Archaeology, environmental justice, and climate change on islands of the Caribbean and southwestern Indian Ocean.
Climate change impacts island communities all over the world. Sea-level rise, an increase in the frequency and intensity of severe weather events, and changes in distribution and health of marine organisms are among the most significant processes affecting island communities worldwide. On islands of the Caribbean and southwestern Indian Ocean (SWIO), however, today's climate change impacts are magnified by historical environmental injustice and colonial legacies, which have heightened the vulnerability of human and other biotic communities. For some islands, archaeological and paleoecological research offers an important record of precolonial climate change and its interplay with human lives and landscapes. The archaeological record suggests strategies and mechanisms that can inform discussions of resilience in the face of climate change. We detail climate-related challenges facing island Caribbean and SWIO communities using archaeological and paleoecological evidence for past climate change and human response and argue that these cannot be successfully addressed without an understanding of the processes that have, over time, disrupted livelihoods, reshaped land- and seascapes, threatened intergenerational ecological knowledge transfer, and led to increased inequality and climate vulnerability.


Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial.
The vasopressin-cAMP-osmolality axis is abnormal in autosomal dominant polycystic kidney disease (ADPKD). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial, a 3-year randomized, placebo-controlled trial in adults, the vasopressin V2 receptor antagonist tolvaptan slowed ADPKD progression in patients with preserved GFR. Here, we investigated the determinants of baseline urine osmolality (Uosm) and its value as a severity marker of ADPKD, the factors influencing the response to tolvaptan, and whether change in Uosm associated with key trial end points. At baseline, lower Uosm independently associated with female sex, presence of hypertension, lower eGFR, higher total kidney volume (TKV), and higher age. Tolvaptan consistently reduced Uosm by 200-300 mOsm/kg over 36 months. The Uosm response to tolvaptan depended on baseline eGFR and Uosm. Subjects with greater change in Uosm experienced a significant reduction in clinical progression events. Among subjects receiving tolvaptan, those with a greater suppression of Uosm had slower renal function decline. Assessment at follow-up, off medication, revealed a significant decrease in Uosm in both placebo and treated groups. Tolvaptan significantly increased plasma osmolality, which returned to baseline at follow-up. In conclusion, baseline Uosm in ADPKD reflects age, renal function, and TKV, and baseline Uosm, eGFR, and TKV influence the effect of tolvaptan on Uosm. The greatest renal benefit occurred in subjects achieving greater suppression of Uosm, that is, those with better eGFR at baseline. These results support the link between vasopressin V2 receptor signaling and ADPKD progression.


Application of frequent itemsets mining to analyze patterns of one-stop visits in Taiwan.
The free choice of health care facilities without limitations on frequency of visits within the National Health Insurance in Taiwan gives rise to not only a high number of annual ambulatory visits per capita but also a unique "one-stop shopping"phenomenon, which refers to a patient' visits to several specialties of the same healthcare facility in one day. The visits to multiple physicians would increase the potential risk of polypharmacy. The aim of this study was to analyze the frequency and patterns of one-stop visits in Taiwan. The claims datasets of 1 million nationally representative people within Taiwan's National Health Insurance in 2005 were used to calculate the number of patients with one-stop visits. The frequent itemsets mining was applied to compute the combination patterns of specialties in the one-stop visits. Among the total 13,682,469 ambulatory care visits in 2005, one-stop visits occurred 144,132 times and involved 296,822 visits (2.2% of all visits) by 66,294 (6.6%) persons. People tended to have this behavior with age and the percentage reached 27.5% (5,662 in 20,579) in the age group ≥80 years. In general, women were more likely to have one-stop visits than men (7.2% vs. 6.0%). Internal medicine plus ophthalmology was the most frequent combination with a visited frequency of 3,552 times (2.5%), followed by cardiology plus neurology with 3,183 times (2.2%). The most frequent three-specialty combination, cardiology plus neurology and gastroenterology, occurred only 111 times. Without the novel computational technique, it would be hardly possible to analyze the extremely diverse combination patterns of specialties in one-stop visits. The results of the study could provide useful information either for the hospital manager to set up integrated services or for the policymaker to rebuild the health care system.


Propranolol treatment of infantile hemangiomas: anticipatory guidance for parents and caretakers.
Infantile hemangiomas (IH) are benign tumors of endothelial-like cells. Occurring in 4.5% of children, they are the most common tumor of childhood. The great majority of patients with IH will not need treatment, but 10% require systemic treatment. Many treatments have been described for the treatment of IH, but the Food and Drug Administration has not approved any. Over the last decade, numerous reports of successful treatment of IH with propranolol have been published. Despite its widespread use, little is known regarding the proper dosing, safety monitoring, and during of treatment or long-term outcomes for propranolol treatment of IH. Given its potential side effects, detailed education regarding proper administration of the medication as well as warning signs to watch for is necessary for parents and caretakers. Herein, we provide a parental handout that practitioners can individually tailor for use in their clinics when educating parents and caretakers about the use of propranolol for IH. Updates will also need to be made as more is learned regarding the optimal dosing and safety monitoring when using propranolol for this indication.


Characterization of triglycerides in vegetable oils by silver-ion packed-column supercritical fluid chromatography coupled to mass spectroscopy with atmospheric pressure chemical ionization and coordination ion spray.
Characterization of triglycerides in vegetable oils was achieved by silver-ion packed-column supercritical fluid chromatography (SI-pSFC) with mass spectrometric detection. Hyphenation was made using commercially available liquid chromatography-mass spectrometry (LC-MS) interfaces without any modification. A make-up fluid was delivered through a T-piece placed before or after the SFC restrictor by means of a high pressure pump. Atmospheric pressure chemical ionization (APCI) and coordination ion spray (CIS) with silver ions were used as ionization modes. Compared to UV detection, the sensitivity was increased by a factor of 100. Both ionization modes are generating similar structural information. Molecular ions [M-H]+ or [M-Ag(-)] are observed in the mass spectra with exception of the saturated triglycerides for which only CIS gives intense molecular ions. The position at which the fatty acids are esterified to the glycerol backbone can be elucidated by pSFC-APCI although it remains speculative whether this is valid for highly unsaturated triglycerides because reference compounds are not available to proof this.


Haemotrophic Mycoplasma infection in horses.
Haemotrophic mycoplasmas (HM) are parasites on the surface of red blood cells and known to infect a wide range of animals. However, there are no previous evidences of HM infections in horses. In this study HM were detected for the first time in the blood of two horses suffering from poor performance, apathy, weight loss, and anaemia. Using a HM specific PCR assay and subsequent sequencing the infective agents isolated from the blood of said horses were confirmed as closely related to the HM species Mycoplasma haemofelis and 'Candidatus Mycoplasma haemobos'.


Autobiographical memory functioning in depression and reports of early abuse.
The authors investigated the memory functioning of depressed women patients with and without a reported history of child physical or sexual abuse using J. M. G. Williams and K. Broadbent's (1986) Autobiographical Memory Test. Whereas latency to recall autobiographical memories was not related to reports of abuse, patients who reported childhood sexual abuse produced more overgeneral memories to positive and negative cues. In addition, patients reporting high levels of avoidance of spontaneous memories of childhood physical or sexual abuse in the past week retrieved more overgeneral memories to positive and negative cues.


Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate.
The binding of [3H]nicotine to mouse brain has been measured and subsequently compared with the binding of [125I]alpha-bungarotoxin (alpha-BTX) and L-[3H]quinuclidinyl benzilate (QNB). The binding of nicotine was saturable, reversible, and stereospecific. The average KD and Bmax were 59 nM and 88 fmoles/mg of protein, respectively. Although the rates of association and dissociation of nicotine were temperature-dependent, the incubation temperature had no effect on either KD or Bmax. When measured at 20 degrees or 37 degrees, nicotine appeared to bind to a single class of binding sites, but a second, very low-affinity, binding site was observed at 4 degrees. Nicotine binding was unaffected by the addition of NaCl, KCl, CaCl2, or MgSO4 to the incubation medium. Nicotinic cholinergic agonists were potent inhibitors of nicotine binding; however, nicotinic antagonists were poor inhibitors. The regional distribution of binding was not uniform: midbrain and striatum contained the highest number of receptors, whereas cerebellum had the fewest. Differences in site densities, regional distribution, inhibitor potencies, and thermal denaturation indicated that nicotine binding was not the same as either QNB or alpha-BTX binding, and therefore that receptors for nicotine may represent a unique population of cholinergic receptors.


Concentrations and number size distribution of fine and nanoparticles in a traditional Finnish bakery.
In bakeries, high concentrations of flour dust can exist and ovens release particles into the air as well. Particle concentrations (mass, number) and number size distribution may vary considerably but the variation is not commonly studied. Furthermore, the role of the smallest size fractions is rarely considered in the exposure assessment due to their small mass. The objectives of this work were to find out how concentrations and number size distribution of fine and nanoparticles vary in a traditional Finnish bakery and to determine the exposure of a dough maker to the nanoparticle fraction of the inhalable dust. Two measurement campaigns were carried out in a traditional, small-scale bakery. Sampling was performed at the breathing zone of the dough maker and three stationary locations: baking area, oven area, and flour depository. Both real-time measurements and conventional gravimetric sampling were conducted. Nanoparticle fraction of the inhalable dust was determined using an IOM sampler with a customized precyclone. Number concentration of fine and nanoparticles, and mass concentrations of both the inhalable dust and nanoparticles were high. The nanoparticle fraction was 9-15% of the inhalable dust at the breathing zone of the dough maker. Different sources, such as ovens and doughnut baking affected the number size distribution. Flour dust contained nanoparticles but most of the fine and nanoparticles were released into the air from the oven operations. However, nanoparticles are not a primary concern in bakeries compared to health effects linked to the large flour particles such as flour-induced sensitization or asthma and development of occupational rhinitis.


Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.
Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements and are sufficient to fully reprogram differentiated GBM cells to "induced" TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies. PAPERCLIP:


4-hydroxytamoxifen leads to PrPSc clearance by conveying both PrPC and PrPSc to lysosomes independently of autophagy.
Prion diseases are fatal neurodegenerative disorders involving the abnormal folding of a native cellular protein, named PrP(C), to a malconformed aggregation-prone state, enriched in beta sheet secondary structure, denoted PrP(Sc). Recently, autophagy has garnered considerable attention as a cellular process with the potential to counteract neurodegenerative diseases of protein aggregation such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. Stimulation of autophagy by chemical compounds has also been shown to reduce PrP(Sc) in infected neuronal cells and prolong survival times in mouse models. Consistent with previous reports, we demonstrate that autophagic flux is increased in chronically infected cells. However, in contrast to recent findings we show that autophagy does not cause a reduction in scrapie burden. We report that in infected neuronal cells different compounds known to stimulate autophagy are ineffective in increasing autophagic flux and in reducing PrP(Sc). We further demonstrate that tamoxifen and its metabolite 4-hydroxytamoxifen lead to prion degradation in an autophagy-independent manner by diverting the trafficking of both PrP and cholesterol to lysosomes. Our data indicate that tamoxifen, a well-characterized, widely available pharmaceutical, may have applications in the therapy of prion diseases.


Inferior myocardial infarction secondary to aortic dissection associated with bicuspid aortic valve.
Aortic dissection (AD) is a life-threatening condition and may present with symptoms which mimic myocardial infarction, leading to misdiagnosis and inappropriate use of anticoagulant and thrombolytic therapy. A 40-year-old woman with no prior history presented in our emergency department with sudden chest pain. Electrocardiography (ECG) showed a ST-segment elevation in leads II, III and avF, suggesting an acute inferior myocardial infarction. The patient was given anticoagulation and antiplatelet treatment. Coronary angiography, transthoracic echocardiography and computed tomography were performed. The patient was diagnosed with DeBakey I aortic dissection extending from ascending aorta to iliac artery, and associated with bicuspid aortic valve.Surgical treatments with a replacement of the ascending aorta, aortic valve replacement and coronary artery bypass grafting were successfully performed. Early imaging examination, if possible, might assist the diagnosis and guide the management of this disease. The condition of myocardial infarction secondary to aortic dissection is discussed.


Conductivity control via minimally invasive anti-Frenkel defects in a functional oxide.
Utilizing quantum effects in complex oxides, such as magnetism, multiferroicity and superconductivity, requires atomic-level control of the material's structure and composition. In contrast, the continuous conductivity changes that enable artificial oxide-based synapses and multiconfigurational devices are driven by redox reactions and domain reconfigurations, which entail long-range ionic migration and changes in stoichiometry or structure. Although both concepts hold great technological potential, combined applications seem difficult due to the mutually exclusive requirements. Here we demonstrate a route to overcome this limitation by controlling the conductivity in the functional oxide hexagonal Er(Mn,Ti)O3 by using conductive atomic force microscopy to generate electric-field induced anti-Frenkel defects, that is, charge-neutral interstitial-vacancy pairs. These defects are generated with nanoscale spatial precision to locally enhance the electronic hopping conductivity by orders of magnitude without disturbing the ferroelectric order. We explain the non-volatile effects using density functional theory and discuss its universality, suggesting an alternative dimension to functional oxides and the development of multifunctional devices for next-generation nanotechnology.


Skin dendritic cell and T cell activation associated with dengue shock syndrome.
The pathogenesis of severe dengue remains unclear, particularly the mechanisms underlying the plasma leakage that results in hypovolaemic shock in a small proportion of individuals. Maximal leakage occurs several days after peak viraemia implicating immunological pathways. Skin is a highly vascular organ and also an important site of immune reactions with a high density of dendritic cells (DCs), macrophages and T cells. We obtained skin biopsies and contemporaneous blood samples from patients within 24 hours of onset of dengue shock syndrome (DSS), and from healthy controls. We analyzed cell subsets by flow cytometry, and soluble mediators and antibodies by ELISA; the percentage of migratory CD1a+ dermal DCs was significantly decreased in the DSS patients, and skin CD8+ T cells were activated, but there was no accumulation of dengue-specific antibodies. Inflammatory monocytic cells were not observed infiltrating the skin of DSS cases on whole-mount histology, although CD14dim cells disappeared from blood.


Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer.
Several sexually transmitted infections (STI) have been reported to interact with human papillomavirus (HPV) in the etiology of cervical cancer. A large cohort study is required to obtain a both unbiased and stable estimate of their effects. Four major biobanks in the Nordic Countries containing samples from about 1,000,000 subjects were linked with nation-wide cancer registries. Serum samples from 604 women with invasive cervical cancer (ICC) diagnosed on average 10 years after sampling and 2,980 matched control women were retrieved and analyzed with serology for key STI. Exposure to HPV16 was the strongest risk factor for cervical cancer [OR = 2.4; 95% confidence interval (CI), 2.0-3.0], particularly for squamous cell carcinoma (OR = 2.9; 95% CI, 2.2-3.7). HPV18 was strongly associated with increased risk for adenocarcinoma (OR = 2.3; 95% CI, 1.3-4.1). Baseline seropositivity for HPV16 did not confer any increased risk for HPV18 DNA-positive cancer and conversely HPV18 seropositivity had no association with HPV16 DNA-positive cancers. HPV6 had no effect on its own (OR = 1.1; 95% CI, 0.9-1.3), but had an antagonistic effect on the risk conferred by HPV16 (P < 0.01). Herpes simplex virus 2 had little or no association (OR = 1.1; 95% CI, 0.8-1.4). Previous exposure to Chlamydia trachomatis, as indicated by serum antibodies, had a strongly increased risk for cervical cancer (OR = 1.9; 95% CI, 1.5-2.3). A large prospective study has assessed the role of different STIs in cervical cancer. Prospective evidence supports cofactor role of some STI in cervical cancer.


Lifespan Disparity as an Additional Indicator for Evaluating Mortality Forecasts.
Evaluating the predictive ability of mortality forecasts is important yet difficult. Death rates and mean lifespan are basic life table functions typically used to analyze to what extent the forecasts deviate from their realized values. Although these parameters are useful for specifying precisely how mortality has been forecasted, they cannot be used to assess whether the underlying mortality developments are plausible. We therefore propose that in addition to looking at average lifespan, we should examine whether the forecasted variability of the age at death is a plausible continuation of past trends. The validation of mortality forecasts for Italy, Japan, and Denmark demonstrates that their predictive performance can be evaluated more comprehensively by analyzing both the average lifespan and lifespan disparity-that is, by jointly analyzing the mean and the dispersion of mortality. Approaches that account for dynamic age shifts in survival improvements appear to perform better than others that enforce relatively invariant patterns. However, because forecasting approaches are designed to capture trends in average mortality, we argue that studying lifespan disparity may also help to improve the methodology and thus the predictive ability of mortality forecasts.


Targeted disinfection of E. coli via bioconjugation to photoreactive TiO2.
The selective control of pathogenic bacteria is an ongoing challenge. A strategy is proposed that combines targeted binding of the bacterium, using antibodies, with their photoactivated oxidative destruction. Photoactive colloidal TiO2 was first derivatized with E. coli antibodies (EA-TiO2). When mixtures of the organisms E. coli and Pseudomonas putida ( P. putida ) were exposed to modified EA-TiO2, the particles preferentially selected E. coli for surface binding. Two consequences arose from surface bioconjugation: bacteria were found to flocculate upon mixing at appropriate ratios of EA-TiO2/ E. coli , and EA-TiO2-bound E. coli underwent cell death after exposure to UV light. In the former case, flocculation of the bacteria was optimal at ~50 EA-TiO2 particles per E. coli . Selective flocculation provides an alternative strategy for pathogen removal. With respect to UV disinfection, as few as 26 EA-TiO2 particles per E. coli gave a 10 000-fold decrease in viable bacteria. Thus, it is possible to selectively target and kill one type of bacteria in a mixture of pathogens. The results give support to the proposal that photocatalytic TiO2 most effectively delivers an oxidizing agent when the titania is bound to the bacterial surface.


Vernier acuity of illusory contours defined by motion.
We present here a series of experiments exploring a special class of visual completion that is strictly tied to the perception of apparent motion. The stimuli consist of sparse random-dot arrays, in which dots remain in place. Changes of luminance or color of the dots at leading and trailing edges of an apparently moving region are integrated over space and time to produce the perception of well-defined contours, shapes, and color. We test how Vernier acuity of apparent motion-defined illusory bars depends on speed, density, and stimulus configurations. We found that higher speed of apparent motion reduces the Vernier acuity thresholds. These thresholds also decrease with increasing density of dots, whose luminance changes provide the apparent motion signal required for the perception of illusory contours. In subsequent experiments, we showed that luminance-defined flankers could seamlessly integrate with and improve the perception of apparent motion-defined contours, reducing their Vernier thresholds.


Effect of prolactin on androgen metabolism by the guinea-pig sex accessory organs.
The in vitro actions of prolactin on the metabolism of testosterone by the guinea-pig liver and sex accessory organs have been investigated under a variety of conditions including various concentrations of ovine or bovine prolactin, addition of reduced nicotinamide adenine dinucleotide phosphatate (NADPH) or nicotinamide adenine dinucleotide (NAD) to incubation media and various lengths of incubations. Treatment of the epithelium and muscle of the guinea-pig seminal vesicle with NAD elicited a shift from normal reductive metabolism of testosterone toward oxidative metabolism. This shift toward oxidative metabolism of testosterone was particularly marked in the muscle of the guinea-pig seminal vesicle. Ovine prolactin was highly effective in inhibiting the reductive metabolism of testosterone by the sex accessory organs. This effect appeared primarily as a decrease in dihydrotestosterone formation and was noted in both the presence and absence of NADPH or NAD. Oxidized metabolites, androstenedione and androstandione, were apparently insensitive to prolactin treatment in vitro. Variations induced by prolactin in the concentrations of intracellular androgens may be important in either the normal or abnormal growth and function of male sex accessory organs.


