A short-chain aldehyde is a major lipoxygenase product in arachidonic acid-stimulated porcine leukocytes.
Porcine leukocytes convert exogenous arachidonic acid to a complex array of products derived via the 5-, 12-, and 15-lipoxygenase pathways of metabolism. The major monohydroxylated metabolite following addition of 100 microM arachidonic acid is 12-hydroxyeicosatetraenoic acid. Of the more polar compounds on reverse-phase high pressure liquid chromatography, the most prominent is a previously uncharacterized arachidonate product which chromatographs near to the omega-oxidized metabolites of leukotriene B4. The structure of this new product was examined by high pressure liquid chromatography, UV, NMR, and also by gas chromatography-mass spectrometry of several derivatives; it was identified as 12-oxododeca-5,8,10-(Z,Z,E)-trienoic acid. It is proposed that this C-12 trienal acid is formed from 12-hydroperoxyeicosatetraenoic acid by a cleavage reaction catalyzed by the leukocyte 12-lipoxygenase in the presence of excess arachidonic acid and under anaerobic conditions. These conditions are satisfied by addition of 100 microM arachidonic acid to the leukocyte suspension (3 X 10(7) cells/ml); 12-hydroperoxyeicosatetraenoic acid is formed as the major product, excess arachidonic acid is available, and the concomitant leukocyte respiratory burst quickly depletes the solution of oxygen. Preliminary experiments indicate that this aldehyde product has significant biological activity in the activation of leukocytes. In the course of an intense inflammatory reaction it is conceivable that the conditions for synthesis of this C-12 trienal acid and related aldehydes could prevail; such aldehydes would constitute an additional class of lipoxygenase product which exacerbates the process of inflammation.


Pentylenetetrazole kindling affects sleep in rats.
The aim of the study was to define sleep disturbances in pentylenetetrazole (PTZ)-kindled rats and to explore the effects of the nootropic drug piracetam (Pir; 100 mg/kg) and the noncompetitive N-methyl-D-aspartate (NMDA)-antagonist MK-801 (0.3 mg/kg), which normalized learning performance in PTZ-kindled rats, on altered sleep parameters. This is the first report showing a significant reduction in paradoxical sleep (PS) as a consequence of PTZ kindling. A correlation analysis revealed a significant correlation between seizure severity and PS deficit. Pir did not interfere with seizure severity, and the substance did not ameliorate the PS deficit. However, the substance disconnected the correlation between seizure severity and PS deficit. MK-801, which reduced the severity of kindled seizures, counteracted the PS deficit efficaciously. The results suggest that seizure severity and alterations in sleep architecture are two factors in the comprehensive network underlying learning impairments associated with epilepsy. Considering the results obtained in the experiments with Pir, reduction of seizure severity does not guarantee the reduction of impairments in the domain of learning.


Prevalence of the third and fourth heart sound in asymptomatic adults.
The prevalence of abnormal diastolic heart sounds in asymptomatic adults has been the subject of great debate. The authors determined the prevalence of an electronically detected S3 and S4 in 1329 asymptomatic adults between the ages of 18 and 94. The authors also investigated the relationship between abnormal diastolic heart sounds, age, and electrocardiography. The overall prevalence of S3 was 10.0% (95% confidence interval [CI], 8.1%-12.2%), S4 was 15.6% (95% CI, 13.2%-18.2%), and both S3 and S4 were 3.5% (95% CI, 2.4%-5.0%). Using multinomial logistic regression, increasing age was found to decrease the odds of an S3 being heard (odds ratio, 0.96; 95% CI, 0.95-0.96) and increase the odds of an S4 being heard (odds ratio, 1.04; 95% CI, 1.03-1.05). We conclude that the prevalence of an S3 is increased earlier in life, that an S4 is less common than previous studies suggest, and that its detection, even in the elderly, should not be ignored.


Unilateral extravesical ureteral reimplantation in children performed on an outpatient basis.
Unilateral extravesical ureteral reimplantation is comparable to intravesical procedures for resolution of primary vesicoureteral reflux (VUR). Defining whether this operation can be consistently performed on an outpatient basis is important. A total of 80 patients with unilateral VUR were treated with extravesical ureteral reimplantation, of whom 20 were treated on an inpatient basis and 60 on an outpatient basis. We retrospectively reviewed these groups and conducted a telephone survey to evaluate overall patient satisfaction, and pain and nausea on postoperative days 1 and 14. There were no significant differences in age, gender, laterality or operative time between the groups. Average length of hospital stay was 31.25 hours (range 20 to 120) for the inpatient group and 6.6 hours (3.25 to 11.20) for the outpatient group. Average intravenous narcotic use in the inpatient group was 0.39 mg/kg, compared to 0.14 mg/kg for the outpatient group (p < 0.005), and included 1.76 mg/kg ketorolac in inpatients and 0.74 ketorolac in outpatients (p < 0.005), and 0.2 mg/kg ondansetron in inpatients and 0.12 mg/kg ondansetron in outpatients (p = 0.004). Four of the 60 outpatients (6.7%) were either hospitalized postoperatively or rehospitalized on postoperative day 1. The results of the survey for the 2 groups were not significantly different. Extravesical ureteral reimplantation for unilateral VUR may be performed without compromise in quality on an outpatient basis with significantly less use of intravenous analgesics and anti-emetics.


Collation of student results in practical class experiments in physiology, using a BBC ECONET computer network.
Funding was provided to Queen's University by the Department of Education and by the Industrial Development Board for Northern Ireland to provide microcomputers for undergraduate use. An allocation from the grant to the Department of Physiology enabled the purchase of 20 BBC Master 128 microcomputers with monitors used as student work-stations connected together by an ECONET network with a file server using a dual floppy disc drive, two printer servers and two demonstrator stations. A BASIC program was written to analyse the students' practical class measurements which they entered manually at their work-station keyboards. Class results were presented to the students in the form of frequency distribution histograms or X/Y graphs. Program modifications to suit different practicals can be made relatively easily. The time taken to analyse data has been shortened. It is easy for the students to get immediate comparison of their own results with those of the rest of the class--particularly advantageous if the student's own experiment did not work. The class can be divided into groups to study different variations of the experiment and provide the data from each group to the whole class. The students' opinions on whether the equipment had (1) improved the teaching of physiology and (2) provided helpful preparation for the use of computers in medical practice were assessed by a questionnaire which showed that a clear majority felt these aims had been fulfilled.


Perceived social support and psychological wellbeing among Nepalese adolescents: the mediating role of self-esteem.
Adolescence is characterized by unique, multiple physical, psychological and social development. Understanding the well-being of adolescents and the factors that contribute to it will help towards clarifying and defining ways to better help adolescents prepare for adult life. Therefore, the present study aims to find out the relationship between Perceived Social Support (PSS) and Psychological Well-Being (PWB) among Nepalese adolescence based on mediating role of Self-esteem (SE). The study was conducted among 348 adolescents studying in grade 9 and 10 of government secondary level schools of Pokhara Metropolitan city, Nepal. Data were collected through self-administered standard tools-Multidimensional Scale of Perceived Social Support (MSPSS), Rosenberg self-esteem scale (RSES) and General Health Questionnaire (GHQ-12). For statistical analysis descriptive statistics, correlation, regression and mediation analyses were used. The statistical significance of mediating effect of the tested model was examined through a path proposed by Baron and Kenny and Bootstrap method. Overall, the finding suggests that PSS indirectly affects PWB of adolescents through mediating variable SE. Adolescents who perceive good social support had higher SE, which in turn contributed to their PWB. Furthermore, the study found no significant gender difference for PSS, SE and PWB. Also among various sources of PSS, both boys and girls were more oriented towards family for social support than friends and others. Adolescents who experience higher social support are likely to have higher SE and are more likely to have better PWB. The findings of the study will be useful to the parents, teachers, counselors, psychologist and researchers to develop strategies to enhance adolescent's mental health.


A giant vesical calculus.
Massive or giant vesical calculus is a rare entity in the recent urological practice. Males are affected more than the females. Vesical calculi are usually secondary to bladder outlet obstruction. These patients present with recurrent urinary tract infection, haematuria or with retention of urine. We report a young male patient who presented with defaecatory problems along with other urinary symptoms. The patient having an average built, non diabetic but hypertensive. The stone could be palpated by physical examination. His urea levels were within normal limits but urine examination shows infection. USG reveals bilateral hydronephrosis with multiple stones in both kidneys along with a giant vesical calculus. After controlling urinary infection and hypertention he underwent an open cystolithotomy. During operation digital rectal help was needed to remove the stone as it was adherent with bladder mucosa. Post operative period was uneventful. His urinary output was quite normal and had no defaecatory problems. Patient left the hospital 10 days after operation.


Novel chimeric antigen receptor T cell-based immunotherapy: a perspective for triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is highly aggressive and does not express estrogen receptor (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2). It has a poor prognosis, and traditional endocrine and anti-HER2 targeted therapies have low efficacy against it. In contrast, surgery, radiotherapy, and/or systemic chemotherapy are relatively effective at controlling TNBC. The resistance of TNBC to currently available clinical therapies has had a significantly negative impact on its treatment outcomes. Hence, new therapeutic options are urgently required. Chimeric antigen receptor T cell (CAR-T) therapy is a type of immunotherapy that integrates the antigen specificity of antibodies and the tumor-killing effect of T cells. CAR-T therapy has demonstrated excellent clinical efficacy against hematological cancers. However, its efficacy against solid tumors such as TNBC is inadequate. The present review aimed to investigate various aspects of CAR-T administration as TNBC therapy. We summarized the potential therapeutic targets of CAR-T that were identified in preclinical studies and clinical trials on TNBC. We addressed the limitations of using CAR-T in the treatment of TNBC in particular and solid tumors in general and explored key strategies to overcome these impediments. Finally, we comprehensively examined the advancement of CAR-T immunotherapy as well as countermeasures that could improve its efficacy as a TNBC treatment and the prognosis of patients with this type of cancer.


