The cardiotoxic effects of acute and chronic grayanotoxin-III in rats.
The purpose of this study is to histologically and immunohistochemically determine the changes created by grayanotoxin-III (GTX-III), which is a sodium channel neurotoxin, on heart tissues in different dosages. Rats were randomly divided into 10 groups to determine the acute and chronic effects of GTX-III. While the rats in groups 1 and 6 were control rats, the rats in groups 2-5 (1, 2, 4, and 8 μg/kg bw GTX-III) received a single dose of intraperitoneal GTX-III, and the rats in groups 7-10 received GTX-III every day for 3 weeks. As a result of the trial, in the heart tissues, histopathological changes were determined by hematoxylin-eosin staining, interleukin-1 (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and brain natriuretic peptide (BNP) were determined by the avidin-biotin peroxidase method, and apoptosis was examined by immunohistochemistry (IHC) analysis and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining method. In the immunohistochemistry sense, while the BNP level in the AGTX-III groups did not vary significantly, an increase in dosage significantly increased the IL-6, IL-1β, and TNF-α levels in comparison to the control groups. In their comparison to the control groups, the BNP levels increase and the IL-6 and IL-1β levels decreased in the CGTX-III groups. TUNEL analysis revealed that apoptosis increased in both the acute and chronic groups.


Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1.
The homeodomain transcription factor Nkx6.1 plays an important role in pancreatic islet beta-cell development, but its effects on adult beta-cell function, survival, and proliferation are not well understood. In the present study, we demonstrated that treatment of primary rat pancreatic islets with a cytomegalovirus promoter-driven recombinant adenovirus containing the Nkx6.1 cDNA (AdCMV-Nkx6.1) causes dramatic increases in [methyl-(3)H] thymidine and 5-bromo-2'-deoxyuridine (BrdU) incorporation and in the number of cells per islet relative to islets treated with a control adenovirus (AdCMV-betaGAL), whereas suppression of Nkx6.1 expression reduces thymidine incorporation. Immunocytochemical studies reveal that >80% of BrdU-positive cells in AdCMV-Nkx6.1-treated islets are beta cells. Microarray, real-time PCR, and immunoblot analyses reveal that overexpression of Nkx6.1 in rat islets causes concerted upregulation of a cadre of cell cycle control genes, including those encoding cyclins A, B, and E, and several regulatory kinases. Cyclin E is upregulated earlier than the other cyclins, and adenovirus-mediated overexpression of cyclin E is shown to be sufficient to activate islet cell proliferation. Moreover, chromatin immunoprecipitation assays demonstrate direct interaction of Nkx6.1 with the cyclin A2 and B1 genes. Overexpression of Nkx6.1 in rat islets caused a clear enhancement of glucose-stimulated insulin secretion (GSIS), whereas overexpression of Nkx6.1 in human islets caused an increase in the level of [(3)H]thymidine incorporation that was twice the control level, along with complete retention of GSIS. We conclude that Nkx6.1 is among the very rare factors capable of stimulating beta-cell replication with retention or enhancement of function, properties that may be exploitable for expansion of beta-cell mass in treatment of both major forms of diabetes.


MAEF-Net: MLP Attention for Feature Enhancement in U-Net based Medical Image Segmentation Networks.
Medical image segmentation plays an important role in diagnosis. Since U-Net was proposed, many improvements have been applied to enhance the performance and broaden its range of applications. With the rise of Transformer in the field of computer vision, self-attention mechanisms have been introduced into U-Net, leading to numerous breakthroughs. However, due to the inherent complexity of the Transformer, these networks are usually parameter-heavy and time-consuming to use. Recent studies show that multilayer perceptrons (MLPs) can perform as well as Transformer in natural language processing and computer vision tasks with a much simpler structure. Based on these advancements, we improve the previously proposed "Enhanced-Feature-Four-Fold-Net" (EF3 -Net) by introducing an MLP-attention block to learn long-range dependencies and expand the receptive field. This net is thus named as "MLP-Attention Enhanced-Feature-four-fold-Net", abbreviated as "MAEF-Net". The newly proposed network is further equipped with other efficient designs to further increase the accuracy and reduce computation complexity. MAEF-Net has been compared with several general and specialized medical image segmentation networks, using four challenging medical image datasets. The results have demonstrated that the proposed network exhibits high computational efficiency and comparable or better performance than EF3 -Net and several state-of-the-art methods, particularly in segmenting blurry objects. The codes will be available on: https://github.com/raik7/ MAEF-Net.


Nonalcoholic fatty liver disease: Noninvasive methods of diagnosing hepatic steatosis.
Hepatic steatosis is the buildup of lipids within hepatocytes. It is the simplest stage in nonalcoholic fatty liver disease (NAFLD). It occurs in approximately 30% of the general population and as much as 90% of the obese population in the United States. It may progress to nonalcoholic steatohepatitis, which is a state of hepatocellular inflammation and damage in response to the accumulated fat. Liver biopsy remains the gold standard tool to diagnose and stage NAFLD. However, it comes with the risk of complications ranging from simple pain to life-threatening bleeding. It is also associated with sampling error. For these reasons, a variety of noninvasive radiological markers, including ultrasound, computed tomography, magnetic resonance spectroscopy, and the controlled attenuation parameter using transient elastography and Xenon-133 scan have been proposed to increase our ability to diagnose NAFLD, hence avoiding liver biopsy. The aim of this review is to discuss the utility and accuracy of using available noninvasive diagnostic modalities for fatty liver in NAFLD.


Healthcare costs incurred by patients repeatedly referred to secondary medical care with medically unexplained symptoms: a cost of illness study.
Some patients are repeatedly referred from primary to secondary care with medically unexplained symptoms (MUS). We aimed to estimate the healthcare costs incurred by such referrals and to compare them with those incurred by other referred patients from the same defined primary care sample. Using a referral database and case note review, all adult patients aged less than 65 years, who had been referred to specialist medical services from one of five UK National Health Service primary care practices in a five-year period, were identified. They were placed in one of three groups: (i) repeatedly referred with MUS (N=276); (ii) infrequently referred (IRS, N=221), (iii) repeatedly referred with medically explained symptoms (N=230). Secondary care activities for each group (inpatient days, outpatient appointments, emergency department attendances and investigations) were identified from primary care records. The associated costs were allocated using summary data and the costs for each group compared. Patients who had been repeatedly referred with MUS had higher mean inpatient, outpatient and emergency department costs than those infrequently referred (£3,539, 95% CI 1458 to 5621, £778 CI 705 to 852 and £99, CI 74 to 123 respectively. The mean overall costs were similar to those of patients who had been repeatedly referred with medically explained symptoms. The repeated referral of patients with MUS to secondary medical care incurs substantial healthcare costs. An alternative form of management that reduces such referrals offers potential cost savings.


Advances in the mechanisms of action of cancer-targeting oncolytic viruses.
Cancer virotherapy mediated by oncolytic viruses (OV), has emerged as a novel and effective strategy in cancer therapeutics. Preclinical models have demonstrated anticancer activity against numerous types of cancer. Currently, a number of recombinant viruses are in late phase clinical trials, many of which have demonstrated promising results regarding the safety and reliability of the treatments, particularly when combined with standard antineoplastic therapies. In addition to molecular-targeted therapeutics, genetic engineering of the viruses allows functional complementation to chemotherapy or radiotherapy agents. Co-administration of chemotherapy or radiotherapy is imperative for an effective treatment regime. Additionally, these approaches may be used in combination with current treatments to assist in cancer management. The near future may reveal whether this renewed interest in oncological virotherapy will result in meaningful therapeutic effects in patients. The aim of the present review was to highlight how the knowledge of oncolytic viral specificity and cytotoxicity has advanced in recent years, with a view to discuss OV in clinical application and the future directions of this field.


Modelling the effect of test-and-slaughter strategies to control bovine tuberculosis in endemic high prevalence herds.
Bovine tuberculosis (bTB) prevalence substantially increased over the past two decades with relatively high impact on large dairy herds, raising the concern of regulatory authorities and industry stakeholders, and threatening animal and public health. Lack of resources, together with the economic and social consequences of whole-herd stamping-out, makes depopulation an impractical disease control alternative in these herds. The increase in bTB prevalence was associated with demographic and management changes in the dairy industry in Uruguay, reducing the efficacy of the current control programme (i.e. status quo) based on intradermal serial testing with caudal fold- and comparative-cervical tuberculin test-and-slaughter of reactors (CFT-CCT). Here, we aimed to assess the epidemiological effectiveness of six alternative control scenarios based on test-and-slaughter of positive animals, using mathematical modelling to infer bTB-within-herd dynamics. We simulated six alternative control strategies consisting of testing adult cattle (>1 year) in the herd every 3 months using one test (in vivo or in vitro) or a combination in parallel of two tests (CFT, interferon-gamma release assay-IGRA- or enzyme-linked immunosorbent assay). Results showed no significant differences overall in the time needed to reach bTB eradication (median ranging between 61 and 82 months) or official bovine tuberculosis-free status (two consecutive negative herd tests) between any of the alternative strategies and the status quo (median ranging between 50 and 59 months). However, we demonstrate how alternative strategies can significantly reduce bTB prevalence when applied for restricted periods (6, 12 or 24 months), and in the case of IGRAc (IGRA using peptide-cocktail antigens), without incurring on higher unnecessary slaughter of animals (false positives) than the status quo in the first 6 months of the programme (p-value < .05). Enhanced understanding bTB-within-herd dynamics with the application of different control strategies help to identify optimal strategies to ultimately improve bTB control and bTB eradication from dairies in Uruguay and similar endemic settings.


Tumor necrosis factor and transforming growth factor β regulate clock genes by controlling the expression of the cold inducible RNA-binding protein (CIRBP).
The circadian clock drives the rhythmic expression of a broad array of genes that orchestrate metabolism, sleep wake behavior, and the immune response. Clock genes are transcriptional regulators engaged in the generation of circadian rhythms. The cold inducible RNA-binding protein (CIRBP) guarantees high amplitude expression of clock. The cytokines TNF and TGFβ impair the expression of clock genes, namely the period genes and the proline- and acidic amino acid-rich basic leucine zipper (PAR-bZip) clock-controlled genes. Here, we show that TNF and TGFβ impair the expression of Cirbp in fibroblasts and neuronal cells. IL-1β, IL-6, IFNα, and IFNγ do not exert such effects. Depletion of Cirbp is found to increase the susceptibility of cells to the TNF-mediated inhibition of high amplitude expression of clock genes and modulates the TNF-induced cytokine response. Our findings reveal a new mechanism of cytokine-regulated expression of clock genes.