Parkin interacts with Ambra1 to induce mitophagy.
Mutations in the gene encoding Parkin are a major cause of recessive Parkinson's disease. Recent work has shown that Parkin translocates from the cytosol to depolarized mitochondria and induces their autophagic removal (mitophagy). However, the molecular mechanisms underlying Parkin-mediated mitophagy are poorly understood. Here, we investigated whether Parkin interacts with autophagy-regulating proteins. We purified Parkin and associated proteins from HEK293 cells using tandem affinity purification and identified the Parkin interactors using mass spectrometry. We identified the autophagy-promoting protein Ambra1 (activating molecule in Beclin1-regulated autophagy) as a Parkin interactor. Ambra1 activates autophagy in the CNS by stimulating the activity of the class III phosphatidylinositol 3-kinase (PI3K) complex that is essential for the formation of new phagophores. We found Ambra1, like Parkin, to be widely expressed in adult mouse brain, including midbrain dopaminergic neurons. Endogenous Parkin and Ambra1 coimmunoprecipitated from HEK293 cells, SH-SY5Y cells, and adult mouse brain. We found no evidence for ubiquitination of Ambra1 by Parkin. The interaction of endogenous Parkin and Ambra1 strongly increased during prolonged mitochondrial depolarization. Ambra1 was not required for Parkin translocation to depolarized mitochondria but was critically important for subsequent mitochondrial clearance. In particular, Ambra1 was recruited to perinuclear clusters of depolarized mitochondria and activated class III PI3K in their immediate vicinity. These data identify interaction of Parkin with Ambra1 as a key mechanism for induction of the final clearance step of Parkin-mediated mitophagy.


Myxopapillary ependymoma with anaplastic features: A case report with review of the literature.
Myxopapillary ependymoma (MPE) with anaplastic features is extremely rare, with only three case reports in the literature. We report the case of a MPE with anaplastic features in a 24-year-old female who presented with a dominant lumbar mass along with intracranial and sacral metastases. Upon gross total resection of the dominant tumor located at L2-L3, it appeared to arise from the filum terminale, and had a solid component in addition to soft or necrotic areas. Histologically, the tumor was composed of the two classic components of MPE: (1) low-grade ependymal cells surrounding blood vessels, producing the papillary appearance and (2) perivascular myxoid material between blood vessels and ependymal cells, creating the myxopapillary appearance. The high-grade anaplastic component showed hypercellularity, brisk mitotic rate, and vascular proliferation, with frequent pleomorphic cells and atypical mitotic figures. It was positive for vimentin and glial fibrillary acidic protein (GFAP); negative for epithelial membrane antigen (EMA), CAM5.2, creatine kinase 7 (CK7), CK20; and the MIB-1 index (Ki-67) was 8-38%. Ten months after initial resection, follow-up magnetic resonance imaging revealed new lesions in (1) the hypothalamus, (2) the left pons, and (3) the left medial temporal lobe, which were treated with radiosurgery. Eight months later (18 months from initial surgery), the patient underwent thoracic laminectomy for a large leptomeningeal metastasis at T6 and T8. The present case of MPE with anaplastic features is the fourth case on record in the medical literature.


Differentially expressed genes during the imbibition of dormant and after-ripened seeds - a reverse genetics approach.
Seed dormancy, defined as the incapability of a viable seed to germinate under favourable conditions, is an important trait in nature and agriculture. Despite extensive research on dormancy and germination, many questions about the molecular mechanisms controlling these traits remain unanswered, likely due to its genetic complexity and the large environmental effects which are characteristic of these quantitative traits. To boost research towards revealing mechanisms in the control of seed dormancy and germination we depend on the identification of genes controlling those traits. We used transcriptome analysis combined with a reverse genetics approach to identify genes that are prominent for dormancy maintenance and germination in imbibed seeds of Arabidopsis thaliana. Comparative transcriptomics analysis was employed on freshly harvested (dormant) and after-ripened (AR; non-dormant) 24-h imbibed seeds of four different DELAY OF GERMINATION near isogenic lines (DOGNILs) and the Landsberg erecta (Ler) wild type with varying levels of primary dormancy. T-DNA knock-out lines of the identified genes were phenotypically investigated for their effect on dormancy and AR. We identified conserved sets of 46 and 25 genes which displayed higher expression in seeds of all dormant and all after-ripened DOGNILs and Ler, respectively. Knock-out mutants in these genes showed dormancy and germination related phenotypes. Most of the identified genes had not been implicated in seed dormancy or germination. This research will be useful to further decipher the molecular mechanisms by which these important ecological and commercial traits are regulated.


Patient self-monitoring of blood pressure and self-titration of medication in primary care: the TASMINH2 trial qualitative study of health professionals' experiences.
Self-monitoring with self-titration of antihypertensives leads to reduced blood pressure. Patients are keen on self-monitoring but little is known about healthcare professional views. To explore health professionals' views and experiences of patient self-management, particularly with respect to future implementation into routine care. Qualitative study embedded within a randomised controlled trial of healthcare professionals participating in the TASMINH2 trial of patient self-monitoring with self-titration of antihypertensives from 24 West Midlands general practices. Taped and transcribed semi-structured interviews with 13 GPs, two practice nurses and one healthcare assistant. Constant comparative method of analysis. Primary care professionals were positive about self-monitoring, but procedures for ensuring patients measured blood pressure correctly were haphazard. GPs interpreted home readings variably, with many not making adjustment for lower home blood pressure. Interviewees were satisfied with patient training and arrangements for blood pressure monitoring and self-titration of medication during the trial, but less sure about future implementation into routine care. There was evidence of a need for training of both patients and professionals for successful integration of self-management. Health professionals wanted more patient involvement in hypertension care but needed a framework to work within. Consideration of how to train patients to measure blood pressure and how home readings become part of their care is required before self-monitoring and self-titration can be implemented widely. As home monitoring becomes more widespread, the development of patient self-management, including self-titration of medication, should follow but this may take time to achieve.


Detection of ductal carcinoma in situ in women undergoing screening mammography.
With the large number of women having mammography-an estimated 28.4 million U.S. women aged 40 years and older in 1998-the percentage of cancers detected as ductal carcinoma in situ (DCIS), which has an uncertain prognosis, has increased. We pooled data from seven regional mammography registries to determine the percentage of mammographically detected cancers that are DCIS and the rate of DCIS per 1000 mammograms. We analyzed data on 653 833 mammograms from 540 738 women between 40 and 84 years of age who underwent screening mammography at facilities participating in the National Cancer Institute's Breast Cancer Surveillance Consortium (BCSC) throughout 1996 and 1997. Mammography results were linked to population-based cancer and pathology registries. We calculated the percentage of screen-detected breast cancers that were DCIS, the rate of screen-detected DCIS per 1000 mammograms by age and by previous mammography status, and the sensitivity of screening mammography. Statistical tests were two-sided. A total of 3266 cases of breast cancer were identified, 591 DCIS and 2675 invasive breast cancer. The percentage of screen-detected breast cancers that were DCIS decreased with age (from 28.2% [95% confidence interval (CI) = 23.9% to 32.5%] for women aged 40-49 years to 16.0% [95% CI = 13.3% to 18.7%] for women aged 70-84 years). However, the rate of screen-detected DCIS cases per 1000 mammograms increased with age (from 0.56 [95% CI = 0.41 to 0.70] for women aged 40-49 years to 1.07 [95% CI = 0.87 to 1.27] for women aged 70-84 years). Sensitivity of screening mammography in all age groups combined was higher for detecting DCIS (86.0% [95% CI = 83.2% to 88.8%]) than it was for detecting invasive breast cancer (75.1% [95% CI = 73.5% to 76.8%]). Overall, approximately 1 in every 1300 screening mammography examinations leads to a diagnosis of DCIS. Given uncertainty about the natural history of DCIS, the clinical significance of screen-detected DCIS needs further investigation.


Fear patterns: a new approach to designing road safety advertisements.
This research studies fear patterns within fear appeal anti-speeding television commercials. A pattern of fear is the sequence of fear arousal and fear reduction, if any, that is felt by the viewing audience when exposed to a fear appeal advertisement. Many road safety advertisers use fear appeals, such as "shock" advertising, that result in fear arousal, leaving the viewer feeling extremely tense. The moment-to-moment reactions of young drivers to 12 road safety commercials are gauged using a dynamic, temporal measure of fear. The fear patterns generated from each ad are analyzed and a new perspective on creating fear appeal road safety advertisements, with an emphasis on fear-relief, fear-partial relief, and fear-only patterns, is discussed.


Working Definitions of the Roles and an Organizational Structure in Health Professions Education Scholarship: Initiating an International Conversation.
Health professions education scholarship (HPES) is an important and growing field of inquiry. Problematically, consistent use of terminology regarding the individual roles and organizational structures that are active in this field are lacking. This inconsistency impedes the transferability of current and future findings related to the roles and organizational structures of HPES. Based on data collected during interviews with HPES leaders in Canada, Australia, New Zealand, the United States, and the Netherlands, the authors constructed working definitions for some of the professional roles and an organizational structure that support HPES. All authors reviewed the definitions to ensure relevance across multiple countries. The authors define and offer illustrative examples of three professional roles in HPES (clinician educator, HPES research scientist, and HPES administrative leader) and an organizational structure that can support HPES participation (HPES unit). These working definitions are foundational and not all-encompassing and, thus, are offered as stimulus for international dialogue and understanding. With these working definitions, scholars and administrative leaders can examine HPES roles and organizational structures across and between national contexts to decide how lessons learned in other contexts can be applied to their local contexts. Although rigorously constructed, these definitions need to be vetted by the international HPES community. The authors argue that these definitions are sufficiently transferable to support such scholarly investigation and debate.


Determining E. coli burden on pasture in a headwater catchment: combined field and modelling approach.
Empirical monitoring studies of catchment-scale Escherichia coli burden to land from agriculture are scarce. This is not surprising given the complexity associated with the temporal and spatial heterogeneity in the excretion of livestock faecal deposits and variability in microbial content of faeces. However, such information is needed to appreciate better how land management and landscape features impact on water quality draining agricultural landscapes. The aim of this study was to develop and test a field-based protocol for determining the burden of E. coli in a small headwater catchment in the UK. Predictions of E. coli burden using an empirical model based on previous best estimates of excretion and shedding rates were also evaluated against observed data. The results indicated that an empirical model utilising key parameters was able to satisfactorily predict E. coli burden on pasture most of the time, with 89% of observed values falling within the minimum and maximum range of predicted values. In particular, the overall temporal pattern of E. coli burden on pasture is captured by the model. The observed and predicted values recorded a disagreement of >1 order of magnitude on only one of the nine sampling dates throughout an annual period. While a first approximation of E. coli burden to land, this field-based protocol represents one of the first comprehensive approaches for providing a real estimate of a dynamic microbial reservoir at the headwater catchment scale and highlights the utility of a simple dynamic empirical model for a more economical prediction of catchment-scale E. coli burden.