Viral hepatitis C, active component, U.S. military service members and beneficiaries, 2008-2016.
Hepatitis C virus (HCV) infection remains an important concern for the Military Health System (MHS). This report updates numbers and incidence rates of HCV infection of U.S. military service members and MHS beneficiaries, incorporating a surveillance period before and after 2012 screening policy changes for military members. From 2008 to 2016, there were 342 and 1,491 incident cases of acute and chronic hepatitis C, respectively, among active component members of the U.S. Armed Forces; crude overall incidence rates during the period were 2.8 (acute) and 12.2 (chronic) cases per 100,000 person-years. Annual incidence rates of chronic hepatitis C decreased over the surveillance period; however, rates of acute hepatitis C remained steady. There were 141 acute and 587 chronic incident cases among reserve/guard service members, with annual counts of both acute and chronic cases decreasing over the surveillance period. In addition, there were 2,541 acute and 21,418 chronic cases among non-service member beneficiaries, with annual counts of acute and chronic cases also decreasing steadily over the surveillance period. Given recent pharmaceutical advances in treatment, screening and linkage to care are critical to improving health outcomes for those with HCV infection.


Centrioles and cilia in non-tumourous anterior lobes and adenomas of the human pituitary.
Electron microscopy revealed the presence of centrioles and cilia in non-tumourous adenohypophysiocytes as well as in various adenomas of the human pituitary gland. Accumulation of centrioles and cilia was evident in sparsely granulated growth hormone cell adenomas. Abundance of centrioles is a valuable sign in establishing the diagnosis of this tumour. The possible functional significance of centrioles and cilia in adenohypophysial cells has been discussed.


'Whore stigma' as a transformative experience: altered cognitive expectations among Jewish-Israeli street-based sex workers.
While the scholarship on sex work is substantial, it neglects to explore whether sex work and associated stigma affect sex workers' cognitive expectations. Drawing on observations of street-based sex work as well as in-depth interviews with Jewish-Israeli sex workers, this study suggests that because stigma is a moral experience that threatens and often destroys what really matters to stigmatised individuals, it leads to recurrent disappointments, which, in turn, may alter sex workers' cognitive expectations. Sex workers learn to see certain life goals, including maintaining healthy social relationships and a workspace free of violence and humiliation, as unobtainable. However, they also begin to see other aspects of their lives, such as economic autonomy, as achievable through sex work. Tracing how whore stigma becomes a transformative experience allows us to add another layer to the heretofore suggested link between the structural, cultural and individual aspects of stigmatisation.


[Evaluation of elevated liver values].
Blood analysis for the purpose of monitoring liver enzymes in the serum is a frequent laboratory examination in everyday clinical practice. Liver values are determined not only in the context of specific liver diseases, but often for the clarification of an unexplained illness, and sometimes in asymptomatic patients as part of a check-up. An evidenced based work-up of abnormal liver values is not easy to perform as there are no controlled clinical trials, on which we can rely for the rational use of further investigations. In the first introductory section of this article we will discuss possible algorithms used for the investigation of elevated liver tests, in the second section, four case reports from daily practice illustrate possible causes for elevated liver enzymes.


Possible role of adenosine deaminase in vaso-occlusive diseases.
To describe several emerging concepts regarding the biosynthesis, metabolism and biological roles of adenosine and to illustrate the possible significance of these ideas to vascular biology by proposing a hypothesis pertaining to the role of erythrocyte-derived adenosine deaminase in vaso-occlusive diseases associated with damaged erythrocytes. Three pathways of adenosine biosynthesis have been well established: the intracellular ATP pathway, the extracellular ATP pathway and the transmethylation pathway. A fourth pathway that has received relatively little attention, but could be particularly important in vascular smooth muscle, is the cyclic AMP-adenosine pathway. This pathway involves the extracellular or intracellular metabolism, or both, of cyclic AMP to AMP and hence to adenosine. Our recent experiments in cultured vascular smooth muscle cells, isolated vascular beds and intact animals support the existence of the cyclic AMP-adenosine pathway. Together these four pathways of adenosine formation should assure pharmacologically active levels of vascular adenosine. ANTIVASO-OCCLUSIVE ACTIONS OF ADENOSINE: The overall pharmacologic profile of adenosine suggests that this nucleoside functions to protect vascular beds from vaso-occlusive events. In this regard, some well known effects of adenosine include vasodilation, release of nitric oxide from vascular endothelial cells and inhibition of platelet aggregation, platelet adhesion, neutrophil-endothelial interactions, renin release and noradrenergic neurotransmission. Moreover, studies indicate that adenosine also releases nitric oxide from cultured vascular smooth muscle cells and inhibits vascular smooth muscle cell growth. Thus, any condition that reduces the levels of adenosine in the blood vessel wall or blood vessel-blood interface might predispose toward vaso-occlusive events. Adenosine deaminase rapidly metabolizes adenosine to inosine, which lacks antivaso-occlusive properties. Because erythrocytes are generously endowed with adenosine deaminase, any condition that damages erythrocytes will cause leakage of adenosine deaminase from erythrocytes directly onto the blood vessel wall, thus diminishing local vascular levels of adenosine. Experiments using dimethyl sulfoxide-induced hemolysis have confirmed the hypothesis that erythrocyte-derived adenosine deaminase can reduce adenosine levels in vivo. THE ROLE OF ERYTHROCYTE-DERIVED ADENOSINE DEAMINASE IN VASO-OCCLUSIVE DISEASES: Because multiple biosynthetic pathways maintain pharmacologically active levels of adenosine within the blood vessel wall and adenosine exerts a number of antivaso-occlusive effects, release of adenosine deaminase from erythrocytes may increase the risk for vaso-occlusive events.


Predictors and outcomes of the Neonatal Oral Motor Assessment Scale (NOMAS) performance: a systematic review.
The NOMAS is by far the most used tool to screen early oral-motor skills in newborns. Here we provide an updated review of scientific literature on the use of the Neonatal Oral Motor Assessment Scale (NOMAS) to screen early oral-motor skills in newborns. An integrative review has been carried out consistent with PRISMA guidelines and standardized qualitative appraisal. Data abstracting and synthesis were executed by two independent co-authors who solved disagreement in conference. Twenty records have been included and reviewed. The efficacy of the NOMAS in screening and identifying precocious oral-motor skills received inconsistent support. Moderate validity and low reliability emerged. Moreover, despite the NOMAS' adequately screen efficient and inefficient feeders, limited evidence emerged for predictive value of NOMAS score on feeding and psychomotor developmental trajectories during the first 2 years of age. The present review highlights benefits and limitations of the NOMAS. Future research is needed to develop observational and clinically-relevant tools to better identify newborns which are at lower- and higher-risk of developing less-than-optimal feeding behaviors and to guide with greater precision the diagnostic and therapeutic journey of these newborns. What is Known: • The assessment of oral-motor skills in newborns and infants is critical for early intervention • The NOMAS is the most adopted tool to assess oral-motor skills in newborns and infants What is New: • The ability of the NOMAS to target newborn at risk for feeding disorders is confirmed • Nonetheless, the capacity to predict long-term developmental outcomes is limited.


Results of cyproheptadine treatment in dogs with pituitary-dependent hyperadrenocorticism.
Administration of cyproheptadine for 2 months to five dogs with pituitary-dependent hyperadrenocorticism (PDH) at a dose rate of 0.3 mg/kg per 24 h (group 1) and to four dogs with PDH at a dose rate of 1 mg/kg per 24 h (group 2) did not result in any clinical improvement. The hyperadrenocorticoid state, as indicated by the circulating cortisol levels, the urinary corticosteroid excretion and the response of the hypothalamo-pituitary-adrenal axis to lysine-vasopressin, thyrotrophin releasing hormone and dexamethasone did not change consistently, although there was a tendency to normalization of some parameters in the dogs of group 2. However, these changes were not found to be consistent for each individual dog but were limited to one parameter per dog. It is concluded that cyproheptadine is not suitable for the treatment of PDH in the dog.


Evolutionary Constraints on the Norovirus Pandemic Variant GII.4_2006b over the Five-Year Persistence in Japan.
Norovirus GII.4 is a major cause of global outbreaks of viral gastroenteritis in humans, and has evolved by antigenic changes under the constantly changing human herd immunity. Major shift in the pandemic GII.4 strain periodically occurs concomitant with changes in the antigenic capsid protein VP1. However, how the newly emerged strain evolves after the onset of pandemic remains unclear. To address this issue, we examined molecular evolution of a pandemic lineage, termed the GII.4_2006b, by using the full-length viral genome and VP1 sequences (n = 317) from stools collected at 20 sites in Japan between 2006 and 2011. Phylogenetic tree showed a radial diversification of the genome sequences of GII.4_2006b, suggesting a rapid genetic diversification of the GII.4_2006b population from a few ancestral variants. Impressively, amino acid sequences of the variable VP1 in given seasons remained as homogeneous as those of viral enzymes under annual increase in the nucleotide diversity in the VP1 coding region. The Hamming distances between the earliest and subsequent variants indicate strong constraints on amino acid changes even for the highly variable P2 subdomain. These results show the presence of evolutionary constraints on the VP1 protein and viral enzymes, and suggest that these proteins gain near maximal levels of fitness benefits in humans around the onset of the outbreaks. These findings have implications for our understanding of molecular evolution, mechanisms of the periodic shifts in the pandemic NoV GII.4 strains, and control of the NoV GII.4 pandemic strain.


Lymphocyte subpopulations and immunoglobulin levels in Hodgkin's disease survivors.
We investigated the frequency of lymphocyte populations (CD3+ /T lymphocytes/, CD4+ /helpers/, CD8+ /suppressor and cytotoxic/, CD3- CD16+ /NK cells/, CD3+ HLA-DR+ /activated T lymphocytes/, and CD20+ /B lymphocytes/) and immunoglobulin G, A, M, and E levels in a group of two hundred twenty nine Hodgkińs disease long term survivors. The most frequent pathological findings were increased IgE levels, decreased CD3+ and CD4+ proportions, an increased CD20+ proportion and especially a low CD4/CD8 proportion. Decreased CD3+ and CD4+ and increased CD20+ proportions were more frequently found in the group with recurrent infections. IgM and IgA levels were positively correlated with plasmatic cholesterol and triacylglycerols levels. We suppose that immunological defects (increase of IgE levels, decreased T and helper lymphocytes) in Hodgkińs disease survivors are inherent and are not related to atopy. Examination of lymphocyte subpopulations may be helpful in the prediction of an increased risk of recurrent infections.