In situ hybridization of interleukin 6 in diabetic nephropathy.
Increased mesangial expansion is one of the most characteristic histological changes in diabetic nephropathy (DN). Although the pathogenesis of DN remains unclear, recent studies associate interleukin (IL) 6 with mesangial proliferative glomerulonephritis. To elucidate the expression and localization of IL-6 mRNA in renal tissues of patients with DN, a high-resolution in situ hybridization using digoxigenin-labeled oligonucleotide was performed. Patients were divided into three groups based on light microscopy findings: mild (group 1), moderate (group 2), and severe (group 3) mesangial expansion. The relationship between the expression of IL-6 mRNA and the degree of glomerular mesangial expansion in DN was examined. Individual cells positive for IL-6 mRNA were observed in glomeruli. These cells were mesangial cells, glomerular epithelial cells, and Bowman's capsule. The signal intensity was strongest in tissues from group 2 but was weak in those from groups 1 and 3. Most cells in the area of mesangial proliferation were strongly stained for IL-6 mRNA, and few positive cells were found in the Kimmelstiel-Wilson nodular lesion. In the interstitium, some tubules, particularly atrophic tubules, and some infiltrating cells were positively stained for IL-6 mRNA. The interstitial expression of IL-6 mRNA correlated significantly with the degree of interstitial injury and was remarkable in tissues from groups 2 and 3. We conclude that IL-6 mRNA is expressed by glomerular resident cells and interstitial cells in the renal tissue of patients with DN and that its expression may be associated with mesangial proliferation and may be involved in the tissue injury of DN.


Numerical techniques for excitation and analysis of defect modes in photonic crystals.
Two numerical techniques for analysis of defect modes in photonic crystals are presented. Based on the finite-difference time-domain method (FDTD), we use plane wave incidences and point sources for excitation and analysis. Using a total-field/scattered-field scheme, an idealplane wave incident at different angles is implemented; defect modes are selectively excited and mode symmetries are probed. All modes can be excited by an incident plane wave along a non-symmetric direction of the crystal. Degenerate modes can also be differentiated using this method. A proper arrangement of point sources with positive and negative amplitudes in the cavity flexibly excites any chosen modes. Numerical simulations have verified these claims. Evolution of each defect mode is studied using spectral filtering. The quality factor of the defect mode is estimated based on the field decay. The far-field patterns are calculated and the Q values are shown to affect strongly the sharpness of these patterns. Animations of the near-fields of the defect modes are presented to give an intuitive image of their oscillating features.


Role of osmolytes in adaptation of osmotically stressed and chill-stressed Listeria monocytogenes grown in liquid media and on processed meat surfaces.
Listeria monocytogenes is a food-borne pathogen that is widely distributed in nature and is found in many kinds of fresh and processed foods. The pervasiveness of this organism is due, in part, to its ability to tolerate environments with elevated osmolarity and reduced temperatures. Previously, we showed that L. monocytogenes adapts to osmotic and chill stress by transporting the osmolyte glycine betaine from the environment and accumulating it intracellularly (R. Ko, L. T. Smith, and G. M. Smith, J. Bacteriol. 176:426-431, 1994). In the present study, the influence of various environmental conditions on the accumulation of glycine betaine and another osmolyte, carnitine, was investigated. Carnitine was shown to confer both chill and osmotic tolerance to the pathogen but was less effective than glycine betaine. The absolute amount of each osmolyte accumulated by the cell was dependent on the temperature, the osmolarity of the medium, and the phase of growth of the culture. L. monocytogenes also accumulated high levels of osmolytes when grown on a variety of processed meats at reduced temperatures. However, the contribution of carnitine to the total intracellular osmolyte concentration was much greater in samples grown on meat than in those grown in liquid media. While the amount of each osmolyte in meat was less than 1 nmol/mg (fresh weight), the overall levels of osmolytes in L. monocytogenes grown on meat were about the same as those in liquid samples, from about 200 to 1,000 nmol/mg of cell protein for each osmolyte. This finding suggests that the accumulation of osmolytes is as important in the survival of L. monocytogenes in meat as it is in liquid media.


Tn glycosylation of the MUC6 protein modulates its immunogenicity and promotes the induction of Th17-biased T cell responses.
The Tn antigen (α-GalNAc-O-Ser/Thr) is one of the most specific human cancer-associated structures. This antigen, together with mucins, the major carriers of O-glycosylated tumor antigens in adenocarcinomas, are being evaluated as anti-cancer immunotherapeutic targets. In particular, the MUC6 protein, which is normally expressed only in gastric tissues, has been detected in intestinal, pulmonary, colorectal, and breast carcinomas. To develop anti-cancer vaccines based on the Tn antigen, we produced MUC6 proteins with different Tn density by using mixtures of recombinant ppGalNAc-T1, -T2, and -T7. The obtained glycoproteins were characterized and analyzed for their immunological properties, as compared with the non-glycosylated MUC6. We show that these various MUC6:Tn glycoproteins were well recognized by both MUC6 and Tn-specific antibodies. However, Tn glycosylation of the MUC6 protein strongly affected their immunogenicity by partially abrogating Th1 cell responses, and promoting IL-17 responses. Moreover, the non-glycosylated MUC6 was more efficiently presented than MUC6:Tn glycoproteins to specific T CD4(+) hybridomas, suggesting that Tn glycosylation may affect MUC6 processing or MHC binding of the processed peptides. In conclusion, our results indicate that Tn glycosylation of the MUC6 protein strongly affects its B and T cell immunogenicity, and might favor immune escape of tumor cells.


Comparison of classic peribulbar anesthesia and new entry point (single percutaneous injection technique) in vitroretinal surgery.
To describe the method that seeks to improve the administration of regional anesthesia for vitroretinal surgery avoiding the risk of potential complications associated with other techniques through comparison of safety and efficacy of classic peribulbar anesthesia versus single percutaneous technique using a prospective, randomized clinical trial. One hundred patients were randomized to classic peribulbar and single percutaneous peribulbar technique after informed consent. Pain during administration of anesthesia, during surgery was graded on a visual analogue pain scale and compared for both techniques. Globe akinesia, analgesia and IOP measurements before and after administration of anesthesia, detection of distribution of local anesthetic agent by ultrasound scanning and complications related were also compared. Twenty out of 50 (40%) patients of group 1(classic pirebulbar) and 36/50 (72%) of group II (single percutaneous technique) experience no pain during administration of anesthesia. Scores for globe akinesia and anesthesia were less satisfactory in group 1 and supplemental blocks required in 8% of the patients while in group II all of the patients (100%) showed proper globe akinesia and anesthesia. There were significant elevation in mean IOP following injection in both groups and the incidence of subconjunctival haemorrhage, chemosis and echymosis were more frequent in group 1. Single percutaneous peribulbar technique proved to be a safe and efficient technique that offers excellent anesthesia and akinesia with less complication for various ophthalmic procedures.


Neuro-fuzzy modeling: an accurate and interpretable method for predicting bladder cancer progression.
New methods are required to improve the prediction of cancer progression as traditional statistical tests have limited accuracy. Accurate predictions would allow physicians to offer specific treatment according to individual patient risk. While predictive improvements are obtained using ANN, the hidden nature of these networks prevents insight and has hindered their widespread implementation. NFM is an alternate form of artificial intelligence using fuzzy logic (which is a multivalued logic which provides reasoning under uncertainty). By defuzzification the NFM rule base becomes transparent to overcome the black box nature of ANN. Combinations of clinicopathological (tumor stage and grade, patient age, gender, and smoking status) and molecular (immunohistochemical expression of p53 and methylation status of 11 loci) data from 117 patients were used to develop and compare predictive models of tumor progression using NFM, ANN and LR. NFM (88% to 100% sensitivity, 97% to 100% specificity and 94% to 100% accuracy) predicted the presence and timing of cancer progression more accurately than ANN (81% to 87%, 95% to 100% and 89% to 90%, p = 0.002) and LR 3%, 61% to 72% and 47% to 53%, p = 0.00005). NFM was able to interrogate the clinicopathological and molecular data, and select the most important parameters (age, grade, stage, smoking, methylation) for progression prediction. Intelligent systems and molecular biomarkers improved the accuracy of cancer progression predictions. NFM appeared superior to ANN in terms of accuracy, sensitivity, specificity and transparency. The use of NFM in routine clinical practice warrants further validation.


Synthesis of chiral self-assembling rhombs and their characterization in solution, in the gas phase, and at the liquid-solid interface.
Chiral, enantiopure metallo-supramolecular rhombs self-assemble in solution through coordination of bis-pyridyl-substituted ligands with (en)M(NO3)2 (en = ethylenediamine, M = Pd(II), Pt(II)). Characterization by NMR and CD spectroscopy in solution and by ESI-FT-ICR mass spectrometry in the gas phase suggests that an equilibrium exists in water/methanol of a major 2:2 complex and a minor 3:3 complex of ligands and metal corners. In the gas phase, doubly charged 2:2 complexes fragment into two identical singly charged halves followed by metal-mediated C-H and C-C bond activation reactions within the ethylenediamine ligands. Electrochemical scanning tunneling microscopy (EC-STM) provides in situ imaging of the complexes even with submolecular resolution. Flat-lying rhombs are deposited under potential control from an aqueous electrolyte on a Cu(100) electrode surface precovered by a tetragonal pattern of chloride anions from the supporting electrolyte. Chirality induces the formation of only one domain orientation. Density functional calculations help to interpret the STM images.