Peramivir injection in the treatment of acute influenza: a review of the literature.
Influenza virus infection is a major cause of morbidity and mortality in children and adults globally. Seasonal epidemics are common due to the rapid virus evolution, whereas the frequent emergence of antigenic variants can result in pandemics and sporadic/endemic avian influenza virus infections. Although annual vaccination is the mainstay for influenza prevention and control, the use of antiviral agents must be considered for treatment and prophylaxis against influenza. Currently available antiviral drugs include neuraminidase inhibitors (NAIs), adamantanes, and a novel polymerase inhibitor (favipiravir). Peramivir is a recently US Food and Drug Administration-approved NAI for the treatment of acute uncomplicated influenza in adults. The chemical structure of peramivir allows it to bind to the influenza neuraminidase with much higher affinity than oseltamivir. Peramivir is effective against a variety of influenza A and B subtypes and has a lower half-maximal inhibitory concentration compared to other NAIs in in vitro studies. Peramivir can be administered intravenously, a route that is favorable for hospitalized, critically ill patients with influenza. The long half-life of peramivir allows for once-daily dosing. The drug is eliminated primarily by the kidneys, warranting dose adjustments in patients with renal dysfunction. Studies have assessed the clinical efficacy of peramivir for treatment of pandemic influenza A (H1N1). Although anecdotal evidence supports the use of peramivir in pediatric patients, pregnant women, and hospitalized patients with severe influenza receiving continuous renal replacement therapy and extracorporeal membrane oxygenation, well-designed, controlled clinical trials should be conducted in order to assess its clinical efficacy in these patient populations.


Exploring microbial diversity and taxonomy using SSU rRNA hypervariable tag sequencing.
Massively parallel pyrosequencing of hypervariable regions from small subunit ribosomal RNA (SSU rRNA) genes can sample a microbial community two or three orders of magnitude more deeply per dollar and per hour than capillary sequencing of full-length SSU rRNA. As with full-length rRNA surveys, each sequence read is a tag surrogate for a single microbe. However, rather than assigning taxonomy by creating gene trees de novo that include all experimental sequences and certain reference taxa, we compare the hypervariable region tags to an extensive database of rRNA sequences and assign taxonomy based on the best match in a Global Alignment for Sequence Taxonomy (GAST) process. The resulting taxonomic census provides information on both composition and diversity of the microbial community. To determine the effectiveness of using only hypervariable region tags for assessing microbial community membership, we compared the taxonomy assigned to the V3 and V6 hypervariable regions with the taxonomy assigned to full-length SSU rRNA sequences isolated from both the human gut and a deep-sea hydrothermal vent. The hypervariable region tags and full-length rRNA sequences provided equivalent taxonomy and measures of relative abundance of microbial communities, even for tags up to 15% divergent from their nearest reference match. The greater sampling depth per dollar afforded by massively parallel pyrosequencing reveals many more members of the "rare biosphere" than does capillary sequencing of the full-length gene. In addition, tag sequencing eliminates cloning bias and the sequences are short enough to be completely sequenced in a single read, maximizing the number of organisms sampled in a run while minimizing chimera formation. This technique allows the cost-effective exploration of changes in microbial community structure, including the rare biosphere, over space and time and can be applied immediately to initiatives, such as the Human Microbiome Project.


Exposure to radiation from single or combined radio frequencies provokes macrophage dysfunction in the RAW 264.7 cell line.
The aim of this study was to determine whether exposure to radiation from single or multiple radio-frequency (RF) signals at 900 and 2450 MHz would induce effects in the RAW 264.7 cell line. Cell cultures were exposed to single or combined RF for 4, 24, 48, or 72 h in a GTEM electromagnetic test chamber. At the end of the radiation exposure time, viability and cell growth were analyzed by flow cytometry, nitric oxide (NO) production was measured by colorimetry, the expression of HSP70 and TNF-α was ascertained by qPCR, and the phagocytic activity was observed by microscopy. NO production increased after 48 h exposure at 2450 MHz, compared with controls. The group subjected to the combined interaction of two RFs showed an increase of HSP70 after 48 h exposure and a significant increase of NO and TNF-α after 72 h. The phagocytic activity of macrophages decreased in all groups as exposure time increased. Our results indicated a decrease in phagocytic activity and an increase in inflammatory, cytoprotective, and cytotoxic responses in macrophages after continuous and combined exposure of multiple RF signals. Multiple RF interact in everyday life, the immune response in humans is unknown.


Dementia-associated mortality and its predictors among older adults in sub-Saharan Africa: results from a 2-year follow-up in Congo (the EPIDEMCA-FU study).
between 2011 and 2012, we carried out a study of dementia prevalence in central Africa throughout the EPIDEMCA (Epidemiology of Dementia in Central Africa) programme. to assess dementia-related mortality among Congolese older people from the EPIDEMCA study after 2 years of follow-up. longitudinal population-based cohort study. Gamboma and Brazzaville, Republic of Congo. older participants were traced and interviewed in rural and urban Congo annually between 2012 and 2014. DSM-IV and NINCDS-ADRDA criteria were required for dementia diagnosis. Data on vital status were collected throughout the follow-up. Cox proportional hazards model was used to assess the link between baseline dementia diagnosis and mortality risk. of 1,029 participants at baseline, 910 (88.4%) have a complete cognitive diagnosis. There were 791 participants (76.87%) with normal cognition, 56 (5.44%) with MCI and 63 (6.12%) with dementia. After 2 years of follow-up, 101 (9.8%) participants had died. Compared with participants with normal cognition, patients with dementia had 2.5 times higher mortality risk (HR = 2.53, 95% CI 1.42-4.49, P = 0.001). Among those with dementia, only clinical severity of dementia was associated with an additional increased mortality risk (HR = 1.91; CI 95%, 1.23-2.96; P = 0.004). Age (per 5-year increase), male sex and living in an urban area were independently associated with increased mortality risk across the full cohort. among Congolese older adults, dementia is associated with increased mortality risk. Our results highlight the need for targeted health policies and strategies for dementia care in sub-Saharan Africa (SSA).


Effects of T2-Weighted MRI Based Cranial Volume Measurements on Studies of the Aging Brain.
Many brain aging studies use total intracranial volume (TIV) as a proxy measure of premorbid brain size that is unaffected by neurodegeneration. T1-weighted Magnetic Resonance Imaging (MRI) sequences are commonly used to measure TIV, but T2-weighted MRI sequences provide superior contrast between the cerebrospinal fluid (CSF) bounding the premorbid brain space and surrounding dura mater. In this study, we compared T1-based and T2-based TIV measurements to assess the practical impact of this superior contrast on studies of brain aging. 810 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, including healthy elders and those with mild cognitive impairment (MCI) and Alzheimer's Disease (AD), received T1-weighted and T2-weighted MRI at their baseline evaluation. TIV was automatically estimated from T1-weighted images using FreeSurfer version 4.3 (T1TIV), and an automated active contour method was used to estimate TIV from T2-weighted images (T2TIV). The correlation between T1TIV and T2TIV was high (.93), and disagreement was greater on larger heads. However, correcting a FreeSurfer-based measure of total parenchymal volume by dividing it by T2TIV led to stronger expected associations with a standardized measure of cognitive dysfunction (MMSE) in Poisson regression models among individuals with AD (z=1.73 vs. 1.09) and MCI (z=3.15 vs. 2.79) than a corresponding parenchymal volume measure divided by T1TIV. This effect was enhanced when the analysis was restricted to the cases where T1TIV and T2TIV disagreed the most. These findings suggest that T2-based TIV measurements may be higher fidelity than T1-based TIV measurements, thus leading to greater sensitivity to detect biologically plausible brain-behavior associations.


Guns, schools, and mental illness: potential concerns for physicians and mental health professionals.
Since the recent shootings in Tucson, Arizona; Aurora, Colorado; and Newtown, Connecticut, there has been an ever-increasing state and national debate regarding gun control. All 3 shootings involved an alleged shooter who attended college, and in hindsight, evidence of a mental illness was potentially present in these individuals while in school. What appears to be different about the current round of debate is that both pro-gun control and anti-gun control advocates are focusing on mentally ill individuals, early detection of mental illness during school years, and the interactions of such individuals with physicians and the mental health system as a way to solve gun violence. This raises multiple questions for our profession about the apparent increase in these types of events, dangerousness in mentally ill individuals, when to intervene (voluntary vs involuntary), and what role physicians should play in the debate and ongoing prevention. As is evident from the historic Tarasoff court case, physicians and mental health professionals often have new regulations/duties, changes in the physician-patient relationship, and increased liability resulting from high-profile events such as these. Given that in many ways the prediction of who will actually commit a violent act is difficult to determine with accuracy, physicians need to be cautious with how the current gun debate evolves not only for ourselves (eg, increased liability, becoming de facto agents of the state) but for our patients as well (eg, increased stigma, erosion of civil liberties, and changes in the physician-patient relationship). We provide examples of potential troublesome legislation and suggestions on what can be done to improve safety for our patients and for the public.


Borrowing Information across Populations in Estimating Positive and Negative Predictive Values.
A marker's capacity to predict risk of a disease depends on disease prevalence in the target population and its classification accuracy, i.e. its ability to discriminate diseased subjects from non-diseased subjects. The latter is often considered an intrinsic property of the marker; it is independent of disease prevalence and hence more likely to be similar across populations than risk prediction measures. In this paper, we are interested in evaluating the population-specific performance of a risk prediction marker in terms of positive predictive value (PPV) and negative predictive value (NPV) at given thresholds, when samples are available from the target population as well as from another population. A default strategy is to estimate PPV and NPV using samples from the target population only. However, when the marker's classification accuracy as characterized by a specific point on the receiver operating characteristics (ROC) curve is similar across populations, borrowing information across populations allows increased efficiency in estimating PPV and NPV. We develop estimators that optimally combine information across populations. We apply this methodology to a cross-sectional study where we evaluate PCA3 as a risk prediction marker for prostate cancer among subjects with or without previous negative biopsy.