Evidence of differential phenotypic plasticity in a desert mustard.
Understanding the effect of the environment on trait variation is critical for ecologically and economically important plants. Here, we asked whether differences in soil moisture are a source of variation in Sahara mustard (Brassica tournefortii). We subjected common garden populations of plants derived from native, invasive, and landrace sources (ranges) to varying water addition treatments. Using principal component analysis, we generated composite variables of life history traits for ANCOVA tests and plotted norms of reaction. Planting time was included as a covariate because we observed differences in seedling emergence despite efforts to standardize germination. We also examined the population coefficient of variation of individual traits (plasticity) and the association of trait CVs with fitness. The amount of plasticity varied but was inconsistent among range sources for all composite traits. Planting time did not affect treatments, but plants from different ranges responded differently to variable planting times. With a surplus of water, plants derived from native and invasive populations plateaued in vegetative trait values but showed a continuous linear increase in reproductive trait values. Possibly as a result of domestication, moderate and high water treatments in landrace plants caused plateaus in composite trait values for flowering phenology, seed count, plant size, and branching. The ecological breadth shown by our plants is likely due to drought tolerance that evolved in Brassica tournefortii source populations.


[Formation of congenital defects during ocular development. II. Genetic background of oculogenesis and developmental birth defects].
The course of oculogenesis is genetically controlled by genes, that are selectively expressed in the developing eye. Many of them, first recognized in studies on model animals, such as fruit fly (Drosophila melanogaster) proved, that they play similar roles in humans. The crucial role in cascade of genetic control of oculogenesis plays a system of genes PAX6-EYA1/SIX3-DACH1. In this work there are described also other genes, that form a network of interactions and regulations, such as: BMP4, BMP7, OPTX2, SOX1, PAX2, PITX2, PAX3, CHX10 and other genes. Describing function of each gene, author presented simultaneously all known congenital defects and syndromes, that are caused by mutations of above mentioned genes, such as: aniridia, anophthalmia, Peters anomaly and others.


Research Reporting Guidelines in Dentistry: A Survey of Editors.
The use of reporting guidelines has an important role in the development of health research, improving the quality and precision of the publications. This study evaluated how dental journals use reporting guidelines. All editors of dental journals registered on the 2013 Journal Citation Reports list (n=81) were invited to participate. The data were collected by a self-reported web-based questionnaire. Information about the profile of journal/editor and on the use of reporting guidelines by journals was gathered. Information/recommendations about the use of reporting guidelines were collected from the websites of all journals. Data were descriptively analyzed and frequencies were summarized. Thirty-four (42%) editors completed the questionnaire. Most journals are members of Committee on Publication Ethics (64.7%) and/or follow the International Committee of Medical Journal Editors recommendations (20.6%), while 26.5% are not members of any editorial group. Most editors are unfamiliar with the EQUATOR Network (55.9%), do not work full time (85.3%) and 88.2% have some income/payment. Most of them received educational training for this position (55.9%). The CONSORT Statement was endorsed by 61.8% of journals. Information from websites showed that 44.4% journals do not recommend any reporting guideline, 51.9% mention CONSORT Statement in the website and 28.4% only recommend the use of CONSORT Statement. There is clearly room for improving the use of reporting guidelines in dental journals. Broadening the understanding and the endorsement/adherence/implementation of reporting guidelines by journals may promote quality and transparence of published dental research.


New advances in the treatment of hypogonadism in the aging male.
The signs and symptoms of low testosterone in the aging male include erectile dysfunction, decreased libido, mood disturbances such as depression, loss of muscle mass, osteoporosis, and increase in body fat. Many of these signs and symptoms were previously believed to be part of the normal aging process, and only recently has treatment of low testosterone in the aging male been shown to provide long-term physical and mental improvement. In the past, oral and injectable testosterone delivery methods had disadvantages that limited their use, but the introduction of transdermal testosterone patches has allowed testosterone to be delivered into the circulation in a consistent fashion. Long-term use of these patches over the last 3 to 10 years has been effective in maintaining sexual function and bone and muscle mass, and from short-term studies it does not appear that testosterone treatment puts men at risk for the development of prostate cancer. A new topical gel formation (Testim) has been designed to provide consistent transdermal absorption of testosterone over 24 hours after a single dose.


Combination of Immunofluorescence and Quantitative Fluorescence In-situ Hybridization for Analysing Differential Gene Expression in the Niche Cells of the Drosophila Lymph Gland.
The Drosophila larval haematopoietic organ or lymph gland consists of multiple cell types arranged in zones. The smallest stem cell compartment consists of 40-45 cells that constitute the haematopoietic niche. In order to analyse the haematopoietic niche, it needs to be labelled with a specific antibody to differentiate it from the other cell types. To characterise a phenotype, it is often necessary to investigate the expression of a gene in a particular stem cell compartment within the lymph gland. In such a situation, in-situ hybridization is performed, as it indicates the localization of gene expression. Although chromogenic in-situ hybridization enables us to compare the signal and tissue morphology simultaneously, it fails to harness the information related to the degree of gene expression. Dual immunofluorescence and in-situ hybridization (IF-FISH) serves as the powerful technique that helps to visualize both protein and mRNA expression within the same cell type. This technique also provides reliable quantification regarding mRNA expression levels. When dealing with a few cells within the organ, like the niche of the larval lymph gland, fluorescently labelled riboprobes allows us to localize and assess the magnitude of gene expression within the niche cells, which are also immunolabelled with a niche-specific marker, to distinguish them from the adjoining cell types.


Toward a community ecology of landscapes: predicting multiple predator-prey interactions across geographic space.
Community ecology was traditionally an integrative science devoted to studying interactions between species and their abiotic environments in order to predict species' geographic distributions and abundances. Yet for philosophical and methodological reasons, it has become divided into two enterprises: one devoted to local experimentation on species interactions to predict community dynamics; the other devoted to statistical analyses of abiotic and biotic information to describe geographic distribution. Our goal here is to instigate thinking about ways to reconnect the two enterprises and thereby return to a tradition to do integrative science. We focus specifically on the community ecology of predators and prey, which is ripe for integration. This is because there is active, simultaneous interest in experimentally resolving the nature and strength of predator-prey interactions as well as explaining patterns across landscapes and seascapes. We begin by describing a conceptual theory rooted in classical analyses of non-spatial food web modules used to predict species interactions. We show how such modules can be extended to consideration of spatial context using the concept of habitat domain. Habitat domain describes the spatial extent of habitat space that predators and prey use while foraging, which differs from home range, the spatial extent used by an animal to meet all of its daily needs. This conceptual theory can be used to predict how different spatial relations of predators and prey could lead to different emergent multiple predator-prey interactions such as whether predator consumptive or non-consumptive effects should dominate, and whether intraguild predation, predator interference or predator complementarity are expected. We then review the literature on studies of large predator-prey interactions that make conclusions about the nature of multiple predator-prey interactions. This analysis reveals that while many studies provide sufficient information about predator or prey spatial locations, and thus meet necessary conditions of the habitat domain conceptual theory for drawing conclusions about the nature of the predator-prey interactions, several studies do not. We therefore elaborate how modern technology and statistical approaches for animal movement analysis could be used to test the conceptual theory, using experimental or quasi-experimental analyses at landscape scales.


Decentering as a potential common mechanism across two therapies for generalized anxiety disorder.
The purpose of this study was to examine decentering as a potential mechanism of action across 2 treatments for generalized anxiety disorder: an acceptance-based behavioral therapy (ABBT) and applied relaxation (AR). Sixty-four individuals who completed at least half of the 16 total sessions of either ABBT or AR (65.6% female; 79.7% identified as White; average age = 34.41 years) completed measures of decentering (Experiences Questionnaire) and of symptoms of anxiety (Depression Anxiety Stress Scale-Stress subscale) at 5 time points over the course of therapy, and a measure of worry (Penn State Worry Questionnaire) at pre- and posttreatment. Initial growth curve models showed that decentering increased significantly over therapy (z = 7.09), and this increase was associated with a decrease in worry symptoms (Penn State Worry Questionnaire) at posttreatment (z = -8.51). The rate of change did not significantly vary across treatments, Δχ2/Δdf = 0.16/1, p = .69. Further, a series of bivariate latent difference score models indicated that the best-fitting model was one in which decentering was a leading indicator of change in symptoms (DASS-Stress). Allowing this coupling to vary across treatments did not significantly improve the fit of the model, Δχ2/Δdf = 0.71/1, p = .40. In this sample, results suggest that increased decentering was associated with decreases in anxiety and that changes in decentering appear to precede changes in symptoms within both ABBT and AR, indicating that decentering may be an important common mechanism of action. (PsycINFO Database Record


Partial cricotracheal resection for pediatric subglottic stenosis: long-term outcome in 57 patients.
We sought to assess the long-term outcome of 57 pediatric patients who underwent partial cricotracheal resection for subglottic stenosis. Eighty-one pediatric partial cricotracheal resections were performed in our tertiary care institution between 1978 and 2004. Fifty-seven patients had a minimal follow-up time of 1 year and were included in this study. Evaluation was based on the last laryngotracheal endoscopy, the responses to a questionnaire, and a retrospective review of the patient's data. The following parameters were analyzed: decannulation rates, breathing, voice quality, and deglutition. A single-stage partial cricotracheal resection was performed in 38 patients, and a double-stage procedure was performed in 19 patients. Sixteen patients underwent an extended partial cricotracheal resection (ie, partial cricotracheal resection combined with another open procedure). At a median follow-up time of 5.1 years, the decannulation rates after a single- or double-stage procedure were 97.4% and 95%, respectively. Two patients remained tracheotomy dependent. One patient had moderate exertional dyspnea, and all other patients had no exertional dyspnea. Voice quality was found to improve after surgical intervention for 1 +/- 1.34 grade dysphonia (P < .0001) according to the adapted GRBAS grading system (Grade, Roughness, Breathiness, Asthenia, and Strain). Partial cricotracheal resection provides good results for grades III and IV subglottic stenosis as primary or salvage operations. The procedure has no deleterious effects on laryngeal growth and function. The quality of voice significantly improves after surgical intervention but largely depends on the preoperative condition.


