Evaluation of the diagnostic utility of cytologic examination of renal fine-needle aspirates from dogs and the use of ultrasonographic features to inform cytologic diagnosis.
OBJECTIVE To describe cytologic characteristics of renal fine-needle aspirate (FNA) samples from dogs, evaluate proportions of cytologic specimens deemed adequate for interpretation (diagnostic yield), assess diagnostic utility of cytologic examination for neoplastic and nonneoplastic diseases, and characterize ultrasonographic features of evaluated kidneys to determine whether the imaging characteristics could be used to inform cytologic interpretations. DESIGN Retrospective, observational study. SAMPLE 102 cytologic specimens and 97 ultrasonographic studies from 100 dogs. PROCEDURES Medical records were reviewed to identify dogs that underwent ultrasound-guided renal FNA. Slides were categorized as adequate or inadequate for interpretation; adequate slides were used for retrospective cytologic diagnosis. Sensitivity, specificity, and predictive values of cytologic examination for detection of neoplastic and nonneoplastic conditions were calculated by comparison with histologic or lymphoid cell clonality assay results. Ultrasonographic characteristics of neoplastic and nonneoplastic renal lesions were described. RESULTS 74 of 102 (72%) specimens had slides adequate for interpretation; 26 were included in the diagnostic accuracy analysis. Sensitivity of cytologic examination was 78% and 50% for detection of neoplastic and nonneoplastic conditions, respectively, with specificities of 50% and 77%, respectively; sensitivity for detection of lymphoma was 100%. Ultrasonographic appearance of kidneys with confirmed neoplasia varied; masses were most commonly found in kidneys with carcinoma (5/5), lymphoma (5/7), or other neoplasia (3/4) and absent in kidneys with nonneoplastic conditions (n = 5). CONCLUSIONS AND CLINICAL RELEVANCE Renal FNA specimens were adequate for interpretation at rates comparable with those reported for other organs and were considered clinically useful for diagnosis of neoplasia. Imaging characteristics may potentially aid differentiation between neoplastic and nonneoplastic lesions; however, further investigation is needed.


Thyroxine affects ventilation, lung morphometry, and necrosis of diaphragm in dystrophic hamsters.
Male dystrophic hamsters (DH) were treated with pellets containing thyroxine (T hamsters) or placebo (P hamsters) for 8 wk. O2 consumption, ventilation, and ventilation in response to 8% CO2 in O2 and 10% O2 in N2 were evaluated 1 and 8 wk after treatment began. O2 consumption was elevated in T hamsters at 1 and 8 wk, whereas ventilation was similar in the two groups on the first week. By 8 wk, ventilation and ventilatory responses to hypoxic and hypercapnic challenges were 100% greater in T than in P hamsters (P < 0.05). Morphometric evaluations at the end of the treatment period indicated that air space surface density, tissue volume density, and surface density-to-air space volume ratio of the lung parenchyma were greater (P < 0.05) in T than in P hamsters. In contrast, chord length within the lung parenchyma was shorter and necrosis in the diaphragm and tongue, but not in the heart, was lower (P < 0.05) in T than in P hamsters. Taken together, these results suggest that T treatment of DH for 8 wk affects O2 consumption, ventilation, lung architecture, and skeletal muscle without increasing triiodothyronine levels.


Central neurocytoma represents a tumor consisting of diverse neuronal phenotypes.
Central neurocytoma (CN) has long been regarded as a neuronal tumor based on the immunohistochemical expression of synaptophysin and the ultrastructural observation of neurosecretory granules, neurites, and synapses. Having diagnosed 11 CNs at our institution over the past thirty years, we set out to conduct an immunohistochemical study to assess the expression profile of neuronal markers across our cases. Markers of interest included synaptophysin, alpha-synuclein, chromogranin, neurofilament, and calretinin. Intriguingly, we observed a dichotomous expression profile between neurofilament and calretinin, suggesting the presence of histologic variants of CN based on the degree of neuronal maturation. We have further provided an overview of the clinico-pathologic heterogeneity within our series with respect to age of onset, overall outcome, and presence of anaplastic features. In highlighting the case of an infant with an incidental CN diagnosed at autopsy, we have discussed the role of a primitive neural cell of origin for driving tumor formation and accounting for our proposed differences in neuronal maturation within CN.


Morning Bright Light Treatment for Chronic Low Back Pain: Potential Impact on the Volatility of Pain, Mood, Function, and Sleep.
Most treatment outcome studies for people with chronic low back pain (CLBP) have based analyses on and reported only the mean levels of these factors. However, high levels of pain, mood, function, and sleep volatility may represent unique factors contributing to diminished quality of life. Our goal was to determine whether bright light treatment affected both mean levels of pain, mood, function, and sleep and reduced volatility in these outcomes. US military veterans with CLBP (N = 22) underwent an open trial with a seven-day baseline, followed by 13 days of a one-hour morning bright light treatment self-administered at their home and a 30-day follow-up. Participants completed daily diary measures at 12 Pm and 6 Pm every day during the three study epochs. Using location scale modeling, results suggested that, in addition to being associated with changes in mean levels of pain intensity, pain interference, negative affect, and sleep quality, bright light treatment was also related to reductions in the volatility of pain intensity and negative affect, reductions that were largely maintained during follow-up. Changes in mean levels and volatility were independent factors, suggesting that bright light treatment was related to participants experiencing fewer "pain flares." These findings underscore the potential importance of volatility as a future treatment target.


Time reordered: Causal perception guides the interpretation of temporal order.
We present a novel temporal illusion in which the perceived order of events is dictated by their perceived causal relationship. Participants view a simple Michotte-style launching sequence featuring 3 objects, in which one object starts moving before its presumed cause. Not only did participants re-order the events in a causally consistent way, thus violating the objective temporal order, but they also failed to recognise the clip they had seen, preferring a clip in which temporal and causal order matched. We show that the effect is not due to lack of attention to the presented events and we discuss the problem of determining whether causality affects temporal order at an early perceptual stage or whether it distorts an accurately perceived order during retrieval. Alternatively, we propose a mechanism by which temporal order is neither misperceived nor misremembered but inferred "on-demand" given phenomenal causality and the temporal priority principle, the assumption that causes precede their effects. Finally, we discuss how, contrary to theories of causal perception, impressions of causality can be generated from dynamic sequences with strong spatiotemporal deviations.


RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells.
Embryonic stem cell (ESC) fate decisions are regulated by a complex circuitry that coordinates gene expression at multiple levels from chromatin to mRNA processing. Recently, ribosome biogenesis and translation have emerged as key pathways that efficiently control stem cell homeostasis, yet the underlying molecular mechanisms remain largely unknown. Here, we identified RSL24D1 as highly expressed in both mouse and human pluripotent stem cells. RSL24D1 is associated with nuclear pre-ribosomes and is required for the biogenesis of 60S subunits in mouse ESCs. Interestingly, RSL24D1 depletion significantly impairs global translation, particularly of key pluripotency factors and of components from the Polycomb Repressive Complex 2 (PRC2). While having a moderate impact on differentiation, RSL24D1 depletion significantly alters ESC self-renewal and lineage commitment choices. Altogether, these results demonstrate that RSL24D1-dependant ribosome biogenesis is both required to sustain the expression of pluripotent transcriptional programs and to silence PRC2-regulated developmental programs, which concertedly dictate ESC homeostasis.


Induction of Protective Immunity by a Single Low Dose of a Master Cell Bank cGMP-rBCG-P Vaccine Against the Human Metapneumovirus in Mice.
Human metapneumovirus (hMPV) is an emergent virus, which mainly infects the upper and lower respiratory tract epithelium. This pathogen is responsible for a significant portion of hospitalizations due to bronchitis and pneumonia in infants and the elderly worldwide. hMPV infection induces a pro-inflammatory immune response upon infection of the host, which is not adequate for the clearance of this pathogen. The lack of knowledge regarding the different molecular mechanisms of infection of this virus has delayed the licensing of effective treatments or vaccines. As part of this work, we evaluated whether a single and low dose of a recombinant Mycobacterium bovis Bacillus Calmette-Guérin (BCG) expressing the phosphoprotein of hMPV (rBCG-P) can induce a protective immune response in mice. Immunization with the rBCG-P significantly decreased neutrophil counts and viral loads in the lungs of infected mice at different time points. This immune response was also associated with a modulated infiltration of innate cells into the lungs, such as interstitial macrophages (IM) and alveolar macrophages (AM), activated CD4+ and CD8+ T cells, and changes in the population of differentiated subsets of B cells, such as marginal zone B cells and plasma cells. The humoral immune response induced by the rBCG-P led to an early and robust IgA response and a late and constant IgG response. Finally, we determined that the transfer of cells or sera from immunized and infected mice to naïve mice promoted an efficient viral clearance. Therefore, a single and low dose of rBCG-P can protect mice from the disease caused by hMPV, and this vaccine could be a promising candidate for future clinical trials.


