Clients' perceptions of support received from health visitors during home visits.
The current study sought to identify how many mothers from 149 visits carried out by seven health visitors identified support as a feature of the visit, whether this type of support was unique to the health visitor and what support meant to them. These responses were then compared with the taxonomies of social support from the social support literature. Some studies of client perceptions describe support as an element of home visits by health visitors. However, the importance, relevance and impact on the client of this support are not described in detail. Social support theory suggests that there are tangible benefits to people's well-being and their ability to cope with various challenges that may arise from individuals' perceptions of receiving support. Qualitative study using semistructured interviews. Seven volunteer health visitors recruited 149 women into the study. These clients were interviewed by the researcher, usually within one week of the home visit by their health visitor. The discussions were audio-taped and the resulting transcripts analysed using content analysis. Thirty-seven women identified receiving support which they said was only available from the health visitor. The relevance of this support to the mother and the impact on her well-being varied within the group suggesting differing perceptions of support by clients according to their personal situation. There was a correspondence between the descriptions of support given by the women and the taxonomies of social support from the social support literature. For some interactions between clients and their health visitors the existing theory of social support may provide an explanation of how health visitors contribute to clients' perceived ability to cope and well-being. Social support may be defined as a possible outcome of health visiting. This concept will have use within educational programmes to demonstrate to students how health visiting can have an impact on clients' well-being. Similarly, the concept could be used to investigate and record health visiting practice.


[An evaluation of neonatal nursing care through an analysis of the records kept by nurses].
The present study evaluates through nursing registers the assistance afforded to two newborns groups. These children were evaluated by the pediatrician in the delivery room. After that they were conducted to newborn unit, where received the first hygienic care. However, the study shows that the evaluation made by the nurse in the newborn admission, resulted in two groups: one of them composed by children which had signals of difficulty to life adaptation, and the other group composed by children with normal reactions. The nursing assistance given to those newborns is the subject of this paper.


Mammaglobin and maspin transcripts in blood may reflect disease progression and the effect of therapy in breast cancer.
Detection of residual tumor cells in the circulation can provide prognostic as well as therapeutic information and help in identifying patients at high risk for developing metastases. Maspin and mammaglobin are two molecules that are specifically associated with breast cancer. We looked for mammaglobin and maspin transcripts in the peripheral blood of patients with breast cancer and evaluated their utility as a marker of the response to therapy. Maspin and mammaglobin transcripts were analyzed in 85 breast-cancer patients by nested RT-PCR, prior to and after treatment. Before therapy, 10 patients were found positive for mammaglobin and 20 patients were positive for maspin. In four patients, both transcripts were detected. Immediately following treatment, only one patient was still positive for mammaglobin while maspin transcripts persisted in three patients. Disease progression was observed mainly in patients in whom maspin transcripts were not detectable. Molecular detection of circulating tumor cells during therapy based on analysis for mammaglobin and maspin transcripts is an easy and practical method that can be applied to follow-up patients. We suggest that detection of mammaglobin mRNA is useful to determine the effect of therapy while maspin transcripts may indicate more aggressive disease.


The burden of apathy for caregivers of patients with amyotrophic lateral sclerosis.
Apathy is the most common behavioral symptom of amyotrophic lateral sclerosis (ALS). Despite its known impact on caregiver wellbeing, apathy is typically considered a unitary construct making assessment and targeting treatment problematic. The aim of this study was to explore the relationship between caregiver burden and the behavioral, cognitive, and emotional symptoms of apathy in ALS. Fifty-one ALS patient-caregiver dyads from an ALS/frontotemporal dementia Clinic were assessed with the Apathy Evaluation Scale which measured the cognitive, behavioral, emotional, and nonspecific symptoms of apathy as well as the Zarit Burden Interview, a measure of perceived burden among caregivers of cognitively impaired older adults. The relationship between apathy and caregiver burden were analyzed using univariate and multivariate methods. Apathy was identified in 18% of ALS patients. Greater behavioral (p = 0.011) and nonspecific (p = 0.010) symptoms of apathy exhibited by patients were reported by caregivers with higher levels of burden compared to caregivers with lower levels of burden. Of the cognitive, behavioral, emotional, and nonspecific symptoms of apathy, only the behavioral symptoms explained a significant amount of variance in caregiver burden (p = 0.031). Apathy, specifically the behavioral symptoms of apathy was associated with higher burden of care among ALS caregivers, highlighting the importance of multidimensional assessment of apathy and provision of behavior management support as part of ALS care.


Cisplatin-induced cytotoxicity in BSO-exposed renal proximal tubular epithelial cells: sex, age, and species.
Cisplatin (CP)-induced kidney damage and effects of DL-buthionine-(S,R)-sulfoximine (BSO) on it are species- and age-different. It remains unclear whether CP-induced cytotoxicity in renal proximal tubular epithelial cells (RTEC), the main target cells of CP, is also species- and age-different; and whether CP-induced cytotoxicity varies with the difference in age and species, if any, is one of the questions. In the present study, the effects of BSO on CP-induced cytotoxicity in primary cultures of RTEC isolated from monkeys and different age and sex rats were studied. The RTEC were isolated from 3-week-old, 2-month-old, or 5-month-old rats, and 6-8 year-old monkeys. After subculturing, RTEC was inoculated into type I collagen-coated 96-well culture plates; after preincubation, 40 microM BSO was added, 16 hours later, varying concentrations of CP were added. At that time, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays were performed to test cell viability. The concentrations of CP that inhibited 50% cell growth (IC50) of RTEC from rats and monkeys were 1.11 and 3.03 mM at 8 hours, and 0.51 and 1.24 mM at 24 hours, respectively. The BSO made the IC50s of RTEC from rats and monkeys lower, down to 0.07 and 0.48 mM at 8 hours, and 0.02 and 0.11 mM at 24 hours, respectively. The IC50s of RTEC from different sex and age rats were almost same. These results suggested that CP-induced cytotoxicity was concentration- and time-dependent, with species-dependent differences, rat RTEC were more susceptible to CP than monkey RTEC, rat RTEC were more dependent on glutathione (GSH) during the stress state were than monkey cells; CP-induced cytotoxicity was without sex- and age-dependent differences in rat RTEC.


Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome.
Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. As in dopamine β-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine β-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561(-/-) mice compared with wild-type mice (P<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (P<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine. This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.


From Dissertation Defense to Dissemination: Jump Start Your Academic Career With a Scholar Mentor Group.
The dissertation provides an excellent source of scholarly productivity for new doctoral faculty, yet is often neglected because of the demands inherent in the faculty role. The purpose of this paper is to present a case study of a scholar mentor group composed of three graduates of a PhD nursing program and their shared dissertation chair, who acted as a senior scholar mentor to the group. By working together, we have been able to enhance our scholarly productivity by disseminating our dissertations through presentations and publications. The paper will present the evolving process of this working group, summarize outcomes, analyze the challenges, and provide suggestions for future doctoral students and faculty who are working with them. Our experience and scholar mentor model captures the best of both worlds-the benefits of interaction with academic peers and the benefits of having a senior scholar mentor. This was accomplished while all members were at different schools in different cities and states. Although other literatures that document successful collaborations using a peer-mentorship model are available, we were unable to locate any that documents a post-doctoral group with a senior scholar mentor who continued working together after graduation.


Lymphoedema after mastectomy for breast cancer: importance of supportive care.
Lymphoedema resulting from axillary lymph node dissection remains a challenging complication after modified radical mastectomy. To examine the effects of supportive therapy such as rehabilitation and medical and physical treatment on the development of lymphoedema, in an attempt to establish non-surgical ways to help prevent or reduce it. Patients (N=5 064) who underwent breast cancer surgery in the Department of General Surgery, Ankara Oncology Research and Training Hospital, Turkey, between 1995 and 2010 were included. Data were collected by retrospectively examining all the patients' files and the pre- and postoperative breast cancer follow-up forms. Of the patients in the study, 19.9% developed lymphoedema. It was significantly less common in patients who participated in physiotherapy than in those who did not, and it was more common in patients with a body mass index (BMI, kg/m²) between 30 and 34.9 than in patients with lower BMIs. Postoperative axillary radiotherapy did not affect the occurrence of lymphoedema. It is clear that the most successful method to reduce the impact of lymphoedema is to prevent it. We believe that educating patients about the risk factors for developing lymphoedema and referring them to postoperative physical therapy and rehabilitation clinics are the most important ways to avoid this distressing condition.


Corneal epithelial regeneration and adhesion following acid burns in the rhesus monkey.
For study of corneal adhesion after chemical injury, sulfuric acid was used to burn the central and peripheral corneal epithelium in rhesus monkeys. The adhesion properties of the regenerating epithelium were sequentially followed by clinical assessment and by serial corneal biopsy specimens examined by transmission electron microscopy. The peripheral burns healed uneventfully, but the central corneal burns resulted in persistently loose adhesion for more than 8 weeks. The pathogenesis of the defective epithelial adhesion appeared to initially the persistence of the original basement membrane that could not be utilized by regenerating epithelium. Later, poor adhesion was related to the slow rate of basement membrane regeneration and also to fragmentation of the Bowman's layer substrate and to mild stromal edema.