Age-dependence of healthcare interventions for COVID-19 in Ontario, Canada.
Patient age is one of the most salient clinical indicators of risk from COVID-19. Age-specific distributions of known SARS-CoV-2 infections and COVID-19-related deaths are available for many regions. Less attention has been given to the age distributions of serious medical interventions administered to COVID-19 patients, which could reveal sources of potential pressure on the healthcare system should SARS-CoV-2 prevalence increase, and could inform mass vaccination strategies. The aim of this study is to quantify the relationship between COVID-19 patient age and serious outcomes of the disease, beyond fatalities alone. We analysed 277,555 known SARS-CoV-2 infection records for Ontario, Canada, from 23 January 2020 to 16 February 2021 and estimated the age distributions of hospitalizations, Intensive Care Unit admissions, intubations, and ventilations. We quantified the probability of hospitalization given known SARS-CoV-2 infection, and of survival given COVID-19-related hospitalization. The distribution of hospitalizations peaks with a wide plateau covering ages 60-90, whereas deaths are concentrated in ages 80+. The estimated probability of hospitalization given known infection reaches a maximum of 27.8% at age 80 (95% CI 26.0%-29.7%). The probability of survival given hospitalization is nearly 100% for adults younger than 40, but declines substantially after this age; for example, a hospitalized 54-year-old patient has a 91.7% chance of surviving COVID-19 (95% CI 88.3%-94.4%). Our study demonstrates a significant need for hospitalization in middle-aged individuals and young seniors. This need is not captured by the distribution of deaths, which is heavily concentrated in very old ages. The probability of survival given hospitalization for COVID-19 is lower than is generally perceived for patients over 40. If acute care capacity is exceeded due to an increase in COVID-19 prevalence, the distribution of deaths could expand toward younger ages. These results suggest that vaccine programs should aim to prevent infection not only in old seniors, but also in young seniors and middle-aged individuals, to protect them from serious illness and to limit stress on the healthcare system.


Endothelial transcriptomics reveals activation of fibrosis-related pathways in hypertension.
Hypertension poses a significant challenge to vasculature homeostasis and stands as the most common cardiovascular disease in the world. Its effects are especially profound on endothelial cells that form the inner lining of the vasculature and are directly exposed to the effects of excess pressure. Here, we characterize the in vivo transcriptomic response of cardiac endothelial cells to hypertension by rapidly isolating these cells from the spontaneous hypertension mouse model BPH/2J and its normotensive BPN/3J control strain and performing and RNA sequencing on both. Comparison of transcriptional differences between these groups reveals statistically significant changes in cellular pathways consistent with cardiac fibrosis found in hypertensive animals. Importantly, many of the fibrosis-linked genes identified also differ significantly between juvenile prehypertensive and adult hypertensive BPH/2J mice, suggesting that these transcriptional differences are hypertension related. We examined the dynamic nature of these transcriptional changes by testing whether blood pressure normalization using either a calcium channel blocker (amlodipine) or a angiotensin II receptor blocker (losartan) is able to reverse these expression patterns associated with hypertension. We find that blood pressure reduction is capable of reversing some gene-expression patterns, while other transcripts are recalcitrant to therapeutic intervention. This illuminates the possibility that unmanaged hypertension may irreversibly alter some endothelial transcriptional patterns despite later intervention. This study quantifies how endothelial cells are remodeled at the molecular level in cardiovascular pathology and advances our understanding of the transcriptional events associated with endothelial response to hypertensive challenge.


Prebiotic-like chemistry on Titan.
Titan, the largest satellite of Saturn, is the only one in the solar system with a dense atmosphere. Mainly composed of dinitrogen with several % of methane, this atmosphere experiences complex organic processes, both in the gas and aerosol phases, which are of prebiotic interest and within an environment of astrobiological interest. This tutorial review presents the different approaches which can be followed to study such an exotic place and its chemistry: observation, theoretical modeling and experimental simulation. It describes the Cassini-Huygens mission, as an example of observational tools, and gives the new astrobiologically oriented vision of Titan which is now available by coupling the three approaches. This includes the many analogies between Titan and the Earth, in spite of the much lower temperature in the Saturn system, the complex organic chemistry in the atmosphere, from the gas to the aerosol phases, but also the potential organic chemistry on Titan's surface, and in its possible internal water ocean.


Fish oil supplementation in type 2 diabetes: a quantitative systematic review.
To determine the effects of fish oil supplementation on lipid levels and glycemic control in patients with type 2 diabetes. A comprehensive search of Medline, Embase, Lilacs, the Cochrane Clinical Trials Registry bibliographies of relevant papers, and expert input updated through September 1998 was undertaken. All randomized placebo-controlled trials were included in which fish oil supplementation was the only intervention in subjects with type 2 diabetes. Three investigators performed data extraction and quality scoring independently with discrepancies resolved by consensus. Eighteen trials including 823 subjects followed for a mean of 12 weeks were included. Doses of fish oil used ranged from 3 to 18 g/day The outcomes studied were glycemic control and lipid levels. Meta-analysis of pooled data demonstrated a statistically significant effect of fish oil on lowering triglycerides (-0.56 mmol/l [95% CI -0.71 to -0.41]) and raising LDL cholesterol (0.21 mmol/l [0.02 to 0.41]). No statistically significant effect was observed for fasting glucose. HbA1c total cholesterol, or HDL cholesterol. The triglyceride-lowering effect and the elevation in LDL cholesterol were most marked in those trials that recruited hypertriglyceridemic subjects and used higher doses of fish oil. Heterogeneity was observed and explained by the recruitment of subjects with baseline hypertriglyceridemia in some studies. Fish oil supplementation in type 2 diabetes lowers triglycerides, raises LDL cholesterol, and has no statistically significant effect on glycemic control. Trials with hard clinical end points are needed.


Vaccination coverage among children in Germany estimated by analysis of health insurance claims data.
In Germany, the national routine childhood immunization schedule comprises 12 vaccinations. Primary immunizations should be completed by 24 mo of age. However, nationwide monitoring of vaccination coverage (VC) is performed only at school entry. We utilized health insurance claims data covering ~85% of the total population with the objectives to (1) assess VC of all recommended childhood vaccinations in birth-cohorts 2004-2009, (2) analyze cross-sectional (at 24 and 36 mo) and longitudinal trends, and (3) validate the method internally and externally. Counting vaccine doses in a retrospective cohort fashion, we assembled individual vaccination histories and summarized VC to nationwide figures. For most long-established vaccinations, VC at 24 mo was at moderate levels (~73-80%) and increased slightly across birth-cohorts. One dose measles VC was high (94%), but low (69%) for the second dose. VC with a full course of recently introduced varicella, pneumococcal, and meningococcal C vaccines increased across birth-cohorts from below 10% above 60%, 70%, and 80%, respectively. At 36 mo, VC had increased further by up to 15 percentage points depending on vaccination. Longitudinal analysis suggested a continued VC increase until school entry. Validation of VC figures with primary data showed an overall good agreement. In conclusion, analysis of health insurance claims data allows for the estimation of VC among children in Germany considering completeness and timeliness of vaccination series. This approach provides valid nationwide VC figures for all currently recommended pediatric vaccinations and fills the information gap between early infancy and late assessment at school entry.


Are goblet cell carcinoids a group of heterogeneous tumors?
Goblet cell carcinoids belong to neuroendocrine tumors, according to the WHO classification. The tumors are diagnosed based on a typical histological pattern and using neuroendocrine markers. However, some tumors do not react with these markers and yet expression of proliferative markers is high. Do these tumors belong to G1 and G2 neuroendocrine tumors? The sample comprised nine cases of tumors of the appendix identified by immunohistological methods as goblet cell carcinoids or adenocarcinoma ex goblet cell carcinoid. In six cases, hematoxylin and eosin staining revealed tumors completely or 90% made of characteristic large tumor cells observed in typical goblet cell carcinoids. The remaining three cases were identified as adenocarcinomas arising ex goblet cell carcinoids. Immunohistological examination revealed that in four cases of typical goblet cell carcinoids, expression of neuroendocrine markers was low or completely negative. Yet in two cases, the Ki-67 proliferative index exceeded the 20% cut-off for inclusion in the G1 and G2 category. Goblet cell carcinoids are a heterogeneous group of tumors that may express neuroendocrine markers in a small number of tumor cells or are negative to these markers. However, high expression of the proliferative marker Ki-67 exceeds the criteria for G1 and G2 neuroendocrine tumors. It is our opinion that these tumors may be classified as a specific type of carcinoma.


Linkage mapping and comparative analysis of bovine expressed sequence tags (ESTs).
Bovine expressed sequence tags (ESTs) containing microsatellites are suitable markers for both linkage and comparative maps. We isolated clones from a bovine fetal thigh skeletal muscle cDNA library that were positive for a (CA)10 probe. Thirty individual clones were isolated and characterised by sequencing. Sequences from the 5' and 3' ends of a clone were considered as separate ESTs until a contiguous sequence was identified. A total of 47 ESTs were sequenced from the 5' and/or 3' ends and full sequence was obtained for the 30 clones. BLAST nucleotide analysis identified significant homology to known mammalian coding regions for 31 of the bovine ESTs, 30 of which also matched human ESTs or sequence-tagged sites (STS). The remaining 16 bovine ESTs represented novel transcripts. Microsatellites were isolated in 27 of the ESTs, 11 of which were developed into markers and placed on the MARC bovine linkage map. Human cytogenetic map positions were available for 20 of the 30 human EST orthologs, and a putative bovine map position for 17 of the sequences could be inferred using comparative mapping data. These results demonstrated that mapping bovine ESTs containing microsatellites is a plausible strategy to increase the density of gene markers on the bovine linkage and comparative maps.


