost path analyses. In both the natural and the managed area, nightjars used remnants of native shrublands as nesting sites, while pinewood patches (either newly planted or natural mature) and roads were selected as roosting and foraging habitats, respectively. Although the fraction of functional habitat was held relatively constant (60.9% vs. 74.1% in the natural and the managed area, respectively), landscape configuration changed noticeably. As a result, least-cost routes (summed linear distances) from nest locations to the nearest roost and foraging sites were three times larger in the natural than in the managed area (mean ± SE: 1356±76 m vs. 439±32 m). It seems likely that the increased proximity of functional habitats in the managed area relative to the natural one is underlying the significantly higher abundances of nightjars observed therein, where breeders should travel shorter distances to link together essential resources, thus likely reducing their energy expenditure and mortality risks. Our results suggest that landscape configuration, but not habitat availability, is responsible for the observed differences between the natural and the managed area in the abundance and movements of breeding nightjars, although no effect on body condition was detected. Agricultural landscapes could be moderately managed to preserve small native remnants and to favor the juxtaposition of functional habitats to benefit those farm species relying on patchy resources.


Deleterious influence of hypothyroidism on evolving myocardial infarction in conscious dogs.
To study the influence of hypometabolism on evolving myocardial infarction in a model with intact autoregulation, we investigated 53 awake dogs after coronary artery occlusion. Severe hypothyroidism was induced by the intravenous administration of 131I. Animals were instrumented to obtain hemodynamic measurements, and regional myocardial blood flow was measured with radioactive microspheres. Infarct size was determined by the creatine kinase depletion method, and dysrhythmia analysis was performed from 24-h Holter monitor tapes in animals matched for infarct size. The microarchitecture of hypothyroid myocardium was determined by the electron microscope. Before coronary occlusion, mean systemic pressure in hypothyroid dogs was reduced by 14% and cardiac output reduced by 32%, with no change in left ventricular end-diastolic pressure, first derivative of left ventricular pressure rise, (dP/dt), or heart rate. After coronary occlusion, there was deterioration in hemodynamic measurements in both groups, with lower absolute levels of mean systemic blood pressure and cardiac output obtained in hypothyroid dogs. Hypothyroidism was detrimental to evolving infarction with a 36% increase in infarct size present in hypothyroid dogs (30 +/- 2%) compared to euthyroid controls (22 +/- 3%), P less than 0.05. Dysrhythmias were more severe in hypothyroid dogs. There were no changes in the relationship between regional myocardial blood flow and the extent of infarction after coronary occlusion. Abnormalities in microarchitecture were present in hypothyroid dog myocardium. Severe hypometabolism in this model was associated with alterations in hemodynamics, more severe dysrhythmias and changes in microarchitecture. The combined effect of these alterations resulted in an overall detrimental influence of hypothyroidism on evolving myocardial necrosis in this model.


Evolutionarily labile responses to a signal of aggressive intent.
Males of many swordtail species possess vertical bar pigment patterns that are used both in courtship and agonistic interactions. Expression of the bars may function as a conventional threat signal during conflicts with rival males; bars intensify at the onset of aggression and fade in the subordinate male at contest's end. We used mirror image stimulation and bar manipulations to compare the aggressive responses of the males of four swordtail species to their barred and barless images. We found that having a response to the bars is tightly linked to having genes for bars, while the nature of the response the bars evoked varied across species. Specifically, we report the first known instance where closely related species exhibited differing and contradictory responses to a signal of aggressive motivation. Demonstrating that a signal conveys the same information across species (aggressive intent) while the response to that information has changed among species suggests that the nature of the responses are more evolutionarily labile than the signal.