Diabetic-like corneal sensitivity loss in galactose-fed rats ameliorated with aldose reductase inhibitors.
This study investigated whether diabetic-like corneal sensory deficits occur in the galactose-fed rat model of diabetic ocular complications and if such deficits could be prevented using either of two structurally different aldose reductase (AR) inhibitors, CT-112 or AL-1576. S-D rats were randomly grouped to receive a diet of Purina chow with either 50% starch (n=25) or 50% D-galactose (n=65). Some of the galactosemic rats received either 0.25% CT-112 topically 3x daily (n=15) or 28 mg/kg body wt/day AL-1576 systemically (n=10). The control and untreated galactosemic rats in the CT-112 portion of the study received equivalent topical doses of the vehicle. Sensitivity measurements were made with a Cochet-Bonnet Aesthesiometer mounted on a micromanipulator. The filament was applied to the central corneal surface (mean pressure of 0.96 g/mm2) and viewed using a slit-lamp biomicroscope. Ten consecutive stimuli were conducted on each cornea and the average number of blink-responses was expressed as a percent of total stimuli effected. Mean initial corneal sensitivities were similar in all groups. Corneal sensitivity in the galactosemic rat was reduced (p<0.01) at each monthly measurement compared to control. Animals treated with CT-112 or AL-1576 showed a significant increase in the mean blink-response compared to untreated galactose-fed rats and did not differ significantly from controls towards the completion of the 7 month study. Animals treated with AL-1576 did not develop cataracts, whereas those treated topically with CT-112 and untreated galactose-fed rats developed bilateral nuclear cataracts within 3 weeks. This is the first study to demonstrate decreased corneal sensitivity in the galactose-fed rat model and its amelioration with AR inhibitors. Thus, aldose reductase, the first enzyme of the polyol pathway, may have an important role in the pathogenesis of decreased corneal sensitivity. The model could be useful for investigating the pathogenic mechanism(s) involved in reduced corneal sensitivity associated with diabetic keratopathy in humans.


Emergency medicine physicians' and pediatricians' use of computed tomography in the evaluation of pediatric patients with abdominal pain without trauma in a community hospital.
There is a paucity of data regarding emergency department (ED) provider type and computed tomography (CT) scan use in the evaluation of pediatric patients with abdominal pain without trauma. The purpose of this retrospective single community hospital study was to determine if there was a difference in CT use between emergency medicine physicians (EMPs) and pediatricians (PEDs) in all patients younger than 18 years with abdominal pain without trauma who presented to the ED during the study period. The study included 165 patients. EMPs saw 83 patients and used CT in 31 compared with PEDs who saw 82 patients and used CT in 12 (P = .002). EMPs used CT significantly more frequently than PEDs in the designated sample. Economic pressures may cause changes in ED provider type in community and rural hospitals and this study shows that ED provider type may affect medical decision making, including CT use.


Lisinopril improves arterial function in hyperlipidaemia.
Endothelial function is defective in hypercholesterolaemia, and animal models have suggested that angiotensin-converting enzyme inhibitors may prevent arterial damage. We studied the effect of 6 months treatment with lisinopril on endothelial function in a group of patients with hypercholesterolaemia. Forty patients were studied. Forearm blood flow responses to acetylcholine and sodium nitroprusside were assessed by venous occlusion plethysmography. Subjects were then randomized in a double-blind fashion to receive either lisinopril, 20 mg/day (n=20), or placebo (n=20) for 6 months. Plethysmography was then repeated. Baseline variables between groups were comparable. In the lisinopril group blood pressure fell significantly [systolic: 145+/-4 to 128+/-4 mmHg (P<0.001); diastolic: 84+/-2 to 74+/-2 mmHg (P<0.001)]. An improvement was found in the vasodilatory response (expressed as a ratio of the infused/control arm) to acetylcholine, e.g. 3.33+/-0.3 (pre) versus 4.45+/-0.48 (post) at 30 microg/ml (P<0.03), and also to nitroprusside, e.g. 3.0+/-0.2 (pre) versus 3.86+/-0.3 (post) at 3.2 microg/ml (P<0.01). In the placebo group vasodilatation did not change significantly in response to acetylcholine, and nitroprusside responses were unchanged. The data presented suggest that 6 months of lisinopril therapy have a beneficial effect on arterial function in subjects with hyperlipidaemia. Further work should now investigate whether angiotensin-converting enzyme inhibitors are beneficial in reducing mortality and morbidity in hypercholesterolaemia.


Therapeutic Hypothermia in ICUs.
Recent research on Therapeutic Hypothermia (TH) post cardiac arrest has raised questions about its implementation and benefits. TH to 32-34 degrees C is still included in international guidelines for post-cardiac arrest care. We investigated how Irish ICUs are utilising TH as part of their management of patients post cardiac arrest using a telephone survey of all Irish ICUs. All 25 ICUs in Ireland participated. As of quarter 2 2014, TH was part of post-cardiac arrest management in 20 ICUs (80%), which is similar to international figures. 2011 was the median year for units to start using TH in Ireland. Over half 13 (52%) of Irish ICUs have experience with cooling more than 10 patients. Despite lack of evidence for its benefit, 12 ICUs (48%) use TH for OHCA non VF-VT arrests. Lack of resources was cited by 2 ICUs (8%) as well as no local consensus by 1 ICU (4%) prevented a small minority adopting the protocol. Similar methods of inducing and maintaining TH were found in Ireland as with overseas. Interest was expressed in recent research on TH and in 2 ICUs local practice had changed because of it. An updated international resuscitation guideline is awaited.


Flavonoid Levels and Antioxidant Capacity of Mulberry Leaves: Effects of Growth Period and Drying Methods.
In recent years, various mulberry leaf dishes have gradually gained in popularity. The harvesting period of mulberry leaves and the preparation of dried samples are critical for the retention of flavonoid content and activity. In this study, changes in flavonoid levels in mulberry leaves during their growth period (3-6 months), and the effects of four different drying methods [sun drying (SD), air drying (AD), oven drying (OD), and freeze drying (FD)] on flavonoid accumulation and antioxidant capacity were determined. The results showed that mulberry leaves grown for 6 months had higher levels of flavonoids, and different drying methods could significantly affect the flavonoid levels and antioxidant capacity of the leaves. Air drying and FD were the best methods in terms of retaining the antioxidant activity of flavonoids, although AD had lower operating costs than FD in the production process. Therefore, to obtain a high flavonoid content and maximum antioxidant activity, AD is recommended for mulberry leaves.


Reference range for the pulsatility index ductus venosus Doppler measurement between 11 and 13 + 6 weeks of gestation in a Brazilian population.
To establish reference range for the pulsatility index (PI) ductus venosus (DV) Doppler measurement between 11 and 13 + 6 weeks of gestation in a Brazilian population. A retrospective cross-sectional study was performed with 430 singleton pregnancies. The PI DV Doppler measurement was performed as routine during the first trimester screening. DV was identified by color Doppler and the pulsed Doppler gate was placed in the distal portion of the umbilical sinus. When at least three typical DV waveforms were obtained, PI DV was measured manually in one waveform. Polynomial regression was used to obtain the best fit using PI DV Doppler measurement and crown-rump length (CRL) with adjustments by the determination coefficient (R(2)). 5th, 50th and 95th percentiles for the PI DV Doppler measurements at each gestational were determined. The mean of PI DV Doppler measurement was 1.1 ± 0.2 (range 0.8-3.7). The linear regression was the best fit: PI DV measurement = 1.288-0.0034*CRL (R(2 )= 0.03). Reference range for the PI DV Doppler measurement between 11 and 13 + 6 weeks of gestation in a Brazilian population was established.


Reovirus oncolysis: the Ras/RalGEF/p38 pathway dictates host cell permissiveness to reovirus infection.
Reovirus is a benign human virus that was recently found to have oncolytic properties and is currently in clinical trials as a potential cancer therapy. We have previously demonstrated that activation of Ras signaling, a common event in cancer, renders cells susceptible to reovirus oncolysis. In this study, we investigate which elements downstream of Ras are important in reovirus infection. By using a panel of NIH 3T3 cells transformed with activated Ras mutated in the effector-binding domain, we found that only the RasV12G37 mutant, which was unable to signal to Raf or phosphatidylinositol 3-kinase but retained signaling capability to guanine nucleotide-exchange factors (GEFs) for the small G protein, Ral (known as RalGEFs), was permissive to reovirus. Expression of the activated mutant of the RalGEF, Rlf, also allowed reovirus replication. Specific inhibition of the Ral pathway by using dominant-negative RalA rendered normally permissive H-Ras cells (cells expressing activated Ras) resistant to reovirus. To further identify elements downstream of RalGEF that promote reovirus infection, we used chemical inhibitors of the downstream signaling elements p38 and JNK. We found that reovirus infection was blocked in the presence of the p38 inhibitor but not the JNK inhibitor. Together, these results implicate a Ras/RalGEF/p38 pathway in the regulation of reovirus replication and oncolysis.


Effects of Ranibizumab and Aflibercept on Human Müller Cells and Photoreceptors under Stress Conditions.
Anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of retinal vascular diseases. However, constitutive VEGF also acts as a trophic factor on retinal nonvascular cells. We have studied the effects of aflibercept and ranibizumab on human Müller cells and photoreceptors exposed to starvation media containing various concentrations of glucose, with or without CoCl2-induced hypoxia. Cell survival was assessed by calcein-AM cell viability assays. Expression of heat shock proteins (Hsp) and redox proteins thioredoxin 1 and 2 (TRX1, TRX2) was studied by Western blots. The production of neurotrophic factors in Müller cells and interphotoreceptor retinoid-binding protein (IRBP) in photoreceptors was measured by enzymelinked immunosorbent assays. Aflibercept and ranibizumab did not affect the viability of both types of cells. Neither aflibercept nor ranibizumab affected the production of neurotrophic factors or expression of Hsp60 and Hsp90 in Müller cells. However, aflibercept but not ranibizumab affected the expression of Hsp60, Hsp9, TRX1 and TRX2 in photoreceptors. Aflibercept and ranibizumab both inhibited the production of IRBP in photoreceptors, aflibercept more so than ranibizumab. Our data indicates that the potential influence of aflibercept and ranibizumab on photoreceptors should be specifically monitored in clinical studies.