Diversity and distribution of Archaea in global estuarine ecosystems.
Estuarine ecosystem is a unique geographical transitional zone between freshwater and seawater, harboring a wide range of microbial communities including Archaea. Although a large number of Archaea have been detected in such ecosystem, the global patterns in archaeal diversity and distribution are extremely scarce. To bridge this gap, we carried out a comprehensive survey of archaeal communities using ca. 4000 publicly available archaeal 16S rRNA gene sequences (>300 bp) collected from 24 estuaries in different latitude regions. These sequences were divided into 1450 operational taxonomic units (OTUs) at 97% identity, suggesting a high biodiversity that increased gradually from the high- to low-latitude estuaries. Phylogenetic analysis showed that estuarine ecosystem was a large biodiversity pool of Archaea that was mainly composed of 12 phyla. Among them, the predominant groups were Bathyarchaeota, Euryarchaeota and Thaumarchaeota. Interestingly, archaeal distribution demonstrated a geographical differentiation in that Thaumarchaeota was dominated in the low-latitude estuaries, Bathyarchaeota in the mid-latitude estuaries, and Euryarchaeota in the high-latitude estuaries, respectively. Furthermore, the majority of the most abundant 20 OTUs demonstrated an overrepresented or underrepresented distribution pattern in some specific estuaries or latitude regions while a few were evenly distributed throughout the estuaries. This pattern indicates a potential selectivity of geographical distribution. In addition, the analysis of environmental parameters suggested that latitude would be one of the major factors driving the distribution of archaeal communities in estuarine ecosystem. This study profiles a clear framework on the diversity and distribution of Archaea in the global estuarine ecosystem and explores the general environmental factors that influence these patterns. Our findings constitute an important part of the exploration of the global ecology of Archaea.


Virtual education strategies in the context of sustainable health care and medical education: A topic modelling analysis of four decades of research.
The growing importance of sustainability has led to the current literature being saturated with studies on the necessity of, and suggested topics for, education for sustainable health care (ESH). Even so, ESH implementation has been hindered by educator unpreparedness and resource scarcity. A potential resolution lies in virtual education. However, research on the strategies needed for successfully implementing virtual education in the context of sustainable health care and medical education is sparse; this study aims to fill the gap. Topic modelling, a computational text-mining method for analysing recurring patterns of co-occurring word clusters to reveal key topics prevalent across the texts, was used to examine how sustainability was addressed in research in medicine, medical education, and virtual education. A total of 17 631 studies, retrieved from Web of Science, Scopus and PubMed, were analysed. Sustainability-related topics within health care, medical education and virtual education provided systematic implications for Sustainable Virtual Medical Education (SVME)-ESH via virtual platforms in a sustainable way. Analyses of keywords, phrases, topics and their associated networks indicate that SVME should address the three pillars of environmental, social and economic sustainability and medical practices to uphold them; employ different technologies and methods including simulations, virtual reality (VR), artificial intelligence (AI), cloud computing, distance learning; and implement strategies for collaborative development, persuasive diffusion and quality assurance. This research suggests that sustainable strategies in virtual education for ESH require a systems approach, encompassing components such as learning content and objectives, evaluation, targeted learners, media, methods and strategies. The advancement of SVME necessitates that medical educators and researchers play a central and bridging role, guiding both the fields of sustainable health care and medical education in the development and implementation of SVME. In this way, they can prepare future physicians to address sustainability issues that impact patient care.


The drosophila Bcl-2 family protein Debcl is targeted to the proteasome by the β-TrCP homologue slimb.
The ubiquitin-proteasome system is one of the main proteolytic pathways. It inhibits apoptosis by degrading pro-apoptotic regulators, such as caspases or the tumor suppressor p53. However, it also stimulates cell death by degrading pro-survival regulators, including IAPs. In Drosophila, the control of apoptosis by Bcl-2 family members is poorly documented. Using a genetic modifier screen designed to identify regulators of mammalian bax-induced apoptosis in Drosophila, we identified the ubiquitin activating enzyme Uba1 as a suppressor of bax-induced cell death. We then demonstrated that Uba1 also regulates apoptosis induced by Debcl, the only counterpart of Bax in Drosophila. Furthermore, we show that these apoptotic processes involve the same multimeric E3 ligase-an SCF complex consisting of three common subunits and a substrate-recognition variable subunit identified in these processes as the Slimb F-box protein. Thus, Drosophila Slimb, the homologue of β-TrCP targets Bax and Debcl to the proteasome. These new results shed light on a new aspect of the regulation of apoptosis in fruitfly that identifies the first regulation of a Drosophila member of the Bcl-2 family.


Use of biguanides and the risk of colorectal cancer: a register-based cohort study.
Observational studies have shown conflicting results on the potential protecting effect of biguanide use with the risk of colorectal neoplasms. In addition, the cellular mechanism can either support or oppose biguanides influence on colorectal carcinoma. Our objective was to evaluate the association between biguanide use and colorectal carcinoma. A population-based cohort study using healthcare data from the Danish National database (1996-2007), was conducted. Oral antidiabetic drug users (n = 177,281) were matched 1:3 with a population-based reference group. Cox proportional hazard models estimated hazard ratios (HRs) of colorectal carcinoma. Stratification was performed to analyse the risk of colorectal cancer in current biguanide users. Two sub-analyses were performed, to investigate the risk of colorectal cancer associated with discontinuous and prolonged use of biguanides. Instead of a protective effect, we found that current biguanide users had a 1.2-fold increased risk of colorectal cancer (HR = 1.19, 95% CI = 1.08-1.30) as compared with the non-diabetes reference group. Prolonged use was not inversely associated with colorectal cancer either. When studying colorectal risk with biguanides, the underlying T2DM should be taken into account since a 1.3-1.6-fold increased risk was found in oral antidiabetic drug users compared to controls unexposed to diabetic medication. This study could not detect a protective effect of biguanide use with colorectal cancer. Therefore, this study does not support a further investigation of the effectiveness of biguanides to prevent colorectal carcinoma in clinical studies.


Initial management of immune thrombocytopaenia in adults based on risk stratification.
Patients with immune thrombocytopaenia (ITP) have a wide spectrum of disease severity and bleeding risk even at similar platelet counts. Hence, additional clinical and laboratory factors may be considered in the evaluation of bleeding risk in ITP. Risk stratification based on predicted bleeding risk may help to identify high-risk patients and guide the initial management of ITP in adults requiring treatment. Recent evidence supports the use of high-dose dexamethasone therapy over prednisone in the initial management of ITP because of improved initial response rates, shorter median time to response and better safety profile. A risk-stratified approach to management of ITP is hoped to reduce bleeding complications in high-risk patients; however, the outcomes of such management approach need to be studied prospectively. Additionally, whether therapy intensification or combination of dual therapy such as intravenous immunoglobulin or rituximab in combination with dexamethasone can reduce bleeding complications in high-risk ITP should be studied in the future.


Reference Production as Search: The Impact of Domain Size on the Production of Distinguishing Descriptions.
When producing a description of a target referent in a visual context, speakers need to choose a set of properties that distinguish it from its distractors. Computational models of language production/generation usually model this as a search process and predict that the time taken will increase both with the number of distractors in a scene and with the number of properties required to distinguish the target. These predictions are reminiscent of classic findings in visual search; however, unlike models of reference production, visual search models also predict that search can become very efficient under certain conditions, something that reference production models do not consider. This paper investigates the predictions of these models empirically. In two experiments, we show that the time taken to plan a referring expression-as reflected by speech onset latencies-is influenced by distractor set size and by the number of properties required, but this crucially depends on the discriminability of the properties under consideration. We discuss the implications for current models of reference production and recent work on the role of salience in visual search.


47Ca turnover in endemic fluorosis and endemic genu valgum.
1. Calcium turnover was determined after intravenous injection of radioactive 47Ca in patients with fluorosis and endemic genu valgum and in age-matched controls. Total Ca turnover in the body, loss of Ca from the body in urine, faeces and sweat (external turnover) and bone mineralization rate were calculated from whole-body retention of 47Ca and specific activity of 47Ca in serum. 2. Total Ca turnover was significantly higher in younger subjects than in older subjects. 3. Total Ca turnover was significantly higher in patients with fluorosis and in those with endemic genu valgum than in age-matched controls, but the external turnover of Ca was lower in both groups of patients than in controls. 4. Bone mineralization rate was significantly higher in patients with fluorosis and in those with genu valgum as compared to age-matched controls. 5. Total body Ca turnover and bone mineralization rates were significantly higher in patients with endemic genu valgum than in those with fluorosis. The differences persited even after adjusting for differences in age between patients with fluorosis and those with genu valgum.