Excitatory amino acid receptors in the human cerebral cortex: a quantitative autoradiographic study comparing the distributions of [3H]TCP, [3H]glycine, L-[3H]glutamate, [3H]AMPA and [3H]kainic acid binding sites.
The excitatory amino acids are probably the major neurotransmitters in the cerebral cortex, and they act through at least three receptors: the N-methyl-D-aspartate, the quisqualate and the kainic acid receptors. Under the appropriate conditions, [3H]1-(1-(2-thienyl)-cyclohexyl)piperidine [( 3H]TCP), [3H]glycine and L-[3H]glutamate label different sites on the N-methyl-D-aspartate receptor, [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [( 3H]AMPA) labels the quisqualate receptor and [3H]kainic acid the kainic acid receptor. The anatomical localizations of these binding sites were studied in sections of blocks removed from the cerebral cortices of eight post-mortem human brains. The results showed that, in the human cerebral cortex, [3H]TCP, [3H]glycine and L-[3H]glutamate binding sites had congruent distributions, with [3H]AMPA binding sites showing a similar distribution. In the hippocampus, these four ligands had high binding site densities in the CA1 region and the dentate gyrus molecular layer. With the exception of the striate cortex, in the neocortex, a tri-laminar pattern was seen consisting of a high density across laminae I-III, a layer of low density corresponding to the region of lamina IV, and a band of moderate density across laminae V and VI, except for [3H]AMPA where the middle zone of low density was usually wider. [3H]Kainic acid showed a binding pattern which was generally complementary to that of the other four ligands. There were low levels of [3H]kainic acid binding sites in the CA1 region of the hippocampus with higher levels in the CA3 region, the hilus, and the inner third of the dentate gyrus molecular layer. In the neocortex there was a band of high density corresponding to laminae V and VI, with a thin band of moderate binding corresponding to lamina I and the outer region of lamina II. An exception was the motor cortex where the highest level of [3H]kainic acid binding was in laminae I and II. The high degree of congruence between the binding patterns of [3H]TCP, [3H]glycine and L-[3H]glutamate (using conditions appropriate for the N-methyl-D-aspartate receptor) supports data indicating that these ligands bind to different regions of the same receptor complex. The similar distribution of [3H]AMPA binding sites, with the exception of the striate cortex, supports observations made in rodents that N-methyl-D-aspartate receptors and quisqualate receptors have similar distributions and perform different but related functions in excitatory transmission.(ABSTRACT TRUNCATED AT 400 WORDS)


[Metastatic hypernephroma of the stomach].
We report a case of renal cell adenocarcinoma (T2-G3) metastatic to the stomach in a patient who underwent a left radical nephrectomy and presented hematemesis and melena two weeks postoperatively. We were prompted to report this case because metastasis to the stomach is rare and the literature is scant. Despite treatment by radical surgery, the short disease-free period following nephrectomy, the high histological grade (G3) and the aggressive nature of the tumor have resulted in a short survival.


Identification of Igh-C-linked determinants on suppressor T cell hybrids and factors specific for L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT).
Hyperimmunization of BALB/c mice with concanavalin A-stimulated blasts from the Ig allotype-congenic strain, C.B20, results in the production of antibodies reactive with T cells in an allotype-restricted manner. Spleen cells from these hyperimmune BALB/c mice were used to generate a panel of hybridomas that secrete monoclonal antibodies, reactive, in an allotype-restricted manner, exclusively with T cells subpopulations, and in particular, reactive with suppressor T cell hybridomas and their secreted soluble factors. Two functional classes of antibodies were identified: those that react with single polypeptide-chain suppressor T cell factors (TsF1) and the suppressor T cell hybridomas that produce such factors, and those that react with two polypeptide-chain suppressor T cell factors (TsF2) and their corresponding suppressor T cell hybridomas. These two classes of antibody were used to isolate molecules from the membranes of the respective suppressor T cell hybrids that are functionally and structurally related to the secreted suppressor T cell factors, suggesting a receptor function for these molecules.


GATA3 maintains the quiescent state of cochlear supporting cells by regulating p27kip1.
Haplo-insufficiency of the GATA3 gene causes hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome. Previous studies have shown that Gata3 is required for the development of the prosensory domain and spiral ganglion neurons (SGNs) of the mouse cochlea during embryogenesis. However, its role in supporting cells (SCs) after cell fate specification is largely unknown. In this study, we used tamoxifen-inducible Sox2CreERT2 mice to delete Gata3 in SCs of the neonatal mouse cochlea and showed that loss of Gata3 resulted in the proliferation of SCs, including the inner pillar cells (IPCs), inner border cells (IBCs), and lateral greater epithelium ridge (GER). In addition, loss of Gata3 resulted in the down-regulation of p27kip1, a cell cycle inhibitor, in the SCs of Gata3-CKO neonatal cochleae. Chromatin immunoprecipitation analysis revealed that GATA3 directly binds to p27kip1 promoter and could maintain the quiescent state of cochlear SCs by regulating p27kip1 expression. Furthermore, RNA-seq analysis revealed that loss of Gata3 function resulted in the change in the expression of genes essential for the development and function of cochlear SCs, including Tectb, Cyp26b1, Slitrk6, Ano1, and Aqp4.


Insolubility classification with accurate prediction probabilities using a MetaClassifier.
Insolubility is a crucial issue in drug design because insoluble compounds are often measured to be inactive although they might be active if they were soluble. We provide and analyze various insolubility classification models based on a recently published data set and compounds measured in-house at Boehringer-Ingelheim. The 2D descriptor sets from pharmacophore fingerprints and MOE and the 3D descriptor sets from ParaSurf and VolSurf were examined in conjunction with support vector machines, Bayesian regularized neural networks, and random forests. We introduce a classifier-fusion strategy, called metaclassifier, which improves upon the best single prediction and at the same time avoids descriptor selection, a potential source of overfitting. The metaclassifier strategy is compared to the simpler fusion strategies of maximum vote and highest probability picking. A prediction accuracy of 72.6% on a three class model is achieved with the metaclassifier, with nearly perfect separation of soluble and insoluble compounds and prediction as good as our calculated maximum possible agreement with experiment.


[Peculiarities of hemodynamics in junior students with a hereditary history of arterial hypertension during examination stresses].
The functional state ofthe students was investigated on the basis ofchanges in central hemodynamic indices immediately during exams, in dependence on family history of hypertension. The significant variation in the character of the response of systemic hemodynamics, as depending on the stage of examination (preparation, answering the ticket, and after the exam), the dominance of the type of the autonomic nervous system, and the family history of hypertension has been revealed These changes in hemodynamics in students with family history of hypertension were established to be more pronounced and prolonged.


The comparative cost of food and beverages at remote Indigenous communities, Northern Territory, Australia.
To determine the average price difference between foods and beverages in remote Indigenous community stores and capital city supermarkets and explore differences across products. A cross-sectional survey compared prices derived from point-of-sale data in 20 remote Northern Territory stores with supermarkets in capital cities of the Northern Territory and South Australia for groceries commonly purchased in remote stores. Average price differences for products, supply categories and food groups were examined. The 443 products examined represented 63% of food and beverage expenditure in remote stores. Remote products were, on average, 60% and 68% more expensive than advertised prices for Darwin and Adelaide supermarkets, respectively. The average price difference for fresh products was half that of packaged groceries for Darwin supermarkets and more than 50% for food groups that contributed most to purchasing. Strategies employed by manufacturers and supermarkets, such as promotional pricing, and supermarkets' generic products lead to lower prices. These opportunities are not equally available to remote customers and are a major driver of price disparity. Food affordability for already disadvantaged residents of remote communities could be improved by policies targeted at manufacturers, wholesalers and/or major supermarket chains.


Feasibility and adherence paradigm to ecological momentary assessments in urban minority youth.
All adolescents in general, including ethnic and racial minorities, report high levels of cell phone use, making mobile technology a useful tool for assessment and intervention. Known health and education disparities based on minority status motivated us to conduct an in-depth investigation regarding feasibility of and adherence to the ecological momentary assessment (EMA) research protocol, studying daily life of urban minority youth. In addition, this paper presents a methodological approach to conceptualizing and reporting adherence in EMA studies. The sample was comprised of 126 youth (41.3% boys; 40.5% 7th and 59.5% 8th graders; 75.4% African American, and 20.6% Hispanic) who carried a mobile phone for 10 days, including 2 weekends and reported on activities, moods, and attitudes. Mean level of adherence was 81% for momentary and 93.8% for daily assessments; it decreased over time and was higher during the week compared to weekends. Adherence was lower on days when participants reported high levels of negative affect and on days when they were engaged in physical activities. Our findings underscore the importance of differentiating between human and technology-related factors when computing adherence rates and portray adherence as a complex and dynamic construct that can vary across individuals. Specific study recommendations and methodological discussion provide guidelines for designing future studies. (PsycINFO Database Record


Eye changes after forty.
The most common "physiologic" change that occurs in the eyes after age 40 is loss of elasticity of the lens, resulting in presbyopia. Xanthelasmas commonly occur at this age and should be removed only for cosmetic reasons. Entropion and ectropion can be quite irritating; both results from laxity of the eyelid tissues. Relaxation of eyelid tissues also contributes to blepharochalasis. Glaucoma and formation of cataracts are not normal changes but do appear with increasing frequency in persons over 40.


Expanding the phenotype of phospholipid remodelling disease due to MBOAT7 gene defect.
MBOAT7 gene codes O-acyltransferase domain containing seven proteins which is one of four enzymes involved in remodeling of phosphoinositol phosphate (PIP) in LANDs cycle. We present clinical, neuroimaging, and genetic findings of 12 patients from 7 families with MBOAT7 gene defect, a recently defined novel phospholipid remodelling disease. To the best of our knowledge, our case series is the second report on patients with MBOAT7 gene defect. The patients present with global developmental delay particularly in speech and language skills, intellectual disability, stereotypical behavior, ataxic gait, early onset epilepsy with well response to medical treatment, strabismus and similar facial features. Common neuroimaging findings of the patients were folium dysgenesis of the cerebellum with a particular appearance, mild-to-moderate cerebellar atrophy, T2 hyperintensity of bilateral globus pallidius and dentate nuclei, enlarged perivascular areas, and mild thinning of the corpus callosum. Genome-wide genotyping and exome sequencing identified five different types of homozygous mutations in the MBOAT7 gene in all seven families which are p.Arg87*, p.Leu227ProfsX65, p.Gln376Lys, p.Trp426*, and chr19:54.666.173-54.677.766/11594 bp del. We conclude that clinical and neuroimaging findings of MBOAT7 gene defect may suggest the diagnosis and guide genetic tests.


