Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer.
A fast, noninvasive test with high sensitivity (SN) and a negative predictive value (NPV), which is able to detect recurrences in bladder cancer (BC) patients, is needed. A newly developed urine assay, Xpert Bladder Cancer Monitor (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC. To validate Xpert characteristics in patients previously diagnosed with non-muscle-invasive BC. Voided precystoscopy urine samples were prospectively collected at 22 sites. Xpert, cytology, and UroVysion were performed. If cystoscopy was suspicious for BC, a histologic examination was performed. Additionally, technical validation was performed and specificity was determined in patients without a history or clinical evidence of BC. Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion. Of the eligible patients, 239 with a history of BC had results for all assays. The mean age was 71 yr; 190 patients were male, 53 never smoked, and 64% had previous intravesical immunotherapy (35%) or chemotherapy (29%). Forty-three cases of recurrences occurred. Xpert had overall SN of 74% (95% confidence interval [CI]: 60-85) and 83% (95% CI: 64-93) for high-grade (HG) tumors. The NPV was 93% (95% CI: 89-96) overall and 98% (95% CI: 94-99) for HG tumors. Specificity was 80% (95% CI: 73-85). Xpert SN and NPV were superior to those of cytology and UroVysion. Specificity in non-BC individuals (n=508) was 95% (95% CI: 93-97). Xpert has an improved NPV compared with UroVysion and cytology in patients under follow-up for BC. It represents a promising tool for excluding BC in these patients, reducing the need for cystoscopy. Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help optimize the follow-up of recurrent bladder cancer patients.


Development of a Retinopathy of Prematurity Activity Scale and Clinical Outcome Measures for Use in Clinical Trials.
To facilitate drug and device development for neonates, the International Neonatal Consortium brings together key stakeholders, including pharmaceutical companies, practitioners, regulators, funding agencies, scientists, and families, to address the need for objective, standardized clinical trial outcome measurements to fulfill regulatory requirements. Retinopathy of prematurity (ROP) is a disease that affects preterm neonates. The current International Classification of Retinopathy of Prematurity does not take into account all of the characteristics of ROP and does not adequately discriminate small changes in disease after treatment. These factors are critical for evaluating outcomes in clinical trials. There is need for an updated ROP acute disease activity and structure scale as well as end-stage structure and ophthalmologic outcome measures designed for use at different ages. The scale and measures, based on current diagnostic methods and treatments, could be used as a guideline for clinical intervention trials. The scale is intended to be validated against retrospective data and revised for use in future trials. An iterative revision process can be accomplished if new measures are added to clinical trials and evaluated at the end of each trial for prognostic value. The new measures would then be incorporated into a new version of the activity scale and the outcome measures revised. An ROP activity scale and outcome measures to obtain the most robust and discriminatory data for clinical trials are needed. The scales should be dynamic and modified as knowledge and imaging modalities improve and then validated using data from well-documented clinical trials. This approach is relevant to improving clinical trial data quality.


Complete characterization of the microRNAome in a patient with acute myeloid leukemia.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and have been implicated in the pathogenesis of cancer. In this study, we applied next generation sequencing techniques to comprehensively assess miRNA expression, identify genetic variants of miRNA genes, and screen for alterations in miRNA binding sites in a patient with acute myeloid leukemia. RNA sequencing of leukemic myeloblasts or CD34(+) cells pooled from healthy donors showed that 472 miRNAs were expressed, including 7 novel miRNAs, some of which displayed differential expression. Sequencing of all known miRNA genes revealed several novel germline polymorphisms but no acquired mutations in the leukemia genome. Analysis of the sequence of the 3'-untranslated regions (UTRs) of all coding genes identified a single somatic mutation in the 3'-UTR of TNFAIP2, a known target of the PML-RARα oncogene. This mutation resulted in translational repression of a reporter gene in a Dicer-dependent fashion. This study represents the first complete characterization of the "miRNAome" in a primary human cancer and suggests that generation of miRNA binding sites in the UTR regions of genes is another potential mechanism by which somatic mutations can affect gene expression.


Diazoxide treatment at onset preserves residual insulin secretion in adults with autoimmune diabetes.
Twenty islet cell antibody (ICA)-positive patients, aged 19-38 years, with IDDM were randomized at onset to treatment with either diazoxide, a K+ channel opener that inhibits the release of insulin, or placebo for 3 months, in addition to multiple insulin injection therapy. The patients who were given diazoxide displayed higher residual insulin secretion than the placebo group after 1 year (basal C-peptide level, 0.40 +/- 0.04 vs. 0.25 +/- 0.04 [mean +/- SE] nmol/l; P < 0.021) and at an 18-month follow-up (0.37 +/- 0.06 vs. 0.20 +/- 0.01 nmol/l, P < 0.033). Metabolic control did not differ between the two groups. During the course of the study, no differences in islet cell or GAD autoantibodies were detected between the two groups. The results of this study warrant further trials to explore the potential of inducing target cell rest in order to halt the loss of insulin-producing cells during the early course of the disease.


Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus.
Parameters of fibrinolysis, including euglobulin fibrinolytic activity, tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PA-inhibitor) activity, and plasmin-alpha 2-antiplasmin complex (PAP) were studied in 62 patients (35 women and 27 men; ages 53 +/- 16 years) with either insulin-dependent (IDDM) or noninsulin-dependent (NIDDM) diabetes mellitus. Compared to a control group of similar age (n = 57), the diabetic patients had a significantly lower mean euglobulin fibrinolytic activity (1.2 +/- 0.7 vs. 1.7 +/- 1.1 ng/ml, p less than 0.01) but significantly higher mean t-PA antigen (15.7 +/- 8.4 vs. 6.6 +/- 2.9 ng/ml, p less than 0.001) and PA-inhibitor activity (2.6 +/- 1.3 vs. 1.5 +/- 0.7 IU/ml, p less than 0.001) levels. Significant univariate correlations were observed between PA-inhibitor activity and age (r = 0.32, p less than 0.05), diastolic blood pressure (r = 0.42, p less than 0.01) and euglobulin fibrinolytic activity (r = -0.40, p less than 0.01). In multivariate analysis, only body mass index (positively) and euglobulin fibrinolytic activity (negatively) remained significantly related to PA-inhibitor activity in the total diabetic population as well as in the NIDDM group. The only parameter in the IDDM group significantly related to PA-inhibitor activity was diastolic blood pressure. These results suggest that PA-inhibitor plays a role in the regulation of fibrinolysis in diabetes patients and that factors like obesity and hypertension may be related to reduced fibrinolysis via PA-inhibitor levels.


Whole-genome sequencing reveals high complexity of copy number variation at insecticide resistance loci in malaria mosquitoes.
Polymorphisms in genetic copy number can influence gene expression, coding sequence, and zygosity, making them powerful actors in the evolutionary process. Copy number variants (CNVs) are however understudied, being more difficult to detect than single-nucleotide polymorphisms. We take advantage of the intense selective pressures on the major malaria vector Anopheles gambiae, caused by the widespread use of insecticides for malaria control, to investigate the role of CNVs in the evolution of insecticide resistance. Using the whole-genome sequencing data from 1142 samples in the An. gambiae 1000 genomes project, we identified 250 gene-containing CNVs, encompassing a total of 267 genes of which 28 were in gene families linked to metabolic insecticide resistance, representing significant enrichment of these families. The five major gene clusters for metabolic resistance all contained CNVs, with 44 different CNVs being found across these clusters and multiple CNVs frequently covering the same genes. These 44 CNVs are widespread (45% of individuals carry at least one of them) and have been spreading through positive selection, indicated by their high local frequencies and extended haplotype homozygosity. Our results demonstrate the importance of CNVs in the response to selection, highlighting the urgent need to identify the contribution of each CNV to insecticide resistance and to track their spread as the use of insecticides in malaria endemic countries intensifies and as the operational deployment of next-generation bed nets targeting metabolic resistance gathers pace. Our detailed descriptions of CNVs found across the species range provide the tools to do so.


Intravenous contrast-enhanced sonography in children and adolescents - a single center experience.
Compared to adult patients, ultrasonography in children and adolescents is much more common, due to lack of ionizing radiation, and its wide availability. With the introduction of contrast-media for use in ultrasonography, one major drawback of the method could be overcome. In Europe, SonoVue(®) is the only widely available agent, which due to improved stability makes it possible to image normal and diseased tissue perfusion and vascularization with high accuracy. Inability to hold the breath and voluntary body movement of the patient is less of an obstacle compared to color Doppler techniques and makes the method very attractive for use in children, which, depending on age, may not be very cooperative. Use of intravenous contrast-medium in minors is currently very limited for several reasons: availability, lack of recommendation in national and international guidelines, and lack of official licensing. The article will touch medical indications, technique, safety considerations, and perspective of intravenous use of contrast-media in children and adolescents, including data from a 6-year period in 37 patients. The purpose of the study was to collect data on ultrasonographic examinations, expanded by intravenous administration of the contrast agent SonoVue(®) in children and adolescents. Besides assessing diagnostic yield, data on adverse medication effects was collected. The study includes contrast-enhanced ultrasound examinations in 37 children at a single institution. Indications for the examinations were tumor lesions, infections, traumatic organ injuries, and parenchymal organ ischemia. Parents of the patients and adolescent patients were informed about the off-label use of the contrast agent. Thirty-nine examinations were performed, the average age of the patient was 11.1 years (range 1 to 17 years). All of the examinations yielded additional diagnostic value, always expanding results from B mode and color coded sonography. Overall, most examinations were done to assess the liver (n=16), followed by the kidney in 10 cases. The different etiologies were encountered in the following order: tumor (n=22), infection (n=9), trauma (n=5), ischemia (n=4). Most examinations were performed to evaluate a hepatic lesion (n=12). There was one incident recorded that fit the criteria of a possible adverse effect. In an 8-year-old girl nausea was noted, that started 15 minutes after the end of the examination and resolved spontaneously. In none of the patients medical treatment for adverse effects was necessary. Ultrasonography in children, enhanced by intravenous use of contrast medium is feasible and allows for further evaluating cystic and solid tumors, and organ perfusion. Given that proper medical equipment and correct ultrasound machine settings are used, it is a robust method without diagnostic failures. In this small-sized case series there were no severe adverse effects, however, off-label use in children needs to be addressed.