Gastric cancer staging with radiologic imaging modalities and UICC staging system.
There are two major stage classification systems for gastric cancer: the tumor-node-metastasis (TNM) stages by the International Union against Cancer (UICC) and the Japanese Classification of Gastric Carcinoma by the Japanese Gastric Cancer Association (JGCA). Preoperative stage classification using either of these systems is essential for deciding on the treatment strategy in the era of various multimodal therapeutic options. Evolution of multidetector computerized tomography with isotropic volumetric imaging and various 3D images has increased the accuracy of T and N staging in patients with gastric cancer, although detection of peritoneal deposits and nodal metastasis in the absence of lymphadenopathy remain problematic with the imaging tools currently available. The TNM and JGCA classifications have undergone revisions independent of each other, and the discrepancies were not helpful when international comparisons and cooperation were needed. More recently, the JGCA and TNM classifications were merged to have identical T and N categories, in addition to the more straightforward M categories that indicate the presence of distant metastasis. The result of these efforts is that researchers in Japan and the rest of the world are now looking at a similar disease when they discuss cancer that belongs to the same stage. A nomogram that incorporates other established prognostic determinants in addition to the TNM component may be a future direction for a more sophisticated means of predicting outcome. The increasing incidence of junctional (esophagogastric junction) cancer in the Far East has spurred researchers from this region to adequately stage the disease and to consider suitable treatment modalities for this disease entity, whereas Western researchers are more inclined to treat this disease as esophageal cancer. This could be an area for future international debate. For the next more accurate staging, we suggest the collaboration between Eastern and Western high-volume centers in gastric cancer because the inconsistency of surgical approaches, especially with respect to nodal resection, remains a barrier to mutual understanding.


Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells.
Fanconi anemia (FA) is an inherited DNA repair deficiency syndrome. FA patients undergo progressive bone marrow failure (BMF) during childhood, which frequently requires allogeneic hematopoietic stem cell transplantation. The pathogenesis of this BMF has been elusive to date. Here we found that FA patients exhibit a profound defect in hematopoietic stem and progenitor cells (HSPCs) that is present before the onset of clinical BMF. In response to replicative stress and unresolved DNA damage, p53 is hyperactivated in FA cells and triggers a late p21(Cdkn1a)-dependent G0/G1 cell-cycle arrest. Knockdown of p53 rescued the HSPC defects observed in several in vitro and in vivo models, including human FA or FA-like cells. Taken together, our results identify an exacerbated p53/p21 "physiological" response to cellular stress and DNA damage accumulation as a central mechanism for progressive HSPC elimination in FA patients, and have implications for clinical care.


Development and use of molecular markers: past and present.
Molecular markers, due to their stability, cost-effectiveness and ease of use provide an immensely popular tool for a variety of applications including genome mapping, gene tagging, genetic diversity diversity, phylogenetic analysis and forensic investigations. In the last three decades, a number of molecular marker techniques have been developed and exploited worldwide in different systems. However, only a handful of these techniques, namely RFLPs, RAPDs, AFLPs, ISSRs, SSRs and SNPs have received global acceptance. A recent revolution in DNA sequencing techniques has taken the discovery and application of molecular markers to high-throughput and ultrahigh-throughput levels. Although, the choice of marker will obviously depend on the targeted use, microsatellites, SNPs and genotyping by sequencing (GBS) largely fulfill most of the user requirements. Further, modern transcriptomic and functional markers will lead the ventures onto high-density genetic map construction, identification of QTLs, breeding and conservation strategies in times to come in combination with other high throughput techniques. This review presents an overview of different marker technologies and their variants with a comparative account of their characteristic features and applications.


The epidemiologic incidence of congenital gastroschisis in Western Australia.
The purpose of this study was to review the population incidence of congenital gastroschisis in Western Australia over the past 2 decades. A population-based incidence study of congenital gastroschisis from 1980 to 2001. Maternal and perinatal outcome data were collected to ascertain incidence, treatment, and outcome trends. One hundred twenty-two cases of gastroschisis were identified. The median maternal age was 23 years (range, 16-35 years). Women aged <20 years were at a 7.82 increased risk (95% CI, 4.34-14.08); women aged 20 to 24 years were at a 3.24 increased risk (95% CI, 1.88-5.61) for fetal gastroschisis compared with women aged >or=25 years. An incidence analysis over time indicated a significant increase of gastroschisis cases from 1 of 10,000 births during the period 1980-1990 to the current rate of 2.4 of 10,000 births (P<.001). The perinatal mortality rate was 12.7% (95% CI, 8.7-16.7) with a 9.8% stillbirth rate (95% CI, 6.3-13.3). There has been a sustained increase in the birth incidence of gastroschisis over the past decade, particularly in teenage women. A significant fetal death rate in the third trimester is observed.


A dominant negative c-jun specifically blocks okadaic acid-induced skin tumor promotion.
Okadaic acid (OA) is a prototypical non-phorbol ester skin tumor-promoting agent that works by inhibiting protein phosphatases, leading to an increase in protein phosphorylation. Increased protein phosphorylation can lead to stimulated signaling through various signal transduction pathways. One or more of the pathways affected by OA leads to increased signaling via the activator protein 1 (AP-1) transcription factor. Because AP-1 signaling has been shown to be required for skin tumor promotion by phorbol ester, studies were undertaken to determine whether AP-1 signaling is also required for 7,12-dimethylbenz(a)anthracene (DMBA)-initiated/OA-promoted skin tumorigenesis. Transgenic mice expressing a dominant negative c-jun (TAM-67) controlled by the keratin 14 promoter in ICR mice were used to determine the effects of OA on AP-1 signaling. By crossing the TAM-67 mice with mice expressing an AP-1-responsive luciferase, it was shown that TAM-67 decreases AP-1 activation in response to OA treatment by 95%. After 7,12-dimethylbenz(a)anthracene initiation, the TAM-67 mice and nontransgenic littermates were promoted with twice weekly applications of OA. These experiments showed that TAM-67 expression decreased tumor multiplicity by 90%. Additional experiments with TAM-67 mice showed that the hyperplastic response to OA is not impaired in these mice, nor were there differences in OA-induced transcription of various genes known to be AP-1 responsive under other conditions. This result suggests that only a subset of AP-1-regulated genes is targeted by TAM-67 when it prevents tumor promotion by OA. A determination of the mechanism by which TAM-67 can block tumor promotion without affecting hyperplasia will be important.


Adapted Physical Activity Can Increase Life Appreciation in Patients with Parkinson's Disease.
Objectives:This study aimed to measure the effect of a treatment of adapted physical activity (APA) on motor symptoms and on positive psychological resources in a group of patients with PD. Methods: 37 patients with PD (Mage= 71.5; 70.3% male) completed measures of disability level, motor performance, distress, well-being, and quality of life before and after participating in a program of APA (duration: 7 months). Analysis of variance - repeated measures was performed to evaluate the effect of APA on disability, distress, and well-being. Results: After intervention, patients reported significant improvements in their motor autonomy, disability level, psychological distress, and in life appreciation. Discussion: A brief physical activity program was beneficial not only to patients' motor functioning, but also to their mental health, by reducing distress and promoting life appreciation.


The treatment of V2 + V3 idiopathic trigeminal neuralgia using peripheral nerve radiofrequency thermocoagulation via the foramen rotundum and foramen ovale compared with semilunar ganglion radiofrequency thermocoagulation.
To compare the advantages and disadvantages of V2 + V3 idiopathic trigeminal neuralgia using peripheral nerve radiofrequency (RF) thermocoagulation (PRF) via the foramen rotundum (FR) and foramen ovale (FO) with those of semilunar ganglion RF thermocoagulation (GRF) under local anesthesia, for exploring a new and available surgical method for patients with V2 + V3 idiopathic trigeminal neuralgia. 102 patients with V2 + V3 idiopathic trigeminal neuralgia were enrolled in this prospective randomized controlled clinical trial, and they were divided into the PRF and GRF group randomly (n = 51 in both groups). The outcome of pain relief was assessed using the Barrow Neurological Institute (BNI) pain score, and grouped as good (BNI Class I or II, no medication required) and bad (BNI Class III-V, medication required or failed). Recurrence was defined as a relapse to a previous lower level after attainment of any higher level of pain relief. The immediate effective rate, the 2-year postoperative effective rate, the 2-year postoperative recurrence rate, and the number of complications were observed and recorded. Their basic conditions (age, gender ratio, side of pain, and disease duration) were similar. Furthermore, we found that the 2-year postoperative effective rate between them had no significant difference. By comparing the two groups, PRF group had the better immediate effective rate of the V2 branch and no severe complications such as corneal ulcer, however, GRF group had lower 2-year postoperative recurrence rate of the V3 branch and fewer facial swelling. The PRF surgery, like GRF, is another prospective treatment for V2 + V3 idiopathic trigeminal neuralgia by virtue of its excellent immediate effect, accurate positioning and high safety.


Tolerance studies with brotizolam in hospitalized patients.
A long-term study of brotizolam (minimum 4 weeks: maximum 26 weeks) was carried out in hospitalized patients (29 to 95 years) who complained of sleep disturbance. 3.0% of the patients used 0.125 mg, 86.4% used 0.25 mg, and 10.0% used 0.5 mg daily. During the trial there was no evidence of tolerance. There were no symptoms of overdosage, physical and psychological dependency or withdrawal, and there were no interactions with the concurrently prescribed drugs. There were no changes in vital functions, haematology, or in the biochemical investigations of blood or urine which could be attributed to the drug.


Effect of aspirin on bleeding time during elective abortion.
The template bleeding time, indicative of a predictable measure of potential blood loss due to altered platelet function, is unaffected by pregnancy or by the first stage of labor. Two tablets of aspirin (650 mg), but not sodium salicylate or acetaminophen, significantly prolongs the template bleeding time for at least 26 hours after consumption in patients undergoing first or second trimester induced abortion. Patients anticipating induced pregnancy interruption should refrain from any aspirin consumption for at least 26 hours prior to abortion.


Mediastinal follicular dendritic cell sarcoma with paraneoplastic pemphigus.
Follicular dendritic cell sarcoma is a rare neoplasm of immune accessory cells. It occurs primarily in lymph nodes. Occurrences in the mediastinum are rarely reported. Diagnosis and management of follicular dendritic cell sarcoma remain unclear, and it is an under-recognized clinical entity. Only a few cases of paraneoplastic pemphigus as the first presentation of follicular dendritic cell sarcoma have been reported. We report an unusual case of follicular dendritic cell sarcoma of the anterior mediastinum, presenting as paraneoplastic pemphigus in a 62-year-old man. Typical histological features confirmed the diagnosis of follicular dendritic cell sarcoma, and surgical resection was successfully performed.