Actin filaments participate in the relocalization of phosphatidylinositol3-kinase to glucose transporter-containing compartments and in the stimulation of glucose uptake in 3T3-L1 adipocytes.
Insulin stimulates the rate of glucose uptake into muscle and adipose cells by translocation of glucose transporters from an intracellular storage pool to the plasma membrane. This event requires the prior activation of phosphatidylinositol 3-kinase (PI 3-kinase). Here we report that insulin causes an increase in wortmannin-sensitive PI 3-kinase activity and a gain in the enzyme's regulatory and catalytic subunits p85alpha and p110beta (but not p110alpha) in the intracellular compartments containing glucose transporters. The hormone also caused a marked reorganization of actin filaments, which was prevented by cytochalasin D. Cytochalasin D also decreased significantly the insulin-dependent association of PI 3-kinase activity and the levels of insulin receptor substrate (IRS)-1, p85alpha and p110beta with immunopurified GLUT4-containing compartments. In contrast, the drug did not alter the insulin-induced tyrosine phosphorylation of IRS-1, the association of PI 3-kinase with IRS-1, or the stimulation of PI 3-kinase by insulin in anti-(IRS-1) or anti-p85 immunoprecipitates from whole cell lysates. Cytochalasin D, and the chemically unrelated latrunculin B, which also inhibits actin filament reassembly, prevented the insulin stimulation of glucose transport by approx. 50%. Cytochalasin D decreased by about one-half the insulin-dependent translocation to the plasma membrane of the GLUT1 and GLUT4 glucose transporters. The results suggest that the existence of intact actin filament is correlated with the full recruitment of glucose transporters by insulin. The underlying function of the actin filaments might be to facilitate the insulin-mediated association of the p85-p110 PI 3-kinase with glucose-transporter-containing compartments.


Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.
Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.


Reducing Inpatient Hospital and Emergency Room Utilization Among Nursing Home Residents.
To examine the association among nursing home residents between strength of relationship with a primary care provider (PCP) and inpatient hospital and emergency room (ER) utilization. Medicare administrative data for beneficiaries residing in a nursing home between July 2007 and June 2009 were used in multivariate analyses controlling for beneficiary, nursing home, and market characteristics to assess the association between two measures-percentage of months with a PCP visit and whether the patient maintained the same usual source of care after nursing home admission-and hospital admissions and ER visits for all causes and for ambulatory care sensitive conditions (ACSCs). Both measures of strength of patient-provider relationships were associated with fewer inpatient admissions and ER visits, except regularity of PCP visits and ACSC ER visits. Policy makers should consider increasing the strength of nursing home resident and PCP relationships as one strategy for reducing inpatient and ER utilization.


Hemorrhagic Cholecystitis. Report of a case with comprensive literature review and treatment algorithm.
Hemorrhagic Cholecystitis is a rare condition and usually represents a complication of acute cholecystitis. The clinical presentation is quite overlapping and usually involves abdominal pain that may be associated with fever, jaundice, nausea, vomiting, and finally haemobilia. It frequently involves patients with preexisting conditions such as chronic kidney disease undergoing hemodialysis or anticoagulation therapy. Due to the deadly potential of this condition attention must be high during diagnostics and treatment in order to avoid an ill-fated conclusion. To our knowledge, there is a lack of a comprehensive review on the subject as most of the literature consists of case reports or small case series. In order to give a contribution to improving the treatment strategy of this condition, we report a case successfully treated with cholecystectomy, and performed a literature review. Using the term "Hemorrhagic Cholecystitis", on PubMed database we found 67 cases reported in the English literature. The cases were analyzed by two researchers and clinical information was extrapolated and organized, aiming to create a comprehensive review on the subject, that may be clear and useful in clinical practice. KEY WORDS: Hemorrhagic cholecystitis, Surgical treatment.


A longitudinal study of the relation of lead in blood to lead in air concentrations among battery workers.
The relation between lead in air (PbA) and lead in blood (PbB), concentrations was investigated among 44 workers in five major operations in a United States high volume, lead acid battery plant. The study covered a 30 month period in which workers received frequent PbA and PbB determinations, workers remained in a single job, and PbA concentrations averaged below the US Occupational Safety and Health Administration (OSHA) permissible exposure limit of 50 micrograms/m3. In both univariate and multivariable linear regressions, longitudinal analyses averaging PbA concentrations over the 30 month study period appeared superior to cross sectional analyses using only six month PbA averages to model PbB concentrations. The covariate adjusted coefficient (alpha value) for PbA (mu/m3) in models of PbB (micrograms/100 g) was 1.14. This figure is strikingly higher than that reported in previous studies in the lead acid battery industry in all of which PbA concentrations were substantially higher than in the current study. Plausible explanations for the difference in alpha values include non-linearity of the PbA-PbB curve, a higher fraction of large size particulate associated with higher PbA concentrations, survivor bias among workers exposed to higher PbA concentrations, and the cross sectional designs of most previous studies. Despite previously reported problems with the model used by OSHA to predict PbA-PbB relations, the findings of this study are in good agreement with the predictions of that model.


Cell-bound autologous immunoglobulin in erythrocyte subpopulations from patients with sickle cell disease.
Previously, we have demonstrated a parallel between most-dense (bouyant density) sickle erythrocyte subpopulations and most-dense aged normal red cells in the organization of membrane components in the intact cell. The present study has addressed the possibility that a corresponding similarity may exist between most-dense sickled red cell subpopulations and aged normal erythrocytes in the development of membrane protein components that function as receptors for autologous immunoglobulin (Ig). Autologous IgG retained by density-fractionated erythrocytes has been estimated by a nonequilibrium 125I-protein A (Staphylococcus aureus) binding assay. Results show that most-dense sickle cell fractions contain more (2.7-fold and 1.8-fold, P less than .005) cell-bound IgG in comparison to younger sickle erythrocyte fractions sedimenting at low density. Parallel findings were obtained after similar analyses of normal (homozygous-A) erythrocyte fractions. Detection of the presence of specific IgG was also carried out by direct binding of fluorescein isothiocyanate-conjugated anti-human IgG to density-separated red cell fractions followed by analyses of the fluorescent cell populations by flow cytometry. Results showed significantly higher levels of IgG bound to most-dense (12.1% +/- 2.5% and 8.8% +/- 0.5%-) sickle red cell subpopulations (P less than .005) in comparison to younger sickle erythrocyte fractions sedimenting at low densities (3.8% +/- 0.32% and 4.7% +/- 1.6% IgG-positive red cell subpopulation). These results indicate that some of the same membrane changes that occur at about 120 days in normal red cells are also apparent in the chronologically younger (life span in vivo, ten to 40 days) sickle erythrocyte. The increased retention of IgG by most-dense irreversibly sickled cell-enriched fractions in comparison to least-dense reversibly sickled cells or pre-irreversibly sickled erythrocyte fractions, suggests that alterations in the topography of the sickle cell membrane during the transformation in vivo to the most-dense irreversibly sickled cell morphology may produce the unmasking of cryptic antigenic sites. In addition, these findings may indicate that opsonization of specific erythrocyte subpopulations may play a role in the pathophysiology of sickle cell disease.


Lack of correlation between known virulence properties of Aeromonas hydrophila and enteropathogenicity for humans.
Five strains of Aeromonas hydrophila were selected for use in volunteer challenge trials. All five strains produced cytotoxin, hemolysin enterotoxin, lysine decarboxylase, acetylmethylcarbinol, and DNase. Two strains hydrolyzed esculin. All strains produced purulent hemorrhagic fluid accumulation in rabbit ileal loops, but failed to induce keratoconjunctivitis in guinea pigs. None of the strains produced mannose-resistant hemagglutinins. In challenge studies, diarrhea was demonstrated in only 2 of 57 human volunteers with doses ranging from 10(4) to 10(10) CFU. One person experienced mild diarrhea with 10(9) CFU of strain 6Y. A second person developed moderate diarrhea with 10(7) CFU of strain 3647. At higher doses, no diarrhea was seen in any of the volunteers. The other three strains (B158, SSU, 3284) failed to cause diarrhea and were not recovered from stools of volunteers. Additional virulence properties of A. hydrophila need to be sought before enteropathogenicity for humans can be established.


Growth of wheat and lettuce and enzyme activities of soils under garlic stalk decomposition for different durations.
Garlic (Allium sativum L.) stalk is a byproduct of garlic production that is normally thought of as waste but is now considered a useful biological resource. It is necessary to utilize this resource efficiently and reasonably to reduce environmental pollution and achieve sustainable agricultural development. The effect of garlic stalk decomposed for different durations was investigated in this study using wheat (Triticum aestivum L.) and lettuce (Lactuca sativa var. crispa L.) as test plants. Garlic stalk in early stages of decomposition inhibited the shoot and root lengths of wheat and lettuce, but it promoted the shoot and root lengths in later stages; longer durations of garlic stalk decomposition significantly increased the shoot and root fresh weights of wheat and lettuce, whereas shorter decomposing durations significantly decreased the shoot and root fresh weights; and garlic stalk at different decomposition durations increased the activities of urease, sucrase and alkaline phosphatase in soil where wheat or lettuce was planted. Garlic stalk decomposed for 30 or 40 days could promote the growth of wheat and lettuce plants as well as soil enzyme activities. These results may provide a scientific basis for the study and application of garlic stalk. © 2016 Society of Chemical Industry.


Protein Storage Vacuoles Originate from Remodeled Preexisting Vacuoles in Arabidopsis thaliana.
Protein storage vacuoles (PSV) are the main repository of protein in dicotyledonous seeds, but little is known about the origins of these transient organelles. PSV are hypothesized to either arise de novo or originate from the preexisting embryonic vacuole (EV) during seed maturation. Here, we tested these hypotheses by studying PSV formation in Arabidopsis (Arabidopsis thaliana) embryos at different stages of seed maturation and recapitulated this process in Arabidopsis leaves reprogrammed to an embryogenic fate by inducing expression of the LEAFY COTYLEDON2 transcription factor. Confocal and immunoelectron microscopy indicated that both storage proteins and tonoplast proteins typical of PSV were delivered to the preexisting EV in embryos or to the lytic vacuole in reprogrammed leaf cells. In addition, sectioning through embryos at several developmental stages using serial block face scanning electron microscopy revealed the 3D architecture of forming PSV. Our results indicate that the preexisting EV is reprogrammed to become a PSV in Arabidopsis.