Developing key-feature problems and examinations to assess clinical decision-making skills.
This article introduces the concept of a key feature and describes its function as the cornerstone of key-feature problems, a new problem format for the written assessment of clinical decision-making skills of medical trainees and practitioners. The rationale for using this problem format and the steps in problem and examination development--including issues of scoring and standard setting--are described. A key feature is defined as a critical step in the resolution of a clinical problem, and a key-feature problem consists of a clinical case scenario followed by questions that focus on only those critical steps. The questions can be presented to require examinees either to write in their responses or to select them from a list of options. For each question, examines can be instructed to supply or select whatever number of responses is appropriate to the clinical task being tested, and answer keys can comprise one or several responses. This problem format, with its focus on only the critical steps in problem resolution, and with its flexibility in question format and scoring keys, effectively addresses the psychometric considerations of content validity and test score reliability, and accommodates the complexity and configurations of actions often required in the resolution of clinical problems.


Frequency and determinants of intracranial atherosclerotic stroke in urban Pakistan.
Intracranial atherosclerosis (ICAD) is a frequent underlying mechanism of ischemic stroke. There is little direct evidence on its frequency and determinants from regions of high prevalence. This study explores the conventional and socioeconomic risk factors of ICAD in a South Asian population. The Karachi Intracranial Stenosis Study is a case-control study of 313 cases of ischemic stroke secondary to ICAD and 331 controls enrolled from 4 major hospitals in Karachi, Pakistan. Stroke subtype was verified by a vascular neurologist using the Trial of Org 10172 in Acute Stroke Treatment classification. Relationships of conventional and socioeconomic risk factors with ICAD-related strokes are reported by calculating odds ratios (ORs) and their 95% confidence intervals (CIs). ICAD was the cause of stroke in 81.1% cases with large-artery atherosclerosis and 19.5% of all stroke events. Along with risk factors like history of hypertension (OR, 3.33; CI, 2.31-4.78), history of diabetes (OR, 2.29; CI, 1.56-3.35), use of tobacco (OR, 1.49; CI, 1.03-2.16), waist-to-hip ratio (OR, 1.58; CI, 1.04-2.41), and family history of stroke (OR, 1.89; CI, 1.21-2.95), other significant social determinants of ICAD strokes were monthly income (OR, 1.59; CI, 1.01-2.51), unemployment (OR, 2.15; CI, 1.21-3.83), and chronic stress (OR, 3.67; CI, 2.13-6.34). These social determinants were independent predictors of the risk of ICAD, in addition to those described in other world populations. ICAD accounted for one fifth of all strokes making it the most common ischemic stroke mechanism. In addition to aggressive risk factor control, data also indicated broader holistic efforts on ameliorating inequity, unemployment, and stress reduction to reduce stroke because of ICAD.


Is there enough trust for the smart city? exploring acceptance for use of mobile phone data in oslo and tallinn.
There are high hopes that a development towards smarter urban environments, backed up by various big data sources, can help solve many of the challenges facing today's large cities related to providing security, mitigating environmental damages, improving services and upscaling innovative and entrepreneurial activities. This study explores the acceptance of use of mobile phone data (MPD) in different areas, and how it is related to different types of trust. Based on a representative survey of citizens in the two smart cities, Oslo and Tallinn, four similar trust cultures are located. The acceptance of use of MPD differed significantly between the trust cultures and, as expected, was significantly stronger in groups with higher levels of trust, either generally or in terms of reliance on technologies. The acceptance of use of MPD for commercial product development was low for all groups. Findings suggest that future users of MPD need to be aware of the significant scepticism toward and rejection of the use of such data in large parts of the population. Unless visions of the smart city are grounded in the needs and wants of citizens, such plans are not likely to succeed, and negative understandings and images of a panoptic state may take stronger hold. As for now, however, there seems to be insufficient social trust to exploit this on a wider scale without creating even more scepticism and distrust.


No country for old men: street use and social diet in urban Newcastle.
Within affluent societies, people who grow up in deprived areas begin reproduction much earlier than their affluent peers, and they display a number of other behaviors adapted to an environment in which life will be short. The psychological mechanisms regulating life-history strategies may be sensitive to the age profile of the people encountered during everyday activities. We hypothesized that this age profile might differ between environments of different socioeconomic composition. We tested this hypothesis with a simple observational study comparing the estimated age distribution of people using the streets in an affluent and a socioeconomically deprived neighborhood which were closely matched in other ways. We were also able to use the UK census to compare the age profile of observed street users with the actual age profile of the community. We found that people over 60 years of age were strikingly less often observed on the street in the deprived than in the affluent neighborhood, whereas young adults were observed more often. These differences were not reflections of the different age profiles of people who lived there, but rather of differences in which residents use the streets. The way people use the streets varies with age in different ways in the affluent and the deprived neighborhoods. We argue that chronic exposure to a world where there are many visible young adults and few visible old ones may activate psychological mechanisms that produce fast life-history strategies.


Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4⁺ memory T Cells.
In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4(+) T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (TSCM) CD4(+) T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies.


Cell cycle-regulated expression of the muscle determination factor Myf5 in proliferating myoblasts.
Myf5 is the earliest-known muscle-specific factor to be expressed in vivo and its expression is associated with determination of the myoblast lineage. In C2 cells, we show by immunocytolocalization that Myf5 disappears rapidly from cells in which the differentiation program has been initiated. In proliferating myoblasts, the levels of Myf5 and MyoD detected from cell to cell are very heterogeneous. We find that some of the heterogeneity of Myf5 expression arises from a posttranscriptional regulation of Myf5 by the cell cycle. Immunoblotting of extracts from synchronized cultures reveals that Myf5 undergoes periodic fluctuations during the cell cycle and is absent from cells blocked early in mitosis by use of nocodazole. The disappearance of Myf5 from mitotic cells involves proteolytic degradation of a phosphorylated form of Myf5 specific to this phase of the cell cycle. In contrast, MyoD levels are not depleted in mitotic C2 cells. The mitotic destruction of Myf5 is the first example of a transcription factor showing cell cycle-regulated degradation. These results may be significant in view of the possible role of Myf5 in maintaining the determination of proliferating cells and in timing the onset of differentiation.


Antigen-specific interferon-gamma responses and innate cytokine balance in TB-IRIS.
Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB patients receiving antiretroviral therapy (ART). TB-IRIS could be associated with an exaggerated immune response to TB-antigens. We compared the recovery of IFNγ responses to recall and TB-antigens and explored in vitro innate cytokine production in TB-IRIS patients. In a prospective cohort study of HIV-TB co-infected patients treated for TB before ART initiation, we compared 18 patients who developed TB-IRIS with 18 non-IRIS controls matched for age, sex and CD4 count. We analyzed IFNγ ELISpot responses to CMV, influenza, TB and LPS before ART and during TB-IRIS. CMV and LPS stimulated ELISpot supernatants were subsequently evaluated for production of IL-12p70, IL-6, TNFα and IL-10 by Luminex. Before ART, all responses were similar between TB-IRIS patients and non-IRIS controls. During TB-IRIS, IFNγ responses to TB and influenza antigens were comparable between TB-IRIS patients and non-IRIS controls, but responses to CMV and LPS remained significantly lower in TB-IRIS patients. Production of innate cytokines was similar between TB-IRIS patients and non-IRIS controls. However, upon LPS stimulation, IL-6/IL-10 and TNFα/IL-10 ratios were increased in TB-IRIS patients compared to non-IRIS controls. TB-IRIS patients did not display excessive IFNγ responses to TB-antigens. In contrast, the reconstitution of CMV and LPS responses was delayed in the TB-IRIS group. For LPS, this was linked with a pro-inflammatory shift in the innate cytokine balance. These data are in support of a prominent role of the innate immune system in TB-IRIS.


[Treatment results in 588 patients with multiple trauma].
Ten to fifteen million wounded and 700,000 deaths each year, around the world, are the consequences of accidents, according to the World Health Organization. In Chile 2,269 deaths occur each year due to accidents. The successful treatment of these patients requires a schematized initial management, that is taught in the Advanced Trauma Life Support Course. To review the results of trauma treatment using this model at Hospital del Trabajador in Santiago. A retrospective review of patients with trauma treated between 1984 and 1994. The severity of trauma was classified according to the Injury Severity Score. Five hundred eighty eight patients (60 female) aged 35.4 +/- 14 years old were treated in the period. Vehicular accidents accounted for 62% of trauma. The most frequently injured corporal segments were limbs and pelvis in 79%, head and neck in 66% and thorax in 44%. There were 2.45 lesions per patient. Mortality was 8% and, among survivors, 79% had a complete recovery and were reintegrated to their usual activities. Fifteen percent of patients were severely injured. Among these, mortality was 28% and 43% of survivors had some sequel. Head injuries had a predominant role in mortality and post traumatic disabilities. These results confirm the efficacy of Advanced Trauma Life Support system in the treatment of patients with multiple trauma.


Optimized alginate-based 3D printed scaffolds as a model of patient derived breast cancer microenvironments in drug discovery.
The cancer microenvironment influences tumor progression and metastasis and is pivotal to consider when designingin vivo-like cancer models. Current preclinical testing platforms for cancer drug development are mainly limited to 2D cell culture systems that poorly mimic physiological environments and traditional, low throughput animal models. The aim of this work was to produce a tunable testing platform based on 3D printed scaffolds (3DPS) with a simple geometry that, by extracellular components and response of breast cancer reporter cells, mimics patient-derived scaffolds (PDS) of breast cancer. Here, the biocompatible polysaccharide alginate was used as base material to generate scaffolds consisting of a 3D grid containing periostin and hydroxyapatite. Breast cancer cell lines (MCF7 and MDA-MB-231) produced similar phenotypes and gene expression levels of cancer stem cell, epithelial-mesenchymal transition, differentiation and proliferation markers when cultured on 3DPS and PDS, contrasting conventional 2D cultures. Importantly, cells cultured on 3DPS and PDS showed scaffold-specific responses to cytotoxic drugs (doxorubicin and 5-fluorouracil) that were different from 2D cultured cells. In conclusion, the data presented support the use of a tunable alginate-based 3DPS as a tumor model in breast cancer drug discovery.