The pre- and post-somatic segments of the human type I spiral ganglion neurons--structural and functional considerations related to cochlear implantation.
Human auditory nerve afferents consist of two separate systems; one is represented by the large type I cells innervating the inner hair cells and the other one by the small type II cells innervating the outer hair cells. Type I spiral ganglion neurons (SGNs) constitute 96% of the afferent nerve population and, in contrast to other mammals, their soma and pre- and post-somatic segments are unmyelinated. Type II nerve soma and fibers are unmyelinated. Histopathology and clinical experience imply that human SGNs can persist electrically excitable without dendrites, thus lacking connection to the organ of Corti. The biological background to this phenomenon remains elusive. We analyzed the pre- and post-somatic segments of the type I human SGNs using immunohistochemistry and transmission electron microscopy (TEM) in normal and pathological conditions. These segments were found surrounded by non-myelinated Schwann cells (NMSCs) showing strong intracellular expression of laminin-β2/collagen IV. These cells also bordered the perikaryal entry zone and disclosed surface rugosities outlined by a folded basement membrane (BM) expressing laminin-β2 and collagen IV. It is presumed that human large SGNs are demarcated by three cell categories: (a) myelinated Schwann cells, (b) NMSCs and (c) satellite glial cells (SGCs). Their BMs express laminin-β2/collagen IV and reaches the BM of the sensory epithelium at the habenula perforata. We speculate that the NMSCs protect SGNs from further degeneration following dendrite loss. It may give further explanation why SGNs can persist as electrically excitable monopolar cells even after long-time deafness, a blessing for the deaf treated with cochlear implantation.


Thirty years of protein translocation into mitochondria: unexpectedly complex and still puzzling.
Mitochondria are essential organelles of the eukaryotic cells that are made by expansion and division of pre-existing mitochondria. The majority of their protein constituents are synthesized in the cytosol. They are transported into and put together within the organelle. This complex process is facilitated by several protein translocases. Here we summarize current knowledge on these sophisticated molecular machines that mediate recognition, transport across membranes and intramitochondrial sorting of many hundreds of mitochondrial proteins.


Varying patterns of brachial artery flow-mediated dilatation in women with polycystic ovary syndrome and controls: An application of the group-based trajectory modeling.
To identify changing patterns of absolute change in brachial artery lumen diameter (LD) after reactive hyperemia in women with polycystic ovary syndrome (PCOS) and controls and to quantify the association of PCOS status and participants' factors with these patterns. Brachial flow-mediated dilation was measured in 128 women with PCOS and 148 controls aged 30-60 years. Group-based trajectory modeling was used to investigate absolute change in LD every 30 seconds for 2 minutes after occluding cuff deflation. Multinomial logistic regression was used to identify factors associated with trajectories. Three patterns emerged, namely nondilators (42.2%), dilators (44.6%), and enhanced dilators (13.0%). The proportion of women with PCOS did not differ across groups. Independently of age and PCOS status, larger baseline LD (odds ratio; 95% confidence interval: 2.51; 1.29, 4.89) and lower insulin levels (0.70; 0.52, 0.93) were associated with nondilators rather than with dilators. Higher total cholesterol was associated with dilators in women with PCOS but with nondilators in controls. Trajectory modeling identified distinct patterns of change in LD and factors associated with the endothelial response. This method may be a useful tool to understand the brachial flow-mediated vasodilator response.


Sexual and physical violence against female sex workers in Kenya: a qualitative enquiry.
Few studies in Africa provide detailed descriptions of the vulnerabilities of female sex workers (FSW) to sexual and physical violence, and how this impacts on their HIV risk. This qualitative study documents FSW's experiences of violence in Mombasa and Naivasha, Kenya. Eighty-one FSW who obtained clients from the streets, transportation depots, taverns, discos and residential areas were recruited through local sex workers trained as peer counsellors to participate in eight focus-group discussions. Analysis showed the pervasiveness of sexual and physical violence among FSW, commonly triggered by negotiation around condoms and payment. Pressing financial needs of FSW, gender-power differentials, illegality of trading in sex and cultural subscriptions to men's entitlement for sex sans money underscore much of this violence. Sex workers with more experience had developed skills to avoid threats of violence by identifying potentially violent clients, finding safer working areas and minimising conflict with the police. Addressing violence and concomitant HIV risks and vulnerabilities faced by FSW should be included in Kenya's national HIV/AIDS strategic plan. This study indicates the need for multilevel interventions, including legal reforms so that laws governing sex work promote the health and human rights of sex workers in Kenya.


Micro sequential injection: fermentation monitoring of ammonia, glycerol, glucose, and free iron using the novel lab-on-valve system.
Using an integrated lab-on-valve manifold in a microfluidic sequential injection format (microSI), automated sample processing has been developed for off-line and on-line monitoring of small-scale fermentations. Spectrophotometric assays of ammonia, glucose, glycerol, and free iron were downscaled to use micro-quantities of commercial reagents. By monitoring the reaction rate, the response curves in a stopped-flow mode generate linear calibration curves for ammonia [r2 = 1.000 (0.9% SE)], glycerol [r2 = 0.999 (1.1% SE)], glucose [r2 = 0.999 (1.1% SE)], and free iron [r2 = 0.999 (1.5% SE)]. Since sample dilution and reagent quantities are easily adjusted within the programmable SI format, the lab-on-valve system can accommodate samples over a wide concentration range (ammonia: 3-1200 ppm; glycerol: 20-120 ppm; glucose: 35-1000 ppm; and free iron: 80-400 ppm). This work demonstrates the key advantages of miniaturization through the reduction of sample and reagent use, minimizing waste and providing a compact yet reliable instrument. The lab-on-valve manifold uses a universal hardware configuration for all analyses, only requiring changes in software protocol and choice of reagents. All of these features are of particular importance to small-scale experimental fermentation where multiple analyte analyses are needed in real-time using small sample volumes. It is hoped that this first real-life application of the lab-on-valve manifold will serve not only as a model system to downscale assays in a practical fashion, but will also inspire and promote the use of the integrated microSI manifold approach for a wider range of biotechnological applications.


Neural Response During a Mechanically Assisted Spinal Manipulation in an Animal Model: A Pilot Study.
Mechanoreceptor stimulation is theorized to contribute to the therapeutic efficacy of spinal manipulation. Use of mechanically-assisted spinal manipulation (MA-SM) devices is increasing among manual therapy clinicians worldwide. The purpose of this pilot study is to determine the feasibility of recording in vivo muscle spindle responses during a MA-SM in an intervertebral fixated animal model. Intervertebral fixation was created by inserting facet screws through the left L5-6 and L6-7 facet joints of a cat spine. Three L6muscle spindle afferents with receptive fields in back muscles were isolated. Recordings were made during MA-SM thrusts delivered to the L7 spinous process using an instrumented Activator IV clinical device. Nine MA-SM thrusts were delivered with peak forces ranging from 68-122N and with thrust durations of less than 5ms. High frequency muscle spindle discharge occurred during MA-SM. Following the MA-SM, muscle spindle responses included returning to pre-manipulation levels, slightly decreasing for a short window of time, and greatly decreasing for more than 40s. This study demonstrates that recording in vivo muscle spindle response using clinical MA-SM devices in an animal model is feasible. Extremely short duration MA-SM thrusts (<5ms) can have an immediate and/or a prolonged (> 40s) effect on muscle spindle discharge. Greater peak forces during MA-SM thrusts may not necessarily yield greater muscle spindle responses. Determining peripheral response during and following spinal manipulation may be an important step in optimizing its' clinical efficacy. Future studies may investigate the effect of thrust dosage and magnitude.


Effects of diphtheria-tetanus-pertussis or tetanus vaccination on allergies and allergy-related respiratory symptoms among children and adolescents in the United States.
Findings from animal and human studies confirm that diphtheria and tetanus toxoids and pertussis (DTP) and tetanus vaccinations induce allergic responses; associations between childhood vaccinations and subsequent allergies have been reported recently. The association of DTP or tetanus vaccination with allergies and allergy-related respiratory symptoms among children and adolescents in the United States was assessed. Data were used from the Third National Health and Nutrition Examination Survey on infants aged 2 months through adolescents aged 16 years. DTP or tetanus vaccination, lifetime allergy history, and allergy symptoms in the past 12 months were based on parental or guardian recall. Logistic regression modeling was performed to estimate the effects of DTP or tetanus vaccination on each allergy. The odds of having a history of asthma was twice as great among vaccinated subjects than among unvaccinated subjects (adjusted odds ratio, 2.00; 95% confidence interval, 0.59 to 6.74). The odds of having had any allergy-related respiratory symptom in the past 12 months was 63% greater among vaccinated subjects than unvaccinated subjects (adjusted odds ratio, 1.63; 95% confidence interval, 1.05 to 2.54). The associations between vaccination and subsequent allergies and symptoms were greatest among children aged 5 through 10 years. DTP or tetanus vaccination appears to increase the risk of allergies and related respiratory symptoms in children and adolescents. Although it is unlikely that these results are entirely because of any sources of bias, the small number of unvaccinated subjects and the study design limit our ability to make firm causal inferences about the true magnitude of effect.


Workplace secondhand smoke exposure: a lingering hazard for young adults in California.
To examine occupational differences in workplace exposure to secondhand smoke (SHS) among young adults in California. Data are taken from the 2014 Bay Area Young Adult Health Survey, a probabilistic multimode cross-sectional household survey of young adults, aged 18-26, in Alameda and San Francisco Counties. Respondents were asked whether they had been exposed to SHS 'indoors' or 'outdoors' at their workplace in the previous 7 days and also reported their current employment status, industry and occupation. Sociodemographic characteristics and measures of health perception and behaviour were included in the final model. Young adults employed in service (p<0.001), construction and maintenance (p<0.01), and transportation and material moving (p<0.05) sectors were more likely to report workplace SHS exposure while those reporting very good or excellent self-rated health were less likely (p<0.001). Despite California's clean indoor air policy, 33% of young adults in the San Francisco Bay Area still reported workplace SHS exposure in the past week, with those in lower income occupations and working in non-office environments experiencing the greatest exposure. Closing the gaps that exempt certain types of workplaces from the Smoke-Free Workplace Act may be especially beneficial for young adults.