Health-related quality of life and long-term sequelae in survivors of epidermal necrolysis: an observational study of 57 patients.
Few studies have investigated the global burden of sequelae and health-related quality of life (HRQoL) for survivors of epidermal necrolysis (EN). To investigate the long-term HRQoL for survivors of EN using validated instruments. We conducted a single-centre study that enrolled patients who were admitted for EN between 2010 and 2017. HRQoL was assessed via phone interview using the Short Form (SF)-36 questionnaire, Hospital Anxiety and Depression (HAD) scale, Impact of Event Scale-Revised, and general quality-of-life outcomes, including EN-specific sequelae. The primary outcome measure was the physical component summary (PCS) score of the SF-36. In total, 57 survivors of EN [19 (33%) with intensive care unit (ICU) admission] were interviewed via telephone at a median of 3·6 years (1·9-6·1) after hospital discharge. The median PCS score was 0·44 SDs below that of the age- and sex-matched reference population and was significantly lower for survivors of EN who were admitted to the ICU vs. those who were not [43·7 (28·7-49·3) vs. 51·2 (39·4-56·5), P = 0·042]. The proportion of patients with EN who had HAD-anxiety score ≥ 8 or HAD-depression score ≥ 5 was 54% and 21%, respectively. Physical and mental outcomes did not differ between patients with EN who were admitted to the ICU and survivors of septic shock. Reported EN-specific sequelae were cutaneous (77%), ocular (70%), psychological (60%), dental/oral (49%), genital (30%) and respiratory (18%), with median intensity on a visual analogue scale. Our study confirms the major burden and long-term impact of EN on quality of life for survivors and emphasizes the need for prolonged close follow-up after the acute phase. What's already known about this topic? Long-term sequelae have been reported in 90% of survivors of epidermal necrolysis (EN). Few studies have investigated the global burden of sequelae and health-related quality of life (HRQoL) in survivors of EN. What does this study add? Survivors of EN, particularly those admitted to the intensive care unit, had poorer physical HRQoL than the French reference population but had comparable HRQoL to survivors of septic shock. Survivors of EN exhibited symptoms of anxiety, depression and post-traumatic stress syndrome. The most frequent sequelae were cutaneous, ocular and psychological, with visual analogue scale scores of 5/10 and 6/10. These results confirm the burden of EN on quality of life.


Biotransformation of fluvastatin sodium in humans.
The metabolic pathways of fluvastatin sodium (FV; Lescol, Sandoz compound XU 62-320), [R*,S*-(E)]-(+-)-sodium-3,5-dihydroxy-7-[3- (4-fluorophenyl)-1-(1-methylethyl)-1H-indole-2-yl]-hept-6-enoate, a potent inhibitor of hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase)--the rate-limiting enzyme in cholesterol biosynthesis--were determined in normal male volunteers at steady state. The metabolite profiles were determined in pooled human blood/plasma, urine, and feces obtained from healthy male volunteers after a single dose of 2 and 10 mg of [3H]FV and at steady state after a single 40 mg daily dose of [3H]FV for 6 sequential days utilizing HPLC coupled with radioactivity monitoring. The two major components in plasma were FV and the desisopropylpropionic acid (4) derivative of FV, the latter a result of oxidative removal of the N-isopropyl group and beta-oxidation of the side chain. Minor amounts of the 4,5-pentenoic acid derivative of FV, the threo-isomer of FV, the trans-lactone of FV, and conjugates of 5-hydroxy FV and 6-hydroxy FV were also present in plasma. Parent FV was not present in feces, the major excretory route, or in urine. In urine, 4 and conjugates of 5-hydroxy FV, and 6-hydroxy FV were present, and each represented < 1% of the dose. In feces 5-hydroxy FV, 6-hydroxy FV, and desisopropyl-FV represented the only peaks of significance. The metabolism of FV leading to the 5-hydroxy FV and 6-hydroxy FV was not stereospecific.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparison of cerebral SPECT abnormalities in HIV-positive homosexual men with and without cognitive impairment.
To determine whether technetium Tc 99m exametazime (HMPAO) single-photon emission computed tomography (SPECT) can distinguish between human immunodeficiency virus (HIV)-positive homosexual men with normal neuropsychologic test results and HIV-positive homosexual men with abnormal neuropsychologic test results. Neurologic, neuropsychologic, magnetic resonance imaging, and Tc 99m HMPAO SPECT examinations were performed on 10 HIV-positive homosexual men without cognitive impairment and five HIV-positive homosexual men with cognitive impairment. Human immunodeficiency virus-positive homosexual men from New York City were recruited for the study. Findings on SPECT scans were evaluated qualitatively for focal defects, heterogeneity of the cortical margin, white matter hypoperfusion, and decreased global cortical uptake. All SPECT focal defects were coregistered with magnetic resonance images; SPECT heterogeneity and global cortical uptake were also measured quantitatively. Coregistration with magnetic resonance imaging revealed that 63% of the focal SPECT defects corresponded to brain gyri and 37% corresponded to sulci. There was no significant difference in the frequency of qualitative or quantitative SPECT abnormalities between HIV-positive homosexual men ith and without cognitive impairment. However, after examining individual neuropsychologic test factors, impaired motor speed performance was associated with decreased quantitative global cerebral uptake. Qualitative SPECT abnormalities are not increased in frequency in HIV-positive homosexual men with global cognitive impairment compared with those in HIV-positive homosexual men without cognitive impairment. Impaired motor speed performance may be associated with decreased quantitative global cerebral uptake.


Oral health status among psychiatric patients in Riyadh, Saudi Arabia.
The purpose of this study is to describe the oral health status among psychiatric patients as compared to psychologically normal controls. A convenience sample of 100 patients who regularly attended a psychiatric clinic in King Saud University, King Khalid Hospital, Riyadh, Saudi Arabia, was selected as the study group. The control group consisted of 84 age- and gender-matched volunteers. All controls were screened using the General Health Questionnaire (GHQ-28) and five persons were excluded based on this. All the participants were interviewed and a comprehensive review questionnaire designed for this survey was completed, then they were examined. The examination involved an extra-oral examination as well as examination of teeth and soft tissues using the decayed, missing, filled teeth (DMFT) index, the Silness and Löe plaque index and the bleeding index. The study group had more tenderness in the masticatory muscles, especially the temporalis muscle. Temporomandbular joint findings showed no significant differences between groups. Decayed, missing, filled teeth index, plaque and bleeding indices were higher among the study group. The incidence of scalloped tongue was significantly higher among psychiatric patients. Oral health status is worse among psychiatric patients, who are more likely to develop some oral conditions, such as temporomandibular disorder and dental caries. It is necessary for both dental and mental healthcare providers to be aware of patients' needs and preventive measures to be instituted for them.


Passive intrinsic-linewidth narrowing of ultraviolet extended-cavity diode laser by weak optical feedback.
We present a simple method for narrowing the intrinsic Lorentzian linewidth of a commercial ultraviolet grating extended-cavity diode laser (TOPTICA DL Pro) using weak optical feedback from a long external cavity. We achieve a suppression in frequency noise spectral density of 20 dB measured at frequencies around 1 MHz, corresponding to the narrowing of the intrinsic Lorentzian linewidth from 200 kHz to 2 kHz. Provided additional active low-frequency noise suppression and long-term drift compensation, the system is suitable for experiments requiring a tunable ultraviolet laser with narrow linewidth and low high-frequency noise, such as precision spectroscopy, optical clocks, and quantum information science experiments.


Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators.
The role of fluorouracil and folinic acid and adjuvant therapy for colon cancer is not clear. We undertook independently three randomised trials to find out the efficacy of fluorouracil and high-dose folinic acid after surgery for Dukes' B and C stage colon cancer. The three studies by the Gruppo Interdisciplinare Valutazione Interventi Oncologia (GIVIO), the National Cancer Institute Canada Clinical Trials Group (NCIC-CTG), and the Fondation Française de Cancerologie Digestive (FFCD) were pooled for combined analysis. Each trial was multicentre and used the same treatment regimen (fluorouracil 370-400 mg/m2 plus folinic acid 200 mg/m2 daily for 5 days, every 28 days for 6 cycles). A pooled analysis of the results was done on the basis of a previously agreed protocol when there were sufficient events to detect at least a 10% reduction in mortality with 80% power. 1526 patients with resected B (56%) and C (44%) carcinoma of the colon were enrolled and 1493 were confirmed as eligible. 736 were assigned to the treatment group and 757 to the control group. Fluorouracil/folinic acid significantly reduced mortality by 22% (95% CI 3-38; p = 0.029) and events by 35% (22-46; p < 0.0001), increasing 3-year event-free survival from 62% to 71% and overall survival from 78% to 83%. Compliance with treatment was good; more than 80% of patients completed the planned treatment. Side-effects were clinically acceptable with only 1 treatment-related death. The commonest side-effects were gastrointestinal, but severe toxic effects (WHO grade 4) occurred in fewer than 3% of cases. We conclude that fluorouracil plus high-dose folinic acid is a well-tolerated and effective 6-month adjuvant regimen for colon cancer.


Assessment of occupational symptoms and chemical exposures for nail salon technicians in Daegu City, Korea.
This study aimed to evaluate occupational symptoms and chemical exposures of nail salon technicians. Work-related symptoms of nail salon technicians in Daegu City were surveyed using a researcher-administered questionnaire, and responses were compared to those of non-exposed office workers as controls. Personal exposure level of airborne volatile organic compounds was also monitored using passive samplers. A total of 159 subjects in 120 salons were interviewed. Average work-shift concentrations of 13 chemicals were measured for 50 workers from 30 salons using personal passive samplers. The most frequently reported respiratory or neurologic symptoms by nail shop technicians compared to controls were nose irritation (odds ratio [OR], 54.0; confidence interval [CI], 21.6 to 134.8), followed by headache (OR, 9.3; CI, 4.7 to 18), and throat irritation (OR, 4.3; CI, 2.2 to 8.5). For eyes and skin, 92% of respondents complained eye irritation (OR, 13.1; CI, 5.7 to 30.1). In musculoskeletal symptoms, workers reported pain or discomfort in shoulders (OR, 20.3; CI, 7.7 to 54) and neck (OR, 19.7; CI, 8.9 to 43.6). From personal measurements, the proportion of exceeding the Korean Occupational Exposure Limit was the highest for acetone with 64%, followed by toluene (50%), butyl acetate (46%), and methyl methacrylate (12%). However, the service was being provided without a proper ventilation system in most surveyed shops. Based on these findings, it is warranted to have appropriate local exhaust ventilation place to ensure adequate health protection of nail shop technicians as well as customers. At the same time, greater policy interests are warranted in nail care business to protect health of both workers and customers.