The intestinal musculature of Derocheilocaris typica (Crustacea, Mystacocarida)--a different and unique pattern.
An ultrastructural study of the intestine of Derocheilocaris typica revealed an organization of the midgut musculature, which is unique in the Crustacea. This species unusual anal skeletomusculature has also not been seen before. The intestinal musculature of D. typica displays different patterns in the fore-, mid-, and hindgut. Around the foregut, eight pairs of dilator muscles complement a contiguous carpet of circular muscles around the foregut. Their coordinated action serves to suck in food and pass it to the midgut. A pair of large glands, each consisting of three cells, opens into the foregut above the mouth. The midgut musculature differs from any previously described. Circular muscles give rise to thin, longitudinal protrusions and short longitudinal muscles. The distribution of all of them is irregular. Thus the short longitudinal muscles, which have a length of approximately one segment, vary from none to five within a segment. The last abdominal segment is exceptional, by having 15-20 short longitudinal muscles. The hindgut has three longitudinal muscle groups each consisting of three muscles, one dorsally and one on each side. The posterior end of the midgut and the hindgut suggests that they act together to achieve defecation. The importance of the peri-intestinal cells as part of the nutritional process is emphasized.


Enhancing patient safety: the importance of direct supervision for avoiding medication errors and near misses by undergraduate nursing students.
Medication errors have been the focus of considerable research attention in nursing; however, the extent to which nursing students might contribute to errors has not been researched. Using a grounded theory approach, in-depth semi-structured interviews were conducted with undergraduate nursing students based in a university in Queensland to explore their experiences of administering medication in the clinical setting. Almost a third of the participants reported making an actual medication error or a near miss. Where medication errors occurred, participants described not receiving direct and appropriate supervision by a registered nurse. Medication errors by nursing students have the potential to impact significantly on patient safety, quality of health care, and on nursing students' perceptions of their professional competence. Ensuring direct supervision is provided at all times must become an urgent priority for undergraduate nursing education.


Regulation of aldosterone synthesis and secretion.
Aldosterone is a steroid hormone synthesized in and secreted from the outer layer of the adrenal cortex, the zona glomerulosa. Aldosterone is responsible for regulating sodium homeostasis, thereby helping to control blood volume and blood pressure. Insufficient aldosterone secretion can lead to hypotension and circulatory shock, particularly in infancy. On the other hand, excessive aldosterone levels, or those too high for sodium status, can cause hypertension and exacerbate the effects of high blood pressure on multiple organs, contributing to renal disease, stroke, visual loss, and congestive heart failure. Aldosterone is also thought to directly induce end-organ damage, including in the kidneys and heart. Because of the significance of aldosterone to the physiology and pathophysiology of the cardiovascular system, it is important to understand the regulation of its biosynthesis and secretion from the adrenal cortex. Herein, the mechanisms regulating aldosterone production in zona glomerulosa cells are discussed, with a particular emphasis on signaling pathways involved in the secretory response to the main controllers of aldosterone production, the renin-angiotensin II system, serum potassium levels and adrenocorticotrophic hormone. The signaling pathways involved include phospholipase C-mediated phosphoinositide hydrolysis, inositol 1,4,5-trisphosphate, cytosolic calcium levels, calcium influx pathways, calcium/calmodulin-dependent protein kinases, diacylglycerol, protein kinases C and D, 12-hydroxyeicostetraenoic acid, phospholipase D, mitogen-activated protein kinase pathways, tyrosine kinases, adenylate cyclase, and cAMP-dependent protein kinase. A complete understanding of the signaling events regulating aldosterone biosynthesis may allow the identification of novel targets for therapeutic interventions in hypertension, primary aldosteronism, congestive heart failure, renal disease, and other cardiovascular disorders.


Hepatic or Cystic Artery Pseudoaneurysms Following a Laparoscopic Cholecystectomy: Literature review of aetiopathogenesis, presentation, diagnosis and management.
Pseudoaneurysms (PSAs) of the hepatic and/or cystic artery are a rare complication following a laparoscopic cholecystectomy (LC). Generally, PSA cases present with haemobilia several weeks following the procedure. Transarterial embolisation (TAE) is considered the optimal management approach. We report a 70-year-old woman who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in 2016 with massive hemoperitoneum two weeks after undergoing a LC procedure in another hospital. She was successfully managed using coil TAE. An extensive literature review revealed 101 cases of hepatic or cystic artery PSAs following a LC procedure. Haemobilia was the main presentation (85.1%) and the mean time of postoperative presentation was 36 days. The hepatic artery was involved in most cases (88.1%), followed by the cystic artery (7.9%) and a combination of both (4.0%). Most cases were managed with TAE (72.3%), with a 94.5% success rate. The overall mortality rate was 2.0%.


Dynamics of interacting Brownian particles in concentrated colloidal suspensions.
We are concerned with dynamic properties of interacting Brownian particles in concentrated colloidal suspensions. An effective diffusion coefficient measured by the modulated in phase low-coherence dynamic light scattering technique is investigated as a function of the volume fraction. The experimental results are compared with the numerical ones calculated under both the Cohen-de Schepper approximation for hydrodynamic interaction and the Percus-Yevick approximations for structural effect. It is confirmed that the Brownian motion of particles in the range of volume fraction from 0.01 to 0.2 is mainly dominated by the hydrodynamic interaction rather than the structural effect, which can be described well by the Cohen-de Schepper approximation.


Fever-like hyperthermia controls T Lymphocyte persistence by inducing degradation of cellular FLIPshort.
Fever has a major impact on immune responses by modulating survival, proliferation, and endurance of lymphocytes. Lymphocyte persistence in turn is determined by the equilibrium between death and survival-promoting factors that regulate death receptor signaling in these cells. A potential integrator of death receptor signaling is the caspase-8 inhibitor c-FLIP, the expression of which is dynamically regulated, either rapidly induced or down-regulated. In this study, we show in activated primary human T lymphocytes that hyperthermia corresponding to fever triggered down-regulation of both c-FLIP-splicing variants, c-FLIPshort (c-FLIP(S)) and c-FLIPlong, with consequent sensitization to apoptosis mediated by CD95 (Fas/APO-1). The c-FLIP down-regulation and subsequent sensitization was specific for hyperthermic stress. Additionally, we show that the hyperthermia-mediated down-regulation was due to increased ubiquitination and proteasomal degradation of c-FLIP(S), the stability of which we have shown to be regulated by its C-terminal splicing tail. Furthermore, the induced sensitivity to CD95 ligation was independent of heat shock protein 70, as thermotolerant cells, expressing substantially elevated levels of heat shock protein 70, were not rescued from the effect of hyperthermia-mediated c-FLIP down-regulation. Our findings indicate that fever significantly influences the rate of lymphocyte elimination through depletion of c-FLIP(S). Such a general regulatory mechanism for lymphocyte removal has broad ramifications for fever-mediated regulation of immune responses.


Are silicone foul-release coatings a viable and environmentally sustainable alternative to biocidal antifouling coatings in the Baltic Sea region?
To combat unwanted fouling on immersed hulls, biocidal antifouling coatings are commonly applied to vessels trafficking the Baltic Sea. Here, the efficacy, environmental sustainability and market barriers of silicone foul-release coatings (FRCs) was assessed for this region to evaluate their viability as replacements for biocidal coatings. Coated panels were exposed statically over a 1 year period at three locations in the Baltic Sea region to assess the long-term performance of a biocide-free FRC and two copper coatings. The FRC was found to perform equally well or significantly better than the copper coatings. Even though most silicone FRCs on the market are biocide-free, a review of the literature regarding toxic effects and the identity and environmental fate of leachables shows that they may not be completely environmentally benign, simply for the lack of biocides. Nonetheless, FRCs are substantially less toxic compared to biocidal antifouling coatings and their use should be promoted.


Prospective paediatric intensive care registry in Latvia: one year outcomes.
In Latvia, there is a single eight-bed paediatric intensive care unit (PICU) where all critically ill children are admitted. A recent retrospective audit of the outcomes of paediatric critical care in this unit revealed a high number of unplanned extubations and excess crude mortality. In 2017, our centre joined the UK and Ireland based Paediatric Intensive Care Audit Network (PICANet) as a pilot project to investigate the feasibility of developing a paediatric critical care registry in Latvia and in the Baltic states. Riga Stradins University Ethics Committee approved the study. Anonymized data on all patients admitted to our unit from 1 June, 2017 to 31 May 2018 were prospectively entered onto the PICANet database. A total of 774 PICU admissions were analysed; 45% of admissions were elective. The median age was 59 months (IQR: 14-149). The highest admission rate was on Wednesdays representing the flow of elective surgical patients. The median length of stay was 0.95 days (IQR: 0.79-1.98). Twenty-five percent required respiratory support. The expected number of deaths estimated using the Paediatric Index of Mortality 3 (PIM 3) 15.16; 15 patients (1.94%) died resulting in Standartized Mortality Ratio (SMR) of 0.99 (95% CI 0.57-1.60). The emergency readmission rate within 48 hours after PICU discharge was 0.9%. There were 1.8 unplanned extubations per 100 invasive ventilation days. Other paediatric intensive care audit networks reported similar adjusted mortality rates but lower rates of unplanned extubations. Thirty days after PICU discharge, 653 (84.36%) patients were alive and outside hospital, 98 (12.66%) were inpatients, six (0.78%) had died, two (0.26%) were lost to the follow-up. We observed a marked peak of infant emergency respiratory admissions in February. This project explored the possibility of prospective paediatric critical care audit in Latvia by joining an established international network. This allowed direct comparison of outcomes between the countries. Excess mortality was not observed during one-year data collection period, however a high rate of unplanned extubations was revealed. The results allowed a better planning of elective patient flow by spreading elective cases over the week to avoid "rush hours".