PTH/PTHrP Receptor Signaling Restricts Arterial Fibrosis in Diabetic LDLR-/- Mice by Inhibiting Myocardin-Related Transcription Factor Relays.
The PTH1R (PTH [parathyroid hormone]/PTHrP [PTH-related protein] receptor) is expressed in vascular smooth muscle (VSM) and increased VSM PTH1R signaling mitigates diet-induced arteriosclerosis in LDLR-/- mice. To study the impact of VSM PTH1R deficiency, we generated mice SM22-Cre:PTH1R(fl/fl);LDLR-/- mice (PTH1R-VKO) and Cre-negative controls. Immunofluorescence and Western blot confirmed PTH1R expression in arterial VSM that was reduced by Cre-mediated knockout. PTH1R-VKO cohorts exhibited increased aortic collagen accumulation in vivo, and VSM cultures from PTH1R-VKO mice elaborated more collagen (2.5-fold; P=0.01) with elevated Col3a1 and Col1a1 expression. To better understand these profibrotic responses, we performed mass spectrometry on nuclear proteins extracted from Cre-negative controls and PTH1R-VKO VSM. PTH1R deficiency reduced Gata6 but upregulated the MADS (MCM1, Agamous, Deficiens, and Srf DNA-binding domain)-box transcriptional co-regulator, Mkl-1 (megakaryoblastic leukemia [translocation] 1). Co-transfection assays (Col3a1 promoter-luciferase reporter) confirmed PTH1R-mediated inhibition and Mkl-1-mediated activation of Col3a1 transcription. Regulation mapped to a conserved hybrid CT(A/T)6GG MADS-box cognate in the Col3a1 promoter. Mutations of C/G in this motif markedly reduced Col3a1 transcriptional regulation by PTH1R and Mkl-1. Upregulation of Col3a1 and Col1a1 in PTH1R-VKO VSM was inhibited by small interfering RNA targeting Mkl1 and by treatment with the Mkl-1 antagonist CCG1423 or the Rock (Rho-associated coiled-coil containing protein kinase)-2 inhibitor KD025. Chromatin precipitation demonstrated that VSM PTH1R deficiency increased Mkl-1 binding to Col3a1 and Col1a1, but not TNF, promoters. Proteomic studies of plasma extracellular vesicles and VSM from PTH1R-VKO mice identified C1r (complement component 1, r) and C1s (complement component 1, s), complement proteins involved in vascular collagen metabolism, as potential biomarkers. VSM C1r protein and C1r message were increased with PTH1R deficiency, mediated by Mkl-1-dependent transcription and inhibited by CCG1423 or KD025. PTH1R signaling restricts collagen production in the VSM lineage, in part, via Mkl-1 regulatory circuits that control collagen gene transcription. Strategies that maintain homeostatic VSM PTH1R signaling, as reflected in extracellular vesicle biomarkers of VSM PTH1R/Mkl-1 action, may help mitigate arteriosclerosis and vascular fibrosis.


Outcomes in children undergoing posterior fossa decompression and duraplasty with and without tonsillar reduction for Chiari malformation type I and syringomyelia: a pilot prospective multicenter cohort study.
Despite significant advances in diagnostic and surgical techniques, the surgical management of Chiari malformation type I (CM-I) with associated syringomyelia remains controversial, and the type of surgery performed is surgeon dependent. This study's goal was to determine the feasibility of a prospective, multicenter, cohort study for CM-I/syringomyelia patients and to provide pilot data that compare posterior fossa decompression and duraplasty (PFDD) with and without tonsillar reduction. Participating centers prospectively enrolled children suffering from both CM-I and syringomyelia who were scheduled to undergo surgical decompression. Clinical data were entered into a database preoperatively and at 1-2 weeks, 3-6 months, and 1 year postoperatively. MR images were evaluated by 3 independent, blinded teams of neurosurgeons and neuroradiologists. The primary endpoint was improvement or resolution of the syrinx. Eight clinical sites were chosen based on the results of a published questionnaire intended to remove geographic and surgeon bias. Data from 68 patients were analyzed after exclusions, and complete clinical and imaging records were obtained for 55 and 58 individuals, respectively. There was strong agreement among the 3 radiology teams, and there was no difference in patient demographics among sites, surgeons, or surgery types. Tonsillar reduction was not associated with > 50% syrinx improvement (RR = 1.22, p = 0.39) or any syrinx improvement (RR = 1.00, p = 0.99). There were no surgical complications. This study demonstrated the feasibility of a prospective, multicenter surgical trial in CM-I/syringomyelia and provides pilot data indicating no discernible difference in 1-year outcomes between PFDD with and without tonsillar reduction, with power calculations for larger future studies. In addition, the study revealed important technical factors to consider when setting up future trials. The long-term sequelae of tonsillar reduction have not been addressed and would be an important consideration in future investigations.


Inferring properties of disordered chains from FRET transfer efficiencies.
Förster resonance energy transfer (FRET) is a powerful tool for elucidating both structural and dynamic properties of unfolded or disordered biomolecules, especially in single-molecule experiments. However, the key observables, namely, the mean transfer efficiency and fluorescence lifetimes of the donor and acceptor chromophores, are averaged over a broad distribution of donor-acceptor distances. The inferred average properties of the ensemble therefore depend on the form of the model distribution chosen to describe the distance, as has been widely recognized. In addition, while the distribution for one type of polymer model may be appropriate for a chain under a given set of physico-chemical conditions, it may not be suitable for the same chain in a different environment so that even an apparently consistent application of the same model over all conditions may distort the apparent changes in chain dimensions with variation of temperature or solution composition. Here, we present an alternative and straightforward approach to determining ensemble properties from FRET data, in which the polymer scaling exponent is allowed to vary with solution conditions. In its simplest form, it requires either the mean FRET efficiency or fluorescence lifetime information. In order to test the accuracy of the method, we have utilized both synthetic FRET data from implicit and explicit solvent simulations for 30 different protein sequences, and experimental single-molecule FRET data for an intrinsically disordered and a denatured protein. In all cases, we find that the inferred radii of gyration are within 10% of the true values, thus providing higher accuracy than simpler polymer models. In addition, the scaling exponents obtained by our procedure are in good agreement with those determined directly from the molecular ensemble. Our approach can in principle be generalized to treating other ensemble-averaged functions of intramolecular distances from experimental data.