Wavelength conversion of optical 64QAM through FWM in HNLF and its performance optimization by constellation monitoring.
All-optical wavelength conversion (AOWC) plays an important role in the future transparent optical networks, in order to enhance the re-configurability and non-blocking capacity. On the other hand, high-order quadrature amplitude modulations (QAMs) have been extensively studied for achieving the high-speed and high-spectral-efficiency optical transmission. Since high-order QAMs are more sensitive to phase and amplitude noise, to implement an AOWC sub-system suitable for high-order QAM signals with minimized power penalty, it is important to optimize the operation conditions in order to avoid extra nonlinear distortions co-existed in the AOWC process. Our experimental results show that, constellation monitoring provides a more intuitive and accurate approach to monitor the converted high-order QAM signals, especially in presence of nonlinear phase noise such as self-phase modulation (SPM). We experimentally demonstrate an AOWC of 64QAM signal through four-wave mixing (FWM) in highly-nonlinear (HNLF). The performance of the AOWC is optimized through the constellation monitoring of the converted signal, achieving a negligible power penalty (<0.3 dB at BER of 10(-3)) for 60-Gbps 64QAM after conversion.


cAMP signaling in neurons: patterns of neuronal expression and intracellular localization for a novel protein, AKAP 150, that anchors the regulatory subunit of cAMP-dependent protein kinase II beta.
In mammalian brain, physiological signals carried by cyclic AMP (cAMP) seem to be targeted to effector sites via the tethering of cAMP-dependent protein kinase II beta (PKAII beta) to intracellular structures. Recently characterized A kinase anchor proteins (AKAPs) are probable mediators of the sequestration of PKAII beta because they contain a high-affinity binding site for the regulatory subunit (RII beta) of the kinase and a distinct intracellular targeting domain. To establish a cellular basis for this targeting mechanism, we have employed immunocytochemistry to 1) identify the types of neurons that are enriched in AKAPs, 2) determine the primary intracellular location of the anchor protein, and 3) demonstrate that an AKAP and RII beta are coenriched and colocalized in neurons that utilize the adenylate cyclase-cyclic AMP-dependent protein kinase (PKA) signaling pathway. Antibodies directed against rat brain AKAP 150 were used to elucidate the regional, cellular and intracellular distribution of a prototypic anchor protein in the CNS. AKAP 150 is abundant in Purkinje cells and in neurons of the olfactory bulb, basal ganglia, cerebral cortex, and other forebrain regions. In contrast, little AKAP 150 is detected in neurons of the thalamus, hypothalamus, midbrain, and hindbrain. A high proportion of total AKAP 150 is concentrated in primary branches of dendrites, where it is associated with microtubules. We also discovered that the patterns of accumulation and localization of RII beta (and PKAII beta) in brain are similar to those of AKAP 150. The results suggest that bifunctional AKAP 150 tethers PKAII beta to the dendritic cytoskeleton, thereby creating a discrete target site for the reception and propagation of signals carried by cAMP.


Combinatory Actions of Co-transmitters in Dopaminergic Systems Modulate Drosophila Olfactory Memories.
Dopamine neurons (DANs) are extensively studied in the context of associative learning, in both vertebrates and invertebrates. In the acquisition of male and female Drosophila olfactory memory, the PAM cluster of DANs provides the reward signal, and the PPL1 cluster of DANs sends the punishment signal to the Kenyon cells (KCs) of mushroom bodies, the center for memory formation. However, thermo-genetical activation of the PPL1 DANs after memory acquisition impaired aversive memory, and that of the PAM DANs impaired appetitive memory. We demonstrate that the knockdown of glutamate decarboxylase, which catalyzes glutamate conversion to GABA in PAM DANs, potentiated the appetitive memory. In addition, the knockdown of glutamate transporter in PPL1 DANs potentiated aversive memory, suggesting that GABA and glutamate co-transmitters act in an inhibitory manner in olfactory memory formation. We also found that, in γKCs, the Rdl receptor for GABA and the mGluR DmGluRA mediate the inhibition. Although multiple-spaced training is required to form long-term aversive memory, a single cycle of training was sufficient to develop long-term memory when the glutamate transporter was knocked down, in even a single subset of PPL1 DANs. Our results suggest that the mGluR signaling pathway may set a threshold for memory acquisition to allow the organisms' behaviors to adapt to changing physiological conditions and environments.SIGNIFICANCE STATEMENT In the acquisition of olfactory memory in Drosophila, the PAM cluster of dopamine neurons (DANs) mediates the reward signal, while the PPL1 cluster of DANs conveys the punishment signal to the Kenyon cells of the mushroom bodies, which serve as the center for memory formation. We found that GABA co-transmitters in the PAM DANs and glutamate co-transmitters in the PPL1 DANs inhibit olfactory memory formation. Our findings demonstrate that long-term memory acquisition, which typically necessitates multiple-spaced training sessions to establish aversive memory, can be triggered with a single training cycle in cases where the glutamate co-transmission is inhibited, even within a single subset of PPL1 DANs, suggesting that the glutamate co-transmission may modulate the threshold for memory acquisition.


DNA sensing by amplifying the number of near-infrared emitting, oligonucleotide-encapsulated silver clusters.
A bifunctional oligonucleotide integrates in situ synthesis of a fluorogenic silver cluster with recognition of a target DNA sequence. With the template C(3)AC(3)AC(3)GC(3)A, a complex forms with 10 silver atoms that possesses electronic transitions in the near-infrared and that is detected at nanomolar concentrations using diode laser excitation. Pendant to this cluster encoding region, the recognition component binds a target DNA strand through hybridization, and decoupling of these two regions of the composite sensor renders a modular sensor for specific oligonucleotides. A target is detected using a quencher strand that bridges the cluster template and recognition components and disturbs cluster binding, as indicated by static quenching. Competitive displacement of the quencher by the target strand restores the favored cluster environment, and our key finding is that this exchange enhances emission through a proportional increase in the number of emissive clusters. DNA detection is also accomplished in serum-containing buffers by taking advantage of the high brightness of this fluorophore and the inherently low endogenous background in the near-infrared spectral region. Cluster stability in this biological environment is enhanced by supplementing the solutions with Ag(+).


Assessment of the common carotid artery wall stiffness by Shear Wave Elastography in Behcet's disease.
To evaluate endothelial dysfunction and subclinical atherosclerosis in Behcet's disease (BD) by measuring the common carotid artery (CCA) wall stiffness and carotid intima-media thickness (CIMT). We prospectively evaluated CIMT and the CCA wall stiffness of 34 BD patients and 28 age/sex-matched controls. CIMT measurements were performed from the posterior wall of the carotid artery approximately 10 mm proximal to the initiation of the carotid bulb using B-mode ultrasound. The stiffness of the CCA was measured from the superficial wall of the CCA using shear wave elastography (SWE). SWE measurements were recorded as shear wave velocity (SWV) using m/s as a unit. The mean right (0.5±0.11 mm) and left (0.5±0.14 mm) CIMT of the patients were significantly higher compared to the mean right (0.41±0.07 mm) and left (0.41±0.11 mm) CIMT of the healthy controls (p=0.001 and p= 0.003 respectively). The mean right (3.72±0.94 m/s) and left (3.57±0.72 m/s) CCA wall stiffness of the patients were significantly higher compared to the mean right (2.42±0.49 m/s) and left (2.56±0.49 m/s) CCA wall stiffness of the controls (p<0.001 for both). SWE seems to be a promising modality to evaluate endothelial dysfunction in BD by interpreting the arterial stiffness, and SWE might be an important adjunct to clinical and laboratory findings, and imaging modalities to assess cardiovascular risk in BD. Moreover, SWE evaluation of the arterial stiffness might assist us to understand pathophysiological aspects of BD.


A density functional theory study of catalytic sites for oxygen reduction in Fe/N/C catalysts used in H₂/O₂ fuel cells.
The oxygen reduction catalytic activity of carbon-supported FeN4 moieties bridging micropores between two graphene sheets was investigated by density functional theory (DFT). Based on the FeN(2+2)/C structure proposed earlier by our group, two types of FeN(2+2)/C structures were considered: one mostly planar and one in which the Fe ion is significantly displaced out of the graphitic plane. A structure in which the FeN4 moiety is embedded in an extended graphene sheet (FeN/C) was also considered. In addition, we have investigated the influence of an axial pyridine group approaching the Fe centre. The formation energy is lowest for the planar FeN(2+2)/C structure. The overall downhill behaviour of the relative free energy vs. the reaction step suggests that most structures have catalytic activity near zero potential. This conclusion is further supported by calculations of the binding energies of adsorbed O2 and H2O and of the O-O bond lengths of adsorbed O2 and OOH. The side-on interaction of adsorbed O2 is preferred over the end-on interaction for the three basic structures without the axial pyridine. The pyridine coordination produces a stronger binding of O2 for the planar FeN(2+2)/C and the FeN/C structures as well as a dominant end-on interaction of O2. The energy levels of the planar FeN(2+2)/C structure with and without the pyridine ligand are nearly equal for iron spin states S = 1 and S = 2, suggesting that both configurations are formed with similar concentration during the preparation process, as also previously found for two of the iron sites by Mössbauer spectroscopy experiments.


Secondary nonresponsiveness to botulinum toxin A in cervical dystonia: the role of electromyogram-guided injections, botulinum toxin A antibody assay, and the extensor digitorum brevis test.
We studied 20 patients with cervical dystonia who had started to respond poorly to botulinum toxin A (BTXA) injections after an initial good response. All patients had extensor digitorum brevis (EDB) tests performed in addition to BTXA immunoprecipition assay (IPA) and mouse bioassay (MBA) antibody testing. The patients were reexamined and then treated with carefully placed electromyogram (EMG)-guided BTXA. Nine patients had a good clinical response to EMG-guided injections and all of these patients showed an obvious decrement on the EDB test. All were BTXA blocking antibodies (Abs)-negative via IPA and MBA (apart from one patient who had low BTXA antibodies titers using IPA but no antibodies by MBA). In the other 11 patients, there was a poor clinical response to EMG-guided BTXA injections. Seven of these 11 had small EDB decrement and BTXA antibodies using IPA, suggesting resistance to BTXA. Of the remaining four patients, two had obvious EDB decrement and low antibody titers via IPA (one of them had no antibodies via MBA), while the other two patients showed obvious decrement on the EDB test and no antibodies via IPA. This study shows that the EDB test correlates better with the clinical response than the antibody assays and that EDB decrement does not always correlate quantitatively with the BTXA antibody titers. In patients with secondary nonresponsiveness, it is recommended that an EDB test is the initial investigation of choice. In those patients where the EDB test does not demonstrate resistance to BTXA, a reexamination of the patients and carefully placed injections under EMG guidance may improve results.