[Dens fracture with concurrent subaxial cervical spine injury in patients with ankylosing spondylitis].
Odontoid process fractures in patients with ankylosing spondylitis (AS) are rare and their finding together with subaxial cervical spine injury is a great exception. Neither the mechanism of such a combined cervical spine injury nor its surgical treatment has so far been reported in the relevant literature (MEDLINE). The authors present two such cases, one in a 30- and the other in a 74-year-old man. Both AS patients showed a common mechanism of injury sustained in a car accident, which involved hitting a solid barrier at 60 to 70 kilometres per hour, resulting in hyperextension of the cervical spine. In both patients the fractures were stabilised from the anterior approach: the dens fractures with one or two screws by the Magerl-Böhler method and the subaxial fractures with long-plate and screw fixation. At 2 post-operative years complete bone union of the subaxial spine was recorded in both patients; complete healing of the dens fracture was achieved in one patient while in the other partial fibrous union of the dens fracture occurred.


Foreign body granulomas of the breast presenting as bilateral spiculated masses.
In Asia, mammography following the injection of foreign materials into the breasts for cosmetic augmentation is frequently seen and diagnosis based on the typical radiologic findings is straightforward. We report the unusual radiologic findings in two patients with foreign body granulomas caused by injected foreign materials and discovered incidentally during screening work up. The mammographic findings were bilateral, hyperdense, spiculated masses, with occasional microcalcification, and at sonography, markedly hypoechoic, spiculated solid masses, located near the pectoralis muscle and partly extending into it, were observed. These radiologic findings mimicked malignancy.


The desmoid tumor. IV. Choice of treatment, results, and complications.
We analyzed the results of treatment in 89 cases of desmoid tumor (DT) with a follow-up period of 9.3 +/- 5.9 years. After surgical removal, the frequency of recurrence was equal, regardless of whether a complete removal of the tumor was obtained or not. After combined operation and radiotherapy, recurrence was higher. A higher frequency of recurrences was observed in extraabdominal (45%) v abdominal (10%) DTs. Recurrence was particularly high in the juvenile variety (70%), and low in the DTs of fertile women (11%). If a recurrence followed the first operation, multiple recurrences were the rule. Spontaneous regression was observed in 4% of the cases. The results emphasize that the basic biologic characteristics of this rare neoplasm have a greater impact on the results than the operation itself. A simple excision at the primary operation is recommended.


Feasibility of weekly intraperitoneal versus intravenous paclitaxel therapy delivered from the day of radical surgery for gastric cancer: a preliminary safety analysis of the INPACT study, a randomized controlled trial.
Peritoneal carcinomatosis is common after curative resection of gastric cancer. Intraperitoneal administration of paclitaxel (PTX) is known to control ovarian peritoneal metastases. Patients with either linitis plastica or T4 cancer with high risk of peritoneal metastasis or recurrence but whose cancer was considered resectable were preregistered. After their cancer had been confirmed intraoperatively as resectable, the patients were randomized into either group A (PTX at 60 mg/m2 intraperitoneally on the day of surgery and on days 14, 21, 28, 42, 49, and 56) or group B (PTX at 80 mg/m2 administered intravenously by the identical schedule) before being treated by evidence-based chemotherapy. The primary end point was the 2-year survival rate. Safety, the secondary end point, was also analyzed. The study has been registered as UMIN000002957. Of 177 preregistered patients, 83 underwent treatment (39 by intraperitoneal administration and 44 by intravenous administration). There was no difference in patient demographics between the two groups. The incidences of surgical complications were similar between the groups, except for transient bowel obstruction observed exclusively in group A. The relative dose intensity of PTX was 81.4 % for group A and 76.3 % for group B. There was one death due to pulmonary thrombosis and a case of anaphylaxis that led to termination of the protocol treatment (group B). Other adverse events were mild and manageable. Intraperitoneal administration of PTX from the day of gastrectomy did not result in a higher incidence of surgical complications and adverse reactions when compared with intravenous administration of PTX.


Multifocal post-traumatic scintigraphic changes mimicking bone metastases in a battered adult.
Several pathologies have been reported to cause scintigraphic patterns similar to multiple bony metastases. Heterotopic bone formation is known to mimic several inflammatory and neoplastic conditions including recurrent tumors. However, no reports on multifocal heterotopic bone formation simulating the typical pattern of randomly distributed foci of increased uptake of metastases on bone scan were found in literature. We present a case of a young adult who was repeatedly assaulted by others over a period of one month and on bone scan had a pattern similar to bony metastasis due to multiple foci of heterotopic bone formation and fractures.


Protein kinase CK2 mediates TGF-beta1-stimulated type IV collagen gene transcription and its reversal by estradiol.
We have previously shown that the transcription factor Sp1 mediates the stimulatory effects of transforming growth factor-beta1 (TGF-beta1) on type IV collagen gene transcription and protein synthesis, and that estradiol reverses these effects by down-regulating Sp1 activity. Protein kinase casein kinase II (CK2) phosphorylates Egr-1 and prevents its binding to Sp1. We hypothesized that TGF-beta1 stimulates CK2 activity, which in turn activates type IV collagen gene transcription via increased availability of free Sp1. The effects of TGF-beta1 and of estradiol on murine mesangial cell type IV collagen gene transcription were measured using a reporter mini gene construct and on collagen IV protein synthesis by Western blotting. Nuclear Egr-1, phosphorylated Egr-1, Sp1, Egr-1/Sp1 complexes and unbound Sp1 were measured using co-immunoprecipitation and Western blotting techniques. TGF-beta1 stimulated CK2 activity in murine mesangial cells. Although TGF-beta1 failed to alter total Egr-1 protein, it increased phosphorylated Egr-1. This led to decreased Egr-1/Sp1 complex formation, increased unbound Sp1, increased binding of nuclear extracts to the collagen IV promoter, and increased type IV collagen gene transcription and protein synthesis. Physiologic concentrations of estradiol reversed these effects. These studies suggest that activation of CK2 mediates the stimulatory effect of TGF-beta1 on type IV collagen gene transcription. Moreover, the ability of estradiol to reverse TGF-beta1-stimulated type IV collagen synthesis is mediated by down-regulating CK2 activity, which ultimately limits the availability of unbound Sp1 to activate gene transcription.


Very Low-Calorie Ketogenic Diet (VLCKD) as Pre-Operative First-Line Dietary Therapy in Patients with Obesity Who Are Candidates for Bariatric Surgery.
Bariatric surgery is currently the most effective method for achieving long-term weight loss and reducing the risk of comorbidities and mortality in individuals with severe obesity. The pre-operative diet is an important factor in determining patients' suitability for surgery, as well as their post-operative outcomes and success in achieving weight loss. Therefore, the nutritional management of bariatric patients requires specialized expertise. Very low-calorie diets and intragastric balloon placement have already been studied and shown to be effective in promoting pre-operative weight loss. In addition, the very low-calorie ketogenic diet has a well-established role in the treatment of obesity and type 2 diabetes mellitus, but its potential role as a pre-operative dietary treatment prior to bariatric surgery has received less attention. Thus, this article will provide a brief overview of the current evidence on the very low-calorie ketogenic diet as a pre-operative dietary treatment in patients with obesity who are candidates for bariatric surgery.


[Determination of multidrug resistance of M. tuberculosis by different methods].
Testing the direct nitrate reductase technique versus the absolute concentration test has indicated that the former may be successfully used for rapid determination of the sensitivity of Mycobacterium tuberculosis (MBT) to isoniazid and rifampicin and it can reduce the time of obtaining a result by 4-5 times in the cases that sputum bacterioscopy yielded a positive result that allows the modified method to be applied. The advantages of the TB-Biochip technique are the time of detection multidrug-resistant MBT (24 hours), a possibility of obtaining these data just when analyzing sputum-isolated MBT DNA, and characterization of the MBT genomic elements that are responsible for drug sensitivity to antituberculous agents, by determining mutations in the examined genes and this all by using one chip. The agreement of results of microbiological and molecular genetic studies study of drug MBT sensitivity was 98%. There were no differences in the results of those using isoniazid. As for rifampicin, there was a difference in two samples (3.8%). Analysis of a combination of mutations forming multidrug resistance indicated that 74.3% of multidrug-resistant MBT isolates had mutations in the codon Ser531 > Lue of the rpoB gene and in the codon Ser315 > Thr of the katG gene. 97.4% of strains with signs of multidrug resistance had mutations in the codon 315 of the katG gene. 20.5% of isoniazid-resistant strains were observed to have mutations in two genes (katG and inhA) and 28.2% of the strains exhibited double mutation in the katG gene - Ser315Thr and Ile335 > Val.