Semliki Forest virus induced, immune mediated demyelination: the effect of irradiation.
Intraperitoneal infection with the avirulent A7(74) strain of the alphavirus Semliki Forest virus (SFV) induces an immune mediated demyelinating encephalomyelitis. The blood and brain virus titres, the serum antibody titres and the histopathological changes in the brains of normal mice and mice immunosuppressed with 5.0 or 8.0 Gy total body irradiation (TBX) were determined. SFV infection of immunosuppressed mice resulted in persistently high blood and brain virus titres, neuronal pycnosis, paralysis and death. No demyelination or central nervous system (CNS) inflammatory response occurred in these immunosuppressed mice despite high and persistent brain virus titres. The CNS inflammatory response and associated demyelination could be restored to infected immunosuppressed mice by adoptive transfer of spleen cells, and these changes were brought forward if the donor spleen cells were from mice previously sensitized to SFV. The results indicate that the immune response following SFV A7(74) infection is both protective and pathogenic, and that the demyelination is immune mediated and does not result from direct viral destruction of oligodendrocytes, or any other direct effect of the virus.


Maternal, fetal and perinatal characteristics of preeclampsia cases with and without abnormalities in uterine artery Doppler indexes.
To compare the maternal and fetal characteristics and perinatal outcome in mild and severe preeclampsia cases with and without uterine artery Doppler abnormalities. Two hundred and fifty-nine mild and severe preeclampsia cases were evaluated retrospectively. Doppler measurements were done in the section where uterine artery raised from the hypogastric artery. Pulsatility index above the 95th percentile of the corresponding gestational age was accepted as abnormal. In mild and severe preeclampsia cases with abnormal Doppler (AD), the rate of intrauterine growth restriction, preterm birth and low birth weight was higher than, but the neonatal intensive care unit stay was similar to the cases with normal Doppler. Base excess was higher in the AD group, in mild and severe preeclampsia. The rate of low Apgar score at 5 min and perinatal mortality was higher in the AD group, in the mild preeclampsia. The strongest independent predictor of the perinatal morbidity and mortality was the presence of prematurity and of the prematurity was the presence of abnormal uterine artery Doppler. Maternal and perinatal morbidity and perinatal mortality increase in mild to severe preeclampsia cases with abnormal uterine artery Doppler. The abnormal uterine artery Doppler increases the morbidity and mortality by increasing the risk of prematurity.


Expectations of health care quality among rural Maya villagers in Sololá Department, Guatemala: a qualitative analysis.
Indigenous populations in Latin America have worse health outcomes than their nonindigenous counterparts. Differences in access to and use of biomedical resources may explain some of the observed disparities. Efforts to address these differences could be aided in part by better understanding the socio-medical contexts in which they occur. We performed a qualitative analysis of field notes collected during a 2008 program evaluation of a health post in a rural Maya village in Sololá Department, Guatemala. Forty-one interviews were conducted among a community-based convenience sample of adult men and women. Interviews focused on experiences, perceptions, and behaviors related to the local biomedical and ethnomedical health care resources. Penetrance of the local health post was high, with most (90%) of respondents having accessed it within the prior five years. The prevailing attitude toward the health post was positive. We identified facilitators and barriers to health post use that corresponded with three thematic areas: clinic operations, visits and consultations, and medical resources. Proximity to the home, free consultations and medications, and social support services were among the most commonly cited facilitators. Barriers included limited clinic hours, medication stock-outs, provision of care that did not meet patient expectations, and unavailability of diagnostic tests. In a rural Maya community in Guatemala, operational and quality-based factors, independent of sociocultural considerations, informed the perception of and decision to access biomedical resources. Interventions that address these factors may increase health care utilization and alleviate some of the health disparities that accompany indigeneity in Guatemala and similar contexts.


Chronic oral nicotine administration and withdrawal regulate the expression of neuropeptide Y and its receptors in the mesocorticolimbic system.
Neuropeptide Y (NPY) and its receptors are involved in the regulation of mood, stress, and anxiety. In parallel, NPY signaling may play a vital role in the negative affective state induced by drug withdrawal. This study examined the changes in the transcript levels of NPY, Y1, Y2, and Y5 receptors in the mesocorticolimbic system during chronic nicotine exposure and withdrawal. Rats were administered with nicotine (initial dose: 25 μg/ml, maintenance dose: 50 μg/ml, free base) in drinking water for 12 weeks. Control group received only tap water. In the final week of the study, some of the nicotine-treated animals continued to receive nicotine (0-W), whereas some were withdrawn for either 24 (24-W) or 48 (48-W) h. All animals were decapitated after the evaluation of somatic signs (frequency of gasps, eye blinks, ptosis, shakes, teeth chatter) and the duration of locomotor activity and immobility. mRNA levels of NPY, Y1, Y2, and Y5 receptors in the mesocorticolimbic system were measured by quantitative real-time PCR (qRT-PCR). Results showed that nicotine withdrawal increased overall somatic signs. Moreover, chronic nicotine treatment increased the duration of locomotor activity, whereas withdrawal increased the duration of immobility. qRT-PCR analysis revealed that chronic nicotine treatment increased NPY mRNA levels in the hippocampus. On the other hand, 24- and 48-h withdrawals increased NPY mRNA levels in the amygdala and medial prefrontal cortex (mPFC), Y1 and Y2 mRNA levels in the nucleus accumbens and mPFC, and Y5 mRNA levels in the mPFC. These findings suggest that nicotine withdrawal enhances NPY signaling in the mesocorticolimbic system, which could be an important mechanism involved in regulating the negative affective state triggered during nicotine withdrawal.


The role of the implementation of policies for the prevention of exposure to Radon in Brazil-a strategy for controlling the risk of developing lung cancer.
Lung cancer is the leading cause of cancer death in the United States and other industrialised countries. The most important risk factor is active smoking. However, given the increased incidence of lung cancer in non-smokers, it is necessary to improve knowledge regarding other risk factors. Radon (Rn) is a noble gas and is the most important natural source of human exposure to ionizing radiation. Exposure to high levels of this radioactive gas is related to an increased risk of developing lung cancer. The objective of this work is to highlight the importance of measuring indoor concentration of this gas and identify which steps should be taken for achieving radiological protection. A survey was conducted on the websites of the National Health Surveillance Agency (ANVISA), LAMIN (Mineral Analysis Laboratory), CPRM (Geological Survey of Brazil), Ministry of Health and PubMed. Using the words 'radon', 'lung', 'cancer', and PubMed®, 1,371 results were obtained; when using the words 'radon', 'lung', 'cancer', and with 'Brazil' or 'Brazilians', only six results were obtained. We emphasise that lung cancer is a major public health problem and the exposure to Rn indoors should be considered as a risk factor for lung cancer in non-smokers. Buildings or houses with high concentrations of Rn should be identified. However, currently in Brazil-a country with great potential for mineral extraction-there are no specific regulated recommendations to control indoor exposure to Rn.


Endothelial Cell Senescence Exacerbates Pulmonary Fibrosis Potentially Through Accelerated Endothelial to Mesenchymal Transition.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by progressive lung fibrosis and obliteration of normal alveolar structures. Myofibroblasts play a central role in the progression of IPF by producing excess amount of extracellular matrix, and these myofibroblasts show heterogenous origins including resident fibroblasts, epithelial cells via epithelial to mesenchymal transition (EMT) and endothelial cell (EC) via endothelial to mesenchymal transition (EndMT). Although lung aging has been considered as essential mechanisms through abnormal activation of epithelial cells and fibroblasts, little is known about a role of EC senescence in the pathogenesis of IPF. Here, we reveal a detrimental role of EC senescence in IPF by utilizing unique EC-specific progeroid mice. EC-specific progeroid mice showed deteriorated pulmonary fibrosis in association with an accelerated EndMT in the lungs after intratracheal bleomycin instillation. We further confirmed that premature senescent ECs were susceptible to EndMT in vitro. Because senescent cells affect nearby cells through senescence-associated secretory phenotype (SASP), we assessed a potential role of the EC-SASP in EMT and myofibroblastic transition of resident fibroblasts. EC-SASP enhanced the myofibroblastic transition in resident fibroblasts, while no effect was detected on EMT. Our data revealed a previously unknown role of EC senescence in the progression of IPF, and thus rejuvenating ECs and/or inhibiting EC-SASP is an attracting therapeutic strategy for the treatment of IPF.


Long non-coding RNA-targeting therapeutics: discovery and development update.
lncRNAs are major players in regulatory networks orchestrating multiple cellular functions, such as 3D chromosomal interactions, epigenetic modifications, gene expression and others. Due to progress in the development of nucleic acid-based therapeutics, lncRNAs potentially represent easily accessible therapeutic targets. Currently, significant efforts are directed at studies that can tap the enormous therapeutic potential of lncRNAs. This review describes recent developments in this field, particularly focusing on clinical applications. Extensive druggable target range of lncRNA combined with high specificity and accelerated development process of nucleic acid-based therapeutics open new prospects for treatment in areas of extreme unmet medical need, such as genetic diseases, aggressive cancers, protein deficiencies, and subsets of common diseases caused by known mutations. Although currently wide acceptance of lncRNA-targeting nucleic acid-based therapeutics is impeded by the need for parenteral or direct-to-CNS administration, development of less invasive techniques and orally available/BBB-penetrant nucleic acid-based therapeutics is showing early successes. Recently, mRNA-based COVID-19 vaccines have demonstrated clinical safety of all aspects of nucleic acid-based therapeutic technology, including multiple chemical modifications of nucleic acids and nanoparticle delivery. These trends position lncRNA-targeting drugs as significant players in the future of drug development, especially in the area of personalized medicine.


LDLR-Gene therapy for familial hypercholesterolaemia: problems, progress, and perspectives.
Coronary artery diseases (CAD) inflict a heavy economical and social burden on most populations and contribute significantly to their morbidity and mortality rates. Low-density lipoprotein receptor (LDLR) associated familial hypercholesterolemia (FH) is the most frequent Mendelian disorder and is a major risk factor for the development of CAD. To date there is no cure for FH. The primary goal of clinical management is to control hypercholesterolaemia in order to decrease the risk of atherosclerosis and to prevent CAD. Permanent phenotypic correction with single administration of a gene therapeutic vector is a goal still needing to be achieved. The first ex vivo clinical trial of gene therapy in FH was conducted nearly 18 years ago. Patients who had inherited LDLR gene mutations were subjected to an aggressive surgical intervention involving partial hepatectomy to obtain the patient's own hepatocytes for ex vivo gene transfer with a replication deficient LDLR-retroviral vector. After successful re-infusion of transduced cells through a catheter placed in the inferior mesenteric vein at the time of liver resection, only low-level expression of the transferred LDLR gene was observed in the five patients enrolled in the trial. In contrast, full reversal of hypercholesterolaemia was later demonstrated in in vivo preclinical studies using LDLR-adenovirus mediated gene transfer. However, the high efficiency of cell division independent gene transfer by adenovirus vectors is limited by their short-term persistence due to episomal maintenance and the cytotoxicity of these highly immunogenic viruses. Novel long-term persisting vectors derived from adeno-associated viruses and lentiviruses, are now available and investigations are underway to determine their safety and efficiency in preparation for clinical application for a variety of diseases. Several novel non-viral based therapies have also been developed recently to lower LDL-C serum levels in FH patients. This article reviews the progress made in the 18 years since the first clinical trial for gene therapy of FH, with emphasis on the development, design, performance and limitations of viral based gene transfer vectors used in studies to ameliorate the effects of LDLR deficiency.