Knowledge and Parity: Perspectives of Usage of Emergency Contraceptive Pills among Women of a Rural Area of Delhi.
Correct use of emergency contraceptive pills (ECPs) may prevent up to 95% of unwanted pregnancies which may significantly decrease unsafe abortions and maternal mortality. Assessment of knowledge and use of ECPs among women and to explore factors associated with them. This was a facility-based cross-sectional study. Data were collected using a prestructured, pretested questionnaire from 381 reproductive age women (15-49 years) selected by systematic random sampling. Statistical Package for the Social Sciences version 16 and Epi info (version 7.0.) were used for all statistical analyses. Descriptive analysis was performed, and results were expressed in terms of frequencies and percentages. The Chi-square and Fisher's exact test were used as tests of significance in univariate analysis. Determinants of use of ECPs were identified using logistic regression. Of 381 women interviewed, awareness level of ECPs (ever heard about ECPs) was found to be 34% (n = 128). Ever use of emergency contraception was reported by 38 (9.7%). Age (odds ratio [OR] = 3.02, 95% confidence interval [CI] [1.88-4.87]), education (OR = 0.086, 95% CI [0.047-0.158]), husband's education (OR = 0.11, 95% CI [0.067-0.187]), socioeconomic status (OR = 6.14, 95% CI [3.28-11.51]), and family status (OR = 2.6, 95% CI [1.59-4.24]) were found to be significantly associated with the use of emergency contraceptives. The study identified that most respondents lack adequate knowledge about ECPs, and ever use of ECPs was very low. Factors that were associated with the use of ECPs were age, literacy, socioeconomic status, and knowledge about the method. Creating a sustainable awareness on ECPs and their use may serve them with power to control their parity.


Release of slow-reacting substance of anaphylaxis from dispersed pig lung cells: effect of cyclo-oxygenase and lipoxygenase inhibitors.
Study of the release of slow-reacting substance of anaphylaxis (SRS-A) from lung cells has been hampered by the lack of suitable animal model. Using both immunologic and pharmacologic stimuli, we have obtained histamine and SRS-A release from dispersed pig lung cells containing 6% mast cells (with a histamine content of 1.9 pg/cell). Lung cells dispersed from actively sensitized (with intratracheal Ascaris antigen) but not unsensitized pigs released both histamine (mean net release 33%) and SRS-A (mean release, 47 units/10(7) cells) when challenged with Ascaris antigen. Greater release of histamine (mean net release 52%) and of slow-reacting substance (SRS) (mean release 701 units/10(7) cells) was induced by challenge with the calcium ionophore A23187. The pharmacologic and physicochemical characteristics of the SRS together with its profile of enzymatic inactivation resembled those described for SRA-A released from human lung. Both antigen-induced and A23187-induced SRS(-A) release were enhanced by indomethacin, a cyclo-oxygenase inhibitor, but inhibited by both phenidone (IC50 35 microM) and eicosatetraenoic acid (IC50 15 microM), inhibitors of both cyclo-oxygenase and lipoxygenase, confirming that generation of SRS(-A) by either stimulus required an intact lipoxygenase pathway of arachidonic acid metabolism.


Phylogenetic origins of antibody structure. 3. Antibodies in the primary immune response of the sea lamprey, Petromyzon marinus.
The sea lamprey, Petromyzon marinus, has been found to produce specific antibodies after immunization with bacteriophage f2. Antibody activity is localized in 6.6S and 14S fractions of lamprey serum. The 6.6S antibodies were purified by a combination of zone electrophoresis, ion exchange chromatography, and gel filtration. Antigenic analysis of the 6.6S antibodies showed them to be free of other serum proteins and antigenically similar or identical to the 14S fraction. Evidence has been obtained which suggests that the 6.6S immunoglobulins consist of light components (molecular weight 25,000) and heavy components (molecular weight 70,000). In the immunoglobulin, these polypeptides appear to be linked via weak interactions but not by interchain disulfide bonds. Molecular weight analyses support the view that the chains can undergo concentration-dependent dissociation in aqueous solutions. Amino acid analyses showed that the compositions of the light and heavy components were similar and that aspartic acid or asparagine was the predominant amino terminal residue. Starch gel electrophoresis indicated that the subunits of lamprey antibodies are diffusely heterogeneous. The heavy chain mobility corresponded to that of micro-chains and resembled that of heavy chains of shark and sting ray immunoglobulins. In the course of the fractionation a 46S natural hemagglutinin composed of lower molecular weight subunits was isolated. This hemagglutinin did not resemble the lamprey immunoglobulin although it had a similar zone electrophoretic mobility in the beta-region. These studies are consistent with the hypothesis that micro-chains were the earliest of the heavy chain classes to emerge and further support the view that the multichain structure of immunoglobulins is a fundamental feature of antibody molecules.


CMUT Electrode Resistance Design: Modelling and Experimental Verification by a Row-Column Array.
This paper addresses the importance of having control over the resistivity of the electrodes for capacitive micromachined ultrasonic transducers (CMUT) devices. The electrode resistivity can vary depending on the fabrication technology used, and resistivity control becomes especially important in the cases where metal electrodes can not be used. This raises the question: When is the resistivity of an electrode sufficiently low? To answer this question we have developed a simple design criterion. The criterion describes the attenuation of AC signals along a CMUT element. It is shown that the non-dimensional product between angular excitation frequency, resistance, and capacitance ωRC of an element has to be smaller than 0.35 to ensure an AC potential drop along the element of less than 1%. The optimal magnitude and directionality of the transmit pressure will be achieved if CMUT elements are designed according to the developed criteria. Hence, the model can be used to estimate device parameters that will ensure the CMUT is suitable for generating ultrasound images. An example is given where the model is used to predict the required electrode thickness for structured electrodes made of Gold, Aluminium, and Indium-Tin-Oxide, respectively. To verify the model, two Row-Column addressed (RCA) CMUT transducers were used to illustrate the effect of high and low electrode resistivity. One transducer had a sufficient electrode resistivity, and the other had an insufficient electrode resistivity. The RCA CMUT transducers were fabricated using fusion bonding, where the top electrode is made of aluminium and the bottom electrode is made of doped silicon. The resistivity of the aluminium top electrode is 2×10-6 Ωcm for both transducers, whereas the resistivity for the bottom electrode is 0.1 Ωcm for the first transducer and 0.005 Ωcm for the second transducer. The transducer with low resistivity emits pressure uniformly along both the rows and columns, whereas the transmit pressure field from the other transducer has a uniformly distributed pressure field along the rows, but a decreasing pressure field along the columns due to the high resistivity in the bottom electrode. The pressure drop, along the columns is frequency dependent and has been observed to be 63%, 74%, and 82% for the excitation frequencies 2 MHz, 4.5 MHz, and 7 MHz, respectively.


TDP-1/TDP-43 regulates stress signaling and age-dependent proteotoxicity in Caenorhabditis elegans.
TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS-associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16-dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan.


Credentialing and Privileging of Acute Care Nurse Practitioners to Do Invasive Procedures: A Statewide Survey.
Acute care nurse practitioners have been successfully integrated into inpatient settings. They perform invasive procedures in the intensive care unit and other acute care settings. Although their general scope of practice is regulated at the state level, local and regional scope of practice is governed by hospitals. To determine if credentialing and privileging of these nurses for invasive procedures varies depending on the institution. Personnel in medical staff offices of 329 hospitals were surveyed by telephone with 6 questions. Data collected included acute care nurse practitioner and hospital demographics, frequency and type of procedures performed, proctoring and credentialing process, and the presence of residents and fellows at the institution. The response rate was 74.8% (246 hospitals). Among these, 48% (118) employed acute care nurse practitioners, of which 43.2% performed invasive procedures. Three hospitals were excluded from the final analysis. Of the hospitals that credentialed and granted privileges to the nurse practitioners for invasive procedures, 60.4% were teaching hospitals. A supervising physician was the proctor in 94% of the nonteaching hospitals and 100% of the teaching hospitals. The most common number of cases proctored was 4 to 7. The majority of hospitals employ acute care nurse practitioners. The most common method of privileging for invasive procedures is proctoring by a supervising physician. However, the amount of proctoring required before privileges and independent practice are granted varies by procedure and institution.


Osteoporosis and health-related quality-of-life outcomes in the Alameda County Study population.
The objective of this study was to identify physical and mental outcomes of osteoporosis that affect quality of life in women. Data were from the Alameda County Study, a longitudinal study of health and mortality that since 1965 has followed a cohort of 6,928 American persons aged 16 to 94 years at baseline. Subjects for this analysis were women who survived until at least 1994 (N = 1,171). The variables analyzed as possible outcomes of osteoporosis included measures of physical health, quality of life, and mental health. Sequential logistic regression models were run, and associations were presented as odds ratios. After controlling for age, ethnicity, education, financial strain, and physical activity, subjects with osteoporosis in 1994 were more likely to report the following outcomes in 1999: frailty, difficulty with balance, weakness, problems with activities of daily living, fair/poor perceived health, never going out for entertainment, and not enjoying free time much. When controlling for chronic medical conditions, the odds ratios were reduced, but remained significant for difficulty with balance and weakness (odds ratio = 2.48) and problems with activities of daily living (odds ratio = 2.80). From this study, it appears that people with osteoporosis are at higher risk of developing problems with physical frailty and difficulties with activities of daily living, and may be at risk for reduced quality of life in terms of going out for entertainment and enjoying free time. Therefore, care should be taken to maintain the quality of life for people with osteoporosis by helping them to keep as physically functional as possible.