Effect of in-vivo supplementation with low-dose vitamin E on susceptibility of low-density lipoprotein and high-density lipoprotein to oxidative modification.
We have examined the effects of in-vivo supplementation with low-dose vitamin E on the susceptibility of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) to oxidative modification, and compared the oxidizability of HDL with that of LDL. Normal humans (n = 8) ingested vitamin E (150 mg/day for 1 week, followed by 300 mg/day for 3 weeks) in divided doses with meals. The subjects did not use any medications or vitamins before being enrolled in this study. Fasting blood samples were drawn before and at the end of supplementation. LDL and HDL were separated by sequential ultracentrifugation and susceptability to copper-mediated oxidation was measured. After vitamin E supplementation, vitamin E content of LDL increased 1.9-fold and that of HDL increased 1.8-fold. Lag time before initiation of LDL oxidation lengthened significantly (+20%, p < 0.01), and the propagation rate of LDL decreased significantly (-10%, p < 0.05). The lag time of HDL oxidation did not change significantly, but the propagation rate of HDL oxidation decreased significantly (-24%, p < 0.001). The lag time of HDL oxidation was shorter than that of LDL. HDL contained the same or higher concentrations of vitamin E relative to lipid mass as LDL, but contained lower concentration of CoQ10 relative to lipid mass and fewer molecules of vitamin E and beta-carotene per particle than LDL. We conclude that in-vivo supplementation of low-dose vitamin E protects LDL against oxidative modification and decreases the propagation rate of HDL oxidation significantly. We suggest that supplementation with low-dose vitamin E would be beneficial for ameliorating atherosclerosis.


Cross-coupling reactions with esters, aldehydes, and alcohols.
Cross-coupling reactions to form biaryls and π bond addition reactions to prepare substituted carbonyls or alcohols represent two of the most frequently performed families of chemical reactions. Recent progress in catalysis has uncovered substantial overlap between these two seemingly distinct topics. In particular, esters, aldehydes, and alcohols have been shown to act as carbon-based coupling partners in a range of Ni- and Pd-catalyzed reactions to prepare amides, ketones, substituted alcohols, alkanes, and more. These reactions provide promising alternatives to commonly used stoichiometric or multi-step reaction sequences. In this feature article, a selection of these transformations will be discussed with an emphasis on the key mechanistic steps that allow these non-traditional substrates to be incorporated into cross-coupling-like catalytic cycles.


Therapeutic challenges of AIDS-related non-Hodgkin's lymphoma in the United States and East Africa.
Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. As we enter the third decade of the acquired immunodeficiency syndrome (AIDS) epidemic, it is apparent that the evolution of antiretroviral therapy and the emergence of combination antiviral strategies have greatly affected the natural history of HIV infection and its neoplastic complications. For example, there may be a trend for declining incidence of AIDS-related lymphoma in the United States for the first time. However, in regions of the world where the burden of HIV infection is greatest, such as in East Africa, AIDS-related lymphoma is an increasing cause of morbidity and mortality. Treatment of lymphoma has evolved coincident with improvements in antiretroviral therapy. Infusional chemotherapy regimens may offer advantages over other regimens and schedules, but comparative trials have not been done. Clinical trial data are available on which to develop therapeutic strategies to treat this disease in East Africa where pragmatic approaches are needed. Both the differences in manifestations of HIV infection and the inherent difficulties in administering cytotoxic chemotherapy in this part of the world must be taken into consideration in planning therapeutic strategies. Improved understanding of the pathogenesis of HIV infection and lymphoma will likely yield improved therapeutic interventions as well.


Sebaceous adenomas of the eyelid and Muir-Torre Syndrome.
Sebaceous adenomas (SAs) are rare, benign sebaceous gland tumours of the eyelid. SAs may be associated with primary internal malignancies. This association is known as Muir-Torre Syndrome (MTS). The purpose of this study was to approximate the prevalence of SAs, to determine the reliability of the clinical diagnosis of SAs and to demonstrate immunohistochemical staining of DNA mismatch repair proteins mutL homologue 1 (MLH1) and mutS homologue 2 (MSH2) for a case of MTS. We reviewed the histopathology reports from all eyelid specimens collected between 1993 and 2013 at the Henry C Witelson Ocular Pathology Laboratory to determine the proportion of SAs. For the SAs identified on histopathology, we looked at patient charts to see what diagnosis was originally suspected on clinical examination. Immunohistochemical staining for MLH1 and MSH2 was performed on all SAs to screen for MTS. Of the 5884 eyelid specimens collected, 9 were SAs (6 women, 3 men; 42-72 years old). The diagnosis of SA was suspected clinically in only one of the nine cases based on the gross appearance of the eyelid lesion. Immunohistochemistry revealed one SA case with positive MLH1 expression and negative MSH2 expression. These findings prompted systemic work-up and this patient was diagnosed with MTS after discovery of a colon adenocarcinoma T2M0N0. The diagnosis of eyelid SA is rare. The importance of this benign eyelid tumour stems from its association with internal malignancies in MTS. Immunohistochemical staining of mismatch repair proteins MLH1 and MSH2 is a valid and accessible strategy for investigating MTS in patients with SAs.


Rheumatoid arthritis: Extra-articular manifestations and comorbidities.
Although synovitis is the pathological hallmark of rheumatoid arthritis (RA), many extra-articular manifestations (EMs) and comorbidities likely occur due to the complex, chronic, inflammatory, and autoimmune features of RA. Cardiovascular (CV) disease is the most common cause of death in patients with RA. Compared to the general population, patients with RA have twice the risk of myocardial infarction and up to 50% increased CV mortality risk. Severe and prolonged disease activity, genetics, and inflammation (e.g. CRP, ACPA, cytokines, matrix-degrading enzymes) play important roles in CV disease and atheroscleroticdamage. The second major cause of death in patients with RA is respiratory disease, which occurs in 30-40% of patients. RA may affect the lung interstitium, airways, and pleurae, while pulmonary vascular involvement is less frequent. Central and peripheral nervous system involvement is usually due to small vessel vasculitis, joint damage, or drug toxicity. There is also evidence that microvascular cerebral damage caused by systemic inflammation is associated with the development of Alzheimer's disease and vascular dementia. Some observational studies have hinted how Disease Modified Anti-Rheumatic Drugs and biologics could reduce the incidence of dementia. Primary gastrointestinal and renal involvements are rare and often relate to drug therapy. To minimize morbidity and mortality, physicians must manage RA disease activity (treat-to-target) and monitor risk factors and concomitant conditions (e.g. smoking cessation; weight regulation; monitoring blood pressure, lipids, thyroid hormone, folic acid and homocysteine; screening for depression, anxiety, atlantoaxial instability, and atherosclerosis). This article aims to provide an overview of the most prevalent and important EMs and comorbidities associated with RA.


The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine.
Epilepsy, one of the most prevalent neurological conditions, presents as a complex disorder of network homeostasis characterized by spontaneous non-provoked seizures and associated comorbidities. Currently used antiepileptic drugs have been designed to suppress neuronal hyperexcitability and thereby to suppress epileptic seizures. However, the current armamentarium of antiepileptic drugs is not effective in over 30% of patients, does not affect the comorbidities of epilepsy, and does not prevent the development and progression of epilepsy (epileptogenesis). Prevention of epilepsy and its progression remains the Holy Grail for epilepsy research and therapy development, requiring novel conceptual advances to find a solution to this urgent medical need. The methylation hypothesis of epileptogenesis suggests that changes in DNA methylation are implicated in the progression of the disease. In particular, global DNA hypermethylation appears to be associated with chronic epilepsy. Clinical as well as experimental evidence demonstrates that epilepsy and its progression can be prevented by biochemical manipulations and those that target previously unrecognized epigenetic functions contributing to epilepsy development and maintenance of the epileptic state. This mini-review will discuss, epigenetic mechanisms implicated in epileptogenesis and biochemical interactions between adenosine and glycine as a conceptual advance to understand the contribution of maladaptive changes in biochemistry as a major contributing factor to the development of epilepsy. New findings based on biochemical manipulation of the DNA methylome suggest that: (i) epigenetic mechanisms play a functional role in epileptogenesis; and (ii) therapeutic reconstruction of the epigenome is an effective antiepileptogenic therapy.


Computer-Aided Detection for Breast Cancer Screening in Clinical Settings: Scoping Review.
With the growth of machine learning applications, the practice of medicine is evolving. Computer-aided detection (CAD) is a software technology that has become widespread in radiology practices, particularly in breast cancer screening for improving detection rates at earlier stages. Many studies have investigated the diagnostic accuracy of CAD, but its implementation in clinical settings has been largely overlooked. The aim of this scoping review was to summarize recent literature on the adoption and implementation of CAD during breast cancer screening by radiologists and to describe barriers and facilitators for CAD use. The MEDLINE database was searched for English, peer-reviewed articles that described CAD implementation, including barriers or facilitators, in breast cancer screening and were published between January 2010 and March 2018. Articles describing the diagnostic accuracy of CAD for breast cancer detection were excluded. The search returned 526 citations, which were reviewed in duplicate through abstract and full-text screening. Reference lists and cited references in the included studies were reviewed. A total of nine articles met the inclusion criteria. The included articles showed that there is a tradeoff between the facilitators and barriers for CAD use. Facilitators for CAD use were improved breast cancer detection rates, increased profitability of breast imaging, and time saved by replacing double reading. Identified barriers were less favorable perceptions of CAD compared to double reading by radiologists, an increase in recall rates of patients for further testing, increased costs, and unclear effect on patient outcomes. There is a gap in the literature between CAD's well-established diagnostic accuracy and its implementation and use by radiologists. Generally, the perceptions of radiologists have not been considered and details of implementation approaches for adoption of CAD have not been reported. The cost-effectiveness of CAD has not been well established for breast cancer screening in various populations. Further research is needed on how to best facilitate CAD in radiology practices in order to optimize patient outcomes, and the views of radiologists need to be better considered when advancing CAD use.