Distribution of cardiovascular disease and retinopathy in patients with type 2 diabetes according to different classification systems for chronic kidney disease: a cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study.
The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF's KDOQI) staging system for chronic kidney disease (CKD) is based primarily on estimated GFR (eGFR). This study aimed at assessing whether reclassification of subjects with type 2 diabetes using two recent classifications based on both eGFR and albuminuria, the Alberta Kidney Disease Network (AKDN) and the Kidney Disease: Improving Global Outcomes (KDIGO), provides a better definition of burden from cardiovascular disease (CVD) and diabetic retinopathy (DR) than the NKF's KDOQI classification. This is a cross-sectional analysis of patients with type 2 diabetes (n = 15,773) from the Renal Insufficiency And Cardiovascular Events Italian Multicenter Study, consecutively visiting 19 Diabetes Clinics throughout Italy in years 2007-2008. Exclusion criteria were dialysis or renal transplantation. CKD was defined based on eGFR, as calculated from serum creatinine by the simplified Modification of Diet in Renal Disease Study equation, and albuminuria, as measured by immunonephelometry or immunoturbidimetry. DR was assessed by dilated fundoscopy. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. Though prevalence of complications increased with increasing CKD severity with all three classifications, it differed significantly between NKF's KDOQI stages and AKDN or KDIGO risk categories. The AKDN and KDIGO systems resulted in appropriate reclassification of uncomplicated patients in the lowest risk categories and a more graded independent association with CVD and DR than the NKF's KDOQI classification. However, CVD, but not DR prevalence was higher in the lowest risk categories of the new classifications than in the lowest stages of the NKF's KDOQI, due to the inclusion of subjects with reduced eGFR without albuminuria. CVD prevalence differed also among eGFR and albuminuria categories grouped into AKDN and KDIGO risk category 1 and moderate, respectively, and to a lesser extent into higher risk categories. Though the new systems perform better than the NKF's KDOQI in grading complications and identifying diabetic subjects without complications, they might underestimate CVD burden in patients assigned to lower risk categories and should be tested in large prospective studies. ClinicalTrials.gov; NCT00715481.


Complement factor H is expressed in adipose tissue in association with insulin resistance.
Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances.


Effect of L-ascorbate on chloride transport in freshly excised sinonasal epithelia.
Chronic rhinosinusitis (CRS) occurs at high frequency in patients with cystic fibrosis, suggesting that the cystic fibrosis transmembrane conductance regulator (CFTR) chloride (Cl) ion channel might be involved in the development of chronic sinusitis in the general population. CFTR Cl ion transport controls the hydration of mucosal surfaces and promotes effective mucociliary clearance. Altered ion transport and, hence, disrupted mucociliary function, could play a role in the pathogenesis of sinus disease. L-ascorbate is a metabolically active component of the nasal and tracheobronchial airway lining fluids and appears to serve as an important biological effector of CFTR-mediated chloride secretion. The purpose of this study was to determine the effects of L-ascorbate on Cl ion transport in freshly excised sinonasal epithelia from normal controls and patients with CRS. Four different types of sinonasal tissue (normal sinus mucosa, sinus mucosa from CRS, normal nasal mucosa, nasal mucosa from CRS) were obtained during endoscopic sinus surgery and mounted on sliders with open areas of 0.03-0.71 cm2 between Ussing hemichambers. Short-circuit current (Isc) was continuously recorded, and a serosa-to-mucosa-directed Cl gradient was applied to increase the electrochemical driving force. L-ascorbate (500 microM) stimulated Cl currents (DeltaI(Cl), microA/cm2) across sinonasal epithelia from normal and CRS patients. The Cl secretory response to L-ascorbate was effectively blocked by the Cl ion transport inhibitors glibenclamide and bumetanide. A maximal dose of L-ascorbate (at 1 mM) stimulated 53-70% of Cl currents elicited by the cAMP agonist forskolin. CRS sinonasal tissue was characterized by impaired Cl secretory responses to L-ascorbate that were reduced by 33% in sinus epithelial tissue and by 70% in nasal epithelial tissue when compared with normal subjects. In nasal epithelial tissue from normal subjects, Cl secretion was approximately twofold increased when compared with sinus epithelial tissue. In contrast, nasal versus sinus epithelial tissue from CRS patients showed no differences. Topical administration of L-ascorbate to freshly excised sinus and nasal mucosa enhances chloride secretion. Given that decreased CFTR-mediated Cl secretion may contribute to the development of CRS, L-ascorbate may offer potential as a therapeutic agent for the improvement of mucociliary clearance.


Utility of ancillary stains for Helicobacter pylori in near-normal gastric biopsies.
Documentation of Helicobacter pylori infection and eradication is important, prompting some clinicians and pathologists to request ancillary stains on all gastric samples that do not demonstrate H. pylori on initial histologic review. Studies evaluating the utility of ancillary stains in patients with minimal inflammation are lacking. We used Giemsa, Warthin-Starry, acridine orange, and immunohistochemical stains to search for organisms in 56 patients with biochemical evidence of H. pylori infection (positive Campylobacter-like organism test) and gastric mucosal samples interpreted to be H pylori negative by hematoxylin and eosin (H&E). We correlated the findings with severity of inflammation and patients' histories of medication use. Nineteen (34%) patients had histologically normal mucosae, 22 (39%) had chronic inflammation with or without focal activity, and 15 (27%) had chemical gastropathy. Fifty (89%) cases were negative for H. pylori with additional stains, and 6 contained bacteria that were detected with all 4 ancillary stains and on retrospective review of H&E-stained sections that also showed chronic inflammation. Eleven (20%) patients were taking proton pump inhibitors, and 4 (7%) had previously received H. pylori eradication therapy. We conclude that H&E stains demonstrate H. pylori in most infected patients, so preemptive stain requests are largely unnecessary. Failure to identify bacteria by H&E evaluation generally reflects their absence in biopsy material, even among Campylobacter-like organism test--positive patients. However, organisms may be overlooked in patients with mild inflammation and in those receiving proton pump inhibitor or antibiotic therapy, so one should consider ordering ancillary stains to enhance detection of bacteria in these settings.


Gender discrimination, victimisation and women's mental health.
Gender inequality and discrimination, as well as violence and victimisation towards women, have recently hit the headlines creating a media furore. We provide a timely discussion surrounding the impact of these issues on women's mental health and a discussion of the role of psychiatry in this context.Declaration of interestK.B. is the editor for the British Journal of Psychiatry but has not played a role in the decision to accept this editorial for publication in this journal. G.H. has no conflict of interest to declare.


Development and Validation of a Risk Tool for Predicting Severe Toxicity in Older Adults Receiving Chemotherapy for Early-Stage Breast Cancer.
Limited tools exist to predict the risk of chemotherapy toxicity in older adults with early-stage breast cancer. Patients of age ≥ 65 years with stage I-III breast cancer from 16 institutions treated with neoadjuvant or adjuvant chemotherapy were prospectively evaluated for geriatric and clinical features predictive of grade 3-5 chemotherapy toxicity. Logistic regression with best-subsets selection was used to identify and incorporate independent predictors of toxicity into a model with weighted variable scoring. Model performance was evaluated using area under the ROC curve (AUC) and goodness-of-fit statistics. The model was internally and externally validated. In 473 patients (283 in development and 190 in validation cohort), 46% developed grade 3-5 chemotherapy toxicities. Eight independent predictors were identified (each assigned weighted points): anthracycline use (1 point), stage II or III (3 points), planned treatment duration > 3 months (4 points), abnormal liver function (3 points), low hemoglobin (3 points), falls (4 points), limited walking (3 points), and lack of social support (3 points). We calculated risk scores for each patient and defined three risk groups: low (0-5 points), intermediate (6-11 points), or high (≥ 12 points). In the development cohort, the rates of grade 3-5 chemotherapy toxicity for these three groups were 19%, 54%, and 87%, respectively (P < .01). In the validation cohort, the corresponding toxicity rates were 27%, 45%, and 76%. The AUC was 0.75 (95% CI, 0.70 to 0.81) in the development cohort and 0.69 (95% CI, 0.62 to 0.77) in the validation cohort. Risk groups were also associated with hospitalizations and reduced dose intensity (P < .01). The Cancer and Aging Research Group-Breast Cancer (CARG-BC) score was developed and validated to predict grade 3-5 chemotherapy toxicity in older adults with early-stage breast cancer.


Combining Landscape Genomics and Ecological Modelling to Investigate Local Adaptation of Indigenous Ugandan Cattle to East Coast Fever.
East Coast fever (ECF) is a fatal sickness affecting cattle populations of eastern, central, and southern Africa. The disease is transmitted by the tick Rhipicephalus appendiculatus, and caused by the protozoan Theileria parva parva, which invades host lymphocytes and promotes their clonal expansion. Importantly, indigenous cattle show tolerance to infection in ECF-endemically stable areas. Here, the putative genetic bases underlying ECF-tolerance were investigated using molecular data and epidemiological information from 823 indigenous cattle from Uganda. Vector distribution and host infection risk were estimated over the study area and subsequently tested as triggers of local adaptation by means of landscape genomics analysis. We identified 41 and seven candidate adaptive loci for tick resistance and infection tolerance, respectively. Among the genes associated with the candidate adaptive loci are PRKG1 and SLA2. PRKG1 was already described as associated with tick resistance in indigenous South African cattle, due to its role into inflammatory response. SLA2 is part of the regulatory pathways involved into lymphocytes' proliferation. Additionally, local ancestry analysis suggested the zebuine origin of the genomic region candidate for tick resistance.