Development of a Murine Model with Optimal Routes for Bacterial Infection and Treatment, as Determined with Bioluminescent Imaging in C57BL/6 Mice.
Mice intragastrically infected with Listeria monocytogenes EGDe and Staphylococcus aureus Xen 36 showed no visible signs of infection over 48 h. However, high numbers (6.2 × 10(5) cfu/mg feces) of S. aureus Xen 36 were detected 4 h, and 3.3 × 10(5) cfu/mg feces of L. monocytogenes EGDe 8 h, after administration. Mice intraperitoneally infected with S. aureus Xen 36 (1 × 10(7) cfu) developed infection immediately after administration and for at least the following 48 h. Injection with higher cell numbers of S. aureus Xen 36 (2 × 10(8) cfu) resulted in more intense bioluminescence (infection) of the peritoneal cavity. Injection of S. aureus Xen 36 in the tail and penile veins resulted in localized tissue infection for the first 120 h. Injection of S. aureus Xen 36 into the thigh produced a faint bioluminescent signal for 15 min. Nisin F injected into the peritoneal cavity at the same area of infection led to an immediate statistically significant decrease in infection (from 2 × 10(6) p/s/cm(2)/sr to 3 × 10(5) p/s/cm(2)/sr) within 2 h. Similar results were recorded when nisin F was injected subcutaneously. Intraperitoneal administration is an optimal administration route for bacterial infection and treatment with antimicrobial peptides.


[Valve replacement in an infant with congenital mitral stenosis--report of a case which showed hemodynamics similar to that of hypoplastic left heart syndrome in neonatal period].
In the neonatal period, the patient showed severely hypoplastic left ventricle, severe mitral stenosis, patent foramen ovale and patent ductus arteriosus with right-to-left shunting, which resulted in the hemodynamics similar to that of hypoplastic left heart syndrome. However, progressive left ventricular growth was recognized after spontaneous closure of the foramen ovale, and the cardiac catheterization at the age of 6 months revealed almost normal left ventricular volume and systolic forward flow from the left ventricle to the descending aorta. The operation was performed at the age of 7 months under cardiopulmonary bypass with moderate hypothermia and cardiac arrest. The mitral leaflets were thickened and dysplastic, two short papillary muscles were hypertrophic and very closely related, and the chordae were extremely short and fused each other making the interchordal space obstructed. Because the mitral annular diameter (13 mm) was too small for conventional valve replacement, the prosthetic valve (CarboMedics #16) was sewn to the left atrial wall 5 to 10 mm above the mitral annulus. The ductus arteriosus was ligated. The postoperative cardiac catheterization showed residual pulmonary hypertension, but pulmonary vascular response to oxygen-inhalation was recognized. We consider that there were two important hemodynamic factors which led to successful biventricular repair in this case. First, early spontaneous closure of the foramen ovale accerelated the left ventricular growth and prevented right ventricular failure resulting from increased pulmonary blood flow. Second, considerable part of the systemic output was supplied through a large ductus arteriosus, and thus over-systemic pulmonary hypertension was avoided.


Patient Willingness to Have Tests to Guide Antibiotic Use for Respiratory Tract Infections: From the WWAMI Region Practice and Research Network (WPRN).
The majority of consultations for acute respiratory tract infections (RTIs) lead to prescriptions for antibiotics, which have limited clinical benefit. We explored patients' willingness to have blood tests as part of the diagnostic work-up for RTIs, and patient knowledge about antibiotics. Patients at 6 family medicine clinics were surveyed. Regression modeling was used to determine independent predictors of willingness to have venous and point-of-care (POC) blood tests, and knowledge of the value of antibiotics for RTIs. Data were collected from 737 respondents (response rate 83.8%), of whom 65.7% were women, 60.1% were white, and 25.1% were current smokers; patients' mean age was 46.9 years. Sex (female), race (white), and a preference to avoid antibiotics were independent predictors of greater level of antibiotic knowledge. A total of 63.1% were willing to have a venous draw and 79% a POC blood test, to help guide antibiotic decision-making. Non-American Indian/Alaskan Native race, current smoking, and greater knowledge of antibiotics were independent predictors of willingness to have a POC test. A large majority of patients seemed willing to have POC tests to facilitate antibiotic prescribing decisions for RTIs. Poor knowledge about antibiotics suggests better education regarding antibiotic use might influence patient attitudes towards use of antibiotics for RTIs.


Patient selection for prostate focal therapy in the era of active surveillance: an International Delphi Consensus Project.
Whole-gland extirpation or irradiation is considered the gold standard for curative oncological treatment for localized prostate cancer, but is often associated with sexual and urinary impairment that adversely affects quality of life. This has led to increased interest in developing therapies with effective cancer control but less morbidity. We aimed to provide details of physician consensus on patient selection for prostate focal therapy (FT) in the era of contemporary prostate cancer management. We undertook a four-stage Delphi consensus project among a panel of 47 international experts in prostate FT. Data on three main domains (role of biopsy/imaging, disease and patient factors) were collected in three iterative rounds of online questionnaires and feedback. Consensus was defined as agreement in ⩾80% of physicians. Finally, an in-person meeting was attended by a core group of 16 experts to review the data and formulate the consensus statement. Consensus was obtained in 16 of 18 subdomains. Multiparametric magnetic resonance imaging (mpMRI) is a standard imaging tool for patient selection for FT. In the presence of an mpMRI-suspicious lesion, histological confirmation is necessary prior to FT. In addition, systematic biopsy remains necessary to assess mpMRI-negative areas. However, adequate criteria for systematic biopsy remains indeterminate. FT can be recommended in D'Amico low-/intermediate-risk cancer including Gleason 4+3. Gleason 3+4 cancer, where localized, discrete and of favorable size represents the ideal case for FT. Tumor foci <1.5 ml on mpMRI or <20% of the prostate are suitable for FT, or up to 3 ml or 25% if localized to one hemi-gland. Gleason 3+3 at one core 1mm is acceptable in the untreated area. Preservation of sexual function is an important goal, but lack of erectile function should not exclude a patient from FT. This consensus provides a contemporary insight into expert opinion of patient selection for FT of clinically localized prostate cancer.


Hydrolysis of urea by Ureaplasma urealyticum generates a transmembrane potential with resultant ATP synthesis.
When urea is added to Ureaplasma urealyticum, it is hydrolysed internally by a cytosolic urease. Under our measuring conditions, and at an external pH of 6.0, urea hydrolysis caused an ammonia chemical potential equivalent to almost 80 mV and, simultaneously, an increase in proton electrochemical potential (delta p) of about 24 mV with resultant de novo ATP synthesis. Inhibition of the urease with the potent inhibitor flurofamide abolished both the chemical potential and the increase of delta p such that ATP synthesis was reduced to approximately 5% of normally obtained levels. Uncouplers of electrochemical gradients had little or no effect on these systems. The electrochemical parameters and ATP synthesis were measured similarly at three other external pH values. Any change in delta p was primarily via membrane potential (delta psi), and the level of de novo ATP synthesis was related to the increase in delta p generated upon addition of urea and more closely to the ammonia chemical potential. Although the organisms lack an effective mechanism for internal pH homeostasis, they maintained a constant delta pH. The data reported are consistent with, and give evidence for, the direct involvement of a chemiosmotic mechanism in the generation of around 95% of the ATP by this organism. Furthermore, the data suggest that the ATP-generating system is coupled to urea hydrolysis by the cytosolic urease via an ammonia chemical potential.


Uteroplacental and fetal haemodynamics and cardiac function of the fetus and newborn after crystalloid and colloid preloading for extradural caesarean section anaesthesia.
We have studied the effects of randomized preloading with either a crystalloid (lactated Ringer's) 15 ml kg-1 or colloid (hydroxyethyl starch) 7.5 ml kg-1 solution in 20 parturients undergoing elective Caesarean section under extradural anaesthesia, on blood flow in maternal placental and non-placental uterine and placental arcuate arteries and in fetal umbilical, renal and middle cerebral arteries, using a pulsed colour Doppler technique. Simultaneously, fetal and neonatal myocardial function were investigated by pulsed Doppler and M-mode echocardiography. We found no changes in maternal or fetal blood velocity waveform indices after crystalloid preloading, but the pulsatility index of the maternal non-placental uterine artery increased significantly after colloid preloading. Fetal heart rate decreased after preloading with crystalloid solution. There were no differences in fetal or neonatal myocardial function between the groups, and the outcome of the newborn infants were uneventful in all cases. These results suggest that preloading with either a crystalloid or colloid solution may lead to different uterine and fetal haemodynamics but these solutions had only minimal effects on fetal and neonatal myocardial performance and no effect on the clinical condition of newborns in uncomplicated pregnancies.


Analysis of HIV using a high resolution melting (HRM) diversity assay: automation of HRM data analysis enhances the utility of the assay for analysis of HIV incidence.
HIV diversity may be a useful biomarker for discriminating between recent and non-recent HIV infection. The high resolution melting (HRM) diversity assay was developed to quantify HIV diversity in viral populations without sequencing. In this assay, HIV diversity is expressed as a single numeric HRM score that represents the width of a melting peak. HRM scores are highly associated with diversity measures obtained with next generation sequencing. In this report, a software package, the HRM Diversity Assay Analysis Tool (DivMelt), was developed to automate calculation of HRM scores from melting curve data. DivMelt uses computational algorithms to calculate HRM scores by identifying the start (T1) and end (T2) melting temperatures for a DNA sample and subtracting them (T2 - T1 = HRM score). DivMelt contains many user-supplied analysis parameters to allow analyses to be tailored to different contexts. DivMelt analysis options were optimized to discriminate between recent and non-recent HIV infection and to maximize HRM score reproducibility. HRM scores calculated using DivMelt were compared to HRM scores obtained using a manual method that is based on visual inspection of DNA melting curves. HRM scores generated with DivMelt agreed with manually generated HRM scores obtained from the same DNA melting data. Optimal parameters for discriminating between recent and non-recent HIV infection were identified. DivMelt provided greater discrimination between recent and non-recent HIV infection than the manual method. DivMelt provides a rapid, accurate method of determining HRM scores from melting curve data, facilitating use of the HRM diversity assay for large-scale studies.


Characterizing VIP Neurons in the Barrel Cortex of VIPcre/tdTomato Mice Reveals Layer-Specific Differences.
Neocortical GABAergic interneurons have a profound impact on cortical circuitry and its information processing capacity. Distinct subgroups of inhibitory interneurons can be distinguished by molecular markers, such as parvalbumin, somatostatin, and vasoactive intestinal polypeptide (VIP). Among these, VIP-expressing interneurons sparked a substantial interest since these neurons seem to operate disinhibitory circuit motifs found in all major neocortical areas. Several of these recent studies used transgenic Vip-ires-cre mice to specifically target the population of VIP-expressing interneurons. This makes it necessary to elucidate in detail the sensitivity and specificity of Cre expression for VIP neurons in these animals. Thus, we quantitatively compared endogenous tdTomato with Vip fluorescence in situ hybridization and αVIP immunohistochemistry in the barrel cortex of VIPcre/tdTomato mice in a layer-specific manner. We show that VIPcre/tdTomato mice are highly sensitive and specific for the entire population of VIP-expressing neurons. In the barrel cortex, approximately 13% of all GABAergic neurons are VIP expressing. Most VIP neurons are found in layer II/III (∼60%), whereas approximately 40% are found in the other layers of the barrel cortex. Layer II/III VIP neurons are significantly different from VIP neurons in layers IV-VI in several morphological and membrane properties, which suggest layer-dependent differences in functionality.