Trends in overweight among women differ by occupational class: results from 33 low- and middle-income countries in the period 1992-2009.
There has been an increase in overweight among women in low- and middle-income countries but whether these trends differ for women in different occupations is unknown. We examined trends by occupational class among women from 33 low- and middle-income countries in four regions. Cross-national study with repeated cross-sectional demographic health surveys. Height and weight were assessed at least twice between 1992 and 2009 in 248,925 women aged 25-49 years. Interviews were conducted to assess occupational class, age, place of residence, educational level, household wealth index, parity, age at first birth and breastfeeding. We used logistic and linear regression analyses to assess the annual percent change in overweight (body mass index >25 kg m(-2)) by occupational class. The prevalence of overweight ranged from 2.2% in Nepal in 1992-1997 to 75% in Egypt in 2004-2009. In all the four regions, women working in agriculture had consistently lower prevalence of overweight, while women from professional, technical, managerial as well as clerical occupational classes had higher prevalence. Although the prevalence of overweight increased in all the occupational classes in most regions, women working in agriculture and production experienced the largest increase in overweight over the study period, while women in higher occupational classes experienced smaller increases. To illustrate, overweight increased annually by 0.5% in Latin America and the Caribbean and by 0.7% in Sub-Saharan Africa among women from professional, technical and managerial classes, as compared with 2.8% and 3.7%, respectively, among women in agriculture. The prevalence of overweight has increased in most low- and middle-income countries, but women working in agriculture and production have experienced larger increases than women in higher occupational classes.


Generation of a focused poly(amino ether) library: polymer-mediated transgene delivery and gold-nanorod based theranostic systems.
A focused library of twenty-one cationic poly(amino ethers) was synthesized following ring-opening polymerization of two diglycidyl ethers by different oligoamines. The polymers were screened in parallel for plasmid DNA (pDNA) delivery, and transgene expression efficacies of individual polymers were compared to those of 25 kDa polyethylenimine (PEI), a current standard for polymer-mediated transgene delivery. Seven lead polymers that demonstrated higher transgene expression than PEI in pancreatic and prostate cancer cells lines were identified from the screen. All seven lead polymers showed highest transgene expression at a polymer:pDNA weight ratio of 5:1 in the MIA PaCa-2 pancreatic cancer cell line. Among the conditions studied, transgene expression efficacy correlated with minimal polymer cytotoxicity but not polyplex sizes. In addition, this study indicated that methylene spacing between amine centers in the monomers, amine content, and molecular weight of the polymers are all significant factors and should be considered when designing polymers for transgene delivery. A lead effective polymer was employed for coating gold nanorods, leading to theranostic nanoassemblies that possess combined transgene delivery and optical imaging capabilities, leading to potential theranostic systems.


Aerobic and anaerobic regulation in Rhodobacter sphaeroides 2.4.1: the role of the fnrL gene.
In Rhodobacter sphaeroides 2.4.1, the cellular requirements for 5-aminolevulinic acid (ALA) are in part regulated by the level of ALA synthase activity, which is encoded by the hemA and hemT genes. Under standard growth conditions, only the hemA gene is transcribed, and the level of ALA synthase activity varies in response to oxygen tension. The presence of an FNR consensus sequence upstream of hemA suggested that oxygen regulation of hemA expression could be mediated, in part, through a homolog of the fnr gene. Two independent studies, one detailed here, identified a region of the R. sphaeroides 2.4.1 genome containing extensive homology to the fix region of the symbiotic nitrogen-fixing bacteria Rhizobium meliloti and Bradyrhizobium japonicum. Within this region that maps to 443 kbp on chromsome I, we have identified an fnr homolog (fnrL), as well as a gene that codes for an anaerobic coproporphyrinogen III oxidase, the second such gene identified in this organism. We also present an analysis of the role of fnrL in the physiology of R. sphaeroides 2.4.1 through the construction and characterization of fnrL-null strains. Our results further show that fnrL is essential for both photosynthetic and anaerobic-dark growth with dimethyl sulfoxide. Analysis of hemA expression, with hemA::lacZ transcriptional fusions, suggests that FnrL is an activator of hemA under anaerobic conditions. On the other hand, the open reading frame immediately upstream of hemA appears to be an activator of hemA transcription regardless of either the presence or the absence of oxygen or FnrL. Given the lack of hemT expression under these conditions, we consider FnrL regulation of hemA expression to be a major factor in bringing about changes in the level of ALA synthase activity in response to changes in oxygen tension.


Identification and mapping of two divergent, unlinked major histocompatibility complex class II B genes in Xiphophorus fishes.
We have isolated two major histocompatibility complex (MHC) class II B genes from the inbred fish strain Xiphophorus maculatus Jp 163 A. We mapped one of these genes, designated here as DXB, to linkage group III, linked to a malic enzyme locus, also syntenic with human and mouse MHC. Comparison of genomic and cDNA clones shows the gene consists of six exons and five introns. The encoded beta1 domain has three amino acids deleted and a cytoplasmic tail nine amino acids longer than in other teleost class II beta chains, more similar to HLA-DRB, clawed frog Xela-F3, and nurse shark Gici-B. Key residues for disulfide bonds, glycosylation, and interaction with alpha chains are conserved. These same features are also present in a swordtail (Xiphophorus helleri) genomic DXB PCR clone. A second type of class II B clone was amplified by PCR from X. maculatus and found to be orthologous to class II genes identified in other fishes. This DAB-like gene is 63% identical to the X. maculatus DXB sequence in the conserved beta2-encoding exon and was mapped to new unassigned linkage group LG U24. The DXB gene, then, represents an unlinked duplicated locus not previously identified in teleosts.


Optimized Repopulation of Tendon Hydrogel: Synergistic Effects of Growth Factor Combinations and Adipose-Derived Stem Cells.
Background: Tendon-derived extracellular matrix (ECM) hydrogel has been shown to augment tendon healing in vivo. We hypothesized that reseeding of the gel with adipose-derived stem cells (ASCs) could further assist repopulation of the gel and that combinations of growth factors (GFs) would improve the survival of these cells after reseeding. Methods: A tendon-specific ECM solution was supplemented with varying concentrations of basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and platelet-derived growth factor-BB (PDGF-BB). Gels were then seeded with ASCs transfected with a green fluorescent protein/luciferin construct. Cell proliferation was determined using the MTT assay and histology, and GF and ASC augmented gels were injected into the back of Sprague Dawley rats. Bioluminescence of seeded gels was continuously followed after reseeding, and cell counts were performed after the gels were explanted at 14 days. Results: Synergistic effects of the GFs were seen, and an optimal combination was determined to be 10 ng/mL bFGF, 100 ng/mL IGF-1, and 100 ng/mL PDGF-BB (2.8-fold increase; P < .05). In vivo bioluminescence showed an improved initial survival of cells in gels supplemented with the optimal concentration of GF compared with the control group (10.6-fold increase at 8 days; P < .05). Cell counts of explants showed a dramatic endogenous repopulation of gels supplemented by GF + ASCs compared with both gels with GF but no ASCs (7.6-fold increase) and gels with ASCs but no GF (1.6-fold increase). Conclusion: Synergistic effects of GFs can be used to improve cellular proliferation of ASCs seeded to a tendon ECM gel. Reseeding with ASCs stimulates endogenous repopulation of the gel in vivo and may be used to further augment tendon healing.


[Antibiotic prophylaxis in liver cirrhosis].
Bacterial infections are frequent and severe complications in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is the most common infection in such patients. The risk of recurrence at one year after a first episode of SBP is higher than 70% and hospital mortality is estimated between 30-50%. Therefore, there is growing interest in antibiotic prophylaxis (ATP) in these patients. Risk factors for the occurrence of SBP include low protein level in ascitis, a history of previous SBP and an episode of gastrointestinal bleeding. In all three situations, the indication of ATP, reviewed in this paper, is recognized and improves survival.


What is the purpose of launching the World Journal of Methodology?
Congratulations to the publisher, members of the editorial board of the journal, all the authors and readers for launching the World Journal of Methodology (WJM) as a new member of the World series journal family! Scientific advances and important breakthroughs have been facilitated by well developed methodologies or techniques and any misleading findings and theories are exclusively attributable to certain methodological defects. Thus, the role of appropriate methodologies in the development of science and technology cannot be overemphasized and the need for inaugurating this new journal is self-evident. The WJM is a peer-reviewed open-access periodical centered in biomedical sciences but with multidisciplinary coverage. If you want to share any new methodologies, any experiences of the application or improvement of such methodologies and any methodology-related academic issues with your peers, you will find the WJM a good media to publish your papers!