Sparsely adherent platelets support capture and immobilization of flowing neutrophils.
Continuous monolayers of activated platelets support selectin-mediated rolling and integrin-mediated immobilization of flowing neutrophils. Because platelets attached to the vessel wall in vivo may not be confluent, we investigated the ability of sparsely adherent platelets to capture flowing neutrophils that were unstimulated or activated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) peptide (10(-7) mol/L). Different degrees of deposition of platelets were obtained by perfusing heparinized blood for varying periods through glass capillaries coated with collagen type III. Perfusion for 10 to 180 seconds gave approximately 1% to approximately 10% coverage of the surface with platelets. When purified neutrophils were subsequently flowed over the platelets at a wall shear stress of 0.1 Pa, they formed repeated short-lived attachments to individual or small groups of platelets. Increasing surface coverage with platelets was associated with increasing numbers of neutrophils adherent at any time, decreasing the overall rate of motion of adherent neutrophils and increasing the stability of adhesion (eg, proportion remaining with time). The net effect was to actually decrease the flux of adherent cells (number of adhesive interactions seen per unit area per unit time), indicating that parameters based on through-flow of adhesive cells must be interpreted with caution. When neutrophils were preactivated with fMLP they formed stable, stationary attachments. The flux of adherent activated cells was low, although the number of cells adherent remained high, reinforcing the conclusion that assays of the adhesion of flowing cells must carefully characterize the different types of adhesive behavior. Overall, small numbers of platelets can support short-lived attachments of flowing neutrophils and allow immobilization of activated cells and may amplify inflammatory processes thereby.


Sickle cell trait and glucose-6-phosphate dehydrogenase deficiency. Effects on health and military performance in black Navy enlistees.
The purpose of this longitudinal study was to compare the Navy performance and health status during a four-year enlistment of four subsamples of black enlistees who began active service between Feb 14 through Sept 15, 1972. On the basis of results obtained from screening procedures for hemoglobinopathies, a sample of 8,725 enlistees was separated into four subgroups: 599 subjects with sickle cell trait, 1,003 subjects with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, 73 subjects with both trait anomalies, and 7,050 normal subjects. Results of comparative analyses indicated that the three trait subsamples did not differ significantly from the normal group on demographic and service-related variables, seven performance criteria, hospitalization rates, or mortality. Thus, the trait anomalies studied were found to be benign under routine conditions of naval service.


Induction of CYP1A and cyp2-mediated arachidonic acid epoxygenation and suppression of 20-hydroxyeicosatetraenoic acid by imidazole derivatives including the aromatase inhibitor vorozole.
Cytochrome P450 (P450) enzymes metabolize the membrane lipid arachidonic acid to stable biologically active epoxides [eicosatrienoic acids (EETs)] and 20-hydroxyeicosatetraenoic acid (20-HETE). These products have cardiovascular activity, primarily acting as vasodilators and vasoconstrictors, respectively. EET formation can be increased by the prototype CYP1A or CYP2 inducers, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or phenobarbital (PB), respectively. We report here that imidazole derivative drugs: the anthelminthics, albendazole and thiabendazole; the proton pump inhibitor, omeprazole; the thromboxane synthase inhibitor, benzylimidazole; and the aromatase (CYP19) inhibitor vorozole (R76713, racemate; and R83842, (+) enantiomer) increased hepatic microsomal EET formation in a chick embryo model. Albendazole increased EETs by transcriptional induction of CYP1A5 and the others by combined induction of CYP1A5 and CYP2H, the avian orthologs of mammalian CYP1A2 and CYP2B, respectively. All inducers increased formation of the four EET regioisomers, but TCDD and albendazole had preference for 5,6-EET and PB and omeprazole for 14,15-EET. Vorozole, benzylimidazole, and TCDD also suppressed 20-HETE formation. Vorozole was a remarkably effective and potent inducer of multiple hepatic P450s at a dose range which overlapped its inhibition of ovarian aromatase. Increased CYP1A activity in mouse Hepa 1-6 and human HepG2 cells by vorozole and other imidazole derivatives demonstrated applicability of the findings to mammalian cells. The findings suggest that changes in P450-dependent arachidonic acid metabolism may be a new source of side effects for drugs that induce CYP1A or CYP2. They demonstrate further that in vivo induction of multiple hepatic P450s produces additive increases in arachidonic acid epoxygenase activity and can occur concurrently with inhibition of ovarian aromatase activity.


The developmental and circadian variation of melatonin receptors in the chicken spinal cord.
The developmental variation of 2-[125I]iodomelatonin binding sites in membrane preparations of the chicken spinal cords was investigated. In 19-day-old embryos, the maximum number of binding sites (Bmax) was the highest during the development. With the increase in age posthatch, the Bmax decreased gradually and significantly from 1-day-old to 4-month-old chickens. However, there were no significant changes in equilibrium dissociation constant (Kd) among all age-groups studied. To study the circadian variation, the 2-[125I]iodomelatonin binding sites in the spinal cords of 3-week-old chickens were determined at 4-hour intervals throughout a 24-hour period under a 12-hour light/12-hour dark cycle. There was a diurnal rhythm in both Bmax and Kd of [125I]iodomelatonin binding sites in which Bmax decreased and Kd increased in the dark period. The characteristics of developmental and circadian variation of melatonin receptors in the chicken spinal cord suggest that melatonin may exert a direct action on spinal cord functions and that it plays a more important role in the young animal.


The gap junction protein connexin32 is a mouse lung tumor suppressor.
Although loss of connexin expression and/or gap junction intercellular communication correlates with decreased growth control and increased neoplastic potential, there is limited evidence directly linking gap junction intercellular communication function with tumor suppression in situ. Here, we show for the first time that a gap junction protein, connexin32 (Cx32), acts as a lung tumor suppressor in a mouse model. Cx32-deficient nontumorous lung tissue exhibited an increased proliferative index (P < 0.001), and, after exposure to the carcinogen diethylnitrosamine, Cx32-deficient mice exhibited a highly statistically significant (P < 0.001) increase in bronchioloalveolar lung tumor incidence (28 of 45, 62%) and a 45% increase in average multiplicity compared with wild-type mice (7 of 29, 24%). Tumors from Cx32-deficient mice also showed increased activation of mitogen-activated protein kinase (P < 0.001) compared with wild-type tumors, implicating this signaling pathway in Cx32/gap junction intercellular communication-associated lung tumorigenesis.


The effects of tin-protoporphyrin administration on hepatic xenobiotic metabolizing enzymes in the juvenile rat.
The heme analogue tin-protoporphyrin IX (SnP) is a potent inhibitor of microsomal heme oxygenase. Administration of SnP to neonatal rats can prevent hyperbilirubinemia by blocking the postnatal increase of heme oxygenase activity. Apparently innocuous at therapeutic doses, it is of potential clinical value for chemoprevention of neonatal jaundice. We found that when 50-g male Sprague-Dawley rats were treated daily with 50 mumol of SnP/kg sc for 6 days, hepatic microsomal cytochromes b5 and P-450 were significantly diminished. Cytochrome P-450 reductase, two P-450-dependent monooxygenases, aminopyrine demethylase and benzo(a)pyrene hydroxylase, and catalase, a peroxisomal hemoprotein, were also significantly diminished. These results suggested that SnP might significantly affect the metabolism of other xenobiotics. This possibility was confirmed by the finding that hexobarbital-induced sleep lasted 4 times longer in SnP-treated rats than in controls. Inhibition of protein synthesis by SnP was ruled out as the cause of hemoprotein loss when administration of [3H]leucine to SnP-treated and control rats demonstrated that proteins of the microsomal, cytosolic, and plasma membrane fractions of the livers from both groups incorporated similar levels of leucine. When 55FeCl3 and [2-14C]glycine were administered to measure heme synthesis, heme extract from the livers of SnP-treated rats contained 4 times more label from iron and glycine than did heme from control livers. Despite the apparent increased rate of heme synthesis in SnP-treated rats, each of the three cell fractions demonstrated a significant loss of heme but contained sizable amounts of SnP. These findings suggest that SnP causes a decrease of functional hemoprotein and partial loss of enzymic activity by displacing intracellular heme.


A C-terminal determinant of GluR6 kainate receptor trafficking.
Intracellular trafficking of ionotropic glutamate receptors is regulated predominantly by determinants in the cytoplasmic C-terminal domain of the subunit proteins. Although AMPA receptors are found at the vast majority of excitatory synapses, synaptic kainate receptors exhibit a much more restricted distribution, suggesting that specific mechanisms exist for selective trafficking of these receptor proteins. In this report, we define a critical forward trafficking motif that is necessary for surface expression of the glutamate receptor 6 (GluR6) kainate receptor as well as chimeric proteins containing only the GluR6 C-terminal domain. The trafficking determinant was identified by tracking surface expression of green fluorescent protein-tagged GluR6 receptors with confocal immunofluorescence in COS-7 cells and cultured neurons and patch-clamp electrophysiology in human embryonic kidney 293 cells. Serial truncation and alanine site mutagenesis of the GluR6 subunit C terminus localized the critical motif to a seven amino acid stretch of predominantly basic residues. Alanine mutation of the trafficking motif reduced kainate receptor current amplitudes by >90% and resulted in retention of the mutated receptors in the endoplasmic reticulum. This forward trafficking domain is the first such identified for kainate receptors.


Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects.
Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Amyloid-beta 1 to 42 peptide (A beta(1-42)), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and A beta(1-42) in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data. CSF A beta(1-42) was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for A beta(1-42), t-tau, and APO epsilon 4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/A beta(1-42) was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. The CSF biomarker signature of AD defined by A beta(1-42) and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD.