Premedication with gabapentin, alprazolam or a placebo for abdominal hysterectomy: Effect on pre-operative anxiety, post-operative pain and morphine consumption.
Utility of gabapentin for pre-operative anxiolysis as compared to commonly administered alprazolam is not evident. The aim of the present study was to compare the effects of pre-operative oral gabapentin 600 mg, alprazolam 0.5 mg or a placebo on pre-operative anxiety along with post-operative pain and morphine consumption. Seventy five patients scheduled for abdominal hysterectomy under general anaesthesia were included. Groups gabapentin, alprazolam and placebo, received oral gabapentin 600 mg, alprazolam 0.5 mg and one capsule of oral B-complex forte with Vitamin C respectively, on the night prior to surgery and 2 h prior to surgery. Visual analogue scale (VAS) was used to measure the anxiety and post-operative pain. All patients received patient-controlled analgesia. Statistical tests used were Kruskal-Wallis test, Wilcoxon signed rank test and one-way ANOVA. Alprazolam provided significant anxiolysis (median [interquartile range] baseline VAS score 35 [15.5, 52] to 20 [6.5, 34.5] after drug administration; P = 0.007). Gabapentin did not provide significant decrease in anxiety (median [interquartile range] VAS score 21 [7.5, 41] to 20 [6.5, 34.5]; P = 0.782). First analgesic request time (median [interquartile range in minutes]) was longer in group gabapentin (17.5 [10, 41.25]) compared to group placebo (10 [5, 15]) (P = 0.019) but comparable to that in group alprazolam (15 [10, 30]). Cumulative morphine consumption at different time periods and total morphine consumption (mean [standard deviation]) at the end of study period (38.65 [18.04], 39.91 [15.73], 44.29 [16.02] mg in group gabapentin, alprazolam and placebo respectively) were comparable. Gabapentin 600 mg does not have significant anxiolytic effect compared to alprazolam 0.5 mg. Alprazolam 0.5 mg was found to be an effective anxiolytic in the pre-operative period. Neither alprazolam nor gabapentin, when compared to placebo showed any opioid sparing effects post-operatively.


Towards efficient and stable perovskite solar cells employing non-hygroscopic F4-TCNQ doped TFB as the hole-transporting material.
Designing an efficient and stable hole transport layer (HTL) material is one of the essential ways to improve the performance of organic-inorganic perovskite solar cells (PSCs). Herein, for the first time, an efficient model of a hole transport material (HTM) is demonstrated by optimized doping of a conjugated polymer TFB (poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-(4,4'-(N-(4-sec-butylphenyl)diphenylamine)]) with a non-hygroscopic p-type dopant F4-TCNQ (2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane) for high-efficiency PSCs. The PSC with the F4-TCNQ doped TFB exhibits the best power conversion efficiency (PCE) of 17.46%, which surpasses that of the reference devices, i.e., 16.64 (LiTFSI + TBP-doped Spiro-OMeTAD as the HTM) and 11.01% (LiTFSI + TBP-doped TFB as the HTM). F4-TCNQ doped TFB was believed to favor efficient charge and energy transfer between the perovskite and the hole transport layer and to reduce charge recombination as evidenced by steady-state photoluminescence (PL) and time-resolved photoluminescence (TRPL) analysis. Moreover, the hydrophobic nature of F4-TCNQ contributed to enhancing the stability of the device under ambient conditions with a RH of 45%. The device reported herein retained ca. 80% of its initial efficiency after 10 days, significantly superior to both LiTFSI + TBP-doped Spiro-OMeTAD (ca. 30%) and LiTFSI + TBP-doped TFB (ca. 10%) based counterparts. This simple yet novel strategy paves the way for demonstrating a promising route for a wide range of highly efficient solar cells and other photovoltaic applications.


Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder that typically exhibits autosomal dominant inheritance. Genomic strategies enable discovery of novel, unsuspected molecular underpinnings of familial DCM. We performed genome-wide mapping and exome sequencing in a unique family wherein DCM segregated as an autosomal recessive (AR) trait. Echocardiography in 17 adult descendants of first cousins revealed DCM in 2 female siblings and idiopathic left ventricular enlargement in their brother. Genotyping and linkage analysis mapped an AR DCM locus to chromosome arm 7q21, which was validated and refined by high-density homozygosity mapping. Exome sequencing of the affected sisters was then used as a complementary strategy for mutation discovery. An iterative bioinformatics process was used to filter >40,000 genetic variants, revealing a single shared homozygous missense mutation localized to the 7q21 critical region. The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched controls, altered a conserved residue of GATAD1, encoding GATA zinc finger domain-containing protein 1. Thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages. Immunohistochemistry demonstrated nuclear localization of GATAD1 in left ventricular myocytes, yet subcellular expression and nuclear morphology were aberrant in the proband. Linkage analysis and exome sequencing were used as synergistic genomic strategies to identify GATAD1 as a gene for AR DCM. GATAD1 binds to a histone modification site that regulates gene expression. Consistent with murine DCM caused by genetic disruption of histone deacetylases, the data implicate an inherited basis for epigenetic dysregulation in human heart failure.


Heterozygous fragile X female: historical, physical, cognitive, and cytogenetic features.
Historical, physical, cognitive, and cytogenetic data were documented in 105 heterozygous fragile X [fra(X)] females and 90 controls in a prospective fashion. For comparisons, we divided heterozygotes and controls into those with cognitive impairment (IQ less than 85) and normal IQ (IQ greater than or equal to 85). The only finding that was significantly more frequent in impaired heterozygotes compared with impaired controls chi 2 analysis was shyness. Features that were more frequent in normal IQ heterozygotes compared with normal controls were voluntary thumb dislocation and hyperextensible metacarpal-phalangeal (MP) joints. Comparisons among heterozygotes demonstrated more math problems, hand biting, strabismus, high-arched palate, hyperextensible finger joints, and flat feet in impaired heterozygotes than in normal heterozygotes. Premature menopause was present in 8 of 61 normal heterozygotes and in none of the impaired heterozygotes. A multiple regression analysis demonstrated a significant inverse correlation between the percent fragility and IQ for the heterozygotes as a group. However, no correlation existed between IQ and fragility when the percent fragility was 2% or greater. However, a higher percentage of fragility was positively correlated with the total number of physical findings present.


Lower Extremity and Trunk Electromyographic Muscle Activity During Performance of the Y-Balance Test on Stable and Unstable Surfaces.
The Star Excursion Balance Test (SEBT) has been used as a rehabilitation exercise. To improve its efficacy, efficiency, and method variations, the Y-Balance Test (YBT) with anterior (A), posterolateral (PL), and posteromedial (PM) directions of the SEBT has been recommended. Electromyographic activity has been reported to change when the same task is performed on various surfaces. To compare the EMG activity of trunk and LE muscles during the performance of the YBT on stable and unstable surfaces. Cross-Sectional study. Healthy adults with no history of chronic ankle instability were recruited for the study. Surface electromyography was collected for bilateral (ipsilateral [i] and contralateral [c]) rectus abdominis (RA), external oblique (EOB), erector spinae (ES). While, gluteus maximus (GMAX), gluteus medius (GMED), medial hamstrings (MH), biceps femoris (BF), vastus medialis (VM), rectus femoris (RF), vastus lateralis (VL), anterior tibialis (AT), and medial gastrocnemius (MG) on the stance leg (ipsilateral side), during the performance of the YBT. The unstable surface was introduced using a Thera-Band stability trainer. Differences in electromyography were examined for each reach direction and muscle between the stable and unstable surfaces (p≤ 0.05). Twenty (10 male, 10 female) subjects participated (age: 27.5 ± 4.0 years, height:167 ± 1.0 cm, weight: 66.5 ± 13.0 kg, body fat: 14.1 ± 6.2%). Significantly higher muscle activity for the unstable surface (p<0.05) with moderate to large effect sizes were observed for the following muscles in the A direction: GMED, GMAX, VM, RF, and MG; PL direction: iEOB, iES, cES, GMED, BF, VM, RF, and MG; and PM direction iEOB, iES, GMED, BF, VM, and RF. Significantly higher muscle activity for the stable surface (p = 0.007) was observed in MH muscle in the A direction. No significant differences (p>0.05) between the stable and unstable surfaces were observed in iRA, cRA, cEOB, VL, and AT for any of the directions of the YBT. An increase in muscle activity was observed during YBT on unstable versus stable surfaces for some muscles. 2B.


A role for H2S in the microcirculation of newborns: the major metabolite of H2S (thiosulphate) is increased in preterm infants.
Excessive vasodilatation during the perinatal period is associated with cardiorespiratory instability in preterm neonates. Little evidence of the mechanisms controlling microvascular tone during circulatory transition exists. We hypothesised that hydrogen sulphide (H2S), an important regulator of microvascular reactivity and central cardiac function in adults and animal models, may contribute to the vasodilatation observed in preterm newborns. Term and preterm neonates (24-43 weeks gestational age) were studied. Peripheral microvascular blood flow was assessed by laser Doppler. Thiosulphate, a urinary metabolite of H2S, was determined by high performance liquid chromatography as a measure of 24 hr total body H2S turnover for the first 3 days of postnatal life. H2S turnover was greatest in very preterm infants and decreased with increasing gestational age (p = 0.0001). H2S turnover was stable across the first 72 hrs of life in older neonates. In very preterm neonates, H2S turnover increased significantly from day 1 to 3 (p =0.0001); and males had higher H2S turnover than females (p = 0.04). A significant relationship between microvascular blood flow and H2S turnover was observed on day 2 of postnatal life (p = 0.0004). H2S may play a role in maintaining microvascular tone in the perinatal period. Neonates at the greatest risk of microvascular dysfunction characterised by inappropriate peripheral vasodilatation--very preterm male neonates--are also the neonates with highest levels of total body H2S turnover suggesting that overproduction of this gasotransmitter may contribute to microvascular dysfunction in preterms. Potentially, H2S is a target to selectively control microvascular tone in the circulation of newborns.