Serum levels of miR-223 but not miR-21 are decreased in patients with neuroendocrine tumors.
MicroRNAs (miRNAs) are profoundly involved into the pathophysiology of manifold cancers. Recent data suggested a pivotal role of miRNAs as biomarkers in different biological processes including carcinogenesis. However, their role in neuroendocrine tumors (NETs) is only poorly understood. We determined circulating levels of miR-21 and miR-223 in 45 samples from patients with NET treated between 2010 and 2019 at our department and compared them to healthy controls. Results were correlated with clinical records. In the total cohort of Patients with NET, miR-223 presented significantly lower levels compared to healthy control samples. In contrast, levels of miR-21 indicated no significant changes between the two groups. Interestingly, despite being significantly downregulated in all NET patients, concentrations of miR-223 were independent of clinical or histopathological factors such as proliferation activity according to Ki-67 index, tumor grading, TNM stage, somatostatin receptor expression, presence of functional/ non-functional disease or tumor relapse. Moreover, in contrast to data from recent publications analyzing other tumor entities, levels of miR-223 serum levels did not reflect prognosis of patients with NET. Lower concentrations of circulating miR-223 rather reflect the presence of NET itself than certain tumor characteristics. The value of miR-223 as a biomarker in NET might be limited to diagnostic, but not prognostic purposes.


Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1 (-) /Abcd2 (-/-) mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients.


Partial purification and characterization of the defective cyclic adenosine 3':5'-monophosphate binding protein kinase from adrenocortical carcinoma.
Previous studies with isolated adrenocortical carcinoma 494 cells from this laboratory have indicated that the lack of cyclic adenosine 3':5'-monophosphate (cyclic AMP) control in steroidogenesis in the tumor may be due to the defective cyclic AMP-dependent protein kinase enzyme system. This paper describes the partial purification of such an enzyme. Purification was achieved by precipitation of the tumor homogenate with 30 and 45% ammonium sulfate, adsorption on 3% calcium phosphate gel, and chromatography on DEAE-cellulose. Four major protein peaks were isolated. Peak 2 showed cyclic AMP-binding activity and was investigated further for its kinetic properties. In contrast to the cyclic AMP-dependent protein kinase enzyme found in the normal adrenal gland, the enzyme specifically bound cyclic AMP but failed to phosphorylate exogenous histone. It is postulated that lack of the cyclic nucleotide-dependent kinase activity of the protein kinase enzyme may be responsible for the loss of cyclic AMP-regulated corticosterone synthesis in adrenocortical carcinoma cell. It is further shown that the tumor cyclic AMP-binding enzyme undergoes endogenous phosphorylation, which indicates that it has kinase activity but it is independent of cyclic AMP.


Drug Delivery of Natural Products Through Nanocarriers for Effective Breast Cancer Therapy: A Comprehensive Review of Literature.
Despite recent advances in the diagnosis and treatment of breast cancer (BC), it remains a global health issue affecting millions of women annually. Poor prognosis in BC patients is often linked to drug resistance as well as the lack of effective therapeutic options for metastatic and triple-negative BC. In response to these unmet needs, extensive research efforts have been devoted to exploring the anti-BC potentials of natural products owing to their multi-target mechanisms of action and good safety profiles. Various medicinal plant extracts/essential oils and natural bioactive compounds have demonstrated anti-cancer activities in preclinical BC models. Despite the promising preclinical results, however, the clinical translation of natural products has often been hindered by their poor stability, aqueous solubility and bioavailability. There have been attempts to overcome these limitations, particularly via the use of nano-based drug delivery systems (NDDSs). This review highlights the tumour targeting mechanisms of NDDSs, the advantages and disadvantages of the major classes of NDDSs and their current clinical status in BC treatment. Besides, it also discusses the proposed anti-BC mechanisms and nanoformulations of nine medicinal plants' extracts/essential oils and nine natural bioactive compounds; selected via the screening of various scientific databases, including PubMed, Scopus and Google Scholar, based on the following keywords: "Natural Product AND Nanoparticle AND Breast Cancer". Overall, these nanoformulations exhibit improved anti-cancer efficacy against preclinical BC models, with some demonstrating biocompatibility with normal cell lines and mouse models. Further clinical studies are, however, warranted to ascertain their efficacy and biocompatibility in humans.


Risk-adapted pre-emptive therapy for cytomegalovirus disease in patients undergoing allogeneic bone marrow transplantation.
We prospectively evaluated a risk-adapted pre-emptive treatment with ganciclovir for CMV diseases in patients undergoing allogeneic bone marrow transplantation (BMT). High-level CMV antigenemia (10 or more positive cells on two slides) or CMV antigenemia at any level in patients with grade II-IV acute graft-versus-host disease (aGVHD) were chosen as risk factors. We also retrospectively evaluated virus reactivation in plasma using quantitative real-time polymerase chain reaction (PCR). Fifty patients were evaluable. None of the 27 patients with or without grade I aGVHD developed high-level CMV antigenemia or CMV disease. Among the 23 patients with grade II-IV aGVHD, 12 patients (52%) developed CMV antigenemia and were treated pre-emptively, of whom two developed CMV gastroenteritis or retinitis in spite of therapy. Six of the remaining 11 patients developed CMV gastroenteritis before CMV antigenemia was detectable. All of the eight patients with CMV diseases were successfully treated with ganciclovir and no deaths directly related to CMV disease occurred. In four of the seven evaluable patients with CMV gastroenteritis, real-time PCR was able to detect virus reactivation earlier than CMV antigenemia. Although our risk-adapted pre-emptive therapy effectively reduced CMV-related mortality, further refinements of this approach, particularly in the prevention of CMV gastroenteritis, may be achieved by incorporating real-time PCR.


Successional stage, fragmentation and exposure to extraction influence the population structure of Euterpe precatoria (Arecaeae).
The neotropical palm Euterpeprecatoria is subject to extraction for its valuable palm heart. The development of management and conservation practices for this species requires understanding of its population structure, dynamics, and traditional use across the range of environments it inhabits, from different successional stages in continuous forest to forest fragments. Here, we analyzed how the population structure of E. precatoria varies with successional stage, fragmentation, and exposure to extraction, Since E. precatoria recruitment increases with disturbance, we expected seedling density to be higher in secondary forests and fragments relative to primary forests. The study was conducted from 2007-2008 in the Caribbean Slope of Costa Rica at Braulio Carrillo National Park (BCNP), La Selva Biological Station (LSBS), Manú Center, and Finca El Progreso (FEP). The first two sites had continuous primary and secondary forests (BCNP had one extracted primary forest); the last two consisted of primary forest fragments. Population structure was variable, with greater densities in the extracted primary forest, and in the secondary forests, as compared to primary forests and fragments. Palms < 5 m across all sites represented 50-90% of the total number of individuals. In sites that suffered historical over-extraction, local communities have lost the tradition of consuming this species. Understanding how population dynamics is affected by extraction and succession is essential to the design of sustainable management programs rooted in community participation.


Image reconstruction of anisotropic conductivity tensor distribution in MREIT: computer simulation study.
We describe a novel method of reconstructing images of an anisotropic conductivity tensor distribution inside an electrically conducting subject in magnetic resonance electrical impedance tomography (MREIT). MREIT is a recent medical imaging technique combining electrical impedance tomography (EIT) and magnetic resonance imaging (MRI) to produce conductivity images with improved spatial resolution and accuracy. In MREIT, we inject electrical current into the subject through surface electrodes and measure the z-component Bz of the induced magnetic flux density using an MRI scanner. Here, we assume that z is the direction of the main magnetic field of the MRI scanner. Considering the fact that most biological tissues are known to have anisotropic conductivity values, the primary goal of MREIT should be the imaging of an anisotropic conductivity tensor distribution. However, up to now, all MREIT techniques have assumed an isotropic conductivity distribution in the image reconstruction problem to simplify the underlying mathematical theory. In this paper, we firstly formulate a new image reconstruction method of an anisotropic conductivity tensor distribution. We use the relationship between multiple injection currents and the corresponding induced Bz data. Simulation results show that the algorithm can successfully reconstruct images of anisotropic conductivity tensor distributions. While the results show the feasibility of the method, they also suggest a more careful design of data collection methods and data processing techniques compared with isotropic conductivity imaging.


Cell adhesion molecules CD11a and CD18 in blood monocytes in old age and the consequences for immunological dysfunction. Preliminary results.
Adhesion molecules, such as leukocyte-function-associated antigen (LFA-1 or CD11a/CD18), intercellular adhesion molecule 1 (ICAM-1 or CD54) and Hermes antigen (HCAM or CD44), have important roles in many adhesive interactions involving cells of the immune system. Since it has been shown that many immunological alterations were present in aged subjects, we studied the expression and density of these molecules on peripheral blood lymphocytes and monocytes from healthy old subjects. A decrease in monocyte subpopulations bearing CD11a/CD18 and an increase in CD11a/CD18 and and CD44 antigen density on lymphocytes and on monocytes, respectively, were observed. These changes might be an event in the mechanism leading to the decreased lymphocyte proliferative response in vitro and to other immunological dysfunctions reported in old subjects.