Morphometric evaluation of stromal vascularization in the endometrium in adenomyosis.
A computerized morphometric investigation of stromal vascularization in the endometrium during adenomyosis was performed retrospectively. Using a polyclonal antibody and a peroxidase-antiperoxidase method, formalin-fixed paraffin sections of the tissue were stained for von Willebrand factor, a marker for endothelium. The subjects were divided into two groups: 42 patients with histologically proven adenomyosis and 29 fertile control subjects, 12 in the proliferative phase and 17 in the secretory phase. Objective quantitative colour image analysis was used to assess the staining intensity and hence the degree of vascularization. In the control group, stromal vascularization increased in the secretory phase. In adenomyosis, vascularization increased markedly, up to 11.6 times that of the controls, in terms of the in total surface area of capillaries per mm2 in the endometrium in the proliferative phase. These findings suggest clinical relevance to severe functional disturbances such as hypermenorrhoea or iron deficiency anaemia.


Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure.
To investigate the importance of splanchnic ischemia in patients with acute circulatory failure by comparing gastric intramucosal pH as measured by tonometry with conventional methods of assessing adequacy of tissue oxygenation. Prospective cohort of patients with acute circulatory failure in first 24 hours after admission to the intensive care unit. Two general intensive care units in London, England. Consecutive sample of 83 patients of varying diagnostic categories that required pulmonary artery catheterization. Gastric intramucosal pH and hemodynamic, oxygen transport, and metabolic variables were measured on admission and at 12 hours and 24 hours after admission. Prediction of outcome (death or survival) by each measurement was assessed by sensitivity, specificity, and logistic regression analysis. Mean 24-hour Acute Physiology and Chronic Health Evaluation (APACHE II) score was 20.3. There were significant differences in mean gastric intramucosal pH between survivors and nonsurvivors on admission and at 24 hours, (7.40 vs 7.28, 7.40 vs 7.24, respectively; P < .001). Admission heart rate was higher (116 vs 101 beats per minute; P < .003) and mean arterial pressure lower (82 vs 97 mm Hg; P < .01) in nonsurvivors. There were no consistent differences in cardiac index, oxygen delivery, and oxygen uptake between survivors and nonsurvivors. Admission arterial pH was significantly lower (7.3 vs 7.36; P < .003), base excess more negative (-5.3 vs -1.9; P < .001), and lactate concentration higher (3.14 vs 1.91 mmol/L; P < .03) in nonsurvivors. Gastric intramucosal pH had a sensitivity of 88% for predicting death and a likelihood ratio of 2.32, higher than for any other variable. Only gastric intramucosal pH at 24 hours independently predicted outcome. Gastric intramucosal pH was the most reliable indicator of adequacy of tissue oxygenation in this group of patients. Inadequate regional blood flow as detected by a reduction in gastric intramucosal pH, but not by systemic measures, is an important contributor to morbidity and mortality in intensive care units.


A Method for Integrating Healthcare Provider Organization and Research Sponsor Systems and Workflows to Support Large-Scale Studies.
Healthcare provider organizations (HPOs) increasingly participate in large-scale research efforts sponsored by external organizations that require use of consent management systems that may not integrate seamlessly with local workflows. The resulting inefficiency can hinder the ability of HPOs to participate in studies. To overcome this challenge, we developed a method using REDCap, a widely adopted electronic data capture system, and novel middleware that can potentially generalize to other settings. In this paper, we describe the method, illustrate its use to support the NIHAll of Us Research Program and PCORI ADAPTABLE studies at our HPO, and encourage other HPOs to test replicability of the method to facilitate similar research efforts. Code is available on GitHub at https://github.com/wcmc-research-informatics/.


Evolving concepts in prognostic scoring of chronic GvHD.
Chronic GvHD (cGvHD) remains one of the most complex and challenging complications after allogeneic hematopoietic cell transplantation. Emerging knowledge about the clinical manifestations and associated organ involvement of cGvHD has led to the establishment of prognostic parameters for post-transplant survival among affected allograft recipients. Studies employing the pre-National Institutes of Health (NIH) consensus data on cGvHD incidence and its risks have led to development of the CIBMTR's cGvHD risk stratification, which serves as the most refined and validated prognostic tool for estimating survival of patients with cGvHD. However, cGvHD global severity scoring has recently evolved as a powerful prognostic tool for patient survival in the post-NIH consensus era. Current use of the substantially redefined NIH criteria of cGvHD diagnosis and measurements of its severity makes it challenging to interpret prognostic scoring systems generated in the pre-NIH era. Some of the pre-NIH prognostic parameters, however, appear to retain their significance in predicting survival independently from the NIH global severity score. Thus, future analyses of prospective cohorts of patients with cGvHD defined by NIH consensus criteria will be critical in reconciling and integrating various prognostic scoring systems of cGvHD.


Preliminary Validation for the "BJR method"-A Possible New Mathematical Approach to Methadone Conversion.
Methadone has been effectively utilized in the palliative care setting as a second-line agent for pain management in cancer patients with refractory pain, or in those who cannot tolerate other opioid medications. The lack of reliable dosing ratios, substantial interindividual variability in methadone pharmacodynamics, the potential for extensive drug interactions, and the high potency of methadone compared with other opioids all pose significant barriers to the use of this drug in routine practice. This article describes a novel approach to methadone conversion, with case studies providing preliminary validation.


All-Digital Galvanically-Coupled BCC Receiver Resilient to Frequency Misalignment.
It is promising for wearable devices to go to a miniature size to alleviate the load of human body. One way to miniaturize the communication nodes on human body is to remove the bulky components such as antenna and crystal. Galvanically-coupled body channel communication (GC-BCC) has a great advantage over conventional wireless communications in reducing the size of wearable devices because it reuses the monitoring electrodes for signal transmission in place of antennas. To remove the crystal as well, the receiver must be immune to different types of frequency misalignments. This paper presents a GC-BCC receiver based on low power all-digital Gaussian frequency shift keying (GFSK) demodulation and clock-data recovery (CDR). A carrier tracking technique is proposed to detect and automatically adapt to the misalignment of carrier frequency. In addition, we also propose a circle-index CDR circuit to deal with the inaccuracy or drift of the clock frequency. The proposed circuit is implemented with 0.18 μm CMOS technology, and it operates at 200 kHz with a BFSK/GFSK modulation index of 1.0. Measured results show that the chip consumes 0.53 mA at a data rate of 100 kb/s. At a 10 cm body channel length, the GC-BCC receiver can tolerate a carrier misalignment up to [Formula: see text] and a clock error up to [Formula: see text], while keeping the bit error rate (BER) below 0.1%.


Association of self-reported symptoms with serum levels of vitamin D and multivariate cytokine profile in healthy women.
Although a large number of studies have investigated possible relationships among serum levels of vitamin D or cytokines with disease progress and prognosis, similar studies on self-reported symptoms are still controversial. The overall objective of this study was to look into the association between serum levels of vitamin D or cytokines with self-reported symptoms related to musculoskeletal pain, sleep disorders, and premenstrual syndrome (PMS) in healthy adult women. Venous blood samples were collected from 117 healthy adult women, and serum levels of vitamin D, pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17, IFN-γ, and TNF-α) and anti-inflammatory cytokines (IL-4, IL-10, and IL-13) were measured. Groups were tested for differences in single parameters, pro-:anti-inflammatory cytokine ratios, and differences in multivariate patterns. There were no significant associations between serum levels of vitamin D and any of the self-reported symptoms studied. However, serum levels of certain pro-inflammatory cytokines were significantly higher in subjects with musculoskeletal pain (IL-8, P=0.008), sleep disorders (IFN-γ, P=0.02), and PMS (IL-8 and TNF-α, P=0.009 and 0.002, respectively) compared to subjects who reported no symptoms. The pro-:anti-inflammatory cytokine ratios showed pro-inflammatory cytokine dominance in subjects with self-reported symptoms, particularly in the groups with deficient levels of vitamin D. However, the multivariate cytokine-pattern analysis was significantly different between PMS groups only. These data point to a possible role of pro-inflammatory cytokines as a contributing factor in self-reported symptoms related to musculoskeletal pain, sleep disorders, and PMS.


Differential effects of distraction during working memory on delay-period activity in the prefrontal cortex and the visual association cortex.
Maintaining relevant information for later use is a critical aspect of working memory (WM). The lateral prefrontal cortex (PFC) and posterior sensory cortical areas appear to be important in supporting maintenance. However, the relative and unique contributions of these areas remain unclear. We have designed a WM paradigm with distraction to probe the contents of maintenance representations in these regions. During delayed recognition trials of faces, selective interference was evident behaviorally with face distraction leading to significantly worse performance than with scene distraction. Event-related fMRI of the human brain showed that maintenance activity in the lateral PFC, but not in visual association cortex (VAC), was selectively disrupted by face distraction. Additionally, the functional connectivity between the lateral PFC and the VAC was perturbed during these trials. We propose a hierarchical and distributed model of active maintenance in which the lateral PFC codes for abstracted mnemonic information, while sensory areas represent specific features of the memoranda. Furthermore, persistent coactivation between the PFC and sensory areas may be a mechanism by which information is actively maintained.