Attitudes, risk of infection and behaviours in the operating room (the ARIBO Project): a prospective, cross-sectional study.
Inappropriate staff behaviours can lead to environmental contamination in the operating room (OR) and subsequent surgical site infection (SSI). This study will focus on the continued assessment of OR staff behaviours using a motion tracking system and their impact on the SSI risk during surgical procedures. This multicentre prospective cross-sectional study will include 10 ORs of cardiac and orthopaedic surgery in 12 healthcare facilities (HCFs). The staff behaviour will be assessed by an objective, continued and prolonged quantification of movements within the OR. A motion tracking system including eight optical cameras (VICON-Bonita) will record the movements of reflective markers placed on the surgical caps/hoods of each person entering the room. Different configurations of markers positioning will be used to distinguish between the staff category. Doors opening will be observed by means of wireless inertial sensors fixed on the doors and synchronised with the motion tracking system. We will collect information on the OR staff, surgical procedures and surgical environment characteristics. The behavioural data obtained will be compared (1) to the 'best behaviour rules' in the OR, pre-established using a Delphi method and (2) to surrogates of the infectious risk represented by microbiological air counts, particle counts, and a bacteriological sample of the wound at closing. Statistics will be performed using univariate and multivariate analysis to adjust on the aerolic and architectural characteristics of the OR. A multilevel model will allow including surgical specialty and HCFs effects. Through this study, we will develop an original approach using high technology tools associated to data processing techniques to evaluate 'automatically' the behavioural dynamics of the OR staff and their impact on the SSI risk. Approbation of the Institutional Review Board of Paris North Hospitals, Paris 7 University, AP-HP (no 11-113, 6 April 2012). The findings will be disseminated through peer-reviewed journals, and national and international conference presentations.


Impact of glycemic control on colonoscopy outcomes: bowel preparation and polyp detection.
The negative effect of diabetes mellitus (DM) on the colonoscopy preparation has been previously established. Metabolic syndrome has been shown to increase risk for malignancy and possibly for premalignant lesions. This study aimed to investigate the impact of DM control on colonoscopy outcomes including bowel preparation and adenoma detection rate (ADR). We included patients with DM who underwent colonoscopy in our hospital and had a documented glycated hemoglobin (HbA1C) within 3 months. Patients were categorized into three groups based on their HbA1C level. The clinical and endoscopic data were collected and analyzed. Our cohort included 352 DM patients. The mean age was 63.5 years. When patients were analyzed based on HBA1C, bowel preparation was poor in 46.7% of patients with good glycemic control, 52.1% of patients with fair control and 50% of patients with poor control. ADR was 24.3% in patients with good glycemic control, 20.2% in patients with fair glycemic control and 27.1% in patients with poor glycemic control. There was no statistically significant difference in the quality of preparation or adenoma detection amongst the groups. The degree of glycemic control did not impact the quality of bowel preparation or ADR.


Identification of a New Candidate Locus for Ebstein Anomaly in 1p36.2.
Ebstein anomaly (EA) is a rare congenital heart defect (CHD) with a poorly characterized genetic etiology. However, some EA patients carry deletions in 1p36, all of which have been reported to carry distal deletions and share loss of the PRDM16 gene, which is currently considered the most likely candidate for EA development in this region. Here, we report a patient with an 11.96-Mb proximal 1p36 deletion, without loss of PRDM16, who presented with EA and a proximal deletion phenotype. This finding suggests that PRDM16 loss is not required for the development of EA in 1p36 deletions and that the loss of an additional proximal locus in 1p36 is also likely associated with EA. Our data suggest that a distal locus containing the SKI gene and a proximal locus containing the CHD-associated genes RERE and UBE4B are the most probable etiological factors for EA in patients with 1p36 deletion syndrome.


Diagnosis and management of acute lower gastrointestinal bleeding: guidelines from the British Society of Gastroenterology.
This is the first UK national guideline to concentrate on acute lower gastrointestinal bleeding (LGIB) and has been commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). The Guidelines Development Group consisted of representatives from the BSG Endoscopy Committee, the Association of Coloproctology of Great Britain and Ireland, the British Society of Interventional Radiology, the Royal College of Radiologists, NHS Blood and Transplant and a patient representative. A systematic search of the literature was undertaken and the quality of evidence and grading of recommendations appraised according to the GRADE(Grading of Recommendations Assessment, Development and Evaluation) methodology. These guidelines focus on the diagnosis and management of acute LGIB in adults, including methods of risk assessment and interventions to diagnose and treat bleeding (colonoscopy, computed tomography, mesenteric angiography, endoscopic therapy, embolisation and surgery). Recommendations are included on the management of patients who develop LGIB while receiving anticoagulants (including direct oral anticoagulants) or antiplatelet drugs. The appropriate use of blood transfusion is also discussed, including haemoglobin triggers and targets.