Intraspecific trait variability shapes leaf trait response to altered fire regimes.
Understanding impacts of altered disturbance regimes on community structure and function is a key goal for community ecology. Functional traits link species composition to ecosystem functioning. Changes in the distribution of functional traits at community scales in response to disturbance can be driven not only by shifts in species composition, but also by shifts in intraspecific trait values. Understanding the relative importance of these two processes has important implications for predicting community responses to altered disturbance regimes. We experimentally manipulated fire return intervals in replicated blocks of a fire-adapted, longleaf pine (Pinus palustris) ecosystem in North Carolina, USA and measured specific leaf area (SLA), leaf dry matter content (LDMC) and compositional responses along a lowland to upland gradient over a 4 year period. Plots were burned between zero and four times. Using a trait-based approach, we simulate hypothetical scenarios which allow species presence, abundance or trait values to vary over time and compare these with observed traits to understand the relative contributions of each of these three processes to observed trait patterns at the study site. We addressed the following questions. (1) How do changes in the fire regime affect community composition, structure and community-level trait responses? (2) Are these effects consistent across a gradient of fire intensity? (3) What are the relative contributions of species turnover, changes in abundance and changes in intraspecific trait values to observed changes in community-weighted mean (CWM) traits in response to altered fire regime? We found strong evidence that altered fire return interval impacted understorey plant communities. The number of fires a plot experienced significantly affected the magnitude of its compositional change and shifted the ecotone boundary separating shrub-dominated lowland areas from grass-dominated upland areas, with suppression sites (0 burns) experiencing an upland shift and annual burn sites a lowland shift. We found significant effects of burn regimes on the CWM of SLA, and that observed shifts in both SLA and LDMC were driven primarily by intraspecific changes in trait values. In a fire-adapted ecosystem, increased fire frequency altered community composition and structure of the ecosystem through changes in the position of the shrub line. We also found that plant traits responded directionally to increased fire frequency, with SLA decreasing in response to fire frequency across the environmental gradient. For both SLA and LDMC, nearly all of the observed changes in CWM traits were driven by intraspecific variation.


First Report of Powdery Mildew Caused by Blumeria graminis on Festuca arundinacea in China.
Tall fescue (Festuca arundinacea Schreb), a predominant cool-season perennial grass, is widely used as forage and turf grasses in China. In July 2013, powdery mildew was observed on 10 F. arundinacea lawns (about 0.5 ha in total) in Urumchi, Xinjiang Province, China, with 20 to 30% of the area being infected. Signs of the disease initially appeared as irregular white mycelial colonies on the adaxial surface of infected leaves. As the disease progressed, the colonies covered the whole adaxial surface and white patches appeared on the abaxial surface of infected leaves. Conidiophores were unbranched and cylindrical with swollen bases, measuring 13.3 to 15 × 16.7 to 20 μm, and borne vertically on hyphae. Each conidiophore produced 10 to 18 conidia in a chain. The conidia were oval, one-celled, and colorless, measuring 8.1 to 9.8 × 26 to 29.7 μm. Cleistothecia were black, spherical, and 164.3 to 207.3 μm in diameter, each of which contained 9 to 26 asci. Asci were oblong or ovate, measuring 32.1 to 40 × 85.7 to 96.4 μm. Asci were petiolate, containing eight ascospores. Ascospores were round to oval, colorless, one-celled, measuring 19.1 to 22.5 × 11.7 to 13.6 μm. Based on morphological characteristics of the anamorph and the teleomorph, the fungus was identified as Blumeria graminis (DC.) Speer. Additionally, the internal transcribed spacer (ITS) of 563 bp was amplified from DNA of conidia using ITS1 and ITS4 primers (4). The ITS sequence was deposited in GenBank (Accession No. KF545644). The ITS sequence showed 100% homogeneity with those of B. graminis on Poa pratensis in Swizerland (AB273540) and on P. bulbosa in Iran (AB273551) (1), which further confirmed the identification. Ten 3-week-old healthy plants were inoculated by spraying a spore suspension (1 × 105 conidia ml-1) made from conidia brushed from infected plants, and 10 plants sprayed with sterile distilled water were served as controls. All the plants were placed in the same growth chamber at 20°C, 80% humidity, and 16-h photoperiod. Twenty days after inoculation, typical signs and symptoms of powdery mildew were observed on all the inoculated plants, whereas no symptoms were observed on the controls. Microscopic and ITS analysis showed that the fungus on the inoculated plants is identical to that on diseased field plants. B. graminis on F. arundinacea has been observed in a few European countries (1), Israel (3), and the United States (2). To our knowledge, this is the first report of powdery mildew caused by B. graminis on F. arundinacea in China, which will increase the difficulty to prevent powdery mildew on grasses including cereals. References: (1) U. Braun. The Powdery Mildews (Erysiphales) of Europe. Gustav Fischer Verlag, Jena-Stuttgart-New York, 1995. (2) F. M. Dugan and G. Newcombe. Pacific Northwest Fungi. 2:1-5, 2007. (3) S. O. Voytyuk et al. Biodiversity of the Powdery Mildew Fungi (Erysiphales, Ascomycota) of Israel Vol. 7. Biodiversity of Cyanoprocaryotes, Algae and Fungi of Israel. Koeltz Scientific Books, 2009. (4) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, 1990.


A review of the effects of FSCV and microdialysis measurements on dopamine release in the surrounding tissue.
Microdialysis is commonly used in neuroscience to obtain information about the concentration of substances, including neurotransmitters such as dopamine (DA), in the extracellular space (ECS) of the brain. Measuring DA concentrations in the ECS with in vivo microdialysis and/or voltammetry is a mainstay of investigations into both normal and pathological function of central DA systems. Although both techniques are instrumental in understanding brain chemistry each has its shortcomings. The objective of this review is to characterize some of the tissue and DA differences associated with each technique in vivo. Much of this work will focus on immunohistochemical and microelectrode measurements of DA in the tissue next to the microdialysis probe and mitigating the response to the damage caused by probe implantation.


[Glutathion as an important component of thiosulfid system of infertility pathogenesis in overweight men].
To study the glutathionic part of thiosulfid system and oxidative stress in infertile men with different body mass index. Examined 60 infertile men with normal and overweight, and 40 healthy men with proven fertility. Active components of the antioxidant defense system of the body was assessed by the level of reduced and oxidized glutathione by the method of PY Hissin, determination of TBA-active products was carried out by the method VB Gavrilova. In the analysis of inter-group differences for independent samples was used parametric Student criterion. The oxidative stress in obese men was characterized by significant elevation of oxidized form of glutathione (GSSG) in comparison with its reduced form. We discussed our results in the context of GSSG "quantivalence" to numerous of cellular processes in the setting of metabolic disorders in infertile and obese men. The ratio of reduced glutathione to oxidized infertile men decreased by 1,5 times in patients with obesity and 1,2 times in those with normal body mass index. Glutathione is the most important link in the study of oxidative stress in men with infertility. Raising the level of oxidized glutathione is due to the presence of his additional functions that are implemented at higher values of body mass index, especially in association with infertility.


Two new class III G6PD variants [G6PD Tunis (c.920A>C: p.307Gln>Pro) and G6PD Nefza (c.968T>C: p.323 Leu>Pro)] and overview of the spectrum of mutations in Tunisia.
We screened 423 patients referred to our laboratory after hemolysis triggered by fava beans ingestion, neonatal jaundice or drug hemolysis. Others were asymptomatic but belonged to a family with a history of G6PD deficiency. The determination of enzymatic activity using spectrophotometric method, revealed 293 deficient (143 males and 150 females). The molecular analysis was performed by a combination of PCR-RFLP and DNA sequencing to characterize the mutations causing G6PD deficiency. 14 different genotypes have been identified : G6PD A(-) (376A>G;202G>A) (46.07%) and G6PD Med (33.10%) were the most common variants followed by G6PD Santamaria (5.80%), G6PD Kaiping (3.75%), the association [c.1311T and IVS11 93c] (3.75%), G6PD Chatham (2.04%), G6PD Aures (1.70%), G6PD A(-) Betica (0.68%), the association [ 376G;c.1311T;IVS11 93c] (0.68%), G6PD Malaga, G6PD Canton and G6PD Abeno respectively (0.34%). Two novel missense mutations were identified (c.920A>C: p.307Gln>Pro and c.968T>C: p.323 Leu>Pro). We designated these two class III variants as G6PD Tunis and G6PD Nefza. A mechanism which could account for the defective activity is discussed.