Heterologous expression and optimization using experimental designs allowed highly efficient production of the PHY US417 phytase in Bacillus subtilis 168.
To attempt cost-effective production of US417 phytase in Bacillus subtilis, we developed an efficient system for its large-scale production in the generally recognized as safe microorganism B. subtilis 168. Hence, the phy US417 corresponding gene was cloned in the pMSP3535 vector, and for the first time for a plasmid carrying the pAMβ1 replication origin, multimeric forms of the resulting plasmid were used to transform naturally competent B. subtilis 168 cells. Subsequently, a sequential optimization strategy based on Plackett-Burman and Box-Behnken experimental designs was applied to enhance phytase production by the recombinant Bacillus. The maximum phytase activity of 47 U ml-1 was reached in the presence of 12.5 g l-1 of yeast extract and 15 g l-1 of ammonium sulphate with shaking at 300 rpm. This is 73 fold higher than the activity produced by the native US417 strain before optimization. Characterization of the produced recombinant phytase has revealed that the enzyme exhibited improved thermostability compared to the wild type PHY US417 phytase strengthening its potential for application as feed supplement. Together, our findings strongly suggest that the strategy herein developed combining heterologous expression using a cloning vector carrying the pAMβ1 replication origin and experimental designs optimization can be generalized for recombinant proteins production in Bacillus.


Laryngeal cancer incidence and mortality in China, 2010.
To analyze the incidence and mortality of laryngeal cancer in cancer registration areas of China in 2010. Until June 1, 2013, 219 population-based cancer registries submitted data of 2010 to the National Central Cancer Registry of China covering about 207,229,403 population, and 120 cancer registries were selected after quality evaluation for this analysis. Laryngeal cancer cases were selected from the database according to International Classification of Diseases 10th Revision coded as "C32." We calculated the crude incidence and mortality rates of laryngeal cancer by sex, age, and location (urban/rural). The China population in 2000 and Segi's population were used as standardized populations for the calculation of age-standardized rates. In 2010, it was estimated that there were 20,272 new cases diagnosed as laryngeal cancer in China, including 17,703 males and 2569 females. The crude incidence rate of laryngeal cancer was 1.54/100,000 in 2010, accounting for 0.66% of overall new cancer cases. The age-standardized by China population (ASRcn) and by world population (ASRwld) were 1.18/100,000 and 1.20/100,000, respectively. Cumulative rate (0-74 years old) and truncated age-standardized rate (35-64 years old) were 0.15% and 1.98/100,000, respectively. Moreover, it was estimated that there were 11 914 cases died in laryngeal cancer in China, including 10,038 males and 1876 females. The crude mortality rate was 0.91/100,000, accounting for 0.61% of overall cancer deaths. The ASRcn and ASRwld were 0.68/100,000 and 0.69/100,000, respectively. Cumulative rate and truncated age-standardized rates were 0.08% and 0.88/100,000, respectively. Both incidence and mortality of laryngeal cancer in China were still low in 2010.


Algorithm for Fourier propagation through the near-focal region.
A standard technique for beam propagation modeling of large and complex optical systems, such as the National Ignition Facility, is the Talanov approach. We describe a modification to the Talanov algorithm that avoids its inherent inability to treat interactions in the Rayleigh region. The algorithm has been validated with analytic and numerical calculations and is demonstrated to function as expected in the case of a NIF spatial filter.


Nutritional knowledge, attitude, and practices among pregnant and lactating women living with HIV in the Manzini region of Swaziland.
The prevalence of HIV infection in Swaziland (26%) is among the highest in the world. We investigated nutritional knowledge, attitude, and practices (KAP) and the influence of sociodemographic factors on KAP among pregnant and lactating women living with HIV in the Manzini region of Swaziland. Interviews were conducted using a structured questionnaire to collect data from 324 subjects seeking healthcare from selected regional hospitals, health centres, and clinics in Manzini region. The results showed mean percentage scores of nutritional knowledge (67%), attitude (67%), and practices (51%) whereby educational level (p = 0.002), employment status (p = 0.009), income (p = 0.008), religion (p = 0.007), type of accommodation (p = 0.006), type of transport used when going for shopping (p = 0.001), and BMI (p = 0.015) were significantly associated with nutritional practices. Significant positive correlations between nutritional KAP were observed: nutritional K and A (r = 0.155, p = 0.005), nutritional K and P (r = 0.456, p = 0.001), and nutritional A and P (r = 0.230, p = 0.001). Multiple linear regression analysis indicated that type of transport used when going for shopping (p = 0.002), educational level (p = 0.001), income (p = 0.001), employment (p = 0.038), knowledge of food proportion in a plate (p = 0.000), a positive attitude towards high-fibre diet (p = 0.004), and eating a variety of foods (p = 0.006) were predictors of nutritional practices. Educational level was identified as a common predictor of nutritional knowledge, attitude, and practices, suggesting that both formal and informal education systems are potential factors influencing dietary practices among pregnant and lactating women living with HIV in Swaziland.


Ischemic infarction in 25 children with tuberculous meningitis.
Twenty-five cases (38%) of ischemic infarction occurred among 65 cases of tuberculous meningitis in patients less than 14 years of age. The male:female ratio was 1.3:1. The most frequent clinical findings were meningeal signs, fever, alteration of consciousness, cranial nerve involvement, seizures, and focal neurologic deficit. Twenty-three patients had anterior circulation infarcts, and two more had infarcts in the vertebrobasilar territories. Distribution of infarcts in the anterior circulation was shown by computed tomography in the territories of the following arteries: lenticulostriate, 10 cases unilateral and 6 bilateral; middle cerebral, 3 cases; internal carotid, 1 case; multiple areas, 3 cases. Of the 25 ischemic infarction cases, 23 (92%) had hydrocephalus, 19 (76%) basal exudates, and 2 (8%) tuberculomas. Outcome was poor since no patient with infarction recovered completely. Six died and bilateral subcortical infarcts led to a considerably higher mortality than unilateral ones, whether cortical or subcortical.


Hormonal induction of mammary tumor viruses and its implications for carcinogenesis.
The purpose of this study was to evaluate the possibility that hormones and mouse mammary tumor virus (MuMTV) are cocarcinogenic for mammary epithelium. Results of our investigations in vivo and in vitro suggest: (a) Hormones promote mammary carcinogenesis in BALB/c females whether MuMTV is germinally (BALB/c) or horizontally (BALB/cfC3H) transmitted; the rate of carcinogenesis in BALB/cfC3H females is substantially faster than it is in BALB/c, but the final mammary carcinoma incidence is approximately the same. The rate-limiting step in malignant transformation in BALB/c, which infectious MuMTV overcomes, is in premalignant transformation from normal. (b) One characteristic of horizontal MuMTV transmission in BALB/c that is not observed in germinal transmission is integration of new MuMTV sequences in mammary cell DNA. Integration is mammary cell specific and constant at 2 to 3 copies/cell from tumor to tumor. (c) MuMTV expression is changed in mammary epithelial cells during hormonal carcinogenesis. The nature of the change is qualitatively similar in both BALB/c and BALB/cfC3H. Expression of envelope glycopeptides (glycoprotein with a molecular weight of 52,000) is induced, which correlates with amplification of MuMTV RNA sequence content. Quantitative differences exist in induced levels in BALB/c and BALB/cfC3H. (d) MuMTV RNA and a glycoprotein with a molecular weight of 52,000 were not inducible with dexamethasone in normal mammary epithelial cells in culture. These structural components were induced in both premalignant (BALB/cfC3H) and malignant (BALB/c and BALB/cfC3H) cells. MuMTV RNA was induced by dexamethasone in normal cells pretreated with 5-iodo-2'-deoxyuridine. (e) Both premalignant and malignant cells have altered (vis-à-vis normal) surfaces, discernible by differences in reactivity with concanavalin A in hemadsorption assays. Indirect evidence suggests that the alteration includes membrane incorporation of MuMTV-related determinants of a glycoprotein with a molecular weight of 52,000. (f) Malignant cells exhibit enhanced sensitivity to insulin for reinitiation of DNA synthesis and mitosis in contact-inhibited homotypical monolayers. These findings have been organized into a hormonal cocarcinogenesis hypothesis in which expression of germinally transmitted MuMTV genes is the proximal cause of neoplastic transformation.


Case Report: Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome.
Background: Intravenous injection of oral opioid substitution drugs (OSD) is widespread among injecting drug users. Several OSDs contain the polymer polyvinylpyrrolidone (PVP) as an excipient. Parenterally administered PVP of high molecular weight may accumulate in tissues and organs. This phenomenon was first described in the 1950s, when PVP was utilised in medication for parenteral use. We report a case of an opioid-addicted patient with extensive PVP-deposition caused by repeated injections of OSDs. Case presentation: A 30-year-old male drug addicted patient in opioid substitution therapy (OST) was repeatedly referred to his local hospital in a poor general condition. Work-up revealed severe normocytic anaemia, renal insufficiency, pancreas insufficiency and pathological fractures. Biopsies from fractured bones, bone marrow and gastric mucosa showed extensive infiltrates of histiocytes with intracytoplasmic vacuoles. Vacuole content stained slightly bluish in hematoxylin and eosin stain, red in Congo red stain and black in periodic acid methenamine silver stain. The morphological appearance and staining properties were in accordance with the diagnosis of PVP deposition. The patient had been injecting both buprenorphine tablets and a specific methadone syrup for several years. The methadone syrup contained large amounts of high molecular weight PVP, making it the most likely cause of the deposition. His health quickly deteriorated and he died, impaired by multi-organ failure and cachexia, five years after the first diagnosis of PVP-deposition. The autopsy revealed extensive PVP-deposition in all sampled organs and tissues. Conclusions: Histological investigation and the correct identification of PVP in the biopsies led to the discovery of a severe adverse effect from long-standing misuse of a drug. The disseminated PVP deposition likely contributed to multi-organ dysfunction and cachexia with a fatal outcome. The deposited PVP likely originated from repeated injections of a certain methadone syrup.