Adapting evidence-informed complex population health interventions for new contexts: a systematic review of guidance.
Adapting interventions that have worked elsewhere can save resources associated with developing new interventions for each specific context. While a developing body of evidence shows benefits of adapted interventions compared with interventions transported without adaptation, there are also examples of interventions which have been extensively adapted, yet have not worked in the new context. Decisions on when, to what extent, and how to adapt interventions therefore are not straightforward, particularly when conceptualising intervention effects as contingent upon contextual interactions in complex systems. No guidance currently addresses these questions comprehensively. To inform development of an overarching guidance on adaptation of complex population health interventions, this systematic review synthesises the content of the existing guidance papers. We searched for papers published between January 2000 and October 2018 in 7 bibliographic databases. We used citation tracking and contacted authors and experts to locate further papers. We double screened all the identified records. We extracted data into the following categories: descriptive information, key concepts and definitions, rationale for adaptation, aspects of adaptation, process of adaptation, evaluating and reporting adapted interventions. Data extraction was conducted independently by two reviewers, and retrieved data were synthesised thematically within pre-specified and emergent categories. We retrieved 6694 unique records. Thirty-eight papers were included in the review representing 35 sources of guidance. Most papers were developed in the USA in the context of implementing evidence-informed interventions among different population groups within the country, such as minority populations. We found much agreement on how the papers defined key concepts, aims, and procedures of adaptation, including involvement of key stakeholders, but also identified gaps in scope, conceptualisation, and operationalisation in several categories. Our review found limitations that should be addressed in future guidance on adaptation. Specifically, future guidance needs to be reflective of adaptations in the context of transferring interventions across countries, including macro- (e.g. national-) level interventions, better theorise the role of intervention mechanisms and contextual interactions in the replicability of effects and accordingly conceptualise key concepts, such as fidelity to intervention functions, and finally, suggest evidence-informed strategies for adaptation re-evaluation and reporting. PROSPERO 2018, CRD42018112714.


Who should be estimating a patient's weight in the emergency department?
Medical personnel often need to estimate a patient's weight rapidly and accurately to administer pharmacologic agents whose dosages are based on weight. Inaccurate estimates of weight may result in administration of either subtherapeutic or, in other cases, toxic doses of medications. The hypothesis of this study was that the patient is a more accurate estimator of his or her own weight than the physician or nurse caring for him or her. This was a prospective study in which adult patients presenting to an urban emergency department (ED) were examined for study eligibility. Patients unable to stand were excluded. The patient, physician, and nurse caring for the patients were independently asked to estimate the patients' weights. The patients were then weighed. A convenience sample of 458 patients were enrolled during a four-week period. The median measured (actual) weight was 172.5 lb. The best estimate of a patient's weight was made by the patient himself or herself: the median difference between patient estimates and actual weights was 0 lb (interquartile range [IQR] = -5 to 5). The physicians and nurses had larger underestimates: -5 lb (IQR = -22 to 12) and -6 lb (IQR = -22 to 10), respectively. Weight was estimated within 10% of actual weight by 90.6% of the patients, 50.4% of the physicians, and 49.6% of the nurses. When a patient is unable to be weighed, the patient's own weight estimate should be used. If neither is possible, the physician or nurse should estimate the patient's weight.


Group education for rheumatoid arthritis patients.
This article reviews the effectiveness of group education programs in improving the knowledge, behavior, and health status of patients with rheumatoid arthritis (RA) and evaluates to what extent various programs fulfill certain criteria for educational self-management programs. Thirty-one studies are reviewed: in 12, patients with various rheumatic diseases including RA were included, and in 19, only RA patients were studied. Group education increased the knowledge of the participants, which was maintained over long intervals. Beneficial behavioral effects were found in mixed populations but less often found in RA patients. Group education often improved physical health status both in mixed and in RA populations, but seldom led to improved psychosocial health status. In general, the beneficial effects of group education were found more often in mixed populations than in strictly RA patients. Further investigations must examine which mechanisms make educational interventions effective and determine the types of interventions or combinations of interventions that are effective. Effects of group education on health status are almost never maintained over long intervals. More research is needed to develop strategies for maintaining and enhancing early gains from group education.


Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease.
Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD.We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers.In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI.We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities.


Bim mediates mitochondria-regulated particulate matter-induced apoptosis in alveolar epithelial cells.
We studied the role of Bim, a pro-apoptotic BCL-2 family member in Airborne particulate matter (PM 2.5 microm)-induced apoptosis in alveolar epithelial cells (AEC). PM induced AEC apoptosis by causing significant reduction of mitochondrial membrane potential and increase in caspase-9, caspase-3 and PARP-1 activation. PM upregulated pro-apoptotic protein Bim and enhanced translocation of Bim to the mitochondria. ShRNABim blocked PM-induced apoptosis by preventing activation of the mitochondrial death pathway suggesting a role of Bim in the regulation of mitochondrial pathway in AEC. Accordingly, we provide the evidence that Bim mediates PM-induced apoptosis via mitochondrial pathway.


In vitro and in vivo characterization of the antimalarial lead compound SSJ-183 in Plasmodium models.
The objective of this work was to characterize the in vitro (Plasmodium falciparum) and in vivo (Plasmodium berghei) activity profile of the recently discovered lead compound SSJ-183. The molecule showed in vitro a fast and strong inhibitory effect on growth of all P. falciparum blood stages, with a tendency to a more pronounced stage-specific action on ring forms at low concentrations. Furthermore, the compound appeared to be equally efficacious on drug-resistant and drug-sensitive parasite strains. In vivo, SSJ-183 showed a rapid onset of action, comparable to that seen for the antimalarial drug artesunate. SSJ-183 exhibited a half-life of about 10 hours and no significant differences in absorption or exposure between noninfected and infected mice. SSJ-183 appears to be a promising new lead compound with an attractive antimalarial profile.


Caregiver perception of apathy in persons with mild cognitive impairment or Alzheimer's disease: a longitudinal study.
Discrepancy between self- and caregiver apathy ratings was examined longitudinally for persons with mild cognitive impairment or Alzheimer's disease. Particular focus was on the distinction between the positive and negative caregiver bias and its predictive value for a clinical diagnosis of apathy. Apathy rating discrepancy was based on the apathy evaluation scale. Dyads were categorized depending on whether the caregiver reported fewer deficits (positive caregiver bias) or more deficits (negative caregiver bias) than the cognitively impaired person did. Caregiver ratings and rating discrepancy showed a significant increase from baseline to follow-up. By contrast, self- and clinician ratings showed no change across the two time points. Ratings with a negative caregiver bias remained stable, while those with a positive caregiver bias showed a significant increase in the caregiver ratings but also a significant decrease in the self-ratings. A negative caregiver bias at baseline was significantly related to greater likelihood of having clinical apathy at follow-up, adjusted for an array of control variables. Positive and negative caregiver bias should be distinguished, as they seem to reflect distinct dyadic processes and are relevant for clinical outcome. Furthermore, negative rating discrepancies can be considered a risk factor for developing apathy.


Prevalence and Associated Risk Factors for Obesity During Pregnancy Over Time.
Objective: The increasing prevalence of obesity is having an impact on morbidity worldwide. Since young mature women are equally affected by the general increase in weight, the aim of the study was to evaluate the prevalence of obesity together with associated maternal risk factors, complications during pregnancy, and fetal outcomes in a local cohort for the years 2006 and 2011. Study Design: Maternal and fetal records of women who delivered at the University of Würzburg, with a 5-year interval (2006 and 2011) between investigations, were retrospectively analyzed. Descriptive statistics included prevalence of obesity, maternal weight gain, as well as several complications during pregnancy and fetal characteristics. The association between maternal or fetal complications and extent of maternal obesity was analyzed. Results: Our analysis included 2838 mothers with singleton pregnancies who delivered in 2006 (n = 1293) or 2011 (n = 1545) in our department. We found that neither pre-pregnancy body mass index (23.77 ± 4.85 vs. 24.09 ± 5.10 kg/m2, p = 0.25) nor weight gain (14.41 ± 5.77 vs. 14.78 ± 5.65 kg; p = 0.09) increased significantly over time. But the majority of all overweight (71 %) or obese (60.4 %) mothers gained more weight than generally recommended. The prevalence of gestational diabetes, gestational hypertension, and preeclampsia increased significantly and was associated with high pre-pregnancy body mass index, as was delivery by cesarean section. However, obesity was not associated with prolonged pregnancy and did not seem to negatively affect fetal outcome. Conclusion: There is a trend to increasing weight gain during pregnancy, and the majority of mothers, especially those with a high pre-pregnancy body mass index, exceeded the weight gain recommendations. Associated risk factors such as gestational diabetes, hypertension, and delivery by cesarean section are increasing.


Mortality of tuberculosis patients in Chennai, India.
We aimed to measure the mortality rate and excess general mortality as well as identify groups at high risk for mortality among a cohort of tuberculosis patients treated in Chennai Corporation clinics in south India. In this retrospective cohort study we followed up 2674 patients (1800 males and 874 females) who were registered and treated under the DOTS strategy in Chennai Corporation clinics in 2000. The follow-up period from the date of start of treatment to either the date of interview, or death was 600 days. The mortality rate among this cohort of tuberculosis patients was 60/1000 person-years. The excess general mortality expressed as standardized mortality ratio (SMR) was 6.1 (95% confidence interval (CI)=5.4-6.9). Younger patients, men, patients with Category II disease, patients who defaulted on, or failed courses of treatment, and male smokers who were alcoholics, all had higher mortality ratios when compared to the rest of the cohort. The excess mortality in this cohort was six times more than that in the general population. Young age, male sex, smear-positivity, treatment default, treatment failure and the combination of smoking and alcoholism were identified as risk factors for tuberculosis mortality. We suggest that mortality rate and excess mortality be routinely used as a monitoring tool for evaluating the efficiency of the national control programme.