Significant improvement in quality of life of patients with incurable cancer after designation to a palliative homecare team.
The aims of this study were to describe and compare quality of life before and after designation to a palliative homecare team in patients with different cancer diagnoses and to identify pre-designation predictors of post-designation global quality of life. We measured patients' quality of life 1 week before designation and 11 days (median time) after with the Assessment of Quality of life at the End of Life (Axelsson & Sjödén 1999). Of 163 eligible patients 63 participated without attrition. Patients' quality of life improved in the physical, psychological, medical and global areas. Six items significantly improved: hours recumbent during the day (P = 0.009), nausea (P = 0.008), anxiety (P = 0.007), getting hold of staff (P = 0.000), received care (P = 0.003) and global quality of life (P = 0.023). Depression/low in mood (r = 0.55) and meaningfulness (r = 0.70) associated to global quality of life. Furthermore, pain (P = 0.028) and meaningfulness (P = 0.028) predicted global quality of life. In the existential area, it is important to further explore how meaningfulness is associated to and predicts global quality of life.


Labor Induction at 39 Weeks Compared with Expectant Management in Low-Risk Parous Women.
Our objective was to compare outcomes among low-risk parous women who underwent elective labor induction at 39 weeks versus expectant management. This is a secondary analysis of an observational cohort of 115,502 mother-infant dyads who delivered at 25 hospitals between 2008 and 2011. The inclusion criteria for this analysis were low-risk parous women with nonanomalous singletons with at least one prior vaginal delivery after 20 weeks, who delivered at ≥390/7 weeks. Women who electively induced between 390/7 and 396/7 weeks were compared with women who expectantly managed ≥390/7 weeks. The primary outcome for this analysis was cesarean delivery. Secondary outcomes were composites of maternal adverse outcome and neonatal adverse outcome. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR). Of 20,822 women who met inclusion criteria, 2,648 (12.7%) were electively induced at 39 weeks. Cesarean delivery was lower among women who underwent elective induction at 39 weeks than those who did not (2.4 vs. 4.6%, adjusted odds ratio [aOR]: 0.70, 95% confidence interval [CI]: 0.53-0.92). The frequency of the composite maternal adverse outcome was significantly lower for the elective induction cohort as well (1.6 vs. 3.1%, aOR: 0.66, 95% CI: 0.47-0.93). The composite neonatal adverse outcome was not significantly different between the two groups (0.3 vs. 0.6%; aOR: 0.60, 95% CI: 0.29-1.23). In low-risk parous women, elective induction of labor at 39 weeks was associated with decreased odds of cesarean delivery and maternal morbidity, without an increase in neonatal adverse outcomes. · 39-week elective induction is associated with decreased cesarean delivery in low-risk parous women.. · Compared with expectant management, maternal adverse outcomes were lower with elective induction.. · Neonatal adverse outcomes are unchanged between elective and expectant management groups..


Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin.
We performed a 22-month trial of topical tretinoin (retinoic acid) in the treatment of photoaging. Thirty patients participated in a 4-month, randomized, blinded, vehicle-controlled study that has been reported previously; 21 patients continued tretinoin therapy on an open-label basis, participating in the study for a total of 10 months, and 16 patients continued for 22 months. During the open-label study, the statistically significant improvement that had occurred in fine and coarse wrinkling and skin texture during our original study was sustained, despite reductions in dose or frequency of application of tretinoin. The number of discrete lentigines decreased by 71% compared with the number before therapy. Histologic findings included a statistically significant thickening of the epidermis. Side effects were limited to a cutaneous retinoid reaction that diminished as therapy proceeded.


The structural model of Salmonella typhimurium ethanolamine ammonia-lyase directs a rational approach to the assembly of the functional [(EutB-EutC)₂]₃ oligomer from isolated subunits.
Ethanolamine ammonia-lyase (EAL) is a 5'-deoxyadenosylcobalamin-dependent bacterial enzyme that catalyzes the deamination of the short-chain vicinal amino alcohols, aminoethanol and (S)- and (R)-2-aminopropanol. The coding sequence for EAL is located within the 17-gene eut operon, which encodes the broad spectrum of proteins that comprise the ethanolamine utilization (eut) metabolosome suborganelle structure. A high-resolution structure of the ∼500 kDa EAL [(EutB-EutC)₂]₃ oligomer from Escherichia coli has been determined by X-ray crystallography, but high-resolution spectroscopic determinations of reactant intermediate-state structures and detailed kinetic and thermodynamic studies of EAL have been conducted for the Salmonella typhimurium enzyme. Therefore, a statistically robust homology model for the S. typhimurium EAL is constructed from the E. coli structure. The model structure is used to describe the hierarchy of EutB and EutC subunit interactions that construct the native EAL oligomer and, specifically, to address the long-standing challenge of reconstitution of the functional oligomer from isolated, purified subunits. Model prediction that the (EutB₂)₃ oligomer assembly will occur from isolated EutB, and that this hexameric structure will template the formation of the complete, native [(EutB-EutC)₂]₃ oligomer, is verified by biochemical methods. Prediction that cysteine residues on the exposed subunit-subunit contact surfaces of isolated EutB and EutC will interfere with assembly by cystine formation is verified by activating effects of disulfide reducing agents. Angstrom-scale congruence of the reconstituted and native EAL in the active site region is shown by electron paramagnetic resonance spectroscopy. Overall, the hierarchy of subunit interactions and microscopic features of the contact surfaces, which are revealed by the homology model, guide and provide a rationale for a refined genetic and biochemical approach to reconstitution of the functional [(EutB-EutC)₂]₃ EAL oligomer. The results establish a platform for further advances in understanding the molecular mechanism of EAL catalysis and for insights into therapy-targeted manipulation of the bacterial eut metabolosome.


Temperature-Dependent Three-Dimensional Anisotropy of the Magnetoresistance in WTe_{2}.
Extremely large magnetoresistance (XMR) was recently discovered in WTe_{2}, triggering extensive research on this material regarding the XMR origin. Since WTe_{2} is a layered compound with metal layers sandwiched between adjacent insulating chalcogenide layers, this material has been considered to be electronically two-dimensional (2D). Here we report two new findings on WTe_{2}: (1) WTe_{2} is electronically 3D with a mass anisotropy as low as 2, as revealed by the 3D scaling behavior of the resistance R(H,θ)=R(ϵ_{θ}H) with ϵ_{θ}=(cos^{2}θ+γ^{-2}sin^{2}θ)^{1/2}, θ being the magnetic field angle with respect to the c axis of the crystal and γ being the mass anisotropy and (2) the mass anisotropy γ varies with temperature and follows the magnetoresistance behavior of the Fermi liquid state. Our results not only provide a general scaling approach for the anisotropic magnetoresistance but also are crucial for correctly understanding the electronic properties of WTe_{2}, including the origin of the remarkable "turn-on" behavior in the resistance versus temperature curve, which has been widely observed in many materials and assumed to be a metal-insulator transition.


Use of microcosms to determine the survival of the fish pathogen Tenacibaculum maritimum in seawater.
The survival of the fish pathogen Tenacibaculum maritimum in different seawater microcosms was investigated during 160 days. The persistence of culturable cells was greater in sterile than in natural seawater. Standard plate counts showed that T. maritimum survived in sterile seawater for more than 5 months at concentration around 10(3) cfu ml(-1). However, T. maritimum proved to be very labile in non-sterile seawater, rendering culturable cells no longer than 5 days. These results were confirmed when DNA-based methods were applied. Regardless of the microcosms used, epifluorescence microscopy counts remained at about 10(6) cells ml(-1) throughout the experiment, even though we can not distinguish T. maritimum in the case of non-sterile microcosms. Resuscitation assays with addition of fresh medium to non-sterile microcosms did not favour the recovery of T. maritimum on solid media. Although morphological changes from filamentous to spheres were observed after 3 days in the non-sterile microcosms, in the case of the sterile microcosms this change was observed at the sixth day. The biochemical, physiological, serological and genetic characteristics were unaffected in the sterile microcosms. The overall results contribute to a better understanding of the behaviour of T. maritimum in natural seawater and suggest that the aquatic bacterial population play an important role in the survival of this fish pathogen.


Integrative oncology: evidence-based medicine - The multidisciplinary experience of the Integrative Medicine Research Group (IMRG).
The purpose of this conference was to explain the relationship between the integrative and complementary medicine and cancer disease through evidence-based medicine. The topics covered are numerous and are characterized by the multidisciplinary approach of the researchers involved in this complex scenario. The Integrative Medicine Research Group (IMRG) studies the complementary and integrative approach in cancer patients with the aim to highlight the risk of drug and nutraceutical interactions and, at the same time, improve the quality of life in this particular set of patients. Our auspicious is to have an integrative medicine approach to all chronic diseases, oncological included.