Cyclo[18]carbon: the smallest all-carbon electron acceptor.
The recently synthesized C18 molecule demonstrates strong electron acceptor properties similar to C60. In this work, we study computationally the ground and excited state properties of C18 and its complexes with several electron-donating molecules. We demonstrate that a high amount of the exact (HF) exchange in the DFT functional leads to a polyynic structure of C18, in agreement with the experiment. We show that in complexes of C18 with electron donors, the lowest excited states are charge separated states formed by electron transfer to C18. This makes C18 the smallest all-carbon electron acceptor reported so far. Because C18 exhibits a larger internal reorganization energy compared to fullerene C60, the electron transfer reactions with relatively high driving force will be shifted from the inverted to the normal Marcus regime when replacing C60 by C18.


Vegan diets and hypothyroidism.
Diets eliminating animal products have rarely been associated with hypothyroidism but may protect against autoimmune disease. Thus, we investigated whether risk of hypothyroidism was associated with vegetarian compared to omnivorous dietary patterns. The Adventist Health Study-2 was conducted among church members in North America who provided data in a self-administered questionnaire. Hypothyroidism was queried at baseline in 2002 and at follow-up to 2008. Diet was examined as a determinant of prevalent (n = 4237 of 65,981 [6.4%]) and incident cases (1184 of 41,212 [2.9%]) in multivariate logistic regression models, controlled for demographics and salt use. In the prevalence study, in addition to demographic characterstics, overweight and obesity increased the odds (OR 1.32, 95% CI: 1.22-1.42 and 1.78, 95% CI: 1.64-1.93, respectively). Vegan versus omnivorous diets tended to be associated with reduced risk (OR 0.89, 95% CI: 0.78-1.01, not statistically significant) while a lacto-ovo diet was associated with increased risk (OR 1.09, 95% CI: 1.01-1.18). In the incidence study, female gender, white ethnicity, higher education and BMI were predictors of hypothyroidism. Following a vegan diet tended to be protective (OR 0.78, 95% CI: 0.59-1.03, not statistically significant). In conclusion, a vegan diet tended to be associated with lower, not higher, risk of hypothyroid disease.


An unusual case of acute motor axonal neuropathy (AMAN) complicating dengue fever.
Neurological complications are increasingly being reported in dengue fever, and the dengue virus is now recognized as a neurotrophic virus. The damage caused by inflammatory cytokines in the febrile phase and molecular mimicry in the recovery phase is responsible for these neurological manifestations. We report such an unusual neurological complication occurring in a 27-year-old female in the recovery phase of dengue fever, who developed an acute onset of ascending symmetric weakness of all four limbs without any sensory, autonomic, cerebellar, or cranial nerve involvement. She was diagnosed as having an acute motor axonal neuropathy (AMAN) variant of Guillain-Barre syndrome (GBS) based on a nerve conduction study (NCS) showing axonal neuropathy and contrast-enhanced magnetic resonance imaging (CE-MRI) showing root enhancement at the region of the cauda equina. She was treated with intravenous immunoglobulin (IVIG) and showed full recovery from symptoms with treatment. Our case highlights the importance of being aware of such rare neurological complications in dengue fever. Early detection and rapid initiation of treatment can lead to the complete reversal of neurological deficits.


Oligonucleotide nanostructured surfaces: effect on Escherichia coli curli expression.
Oligonucleotide model surfaces allowing independent variation of topography and chemical composition were designed to study the adhesion and biofilm growth of E.coli. Surfaces were produced by covalent binding of oligonucleotides and immobilization of nucleotide-based vesicles. Their properties were confirmed through a combination of fluorescence microscopy, XPS, ellipsometry, AFM and wettability studies at each step of the process. These surfaces were then used to study the response of three different strains of E.coli quantified in a static biofilm growth mode. This study led to convincing evidence that oligonucleotide-modified surfaces, independent of the topographical feature used in this study, enhanced curli expression without an increase in the number of adherent bacteria.


Automatic mining of symptom severity from psychiatric evaluation notes.
As electronic mental health records become more widely available, several approaches have been suggested to automatically extract information from free-text narrative aiming to support epidemiological research and clinical decision-making. In this paper, we explore extraction of explicit mentions of symptom severity from initial psychiatric evaluation records. We use the data provided by the 2016 CEGS N-GRID NLP shared task Track 2, which contains 541 records manually annotated for symptom severity according to the Research Domain Criteria. We designed and implemented 3 automatic methods: a knowledge-driven approach relying on local lexicalized rules based on common syntactic patterns in text suggesting positive valence symptoms; a machine learning method using a neural network; and a hybrid approach combining the first 2 methods with a neural network. The results on an unseen evaluation set of 216 psychiatric evaluation records showed a performance of 80.1% for the rule-based method, 73.3% for the machine-learning approach, and 72.0% for the hybrid one. Although more work is needed to improve the accuracy, the results are encouraging and indicate that automated text mining methods can be used to classify mental health symptom severity from free text psychiatric notes to support epidemiological and clinical research.


Integrative systems biology visualization with MAYDAY.
Visualization is pivotal for gaining insight in systems biology data. As the size and complexity of datasets and supplemental information increases, an efficient, integrated framework for general and specialized views is necessary. MAYDAY is an application for analysis and visualization of general 'omics' data. It follows a trifold approach for data visualization, consisting of flexible data preprocessing, highly customizable data perspective plots for general purpose visualization and systems based plots. Here, we introduce two new systems biology visualization tools for MAYDAY. Efficiently implemented genomic viewers allow the display of variables associated with genomic locations. Multiple variables can be viewed using our new track-based ChromeTracks tool. A functional perspective is provided by visualizing metabolic pathways either in KEGG or BioPax format. Multiple options of displaying pathway components are available, including Systems Biology Graphical Notation (SBGN) glyphs. Furthermore, pathways can be viewed together with gene expression data either as heatmaps or profiles. We apply our tools to two 'omics' datasets of Pseudomonas aeruginosa. The general analysis and visualization tools of MAYDAY as well as our ChromeTracks viewer are applied to a transcriptome dataset. We furthermore integrate this dataset with a metabolome dataset and compare the activity of amino acid degradation pathways between these two datasets, by visually enhancing the pathway diagrams produced by MAYDAY.


31P NMR spectroscopy of hypertrophied rat heart: effect of graded global ischemia.
To investigate the cause for the greater susceptibility of hypertrophied hearts to ischemic injury, we determined the interrelations of total work output, contractile function and energy metabolism in isolated, perfused normal and hypertrophied rat hearts subjected to graded global ischemia. Cardiac hypertrophy was induced by giving rats seven daily injections of either triiodothyronine (0.2 mg/kg) or isoproterenol (5 mg/kg). All hearts were perfused at an aortic pressure of 100 mmHg in the isovolumic mode in an NMR spectrometer (7.05 Tesla). Heart rate, developed pressure, and coronary flow were monitored simultaneously with changes in pH, creatine phosphate, ATP and inorganic phosphate. During pre-ischemic perfusion, the total work output (rate-pressure product) of hyperthyroid hearts was 28% higher than that of control hearts, whereas hearts from isoproterenol-treated animals showed no difference. However, when related to unit muscle mass, work was normal in hyperthyroid hearts and 26% lower after isoproterenol. Contractile function per unit myocardium (developed pressure/g wet weight) was lower in the hypertrophied hearts. ATP content was the same in all groups. Creatine phosphate decreased 41% after triiodothyronine and 25% after isoproterenol. Inorganic phosphate levels and intracellular pH were similar in control and isoproterenol-treated rat hearts, but were higher in the hyperthyroid rat hearts. The phosphorylation potential and the free energy change of ATP hydrolysis were lowered by hypertrophy, the levels correlating with the depressed contractile function. At each ischemic flow rate, both work and contractile function per unit myocardium were the same for all hearts, but the relations between flow and phosphorylation potential were different for each type of heart. Thus, at low flow rates, hypertrophied hearts perform the same amount of work and have the same contractile function as control hearts, but with abnormal changes in energy metabolism, indicating that the relations of energy status to coronary flow, total work output and contractile function are altered during the process of hypertrophy.


Viscoelastic cell mechanics and actin remodelling are dependent on the rate of applied pressure.
Living cells are subjected to external and internal mechanical stresses. The effects of these stresses on the deformation and subsequent biological response of the cells remains unclear. This study tested the hypothesis that the rate at which pressure (or stress) is applied influence the viscoelastic properties of the cell associated with differences in the dynamics of the actin cytoskeleton. Micropipette aspiration was used to determine the instantaneous and equilibrium moduli and the viscosity of isolated chondrocytes based on the standard linear solid (SLS) model and a variation of this incorporating Boltzmann superposition. Cells were visualised for 180 seconds following aspiration to 7 cmH(2)O at 0.35, 0.70 and 5.48 cmH(2)O/sec. Cell recovery was then examined for a further 180 seconds once the pressure had been removed. Reducing the rate of application of pressure reduced the levels of cell deformation and recovery associated with a significant increase in modulus and viscosity. Using GFP transfection and confocal microscopy, we show that chondrocyte deformation involves distortion, disassembly and subsequent reassembly of the cortical actin cytoskeleton. At faster pressure rates, cell deformation produced an increase in cell volume associated with membrane bleb formation. GFP-actin transfection inhibited the pressure rate dependent variation in cell mechanics indicating that this behaviour is regulated by GFP-sensitive actin dynamics. We suggest that slower rates of aspiration pressure enable greater levels of cortical actin distortion. This is partially inhibited by GFP or faster aspiration rates leading to membrane bleb formation and an increase in cell volume. Thus the rate of application of pressure regulates the viscoelastic mechanical properties of living cells through pressure rate sensitive differences in actin dynamics. Therefore cells appear softer when aspirated at a faster rate in contrast to what is expected of a normal viscoelastic material.