Liquid filling method for nanofluidic channels utilizing the high solubility of CO2.
We developed a fabrication method and a liquid filling method for a nano chemical reactor that used Y-shaped nanochannels specially designed for mixing and reacting. In order to reduce the pressure loss and to utilize the characteristics of the nanochannel, inlet microchannels were fabricated just beside the nanochannels. We investigated an initial liquid filling method into the nanochannels that ensured there were no air bubbles that could cause a flow stack due to the capillary pressure. In our method, the micro- and nanochannels were filled with carbon dioxide and any remaining air during the initial liquid introduction was dissolved utilizing the high solubility of carbon dioxide. We propose that chemical reactions in nanospaces can be realized by utilizing these fabrication and liquid introduction techniques.


An exocyst component, Sec5, is essential for ascospore formation in Bipolaris maydis.
In this study, we identified Sec5 in Bipolaris maydis, a homologue of Sec5 in Saccharomyces cerevisiae and a possible exocyst component of the fungus. To examine how Sec5 affects the life cycle of B. maydis, we generated null mutant strains of the gene (Δsec5). The Δsec5 strains showed a strong reduction in hyphal growth and a slight reduction in pathogenicity. In sexual reproduction, they possessed the ability to develop pseudothecia. However, all ascospores were aborted in any of the asci obtained from crosses between Δsec5 and the wild-type. Our cytological study revealed that the abortion was caused by impairments of the post-meiotic stages in ascospore development, where ascospore delimitation and young spore elongation occur.


Design, recruitment, and retention of African-American smokers in a pharmacokinetic study.
African-Americans remain underrepresented in clinical research despite experiencing a higher burden of disease compared to all other ethnic groups in the United States. The purpose of this article is to describe the study design and discuss strategies used to recruit and retain African-American smokers in a pharmacokinetic study. The parent study was designed to evaluate the differences in the steady-state concentrations of bupropion and its three principal metabolites between African-American menthol and non-menthol cigarette smokers. Study participation consisted of four visits at a General Clinical Research Center (GCRC) over six weeks. After meeting telephone eligibility requirements, phone-eligible participants underwent additional screening during the first two GCRC visits. The last two visits (pharmacokinetic study phase) required repeated blood draws using an intravenous catheter over the course of 12 hours. Five hundred and fifteen African-American smokers completed telephone screening; 187 were phone-eligible and 92 were scheduled for the first GCRC visit. Of the 81 who attended the first visit, 48 individuals were enrolled in the pharmacokinetic study, and a total of 40 individuals completed the study (83% retention rate). Although recruitment of African-American smokers into a non-treatment, pharmacokinetic study poses challenges, retention is feasible. The results provide valuable information for investigators embarking on non-treatment laboratory-based studies among minority populations.


Association of daptomycin dosing regimen and mortality in patients with VRE bacteraemia: a review.
VRE are associated with ∼1300 deaths per year in the USA. Recent literature suggests that daptomycin, a cyclic lipopeptide antibiotic with concentration-dependent bactericidal activity, is the preferred treatment option for VRE bacteraemia, yet the optimal dosing strategy for this indication has not been established. In vitro evidence suggests that higher-than-labelled doses of daptomycin are required to optimally treat VRE bacteraemia and to inhibit the development of resistance. However, concern of dose-dependent toxicities, notably increases in creatine phosphokinase and the development of rhabdomyolysis, are a barrier to initiating high-dose schemes in clinical practice. Thus, the effectiveness and safety of high-dose daptomycin regimens in clinical practice have remained unclear. While early studies failed to identify differences in mortality, newer, larger investigations suggest high-dose (≥9 mg/kg) daptomycin is associated with reduced mortality in patients with VRE bacteraemia compared with standard (6 mg/kg) dosing regimens. Additionally, the high-dose regimens appear to be safe and may be associated with improved microbiological outcomes. The purpose of this review is to examine the published evidence on the effectiveness and safety of high-dose daptomycin compared with standard dosing regimens for VRE bacteraemia.


Kidney disease in diabetes: From mechanisms to clinical presentation and treatment strategies.
Metabolic and haemodynamic perturbations and their interaction drive the development of diabetic kidney disease (DKD) and its progression towards end stage renal disease (ESRD). Increased mitochondrial oxidative stress has been proposed as the central mechanism in the pathophysiology of DKD, but other mechanisms have been implicated. In parallel to increased oxidative stress, inflammation, cell apoptosis and tissue fibrosis drive the relentless progressive loss of kidney function affecting both the glomerular filtration barrier and the renal tubulointerstitium. Alteration of glomerular capillary autoregulation is at the basis of glomerular hypertension, an important pathogenetic mechanism for DKD. Clinical presentation of DKD can vary. Its classical presentation, often seen in patients with type 1 diabetes (T1DM), features hyperfiltration and albuminuria followed by progressive fall in renal function. Patients can often also present with atypical features characterised by progressive reduction in renal function without albuminuria, others in conjunction with non-diabetes related pathologies making the diagnosis, at times, challenging. Metabolic, lipid and blood pressure control with lifestyle interventions are crucial in reducing the progressive renal function decline seen in DKD. The prevention and management of DKD (and parallel cardiovascular disease) is a huge global challenge and therapies that target haemodynamic perturbations, such as inhibitors of the renin-angiotensin-aldosterone system (RAAS) and SGLT2 inhibitors, have been most successful.


Ser-752-->Pro mutation in the cytoplasmic domain of integrin beta 3 subunit and defective activation of platelet integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia.
Integrins are membrane receptors which mediate cell-cell or cell-matrix adhesion. Integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) acts as a fibrinogen receptor of platelets and mediates platelet aggregation. Platelet activation is required for alpha IIb beta 3 to shift from noncompetent to competent for binding soluble fibrinogen. The steps involved in this transition are poorly understood. We have studied a variant of Glanzmann thrombasthenia, a congenital bleeding disorder characterized by absence of platelet aggregation and fibrinogen binding. The patient's platelets did not bind fibrinogen after platelet activation by ADP or thrombin, though his platelets contained alpha IIb beta 3. However, isolated alpha IIb beta 3 was able to bind to an Arg-Gly-Asp-Ser affinity column, and binding of soluble fibrinogen to the patient's platelets could be triggered by modulators of alpha IIb beta 3 conformation such as the Arg-Gly-Asp-Ser peptide and alpha-chymotrypsin. These data suggested that a functional Arg-Gly-Asp binding site was present within alpha IIb beta 3 and that the patient's defect was not secondary to a blockade of alpha IIb beta 3 in a noncompetent conformational state. This was evocative of a defect in the coupling between platelet activation and alpha IIb beta 3 up-regulation. We therefore sequenced the cytoplasmic domain of beta 3, following polymerase chain reaction (PCR) on platelet RNA, and found a T-->C mutation at nucleotide 2259, corresponding to a Ser-752-->Pro substitution. This mutation is likely to be responsible for the uncoupling of alpha IIb beta 3 from cellular activation because (i) it is not a polymorphism, (ii) it is the only mutation in the entire alpha IIb beta 3 sequence, and (iii) genetic analysis of the family showed that absence of the Pro-752 beta 3 allele was associated with the normal phenotype. Our data thus identify the C-terminal portion of the cytoplasmic domain of beta 3 as an intrinsic element in the coupling between alpha IIb beta 3 and platelet activation.


[The concept of the "artificial tumor"].
Basic theoretical and experimental preconditions for the creation of the so-called "artificial tumour" are examined. It should be an operated extracorporeal analog of the spontaneously growing blastoma with autologous tumour cells as the main structural and functional element. Construction principles and immunological aspects of the "artificial tumour" are discussed. The real potentialities of its usage for the selective elimination of the tumour-stimulating humoral factors of different origin out of the organism as well as for the specific activation of autologous effector immunocytes are analyzed.


Activation of Polynuclear Aromatic Hydrocarbons to Mutagens by the Marine Ciliate Parauronema acutum.
The marine ciliate Parauronema acutum converted 2-aminofluorene and 2-acetylaminofluorene to compounds with mutagenic activity in the Ames Salmonella test. The ciliate, however, did not activate benzo (alpha)pyrene or benzanthracene or destroy the mutagenic properties of nitrosoguanidine. Homogenates, when substituted for the liver S-9 fraction in the Salmonella/microsome test, activated 2-aminofluorene and 2-acetylaminofluorene to mutagens. Benzo(alpha)pyrene and benzanthracene were not activated, nor was nitrosoguanidine inactivated. Phenobarbitol did not induce or increase the amount of activating activity. The activation showed no requirement for the reduced nicotinamide adenine dinucleotide phosphate-regenerating system required by liver P-450 cytochromes. Upon differential sedimentation of a cell homogenate, the majority of the activity sedimented with a small-particle fraction with sedimentation properties like those of microsomes from higher eucaryotes. Benzo(alpha)pyrene, although not metabolized, was accumulated by cultures of P. acutum at a linear rate and was not appreciably released (10%) after removal of benzo(alpha)pyrene from the incubation medium. Hence, this ciliate could convert certain polynuclear aromatic hydrocarbons to mutagens and accumulate others.