Tissue patterning in the developing mouse limb.
The developing mouse fore- and hindlimbs begin as bumps on the flank of the embryo and grow out to form miniature models of the adult limb during a five day period from E9.5 to E14.5. In this paper I show a series of embryos taken at half-day intervals during limb development and outline the timetable of patterning for each of the component tissues of a limb: epidermis, connective tissues, muscle, nerves and blood vessels. Scanning electron micrographs, supplemented by histological sections, are presented to define a set of standard stages for the description of mouse limb development. I discuss my observations of the mouse limb in the light of current theories of vertebrate limb development, which are based on classic manipulation experiments in the chick as well as more recent molecular data from the mouse system. The limb skeletal pattern in a mouse is laid down in a proximodistal direction, as it is in a bird: the E11.5 forelimb reveals the first signs of a humerus and by E14.5 even the most distal phalanges of the hand are formed. At this late stage ossification sleeves are seen around the proximal limb elements as the cartilage template begins to be converted to a bony skeleton. Myogenic cells stainable with the MF20 antibody against early muscle myosin heavy chain are first seen in the mouse forelimb at E11.5, which is also when the first nerve fascicles begin to enter the limb. From E11.5 to E14.5 both muscle and nerve patterns mature to give distinct muscles at all proximodistal levels of the limb, each muscle with its own nerve branch, and a cutaneous nerve plexus that extends to the fingertips. The developing skin of the mouse limb matures from a bi-layered epidermis overlying an avascular, but otherwise nondescript, prospective dermal layer of mesenchyme at E9.5, to a 4- or 5-layered epidermis with early hair placodes and the first signs of a distinct dermal layer at E14.5. Notable differences between mouse and chick limb development lie in the relatively late formation of the apical ectodermal ridge in the mouse and its unexpectedly close relations with blood vessels, in the absence of anterior and posterior necrotic zones and, possibly, in a late migration of myogenic cells into the mouse limb bud.


Differential degradation rates in vivo and in vitro of biocompatible poly(lactic acid) and poly(glycolic acid) homo- and co-polymers for a polymeric drug-delivery microchip.
The biocompatibility and biodegradation rate of component materials are critical when designing a drug-delivery device. The degradation products and rate of degradation may play important roles in determining the local cellular response to the implanted material. In this study, we investigated the biocompatibility and relative biodegradation rates of PLA, PGA and two poly(lactic-co-glycolic acid) (PLGA) polymers of 50:50 mol ratio, thin-film component materials of a drug-delivery microchip developed in our laboratory. The in vivo biocompatibility and both in vivo and in vitro degradation of these materials were characterized using several techniques. Total leukocyte concentration measurements showed normal acute and chronic inflammatory responses to the PGA and low-molecular-weight PLGA that resolved by 21 days, while the normal inflammatory responses to the PLA and high-molecular-weight PLGA were resolved but at slower rates up to 21 days. These results were paralleled by thickness measurements of fibrous capsules surrounding the implants, which showed greater maturation of the capsules for the more rapidly degrading materials after 21 days, but less mature capsules of sustained thicknesses for the PLA and high-molecular-weight PLGA up to 49 days. Gel-permeation chromatography of residual polymer samples confirmed classification of the materials as rapidly or slowly degrading. These materials showed thinner fibrous capsules than have been reported for other materials by our laboratory and have suitable biocompatibility and biodegradation rates for an implantable drug-delivery device.


Micro to nanoneedles: a trend of modernized transepidermal drug delivery system.
The transdermal route of drug delivery is convenient, pain-free and follows controlled rate release pattern. However, many therapeutically active drugs cannot cross the stratum corneum effectively. Lipophilic drugs like nifedipine cross the outer skin barrier easily and polar drugs, such as epinephrine are ineffective in showing the same effect. Due to these reasons, advancements in drug delivery have taken place to deliver a wide range of drugs, especially macromolecules through the transdermal route and directly into systemic circulation bypassing hepatic metabolism and GIT degradation. So there is a need for advanced drug delivery systems like microneedles and nanoneedles through transdermal route. These tiny needles will also serve as non-toxic, safe and stable systems for advanced drug delivery. Thus, macro to nanoformulation is the fast emerging fields nowadays. These have additional advantages to transdermal patches, such as better penetration, permeation, controlled release and direct delivery to the cytoplasm.


Spontaneous Emulsification as a Function of Material Exchange.
Direct visualization at 1873 K of 0% to 8% molten FeAl droplets suspended in a SiO2 enriched oxide medium was carried out to image the evolution of droplet morphology during reaction between Al and SiO2. Phenomena such as perturbation growth, necking and budding of offspring droplets from a bulk body are observed. The observations are used to discuss and inform a new approach to the nature of interfacial tension and the impact this has on concepts used to define interfacial tension for a two phase system with material exchange across the interface. The mapping of global interfacial tension coupled with free energy dissipation has been used to give an energetic reasoning as to the behaviour seen with respect to aluminium content in the metal phase.


Simultaneous ultrafiltration and affinity sorptive separation of proteins in a hollow fiber membrane module.
A protein separation scheme combining affinity or ion exchange sorption with hollow fiber cross-flow filtration is described. Sorptive gel particles were loaded into the shell side of a hollow fiber membrane module. In the adsorption step, crude protein mixtures were passed through the lumen and permeating proteins passed through the membrane to bind on the gel particles in the shell. During elution, a buffer of adequate ionic strength to desorb the bound proteins was passed through the lumen and permeated through the shell. The eluant was then collected at the outlet to the shell of the hollow fiber module. The concept is illustrated by two examples: the purification of butyrylcholinesterase (EC 188.8.131.52) from raw horse serum using the affinity gel procainamide-Sepharose as the packing and the separation of carboxylesterase (EC 188.8.131.52) from beef liver homogenate using DEAE-Sephadex as the packing. The technique has the advantage of high volumetric throughputs typical of hollow fiber membrane modules as well as the high capacity characteristic of chromatographic packings. In addition, cross-flow filtration of particulates, agglomerates, and debris in passing protein from lumen to shell side can help eliminate the need for extensive pretreatment.


Eosinophilic myocarditis associated with toxicodermia caused by phenobarbital.
We report on a 37-year-old man with congestive heart failure caused by eosinophilic myocarditis associated with toxicodermia. He developed many annular skin eruptions and peripheral eosinophilia due to reactions against phenobarbital. Right ventricular endomyocardial biopsy revealed extensive infiltration of eosinophils in the myocardium. A drug lymphocyte-stimulating test (DLST) for phenobarbital was positive. His symptoms, cardiomegaly, and cardiac function were improved by discontinuing phenobarbital followed by oral administration of prednisolone. We conclude that this eosinophilic myocarditis must have been induced by an allergic reaction to phenobarbital and that long-term eosinophilia contributed to the myocardial injury.


Ameliorating effect of Citrus trifoliata L. fruits extract on motor incoordination, neurodegeneration and oxidative stress in Parkinson's disease model.
Citrus trifoliate fruit (also known as Trifoliate orange) is one of the commercially-cultivated Citrus genus of plants belonging to the Rutaceae family. It has been traditionally-utilized in treatment of neurodegenerative disorders. However, the scientific evidence verifying this utilization needs further elucidation. Characterization of the bioactive constituents of C. trifoliata L. fruits extract and evaluating its effect on Parkinson's disease (PD) model. Rats were classified into 5 groups; control, PD, PD-treated by L-dopa/Carpidopa and PD-treated by oral Citrus trifoliata L. fruits extract (50 and 100 mg/kg). Deterioration in brain functions was evaluated through an in vivo open field, grid and catalepsy tests. The study also assessed the striatal neurotransmitters, oxidative stress markers and histopathological changes. Citrus trifoliata L. fruit extract has revealed motor improvement comparable to L-dopa and carbidopa. It has also effectively-improved oxidative stress via reduction of striatal malondialdehyde & nitric oxide along with replenishment of the striatal glutathione and superoxide dismutase. The extract caused significant reduction of the striatal myeloperoxidase activity and restoration of dopamine, γ-amino butyric acid (GABA), and acetylcholinesterase. This effect was further confirmed by amelioration of neuronal apoptosis, microgliosis and peri-neuronal vacuolation. Metabolite profiling revealed 40 constituents, with flavonoids representing the main identified class. The neuro-protective effect of Citrus trifoliata extract was achieved through the antioxidant and anti-inflammatory activities of its flavonoids, particularly hesperidin and naringin. This neuro-protective effect was evident at the behavioral, histological and neurotransmitter levels.


Relationship between Thyroid and Kidney Function: Analysis from the Korea National Health and Nutrition Examination Survey Between 2013 and 2015.
Thyroid function is evaluated by thyroid stimulating hormone (TSH) and free thyroxine (fT4). Although many studies have indicated an intimate relationship between thyroid hormones and kidney functions, reports about the simultaneous evaluation of TSH and fT4 are rare. We aimed to analyze the association between TSH and kidney function, with emphasis on a potential nonlinear relationship, and identify an independent relationship between fT4 and kidney function. We reviewed the data of 7,061 subjects in the Korea National Health and Nutrition Examination Surveys who were randomly subsampled for thyroid function evaluation between 2013 and 2015. A total of 5,578 subjects were included in the final analysis, after excluding people <18 years old, and those with a short fasting time, abnormal fT4 levels, and thyroid disease or related medications. Creatinine-based estimated glomerular filtration rate (eGFR) was used to define kidney function. A 1 mmol/L increase of logarithmic TSH was associated with decreased eGFR (β: -1.8; 95% CI -2.3 to -1.2; p < 0.001), according to multivariate linear regression analysis. On the multivariate generalized additive model plot, TSH demonstrated an L-shaped relationship with eGFR, showing a steeper slope for 0-4 mIU/L of TSH. A 1 µg/dL increase of fT4 was also associated with decreased eGFR (β: -7.0; 95% CI -0.94 to -4.7; p < 0.001) on the multivariate linear regression analysis; this association was reversed after adjusting for age. On the mediation analysis, the indirect effect via age and direct effect per 1 µg/dL increase of fT4 on eGFR was 9.9 (8.1 to 11.7, p < 0.001) and -7.1 (-9.3 to -4.8, p < 0.001), respectively. Increased TSH was associated with decreased eGFR, particularly in the reference range. The direct effect of increased fT4 was decreased eGFR, which may be affected indirectly by age.


Fluorogenic resolution of ligand binding by a nucleic acid aptamer.
An ATP-binding nucleic acid aptamer was converted into a solution-phase fluorescence-detected sensor by incorporating a 2'-amine group in a structure that is sensitive to a ligand-induced conformational change in the aptamer. The 2'-amine substitution in the free aptamer reacts efficiently with fluorescamine to yield a fluorescent product detectable by energy transfer to a tethered fluor emitting at 615 nm. In the presence of ATP, the fluorogenic reaction is substantially reduced, both under simplified conditions and in a urine background. Fluorogenic chemistry represents a potentially general approach for creating sensors from aptamers that bind their ligands via induced fit.