Gender: shaping personality, lives and health of women in Pakistan.
Gender norms determine the status of Pakistani women that influence their life including health. In Pakistan, the relationship between gender norms and health of women is crucial yet complex demanding further analysis. This paper: determines the reasons for reiteration of gender roles; describes the societal processes and mechanisms that reproduce and reinforce them; and identifies their repercussions on women's personality, lives and health especially reproductive health. As part of a six-country study titled 'Women's Empowerment in Muslim Contexts', semi-structured group discussions (n = 30) were conducted with women (n = 250) who were selected through snowballing from different age, ethnic and socio-economic categories. Discussion guidelines were used to collect participant's perceptions about Pakistani women's: characteristics, powers, aspirations, needs and responsibilities; circumstances these women live in such as opportunities, constraints and risks; and influence of these circumstances on their personality, lifestyle and health. The society studied has constructed a 'Model' for women that consider them 'Objects' without rights and autonomy. Women's subordination, a prerequisite to ensure compliance to the constructed model, is maintained through allocation of lesser resources, restrictions on mobility, seclusion norms and even violence in cases of resistance. The model determines women's traits and responsibilities, and establishes parameters for what is legitimate for women, and these have implications for their personality, lifestyle and health, including their reproductive behaviours. There is a strong link between women's autonomy, rights, and health. This demands a gender sensitive and a, right-based approach towards health. In addition to service delivery interventions, strategies are required to counter factors influencing health status and restricting access to and utilization of services. Improvement in women's health is bound to have positive influences on their children and wider family's health, education and livelihood; and in turn on a society's health and economy.


Further evidence that local cues to shape in RF patterns are integrated globally.
Radial frequency (RF) patterns, paths deformed from circular by a sinusoidal modulation of radius, have proved valuable stimuli for investigation of visual shape processing. Their utility relies upon evidence that thresholds for detection of modulation decrease, as cycles of modulation are added, at a rate that cannot be accounted for by the improving probability of detection of any single cycle (probability summation). This has been interpreted as indicative of global processing. Recently Mullen, Beaudot, and Ivanov (2011), using low contrast RF patterns viewed in cosine phase through a Gaussian window, demonstrated the existence of a local cue to modulation that was more salient than the global shape cue present in sectors of RF patterns. The experiments reported here investigate why this cue has not previously obscured global integration of shape information in RF patterns. Using stimuli modulated in sine phase, Experiment 1 showed that the presence of a circular sector of path, used to complete a partially modulated RF pattern, does not raise thresholds, contrary to the suggestion of Mullen et al. (2011). Experiment 2 demonstrated integration for high and low contrast RF patterns viewed in sine phase through a Gaussian window and Experiment 3 showed the same for patterns in cosine phase if the use of a local phase specific curvature cue was precluded. Effective use of local curvature in the test comparison, then, requires knowledge of pattern orientation to define the sign of curvature. Experiment 4 demonstrated global processing of shape information for a range of radial frequencies and also showed that the local maximum gradient with respect to circular within an RF pattern covaries with threshold. This implies that it is this cue, or one that covaries linearly with it, that is integrated across cycles of modulation by the global processing mechanism.


Modeling DNA oxidation in water.
A novel set of hole-site energies and electronic coupling parameters to be used, in the framework of the simplest tight-binding approximation, for predicting DNA hole trapping efficiencies and rates of hole transport in oxidized DNA is proposed. The novel parameters, significantly different from those previously reported in the literature, have been inferred from reliable density functional calculations, including both the sugar-phosphate ionic backbone and the effects of the aqueous environment. It is shown that most of the experimental oxidation free energies of DNA tracts and of oligonucleotides available from photoelectron spectroscopy and voltammetric measurements are reproduced with great accuracy, without the need for introducing sequence dependent parameters.


A Structural Data Mining Approach for the Classification of Secondary RNA structure.
There exist many methods for classifying genomic data by aligning, comparing, and analyzing primary nucleotide sequences using such algorithms as dynamic programming and kinetic folding, etc.. These methods are, however, not always effective as motifs are more conserved in structures than in sequences. Instead of performing classification based on primary sequences, we therefore propose to perform the task from structure, exploiting the phenomenon in which molecules form from a sequence of nucleotides, beginning with a primary sequence that can fold back onto itself to form a secondary structure and then a tertiary structure. The algorithm we propose is able to perform data mining in structural data and is called the Random Multi-Level Attributed (RMLA) graph algorithm for mining and representing secondary genomic structure from such biomolecule as tRNA. The identification of structural similarity is implemented with information measure concept to characterize the resultant class. Experiments are based on known tRNA structural data from database of compilation of tRNA genes. The results show that our approach is able to effectively classify different class of tRNA secondary structure. We also compare our result with other classification algorithms to prove the effectiveness. Our approach shows a better way to classify structural data. In fact, RMLA graph is not suitable only for the classification of genomic data, wherever graphs are used to model data, it is useful for discovering patterns in the databases.


Merging carbohydrate chemistry with lectin histochemistry to study inhibition of lectin binding by glycoclusters in the natural tissue context.
Recognition of glycans by lectins leads to cell adhesion and growth regulation. The specificity and selectivity of this process are determined by carbohydrate structure (sequence and shape) and topology of its presentation. The synthesis of (neo)glycoconjugates with bi- to oligo-valency (glycoclusters) affords tools to delineate structure-activity relationships by blocking lectin binding to an artificial matrix, often a glycoprotein, or cultured cell lines. The drawback of these assays is that glycan presentation is different from that in tissues. In order to approach the natural context, we here introduce lectin histochemistry on fixed tissue sections to determine the susceptibility of binding of two plant lectins, i.e., GSA-II and WGA, to a series of 10 glycoclusters. Besides valency, this panel covers changes in the anomeric position (α/β) and the atom at the glycosidic linkage (O/S). Flanked by cell and solid-phase assays with human tumor lines and two mucins, respectively, staining (intensity and profile) was analyzed in sections of murine jejunum, stomach and epididymis as a function of glycocluster presence. The marked and differential sensitivity of signal generation to structural aspects of the glycoclusters proves the applicability of this method. This enables comparisons between data sets obtained by using (neo)glycoconjugates, cells and the tissue context as platforms. The special advantage of processing tissue sections is the monitoring of interference with lectin association at sites that are relevant for functionality. Testing glycoclusters in lectin histochemistry will especially be attractive in cases of multi-target recognition (glycans, proteins and lipids) by a tissue lectin.


Differences in the expressed HLA class I alleles effect the differential clustering of HIV type 1-specific T cell responses in infected Chinese and caucasians.
China is a region of the world with a rapidly spreading HIV-1 epidemic. Studies providing insights into HIV-1 pathogenesis in infected Chinese are urgently needed to support the design and testing of an effective HIV-1 vaccine for this population. HIV-1-specific T cell responses were characterized in 32 HIV-1-infected individuals of Chinese origin and compared to 34 infected caucasians using 410 overlapping peptides spanning the entire HIV-1 clade B consensus sequence in an IFN-gamma ELISpot assay. All HIV-1 proteins were targeted with similar frequency in both populations and all study subjects recognized at least one overlapping peptide. HIV-1-specific T cell responses clustered in seven different regions of the HIV-1 genome in the Chinese cohort and in nine different regions in the caucasian cohort. The dominant HLA class I alleles expressed in the two populations differed significantly, and differences in epitope clustering pattern were shown to be influenced by differences in class I alleles that restrict immunodominant epitopes. These studies demonstrate that the clustering of HIV-1-specific T cell responses is influenced by the genetic HLA class I background in the study populations. The design and testing of candidate vaccines to fight the rapidly growing HIV-1 epidemic must therefore take the HLA genetics of the population into account as specific regions of the virus can be expected to be differentially targeted in ethnically diverse populations.


Recruitment of TIF1γ to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities.
The interplay between sequence-specific DNA-binding transcription factors, histone-modifying enzymes, and chromatin-remodeling enzymes underpins transcriptional regulation. Although it is known how single domains of chromatin "readers" bind specific histone modifications, how combinations of histone marks are recognized and decoded is poorly understood. Moreover, the role of histone binding in regulating the enzymatic activity of chromatin readers is not known. Here we focus on the TGF-β superfamily transcriptional repressor TIF1γ/TRIM33/Ectodermin and demonstrate that its PHD finger-bromodomain constitutes a multivalent histone-binding module that specifically binds histone H3 tails unmethylated at K4 and R2 and acetylated at two key lysines. TIF1γ's ability to ubiquitinate its substrate Smad4 requires its PHD finger-bromodomain, as does its transcriptional repressor activity. Most importantly, TIF1γ's E3 ubiquitin ligase activity is induced by histone binding. We propose a model of TIF1γ activity in which it dictates the residence time of activated Smad complexes at promoters of TGF-β superfamily target genes.


Exercise-induced oxidant stress in the lung tissue: role of dietary supplementation of vitamin E and selenium.
Strenuous physical exercise in the form of swimming in female albino rats increased the oxidative reactions, probably leading to the generation of oxy-free radicals in the lung tissue. Free radical-mediated lipid peroxidation measured in the form of lipid peroxides increased in the pulmonary tissue in response to exhaustive exercise, indicating such a possibility. Dietary supplementation of vitamin E (Vit.E) and selenium (Se) for a period of 12 weeks reduced the oxidative reactions and the ensuing lipid peroxidation in the pulmonary tissue. Physical exercise in control animals induced the activity of superoxide dismutase (SOD), the superoxide anion radical (O2-.) quencher. However, the SOD levels in nutrient-fed animals at rest and after exercise remained well below the control levels, indicating the decreased generation of oxy-free radicals in them. Similarly, selenium-dependent glutathione peroxidase (Se-GSH Px), the enzyme involved in the reduction of organic and inorganic peroxides, and glutathione S- transferase (GST), the multifunctional protein involved in the detoxification of a number of xenobiotics, were increased in response to exercise in control animals, but were significantly decreased in nutrient-fed animals upon exercise. The induction of GST seems to be more towards the peroxidase activity of GST, i.e., non-selenium glutathione peroxidase (Non-Se-GSH Px), which is primarily involved in the reduction of endoperoxides. The studies thus indicate the induction of oxidative stress in the pulmonary tissue upon exhaustive physical exercise and the effectiveness of vit.E and Se independently and more so in combination in combating the exercise-induced oxidant stress.