High-dose vitamin D supplementation in pregnancy and 25(OH)D sufficiency in childhood reduce the risk of fractures and improve bone mineralization in childhood: Follow-up of a randomized clinical trial.
Exposure to vitamin D in early life has been associated with improved bone mineralization, but no studies have investigated the combined effect of pregnancy supplementation and childhood 25(OH)D concentrations on bone health. We analyzed the effect of serum 25(OH)D concentrations at age 6 months and 6 years and the combined effect with prenatal high-dose vitamin D (2800 vs. 400 IU/day) on bone mineral density (BMD) and content (BMC) assessed by dual-energy X-ray absorptiometry (DXA) scans at age 3 and 6 years and longitudinal risk of fractures in a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother-child cohort with enrollment from March 4, 2009, to November 17, 2010, and clinical follow-up until January 31, 2019 (NCT00856947). All participants randomized to intervention and with complete data were included in the analyses. At age 6 months, serum 25(OH)D concentration was measured in 93% (n = 541) of 584 children. Children with sufficient (≥ 75 nmol/l) vs. insufficient (< 75 nmol/l) concentrations did not have lower risk of fractures: incidence rate ratio (95% CI); 0.64 (0.37;1.11), p = 0.11. However, vitamin D sufficient children from mothers receiving high-dose supplementation during pregnancy had a 60% reduced incidence of fractures compared with vitamin D insufficient children from mothers receiving standard-dose: 0.40 (0.19;0.84), p = 0.02.At age 6 years, serum 25(OH)D concentration was measured in 83% (n = 318) of 383 children with available DXA data. Whole-body bone mineralization was higher in vitamin D sufficient children at age 6 years; BMD, adjusted mean difference (aMD) (95% CI): 0.011 g/cm2 (0.001;0.021), p = 0.03, and BMC, aMD: 12.3 g (-0.8;25.4), p = 0.07, with the largest effect in vitamin D sufficient children from mothers receiving high-dose vitamin D supplementation; BMD, aMD: 0.016 g/cm2 (0.002;0.030), p = 0.03, and BMC, aMD: 23.5 g (5.5;41.5), p = 0.01. Childhood vitamin D sufficiency improved bone mineralization and in combination with prenatal high-dose vitamin D supplementation reduced the risk of fractures. The study was supported by The Lundbeck Foundation R16-A1694, The Danish Ministry of Health 903,516, The Danish Council for Strategic Research 0603-00280B and The European Research Council 946,228.


Fractional Exhaled Nitric Oxide (FeNO) Integrating Airway Hyperresponsiveness (AHR) Examination Promotes Etiologic Diagnosis and Treatment for Children with Chronic Cough.
BACKGROUND Chronic cough is the main reason why parents seek medical treatment for their children. This study aimed to evaluate changes in airway function and inflammation levels and associated values in diagnosing and treating chronic cough. MATERIAL AND METHODS This study involved 118 children with chronic cough, including 45 cough-variant asthma (CVA) patients, 53 upper-airway cough syndrome (UACS) patients, and 20 post-infection cough (PIC) patients. Chronic cough was diagnosed as described by guidelines of the American College of Chest Physicians for evaluating chronic cough. Pulmonary ventilation function and airway hyperresponsiveness (AHR) were evaluated. Fractional exhaled nitric oxide (FeNO) levels and eosinophilic airway inflammation were measured. Eosinophil (EOS) count in sputum was also examined. CVA patients were treated with inhaled glucocorticoids, which have anti-inflammatory effects. RESULTS FeNO and sputum EOS levels were higher in CVA patients compared with UACS and PIC patients (P<0.05). CVA patients demonstrated significantly higher small airway indexes, including 25% forced expiratory flow (FEF), 50% FEF, and 75% FEF, compared with UACS and PIC patients (P<0.05). FeNO level was positively correlated with EOS in sputum (r=0.468, P=0.0001) and cough symptom scores (r=0.402, P<0.05). FeNO, EOS, and cough symptoms were significantly improved in CVA patients after glucocorticoid treatment. AHR was improved in all chronic cough patients after treatment. Cough-relief CVA patients demonstrated significantly higher FeNO levels compared with those without cough relief (P<0.05). CONCLUSIONS FeNO integrating pulmonary function and AHR examination can improve etiologic diagnosis and treatment for chronic cough in children.


Red Fluorescent Proteins for Gene Expression and Protein Localization Studies in Streptococcus pneumoniae and Efficient Transformation with DNA Assembled via the Gibson Assembly Method.
During the last decades, a wide range of fluorescent proteins (FPs) have been developed and improved. This has had a great impact on the possibilities in biological imaging and the investigation of cellular processes at the single-cell level. Recently, we have benchmarked a set of green fluorescent proteins (GFPs) and generated a codon-optimized superfolder GFP for efficient use in the important human pathogen Streptococcus pneumoniae and other low-GC Gram-positive bacteria. In the present work, we constructed and compared four red fluorescent proteins (RFPs) in S. pneumoniae. Two orange-red variants, mOrange2 and TagRFP, and two far-red FPs, mKate2 and mCherry, were codon optimized and examined by fluorescence microscopy and plate reader assays. Notably, protein fusions of the RFPs to FtsZ were constructed by direct transformation of linear Gibson assembly (isothermal assembly) products, a method that speeds up the strain construction process significantly. Our data show that mCherry is the fastest-maturing RFP in S. pneumoniae and is best suited for studying gene expression, while mKate2 and TagRFP are more stable and are the preferred choices for protein localization studies. The RFPs described here will be useful for cell biology studies that require multicolor labeling in S. pneumoniae and related organisms.


Overestimation of NADH-driven vascular oxidase activity due to lucigenin artifacts.
Several limitations have recently been described for lucigenin, a probe frequently used to assess the activity of vascular NAD(P)H oxidase, a major superoxide source. The preferential reducing substrate of such oxidase remains unclear. We assessed whether lucigenin artifacts could affect detection of NAD(P)H oxidase activity. Initial chemiluminescence assays were performed with vascular rings or homogenates at 5, 50, or 250 microM concentrations. Results showed preferential signals with NADPH (vs. NADH) with 5 and 50 microM lucigenin, which were blocked by diphenylene iodonium (DPI), superoxide dismutase (SOD), or its cell-permeable mimetic MnTBAP. With 250 microM lucigenin, the relative signal with NADH became larger than with NADPH, and was poorly inhibited by all three antagonists above. All SOD/DPI-resistant signals were effectively blocked by the electron acceptor nitrobluetetrazolium. Spin trapping with DMPO showed an approximate doubling of DMPO-OH radical adduct signal upon addition of 5 microM lucigenin to homogenates incubated with either NADPH or NADH. With 50 or 250 microM lucigenin, much larger increases were observed with NADH, as opposed to NADPH. Furthermore, oxygen consumption measurements showed analogous results. In summary, our data suggest that: (i) Lucigenin redox-cycling is detectable in vascular tissue even at 5 microM concentrations, while at 250 microM redox-cycling becomes predominant and is markedly increased when NADH is the assayed substrate; and (ii) With 250 microM lucigenin, preferentially with NADH, signals are further overestimated by direct, oxidase-dependent, superoxide-independent two-electron transfer. Therefore, previous reports of preferential NADH affinity of the vascular oxidase may have been due to these artifacts.


MR imaging of cartilage repair in the knee and ankle.
Because of the relative avascularity of articular cartilage, lesions that are caused by trauma or degeneration of the cartilage do not heal spontaneously and must be repaired surgically. The interventional procedures that have been developed for the repair of such lesions include abrasion, microfracture, autologous osteochondral transplantation, allograft transplantation, and autologous chondrocyte implantation. An accurate imaging assessment of the repair tissue is necessary in order to objectively evaluate the postoperative outcome. Magnetic resonance (MR) imaging and arthroscopy provide complementary information and are especially useful for follow-up evaluation of cartilage repair in the knee and ankle. Standard MR imaging techniques may be used postoperatively to evaluate the success of implantation and the state of cartilage healing. Newer matrix assessment techniques, which include delayed gadolinium-enhanced MR imaging and mapping of T1rho and T2 values, may provide useful supplemental information about the histologic and biochemical contents of reparative tissue. The normal postoperative appearance of the joints after cartilage repair varies according to the surgical technique used and the stage of healing. To identify potential complications, it is important to be familiar with the various repair procedures and the characteristic MR imaging features of the repair tissue at various postoperative intervals.


Possibility of scanning electron microscope observation and energy dispersive X-ray analysis in microscale region of insulating samples using diluted ionic liquid.
The possibility of scanning electron microscope (SEM) observation and energy dispersive X-ray (EDX) spectrometry analysis in microscale regions of insulating samples using diluted ionic liquid was investigated. It is possible to obtain clear secondary electron images of insulating samples such as a rock and mineral at 5,000 times magnification by dropping 10 μL of 1 wt% of 1-ethyl-3-methylimidazolium acetate (EMI-CH₃COO) diluted with ethanol onto the samples. We also obtained EDX spectra of the samples in microscale regions (~5 μm²) without overlapping EDX spectra of other minerals with different composition. It might be possible to perform quantitative analysis of the samples if a method that does not need standard samples is applied or an X-ray detector sensitive for light elements was attached. The method of dropping 1 wt% EMI-CH₃COO diluted with ethanol onto insulating samples is useful for SEM observation, EDX analysis in microscale regions, and the preservation of scarce rock and mineral samples because ionic liquid can be easily removed with acetone.


In Their Own Words: The Experience of Professional Nurses in a Northern Vietnamese Women's Hospital.
Abstract Background Nurses in Vietnam, as is typical of many low-income countries, are hampered from impacting health outcomes by low occupational status, overcrowded hospitals and few career development opportunities. In order to understand the current practice environment encountered by nurses in Vietnam in the most realistic way, we listened to the voices of nurses currently performing nursing roles in Vietnam. Purpose The purpose of this study was to explore the emic (insider) perspectives on cultural meaning applied by nurses at a northern Vietnamese women�s hospital to influence professional practice and interpret experience. Design A micro-ethnography approach was used. Methods Seven nurses and one vice-Dean of a school of nursing were interviewed. Data collection consisted of open-ended interviews, participant observation and journal recordings. Spradley�s (1979, 1980) Development Research Sequence was used to guide data collection and analysis. Results/Findings Five themes emerged. These were the big number of patients is a burden for nurses; nurses do not, cannot make their own decisions (but they can and do); my feeling depends on doctor's feeling; nurses learn more from doctor; and just a few nurses can attend the [Vietnamese Nurses Association] meeting. Conclusion The experiences described by the nurses and the vice-Dean of a nursing school reflect the challenges of practicing nursing in one Vietnamese hospital and the resourcefulness of nurses in overcoming those challenges. Recurrent themes highlight the need to better position nurses in Vietnam to advance towards full expression of the professional nursing role.