Fracture Prediction With Modified-FRAX in Older HIV-Infected and Uninfected Men.
FRAX is a validated, computer-based clinical fracture risk calculator that estimates the 10-year risk of major osteoporotic (clinical spine, forearm, hip, or shoulder) fracture, and hip fracture alone. It is widely used for decision making in fracture prevention, but it may underestimate the risk in HIV-infected individuals. Some experts recommend considering HIV as a cause of secondary osteoporosis when calculating FRAX in HIV-infected individuals. From the Veterans Aging Cohort Study Virtual Cohort, we included 24,451 HIV-infected and uninfected men aged 50-70 years with complete data in the year 2000 to approximate all but 2 factors (ie, history of secondary osteoporosis and parental hip fracture) for modified-FRAX calculation without bone density and 10-year observational data for incident fragility fracture. The accuracy of the modified-FRAX calculation was compared by the observed/estimated (O/E) ratios of fracture by HIV status. The accuracy of modified-FRAX was less for HIV-infected [O/E = 1.62, 95% confidence interval (CI) 1.45 to 1.81] than uninfected men (O/E = 1.29, 95% CI: 1.19 to 1.40), but improved when HIV was included as a cause of secondary osteoporosis (O/E = 1.20, 95% CI: 1.08 to 1.34). However, only 3%-6% of men with incident fractures were correctly identified by the modified-FRAX using accepted FRAX thresholds for pharmacologic therapy. Modified-FRAX underestimated the fracture rates more in older HIV-infected than in otherwise similar uninfected men. The accuracy improved when HIV was included as a cause of secondary osteoporosis, but it still performed poorly for case finding. Further studies are necessary to determine how to use FRAX or define an HIV-specific index to risk stratify for screening and treatment in older HIV-infected individuals.


In utero hypoxia altered Ang II-induced contraction via PKCβ in fetal cerebral arteries.
Cerebral circulation is important in fetal brain development, and angiotensin II (Ang II) plays vital roles in regulation of adult cerebral circulation. However, functions of Ang II in fetal cerebral vasculature and influences of in utero hypoxia on Ang II-mediated fetal cerebral vascular responses are largely unknown. This study investigated the effects and mechanisms of in utero hypoxia on fetal middle cerebral arteries (MCA) via Ang II. Near-term ovine fetuses were exposed to in utero hypoxia, and fetal MCA responses to Ang II were tested for vascular tension, calcium transient, and molecular analysis. Ang II caused significant dose-dependent contraction in control fetal MCA. Ang II-induced MCA constriction was decreased significantly in hypoxic fetuses. Neither losartan (AT1R antagonist, 10-5 mol/L) nor PD123,319 (AT2R antagonist, 10-5 mol/L) altered Ang II-mediated contraction in fetal MCA. Phenylephrine-mediated constriction was also significantly weaker in hypoxic fetuses. Bay K8644 caused similar contractions between the two groups. Protein expression of L-type voltage-dependent calcium channels was unchanged. There were no differences in caffeine-mediated vascular tension or calcium transients. Contraction induced by PDBu (PKC agonist) was obviously weaker in hypoxic MCA. Protein expression of PKCβ was reduced in the hypoxic compared with the control, along with no differences in phosphorylation levels. The results showed that fetal MCA was functionally responsive to Ang II near term. Intrauterine hypoxia reduced the vascular agonist-mediated contraction in fetal MCA, probably via decreasing PKCβ and its phosphorylation, which might play protective effects on fetal cerebral circulation against transient hypoxia.


Rapid adaptive divergence between ecotypes of an aquatic isopod inferred from F-Q analysis.
Divergent natural selection is often thought to be the principal factor driving phenotypic differentiation between populations. We studied two ecotypes of the aquatic isopod Asellus aquaticus which have diverged in parallel in several Swedish lakes. In these lakes, isopods from reed belts along the shores colonized new stonewort stands in the centre of the lakes and rapid phenotypic changes in size and pigmentation followed after colonization. We investigated if selection was likely to be responsible for these observed phenotypic changes using indirect inferences of selection (F(ST)-Q(ST) analysis). Average Q(ST) for seven quantitative traits were higher than the average F(ST) between ecotypes for putatively neutral markers (AFLPs). This suggests that divergent natural selection has played an important role during this rapid diversification. In contrast, the average Q(ST) between the different reed ecotype populations was not significantly different from the mean F(ST). Genetic drift could therefore not be excluded as an explanation for the minor differences between allopatric populations inhabiting the same source habitat. We complemented this traditional F(ST)-Q(ST) approach by comparing the F(ST) distributions across all loci (n = 67-71) with the Q(ST) for each of the seven traits. This analysis revealed that pigmentation traits had diverged to a greater extent and at higher evolutionary rates than size-related morphological traits. In conclusion, this extended and detailed type of F(ST)-Q(ST) analysis provides a powerful method to infer adaptive phenotypic divergence between populations. However, indirect inferences about the operation of divergent selection should be analyzed on a per-trait basis and complemented with detailed ecological information.


[Attributable factors to the emergence of multidrug-resistant Mycobacterium tuberculosis based on the observation of consecutive drug resistance test results].
Thirty six cases with multidrug-resistant tuberculosis were retrospectively studied to define the causes attributable to the emergence of multidrug-resistant M. tuberculosis. All these tuberculosis cases were microbiologically confirmed and resistant to at least isoniazid and rifampicin. Data analysis using matched-pair sampling methods (1:3) demonstrated that the followings are the significant risk factors for the emergence of multidrug-resistant tuberculosis; incompliance to treatment (Odds ratio 21.0: 95% CI 4.10-107.63), alcohol abuse (Odds ratio 15.0: 95% CI 2.34-96.1) and the history of previous treatment (Odds ratio 5.0: 95% CI 2.04-12.21), while diabetes mellitus is not statistically significant. The incompliance to treatment which is primarily thought to be patient's responsibility results in non-optimal administration of antituberculous agents, leading to the multidrug-resistant tuberculosis. Other factors that may have contributed to the emergence of resistance included the unnecessary change of regimen before completion of chemotherapy. This is patient-unrelated situation where responsibility lies in the medical side. A clinical case presented here is an example. In this case RFP was replaced with ethambutol 3-months after the initiation of regimen including SM, INH and RFP because of abnormal elevation of GOT and GPT without any supporting evidence that RFP was causative. The readministration of RFP after 1-year cessation did not induce liver dysfunction, while the drug resistance was observed not only to RFP but also to INH. This case suggests unnecessary interruption of RFP could lead to the emergence of resistance to INH as well as RFP. One known mechanism of drug resistance is random mutation and the selection by drugs administered during the course of chemotherapy. The cases with advanced cavitary lesions would have a higher probability of the occurrence of mutation. The more the number of mutant bacilli, the higher the probability of emergence of multidrug resistance. Those cases in which longer period of time is needed for the negative conversion of M. tuberculosis should be treated with potent chemotherapy regimens under the intense supervision. Since both INH and RFP are the most potent among currently available antituberculous agents. It is crucial to preserve the potency of these essential agents before novel antituberculous are developed.


Physical Exercise Moderates the Relationship of Apolipoprotein E (APOE) Genotype and Dementia Risk: A Population-Based Study.
Genetics and lifestyle independently determine dementia risk, but the interaction is unclear. We assessed the interactive relationship of apolipoprotein E (APOE) genotype and physical exercise on dementia risk over a 5-year period in 1,646 older adults from the Canadian Study of Health and Aging who were dementia-free at baseline. Physical exercise moderated the relationship between genotype and dementia (p < 0.01). Specifically, for APOE ɛ4 non-carriers, the odds of developing dementia were higher in non-exercisers than exercisers (OR = 1.98, 95% CI = 1.44, 2.71, p < 0.001), whereas, for APOE ɛ4 carriers, the odds of developing dementia were not significantly different between non-exercisers and exercisers (OR = 0.71, 95% CI = 0.46, 1.31, p = 0.34). Given that most individuals are not at genetic risk, physical exercise may be an effective strategy for preventing dementia.


A Candidate Regulatory Variant at the TREM Gene Cluster Confer Alzheimer's Disease Risk by Modulating Both Amyloid-β Pathology and Neuronal Degeneration.
Background: rs9357347 located at the triggering receptor expressed on myeloid cells (TREM) gene cluster could increase TREM2 and TREM-like transcript 1 (TREML1) brain gene expression, which is considered to play a protective role against Alzheimer's disease (AD). Objectives: To investigate the role of rs9357347 in AD pathogenesis by exploring the effects of rs9357347 on AD specific biomarkers. Methods: This study analyzed the association of rs9357347 with AD-related cerebrospinal fluid (CSF) and neuroimaging markers from 201 cognitively normal (CN) older adults, 349 elders with mild cognitive impairment (MCI), and 172 elders with AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We next analyzed the association in 259 amyloid-β positive (Aβ+) elders and 117 amyloid-β negative (Aβ-) elders (Aβ+: CSF Aβ1-42 ≤ 192 pg/ml; Aβ-: CSF Aβ1-42 > 192 pg/ml). Associations were tested using multiple linear regression models at baseline. Furthermore, multiple mixed-effects models were used in a longitudinal study which lasted 4 years. Results: At baseline, we found that rs9357347 had association with CSF Aβ1-42 in CN group (β = 0.357, P = 0.009). In AD group, rs9357347 was associated with total tau (T-tau) level (β = -0.436, P = 0.007). Moreover, the strong influence exerted by rs9357347 on T-tau was also seen in Aβ+ group (β = -0.202, P = 0.036). In the longitudinal study, rs9357347 was also found to be associated with Aβ1-42 in CN group (β = 0.329, P = 0.023). In AD group, the mutation of rs9357347 was associated with slower accumulation of T-tau (β = -0.472, P = 0.002) and tau phosphorylated at threonine 181 [P-tau 181 (β = -0.330, P = 0.019)]. Furthermore, the obvious influence exerted by rs9357347 on T-tau was also seen in Aβ+ group (β = -0.241, P = 0.013). Conclusion: This study suggested that rs9357347 reduced the risk of AD by modulating both amyloid-β pathology and neuronal degeneration.