WNT10A mutations account for ¼ of population-based isolated oligodontia and show phenotypic correlations.
A large proportion (>50%) of patients with isolated oligodontia were recently reported with WNT10A mutations. We have analyzed a population-based cohort of 102 individuals diagnosed with non-syndromic oligodontia and a mean of 8.2 missing teeth. The cohort included 94 families and screening of WNT10A identified that 26 probands (27.7%) had at least one WNT10A variant. When we included the MSX1, PAX9, AXIN2, EDA, EDAR, and EDARADD genes, 38.3% of probands were positive for a mutation. Biallelic WNT10A mutations were strongly associated with a larger number of missing teeth (11.09) when compared to both monoallelic WNT10 mutations (6.82) and the group without mutations in WNT10A, MSX1, PAX9, AXIN2, EDA, EDAR, or EDARADD (7.77). Genotype-phenotype analysis of individuals with WNT10A mutations showed that premolars were the most common missing teeth. Furthermore, biallelic WNT10A mutations were associated with absence of maxillary and mandibular molars as well as mandibular central incisors. Maxillary central incisors were always present. Thus, our study indicates that WNT10A mutations are associated with both the type and numbers of missing teeth. Furthermore, we show that this population-based cohort of isolated oligodontia had a considerably lower frequency of mutated WNT10A alleles and a lower mean number of missing teeth when compared to patients recruited from dental specialist centers.


Neural mechanism underlying acupuncture analgesia.
Acupuncture has been accepted to effectively treat chronic pain by inserting needles into the specific "acupuncture points" (acupoints) on the patient's body. During the last decades, our understanding of how the brain processes acupuncture analgesia has undergone considerable development. Acupuncture analgesia is manifested only when the intricate feeling (soreness, numbness, heaviness and distension) of acupuncture in patients occurs following acupuncture manipulation. Manual acupuncture (MA) is the insertion of an acupuncture needle into acupoint followed by the twisting of the needle up and down by hand. In MA, all types of afferent fibers (Abeta, Adelta and C) are activated. In electrical acupuncture (EA), a stimulating current via the inserted needle is delivered to acupoints. Electrical current intense enough to excite Abeta- and part of Adelta-fibers can induce an analgesic effect. Acupuncture signals ascend mainly through the spinal ventrolateral funiculus to the brain. Many brain nuclei composing a complicated network are involved in processing acupuncture analgesia, including the nucleus raphe magnus (NRM), periaqueductal grey (PAG), locus coeruleus, arcuate nucleus (Arc), preoptic area, nucleus submedius, habenular nucleus, accumbens nucleus, caudate nucleus, septal area, amygdale, etc. Acupuncture analgesia is essentially a manifestation of integrative processes at different levels in the CNS between afferent impulses from pain regions and impulses from acupoints. In the last decade, profound studies on neural mechanisms underlying acupuncture analgesia predominately focus on cellular and molecular substrate and functional brain imaging and have developed rapidly. Diverse signal molecules contribute to mediating acupuncture analgesia, such as opioid peptides (mu-, delta- and kappa-receptors), glutamate (NMDA and AMPA/KA receptors), 5-hydroxytryptamine, and cholecystokinin octapeptide. Among these, the opioid peptides and their receptors in Arc-PAG-NRM-spinal dorsal horn pathway play a pivotal role in mediating acupuncture analgesia. The release of opioid peptides evoked by electroacupuncture is frequency-dependent. EA at 2 and 100Hz produces release of enkephalin and dynorphin in the spinal cord, respectively. CCK-8 antagonizes acupuncture analgesia. The individual differences of acupuncture analgesia are associated with inherited genetic factors and the density of CCK receptors. The brain regions associated with acupuncture analgesia identified in animal experiments were confirmed and further explored in the human brain by means of functional imaging. EA analgesia is likely associated with its counter-regulation to spinal glial activation. PTX-sesntive Gi/o protein- and MAP kinase-mediated signal pathways as well as the downstream events NF-kappaB, c-fos and c-jun play important roles in EA analgesia.


Eliminating the threat of chronic hepatitis B in the Asian and Pacific Islander community: a call to action.
Chronic hepatitis B in the Asian and Pacific Islander (API) population is among our nation's greatest ethnic and racial health disparities. Despite comprising 4.3% of the population, API make up a disproportionate half of the 1.2-2 million Americans living with chronic hepatitis B. As many as two-thirds of API are not aware of their infection because they have not been tested. This lack of knowledge prevents them from undergoing life-saving liver cancer screening and potential treatment. Likewise, those not protected are unaware that they should be vaccinated. Instead, there is a pervasive lack of awareness among API and healthcare providers. New concerted public health actions are needed to eliminate this major health disparity.


A beta-spectrin isoform from Drosophila (beta H) is similar in size to vertebrate dystrophin.
Spectrins are a major component of the membrane skeleton in many cell types where they are thought to contribute to cell form and membrane organization. Diversity among spectrin isoforms, especially their beta subunits, is associated with diversity in cell shape and membrane architecture. Here we describe a spectrin isoform from Drosophila that consists of a conventional alpha spectrin subunit complexed with a novel high molecular weight beta subunit (430 kD) that we term beta H. The native alpha beta H molecule binds actin filaments with high affinity and has a typical spectrin morphology except that it is longer than most other spectrin isoforms and includes two knoblike structures that are attributed to a unique domain of the beta H subunit. Beta H is encoded by a different gene than the previously described Drosophila beta-spectrin subunit but shows sequence similarity to beta-spectrin as well as vertebrate dystrophin, a component of the membrane skeleton in muscle. By size and sequence similarity, dystrophin is more similar to this newly described beta-spectrin isoform (beta H) than to other members of the spectrin gene family such as alpha-spectrin and alpha-actinin.


Improving Fluid Management in Critical Care - Towards the ICU of the Future.
The calculation of daily fluid balances is essential in perioperative and postoperative fluid management in order to prevent severe hypervolemia or hypovolemia in critically ill patients. In this context, modern health information technology has the potential to reduce the workload for health care professionals by not only automating data collection but also providing appropriate decision support. Within this work, current problems and barriers regarding fluid balancing in cardiac intensive care patients are outlined and improvement activities are specified. Literature research and qualitative interviews with health care professionals were conducted to assess the state-of-the-art technological setting within an intensive care unit. An example case shows that interconnecting not only devices but also wards can facilitate daily clinical tasks. Smart devices and decision support systems can improve fluid management. Several technologies, which today are sometimes still considered to be futuristic, are in fact not that far away or already available. However, they need proper implementation with respect to intensivists', nurses' and patients' needs.


The incidence of staining of permanent teeth by the tetracyclines.
In this investigation an attempt has been made to determine the relationship between the staining of permanent teeth by tetracycline administered during the period of tooth formation with the dosage of the drug and the duration of therapy. Of 238 subjects whose hospital records indicated ingestion of stated doses of tetracycline, some 49 were seen to have staining which was confirmed by fluorescence, and a further six had staining which did not fluoresce and hence could not be confirmed. A definite relationship between total dosage and staining and duration of administration and staining was established; the condition occurred with greater frequency (in more than one-third of the children) when the total dosage exceeded 3 g. or the duration of treatment was longer than 10 days. However, as staining was seen at all dosage levels, whatever the duration, physicians should continue to follow previous advice and prescribe other antibiotics where possible for children under 8 years of age or for women in the last trimester of pregnancy.


Perception of risk for coronary heart disease in women undergoing coronary angiography.
Even though coronary heart disease (CHD) is the leading cause of death among women in the United States, most women underestimate their risk of developing CHD. Survey to examine the relationship between women's recollection of being told they were at risk for CHD and the presence of risk factors. A convenience sample of 450 women undergoing coronary angiography at 1 university hospital. Self-recollection of being told one was at risk for CHD and presence of CHD risk factors. Most women (83.6%) had 3 or more risk factors, 12.2% had 1 or 2 risk factors, and 0.9% had no risk factors. Only 35% of women recalled being told that they were at risk for CHD. Few relationships were found between being told one was at risk for CHD and the presence of individual risk factors. No difference was found in the mean number of risk factors among women who did and did not recall being told they were at risk. In logistic regression analysis, only 5% of the variance in recollection of being told one was at risk was predicted, with only age, education, and having a high cholesterol level significantly contributing to the equation. Even though women may not remember conversations with their health care provider about CHD risk, the possibility that risk factors were not adequately assessed cannot be discounted. Patient-provider conversations about CHD risk factors should be encouraged as the first step toward successful risk reduction.


Identification of a selective manganese ionophore that enables nonlethal quantification of cellular manganese.
Available assays for measuring cellular manganese (Mn) levels require cell lysis, restricting longitudinal experiments and multiplexed outcome measures. Conducting a screen of small molecules known to alter cellular Mn levels, we report here that one of these chemicals induces rapid Mn efflux. We describe this activity and the development and implementation of an assay centered on this small molecule, named manganese-extracting small molecule (MESM). Using inductively-coupled plasma-MS, we validated that this assay, termed here "manganese-extracting small molecule estimation route" (MESMER), can accurately assess Mn in mammalian cells. Furthermore, we found evidence that MESM acts as a Mn-selective ionophore, and we observed that it has increased rates of Mn membrane transport, reduced cytotoxicity, and increased selectivity for Mn over calcium compared with two established Mn ionophores, calcimycin (A23187) and ionomycin. Finally, we applied MESMER to test whether prior Mn exposures subsequently affect cellular Mn levels. We found that cells receiving continuous, elevated extracellular Mn accumulate less Mn than cells receiving equally-elevated Mn for the first time for 24 h, indicating a compensatory cellular homeostatic response. Use of the MESMER assay versus a comparable detergent lysis-based assay, cellular Fura-2 Mn extraction assay, reduced the number of cells and materials required for performing a similar but cell lethality-based experiment to 25% of the normally required sample size. We conclude that MESMER can accurately quantify cellular Mn levels in two independent cells lines through an ionophore-based mechanism, maintaining cell viability and enabling longitudinal assessment within the same cultures.