Subpectoral Implant Placement Is Not Protective against Postmastectomy Radiotherapy-Related Complications Compared to Prepectoral Placement.
Postmastectomy radiotherapy (PMRT) is associated with altered cosmetic outcomes and higher complication rates in implant-based breast reconstruction (IBR). Conventional wisdom suggests that muscle coverage is somewhat protective against PMRT-related complications. In this study, the authors compared surgical outcomes in patients who underwent two-stage prepectoral versus subpectoral IBR in the setting of PMRT. The authors performed a retrospective cohort study of patients who underwent mastectomy and PMRT with two-stage IBR from 2016 to 2019. The primary outcome was breast-related complications, including device infection; the secondary outcome was device explantation. The authors identified 179 reconstructions (101 prepectoral and 78 subpectoral) in 172 patients with a mean follow-up time of 39.7 ± 14.4 months. There were no differences between the prepectoral and subpectoral reconstructions in rates of breast-related complications (26.7% and 21.8%, respectively; P = 0.274), device infection (18.8% and 15.4%, respectively; P = 0.307), skin flap necrosis (5.0% and 1.3%, respectively; P = 0.232), or device explantation (20.8% and 14.1%, respectively; P = 0.117). In adjusted models, compared with prepectoral device placement, subpectoral device placement was not associated with a lower risk of breast-related complications [hazard ratio (HR), 0.75; 95% confidence interval (CI), 0.41 to 1.36], device infection (HR, 0.73; 95% CI, 0.35 to 1.49), or device explantation (HR, 0.58; 95% CI, 0.28 to 1.19). Device placement plane was not predictive of complication rates in IBR in the setting of PMRT. Two-stage prepectoral IBR provides safe long-term outcomes with acceptable postoperative complication rates comparable to those with subpectoral IBR, even in the setting of PMRT. Therapeutic, III.


General practitioner management of comorbid insomnia and sleep apnoea.
Insomnia and obstructive sleep apnoea are the two most common sleep disorders and frequently co-exist. Patients with comorbid insomnia and sleep apnoea experience worse daytime function, mental health and physical health than patients with either disorder alone. General practitioners may face unique challenges in the assessment and management of this prevalent and debilitating condition. This article aims to provide an overview of the prevalence, consequences, assessment and management of patients with comorbid insomnia and sleep apnoea in Australian general practice. Patients with either insomnia or sleep apnoea should be assessed for both conditions. Treatments for both disorders should be offered to patients with both conditions. The recommended treatment for insomnia is cognitive behavioural therapy, whereas the recommended first-line treatment for moderate and severe obstructive sleep apnoea is lifestyle/weight management advice (where relevant) and continuous positive airway pressure therapy.


Long-term clinical outcomes in patients with refractory uveitis associated with Behçet disease treated with infliximab.
To assess long-term efficacy and safety of infliximab for refractory Behçet disease (BD) uveitis and to evaluate the effect of withdrawal of infliximab after achieving long-term remission. Retrospective study of 19 patients. Mean follow-up was 44.1 ± 36.5 months and mean number of infliximab infusions was 21.6 ± 14.6. At end of follow-up, there was significant improvement of visual acuity and reduction of central macular thickness. All patients achieved remission, 14 of whom were able to discontinue corticosteroids. Ten patients developed autoantibodies and 1 patient developed infusion reactions. Eight eyes underwent intraocular surgery without exacerbation of quiescent uveitis. After achieving complete remission, 5 patients discontinued infliximab and maintained remission during a mean of 24.6 ± 5.5 months. Infliximab is effective and safe for long-term treatment for refractory BD uveitis. Repeated infusions are required to maintain long-term remission, which may be sustained despite withdrawal of infliximab. Induction of autoantibodies is common.


Bungowannah Pestivirus Chimeras as Novel Double Marker Vaccine Strategy against Bovine Viral Diarrhea Virus.
Marker or DIVA (differentiation of infected from vaccinated animals) vaccines are beneficial tools for the eradication of animal diseases in regions with a high prevalence of the designated disease. Bovine viral diarrhea virus (BVDV)-1 (syn. Pestivirus A) is a flavivirus that infects predominantly cattle resulting in major economic losses. An increasing number of countries have implemented BVDV eradication programs that focus on the detection and removal of persistently infected cattle. No efficient marker or DIVA vaccine is yet commercially available to drive the eradication success, to prevent fetal infection and to allow serological monitoring of the BVDV status in vaccinated farms. Bungowannah virus (BuPV, species Pestivirus F), a related member of the genus Pestivirus with a restricted prevalence to a single pig farm complex in Australia, was chosen as the genetic backbone for a marker vaccine candidate. The glycoproteins E1 and E2 of BuPV were substituted by the heterologous E1 and E2, which are major immunogens, of the BVDV-1 strain CP7. In addition, the candidate vaccine was further attenuated by the introduction of a deletion within the Npro protein coding sequence, a major type I interferon inhibitor. Immunization of cattle with the chimeric vaccine virus BuPV_ΔNpro_E1E2 CP7 (modified live or inactivated) followed by a subsequent experimental challenge infection confirmed the safety of the prototype strain and provided a high level of clinical protection against BVDV-1. The serological discrimination of vaccinated cattle could be enabled by the combined detection of BVDV-1 E2- in the absence of both BVDV NS3- and BVDV Erns-specific antibodies. The study demonstrates for the first time the generation and application of an efficient BVDV-1 modified double marker vaccine candidate that is based on the genetic background of BuPV accompanied by commercially available serological marker ELISA systems.


Finger ridge patterns and tactile sensitivity.
Tactile sensitivity has been measured in 101 normal individuals (38 females and 63 males) of European origin, and compared with ridge pattern characteristics of the fourth fingertip of the right hand. There is a relationship of tactile sensitivity performance with the type of pattern, particularly in females, and also with the number of junctions within the pattern, particularly in males. The possible origin of sex differences in tactile sensitivity and in its relationships with dermatoglyphic variables is discussed. In spite of sex differences, optimal tactile sensitivity performance seems to be associated with medium-sized loop patterns which have a greater number of junctions than ends and also have grooves wider than ridges. The possible evolutionary significance of these associations is discussed in relation to evidence for epistatic genetic variation for pattern intensity.


The Rho GTPase Cdc42 Is Essential for the Activation and Function of Mature B Cells.
The Rho GTPase Cdc42 coordinates regulation of the actin and the microtubule cytoskeleton by binding and activating the Wiskott-Aldrich syndrome protein. We sought to define the role of intrinsic expression of Cdc42 by mature B cells in their activation and function. Mice with inducible deletion of Cdc42 in mature B cells formed smaller germinal centers and had a reduced Ab response, mostly of low affinity to T cell-dependent Ag, compared with wild-type (WT) controls. Spreading formation of long protrusions that contain F-actin, microtubules, and Cdc42-interacting protein 4, and assumption of a dendritic cell morphology in response to anti-CD40 plus IL-4 were impaired in Cdc42-deficient B cells compared with WT B cells. Cdc42-deficient B cells had an intact migratory response to chemokine in vitro, but their homing to the B cell follicles in the spleen in vivo was significantly impaired. Cdc42-deficient B cells induced a skewed cytokine response in CD4(+) T cells, compared with WT B cells. Our results demonstrate a critical role for Cdc42 in the motility of mature B cells, their cognate interaction with T cells, and their differentiation into Ab-producing cells.


Associations between medical cannabis and other drug use among unstably housed women.
Several studies suggest that U.S. state-level legalization of cannabis for medical purposes may be associated with reductions in opioid use; yet its relationship with stimulant use, particularly in high-risk populations like unstably housed women, has received less attention. The purpose of this study was to estimate independent associations between medical and non-medical use of cannabis and use of stimulants and opioids among unstably housed women. Cross-sectional data were analyzed from 245 women in the SHADOW study, a community based cohort in San Francisco, CA, in which HIV+ women were oversampled (126 HIV+ and 119 HIV-). Compared to no cannabis use in the past 6 months (51%), non-medical cannabis use (28%) was associated with a higher adjusted odds of using stimulants (Adjusted Odds Ratio [AOR]=4.34, 95% confidence interval [CI]: 2.17-8.70) and opioids (AOR=3.81, 95% CI: 1.78-8.15). Compared to no cannabis use, medical cannabis use (21%) was not significantly associated with stimulant or opioid use. Compared to non-medical cannabis use, however, medical cannabis use was associated with lower adjusted odds of using stimulants (AOR=0.42, 95% CI: 0.18-0.96). These associations were not modified by HIV status. Associations between use of cannabis and "street drugs" depend on whether the cannabis is obtained through a medical context. Interventions, research, and policy considering the influence of cannabis on the use of other drugs may benefit by distinguishing between medical and non-medical cannabis use.


De novo cerebral arteriovenous malformation: case report.
Arteriovenous malformations (AVMs) are generally thought to have a congenital cause. This is the first report of an angiographically proven de novo cerebral AVM in an adult patient without previous vascular abnormality. A 26-year-old African-American woman developed multiple cranial nerve deficits and ataxia over the course of a few days after a streptococcal throat infection. T2-weighted magnetic resonance imaging scans revealed a hyperintense signal in the midbrain with extension into the diencephalon. A cerebral angiogram performed at that time to exclude vasculitis revealed normal cerebral vasculature. The patient was treated with corticosteroids, and symptoms resolved. Subsequently, at the age of 32, this patient presented with a severe headache and emesis, but with no focal neurological deficit. The patient's cranial computed tomographic and magnetic resonance imaging scans revealed a right posterior temporal intraparenchymal hemorrhage, and cerebral angiography revealed a new 3- by 2-cm AVM. The patient underwent microsurgical resection of the AVM and associated hematoma. Postoperative angiography revealed no evidence of residual AVM. This study details the case of a woman who developed a de novo cerebral AVM during a 6-year period. This report challenges the conventional belief that all AVMs have a congenital cause.