Increased stress-evoked nitric oxide signalling in the Flinders sensitive line (FSL) rat: a genetic animal model of depression.
Stress engenders the precipitation and progression of affective disorders, while stress-related release of excitatory mediators is implicated in the degenerative pathology observed especially in the hippocampus of patients with severe depression. Nitric oxide (NO) release following stress-evoked N-methyl-d-aspartate (NMDA) receptor activation modulates neurotransmission, cellular memory and neuronal toxicity. We have investigated the Flinders rat (FSL/FRL), a genetic animal model of depression, regarding the response of the hippocampal nitrergic system following exposure to an escapable stress/inescapable stress (ES-IS) paradigm. Hippocampal tissue from naive FSL/FRL rats and those exposed to ES-IS were studied with respect to constitutive nitric oxide synthase (cNOS) activity and neuronal nitric oxide synthase (nNOS) protein levels, as well as transcript expression of upstream regulatory proteins in the NMDA-NO signalling pathway, including NMDAR1, nNOS, CAPON, PIN and PSD95. Within stress-naive animals, no differences in hippocampal cNOS activity and nNOS expression or PIN were evident in FSL and FRL rats, although transcripts for NMDAR1 and CAPON were increased in FSL rats. Within the group of ES-IS animals, we found an increase in total hippocampal cNOS activity, nNOS protein levels and mRNA expression in FSL vs. FRL rats, together with an increase in PSD95 transcripts, and a reduction in PIN. In conclusion, ES-IS enhanced hippocampal cNOS activity in FSL rats, but not FRL rats, confirming the NMDA-NO cascade as an important vulnerability factor in the depressive phenotype of the FSL rat.


Structure in time-frequency binary masking errors and its impact on speech intelligibility.
Although requiring prior knowledge makes the ideal binary mask an impractical algorithm, substantial increases in measured intelligibility make it a desirable benchmark. While this benchmark has been studied extensively, many questions remain about the factors that influence the intelligibility of binary-masked speech with non-ideal masks. To date, researchers have used primarily uniformly random, uncorrelated mask errors and independently presented error types (i.e., false positives and negatives) to characterize the influence of estimation errors on intelligibility. However, practical estimation algorithms produce masks that contain errors of both types and with non-trivial amounts of structure. This paper introduces an investigation framework for binary masks and presents listener studies that use this framework to illustrate how interactions between error types and structure affect intelligibility. First, this study demonstrates that clustering (i.e., a form of structure) of mask errors reduces intelligibility. Furthermore, while previous research has suggested that false positives are more detrimental to intelligibility than false negatives, this study indicates that false negatives can be equally detrimental to intelligibility when they contain structure or when both error types are present. Finally, this study shows that listeners tolerate fewer mask errors when both types of errors are present, especially when the errors contain structure.


Relationship Between Adherence to Antihypertensive Medication Regimen and Out-of-Pocket Costs Among People Aged 35 to 64 With Employer-Sponsored Health Insurance.
We used administrative claims data from 2014 on people with employer-sponsored health insurance to assess the proportion of patients taking antihypertensive medications, rates of nonadherence to these medication regimens, and out-of-pocket costs paid by patients. We performed multivariate logistic regression analysis to examine the association between out-of-pocket costs and nonadherence. Results indicated that patients filled the equivalent of 13 monthly prescriptions and paid $76 out of pocket over the calendar year; the likelihood of nonadherence increased as out-of-pocket costs increased (adjusted odds ratios ranged from 1.04 to 1.78; P < .001). These findings suggest a need for improvement in adherence among patients with employer-sponsored insurance.


One dimensional resonant Fibonacci quasicrystals: noncanonical linear and canonical nonlinear effects.
A detailed experimental and theoretical study of the linear and nonlinear optical properties of different Fibonacci-spaced multiple-quantum-well structures is presented. Systematic numerical studies are performed for different average spacing and geometrical arrangement of the quantum wells. Measurements of the linear and nonlinear (carrier density dependent) reflectivity are shown to be in good agreement with the computational results. As the pump pulse energy increases, the excitation-induced dephasing broadens the exciton resonances resulting in a disappearance of sharp features and reduction in peak reflectivity.


Processing by the thymus is not required for cells that cure and populate W/WV recipients.
Adult marrow, fetal liver or nu/nu mouse marrow from histocompatible donors was grafted into genetically anemic W/WV recipients, and all three types of grafts cured thymectomized as well as intact W-anemic recipients. With the latter two types of graft, the genetic anemia was cured by cells that could not have been processed in a mature thymus, since the adult recipients were thymectomized before receiving the grafts, the nu/nu donors were congenitally thymusless, and the fetal donors were used at 16 days of gestation. Chromosome-marked marrow grafts were used to show that immune systems were populated to similar degrees in thymectomized and intact W/WV recipients. Therefore, the cells derived from the donor marrow graft that partially populate the immune systems of W-anemic recipients do not require thymus processing. Small numbers of liver rudiment or yolk sac cells from fetal donors less than 12 days old failed to cure W/WV recipients, even when mixed with adult thymus cells. Therefore, the lack of adequately developed thymic helper cells appears not to be the reason why early fetal hemopoietic stem cells fail to cure W/WV recipients.


Frequency and determinants of erectile dysfunction in Turkish diabetic men.
Erectile dysfunction (ED) or impotence is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance. ED is observed more frequently and manifests earlier in diabetic patients compared to the normal population. One hundred and seventeen consecutive male type 2 diabetes patients seen in our Diabetes Outpatient Clinic were included in our study and these patients were evaluated in terms of the presence and duration of ED, treatment and response to treatment of ED, duration of diabetes mellitus, HbA1c levels, and the presence of microalbuminuria, estimated from 24-hour urine collections. The patients included in our study were divided into three groups: Patients with no ED, mild-to-moderate ED, and severe ED. Twenty-nine patients (24.8%) fell in the no ED group, 28 (23.9%) in the mild-to-moderate ED group, and 60 (51.3%) in the severe ED group. There were statistically significant differences between these three groups in terms of age ( P = 0.015) and duration of diabetes mellitus ( P = 0.03). The groups were similar in terms of microalbuminuria measured from 24-hour urine collections and HbA1c levels ( P = 0.328 and P = 0.905, respectively). Twenty-three of the 88 patients with ED (26.1%) were on ED treatment and 43.5% of these patients reported benefit from the therapy. Age and duration of diabetes were the main determinants of the presence and severity of ED in male Turkish type 2 diabetic patients. The HbA1c levels were higher in patients with ED, but the differences in levels between the groups did not reach statistical significance.


PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt(high) metastatic colon cancer cells.
The Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a pro-apoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1(+) cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1(+) cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.


Tri-layered composite plug for the repair of osteochondral defects: in vivo study in sheep.
Cartilage defects are a source of pain, immobility, and reduced quality of life for patients who have acquired these defects through injury, wear, or disease. The avascular nature of cartilage tissue adds to the complexity of cartilage tissue repair or regeneration efforts. The known limitations of using autografts, allografts, or xenografts further add to this complexity. Autologous chondrocyte implantation or matrix-assisted chondrocyte implantation techniques attempt to introduce cultured cartilage cells to defect areas in the patient, but clinical success with these are impeded by the avascularity of cartilage tissue. Biodegradable, synthetic scaffolds capable of supporting local cells and overcoming the issue of poor vascularization would bypass the issues of current cartilage treatment options. In this study, we propose a biodegradable, tri-layered (poly(glycolic acid) mesh/poly(l-lactic acid)-colorant tidemark layer/collagen Type I and ceramic microparticle-coated poly(l-lactic acid)-poly(ϵ-caprolactone) monolith) osteochondral plug indicated for the repair of cartilage defects. The porous plug allows the continual transport of bone marrow constituents from the subchondral layer to the cartilage defect site for a more effective repair of the area. Assessment of the in vivo performance of the implant was conducted in an ovine model (n = 13). In addition to a control group (no implant), one group received the implant alone (Group A), while another group was supplemented with hyaluronic acid (0.8 mL at 10 mg/mL solution; Group B). Analyses performed on specimens from the in vivo study revealed that the implant achieves cartilage formation within 6 months. No adverse tissue reactions or other complications were reported. Our findings indicate that the porous biocompatible implant seems to be a promising treatment option for the cartilage repair.


Automation and prothrombin time: a United Kingdom field study of two widely used coagulometers.
Current performance in the prothrombin time (PT) of the two main United Kingdom coagulometer/thromboplastin systems was assessed in a field survey. Twenty abnormal samples covering a wide spectrum of International Normalised Ratio (INR) were distributed to users of the KC4/KC10 and Coag-a-Mate instruments. Coagulometer results were compared with those of the manual method. A substantial minority with each system showed good agreement with the manual reference values. There was, however, a considerable variation between instruments, meaningful in clinical terms, evidenced by varying regression slopes and local system International Sensitivity Indices (ISI). For intense anticoagulation (3.0 to 4.5 INR) a larger dose of warfarin is needed with the Coag-a-Mate than with the KC instruments. With a manual INR of 4.0 the KC instruments tended to give longer PT (mean INR + 0.3); the Coag-a-Mate PT was generally shorter (mean INR -0.1). With both systems the mean normal PT were shorter than the manual but the degree of shortening did not parallel that of the abnormal samples. This effect undermines the use of a simple prothrombin ratio and of an INR value derived from it, based on a manual ISI. The use of a system related ISI cannot, however, be recommended until local instrument variables are controlled.