Limitations in Activities of Daily Living in Community-Dwelling People Aged 75 and Over: A Systematic Literature Review of Risk and Protective Factors.
Most older people wish to age in place, for which functional status or being able to perform activities of daily living (ADLs) is an important precondition. However, along with the substantial growth of the (oldest) old, the number of people who develop limitations in ADLs or have functional decline dramatically increases in this part of the population. Therefore, it is important to gain insight into factors that can contribute to developing intervention strategies at older ages. As a first step, this systematic review was conducted to identify risk and protective factors as predictors for developing limitations in ADLs in community-dwelling people aged 75 and over. Four electronic databases (CINAHL (EBSCO), EMBASE, PsycINFO and PubMed) were searched systematically for potentially relevant studies published between January 1998 and March 2016. After a careful selection process, 6,910 studies were identified and 25 were included. By far most factors were examined in one study only, and most were considered risk factors. Several factors do not seem to be able to predict the development of limitations in ADLs in people aged 75 years and over, and for some factors ambiguous associations were found. The following risk factors were found in at least two studies: higher age, female gender, diabetes, hypertension, and stroke. A high level of physical activity and being married were protective in multiple studies. Notwithstanding the fact that research in people aged 65 years and over is more extensive, risk and protective factors seem to differ between the 'younger' and 'older' olds. Only a few risk and protective factors in community-dwelling people aged 75 years and over have been analysed in multiple studies. However, the identified factors could serve both detection and prevention purposes, and implications for future research are given as well.


[Dietary intake and hyperlipoproteinemias].
The role of nutrition on the prevalence of cardiovascular diseases is largely, but not exclusively linked to the effect of dietary intake on plasma lipids and lipoproteins. Among the regular nutrients, saturated fats, and to a lesser extent cholesterol, do raise plasma cholesterol, namely in the LDL fraction. Classical recommendations consist of reducing dietary lipids to < or = 30% and saturated fats to < or = 10% of total caloric intake. However, recent findings demonstrate that not all saturated fatty acids are exerting a similar effect on cholesterol metabolism. Likewise, whether saturated fatty acids should be most appropriately replaced by carbohydrates or monounsaturated lipids is a matter of controversy, especially when managing patients with high plasma triglycerides and/or insulin resistance. In contrast, there is currently some agreement for limiting the intake of polyunsaturated fatty acids; and for considering separately the essential n-6 or omega 6 fatty acids (largely present in many vegetable oils) and the n-3 or omega 3 derivatives (present in algae and fish oils). This leads to evaluate other properties of fatty acids (and of other dietary components) such as the capacity to modulate inflammatory responses and thrombotic reactions, as well as to influence cell sensitivity to stimuli, cell to cell communication, and cell proliferation. Finally, the confirmation that peroxidative processes are playing an important role in lipoprotein metabolism and the development of atherosclerotic lesions largely explains the present interest to antioxidants.


Metabolomics in human nutrition: opportunities and challenges.
Metabolomics has been widely adopted in pharmacology and toxicology but is relatively new in human nutrition. The ultimate goal, to understand the effects of exogenous compounds on human metabolic regulation, is similar in all 3 fields. However, the application of metabolomics to nutritional research will be met with unique challenges. Little is known of the extent to which changes in the nutrient content of the human diet elicit changes in metabolic profiles. Moreover, the metabolomic signal from nutrients absorbed from the diet must compete with the myriad of nonnutrient signals that are absorbed, metabolized, and secreted in both urine and saliva. The large-bowel microflora also produces significant metabolic signals that can contribute to and alter the metabolome of biofluids in human nutrition. Notwithstanding these possible confounding effects, every reason exists to be optimistic about the potential of metabolomics for the assessment of various biofluids in nutrition research. This potential lies both in metabolic profiling through the use of pattern-recognition statistics on assigned and unassigned metabolite signals and in the collection of comprehensive data sets of identified metabolites; both objectives have the potential to distinguish between different dietary treatments, which would not have been targeted with conventional techniques. The latter objective sets out a well-recognized challenge to modern biology: the development of libraries of small molecules to aid in metabolite identification. The purpose of the present review was to highlight some early challenges that need to be addressed if metabolomics is to realize its great potential in human nutrition.


Implementation of problem-based learning in child and adolescent psychiatry: shared experiences of a special-interest study group.
Problem-based learning (PBL) represents a major development and change in educational practice that continues to have a large impact across subjects and disciplines worldwide. It would seem that child and adolescent psychiatry, because of its inherently integrative, bio-psycho-social nature and emphasis on teamwork and collaboration, would be a specialty learned optimally through PBL. Thus, there was a need to establish an international group where experiences in implementing PBL in child and adolescent psychiatry could be shared. This article reports on the first meeting and plans of the Problem-Based Learning in Child and Adolescent Psychiatry (CAP) Special Interest Study Group (SISG), held at the annual meeting of the American Academy of Child and Adolescent Psychiatry. Through international collaboration and information-sharing, the SISG aims to promote knowledge among Child and Adolescent Psychiatrists on PBL, to explore evaluation methods of PBL in CAP, and to discuss development of PBL-based curricula. Problem-based learning (PBL) represents a major change in education that has had a large impact across disciplines worldwide. The core steps in PBL are the following: presentation of the initial problem; discussion of the problem, and development of learning objectives; independent learning focused on the objectives; and discussion, exploration of new ideas, and discovery of solutions in the reconvened group. Different from the traditional teacher's role, the PBL tutor is an active facilitator who guides learners to identify issues and ways to learn, rather than a "content expert" who provides facts.


Improvements in photoelectric performance of dye-sensitised solar cells using ionic liquid-modified TiO2 electrodes.
One of the major problems in dye-sensitised solar cells (DSSCs) is the aggregation of dyes on TiO2 electrodes, which leads to undesirable electron transfer. Various anti-aggregation agents, such as deoxycholic acid, have been proposed and applied to prevent dye aggregation on the electrodes. In this study, we designed and synthesised a phosphonium-type ionic liquid that can be modified on the TiO2 electrode surface and used as a new anti-aggregation agent. Although the modification of the ionic liquid onto the electrode reduced the amount of dye adsorbed on the electrode, it showed a significant anti-aggregation effect, thereby improving the photovoltaic performance of DSSCs with N3 and J13 dyes. This finding suggests that ionic liquids are effective as anti-aggregation agents for DSSCs.


Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors.
The combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors. This is a multicenter phase IB dose-escalation study of the combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in programmed cell death protein 1 (PD-1)/programmed death-ligand 1(PD-L1)-naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (CRC), and ovarian cancer. The primary objective was to determine maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy with tumor and peripheral immune population densities. Overall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose-expansion cohort was 16.7% (5/30, 90% CI 7% to 32%). Complete responses occurred in melanoma (n=2); partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Median OS was as follows: melanoma, not reached (NR); RCC, 15.7 months (90% CI 2.5 to 15.7); CRC, 3.3 months (90% CI 0.6 to 3.4); ovarian, 12.5 months (90% CI 3.8 to 13.6); other solid tumors, NR. Activated tumor-infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression, and increased peripheral memory CD8 T cells correlated with clinical response. The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1-resistant melanoma. NCT02298959.


Measurement of the susceptibility of paramagnetically labeled cells with paramagnetic solutions.
A method of measuring the volumetric magnetic susceptibility, in which magnetically labeled cells or other particles are suspended in a paramagnetic solution of known susceptibility over the poles of a magnet, is presented. If the cells are more magnetic than the solution, they are attracted toward the poles; if they are less magnetic, they are repelled. If they have the same susceptibility as the solution, they do not move. Under this condition, the cells are said to be "isomagnetic" with the surrounding solution. Since the volumetric susceptibility of this solution is known, the susceptibility of the cells is obtained. Using the "isomagnetic" method, the volumetric susceptibilities of test metal powders were determined within +/- 8 X 10(-6) SI units. Yeast, colonic carcinoma, and liver cells, rendered magnetic with erbium chloride, had susceptibilities ranging from 13 to 20 X 10(-6). Particles of articular cartilage treated with erbium chloride were heterogeneous, with susceptibilities ranging between 50 and 125 X 10(-6), while particles of bone had a susceptibility of 560 to 580 X 10(-6). Eukaryotic cells labeled with ferritin attained susceptibilities of less than 1 X 10(-6).


Changes in ovarian gene expression profiles and plasma hormone levels in maturing European eel (Anguilla anguilla); Biomarkers for broodstock selection.
Complete sexual maturation of European eels (Anguilla anguilla) in captivity can only be achieved via injections with gonadotropins. For female eels this procedure takes 4-6months and the response ranges from "unresponsive" to final maturation and ovulation. Reproductive success could be significantly increased via early selection of responders based on predictive markers and minimally invasive sampling methods. To get a better understanding of the genetic background of ovarian maturation of the European eel we performed a pilot deep-sequencing transcriptome analysis of ovarian tissue derived from a yellow eel, a prepubertal silver eel and a post-spawning matured eel. Two key players in steroidogenesis were strongly correlated with advanced sexual maturation, namely P450c17 and liver receptor homolog-1, suggesting that blood plasma steroids might qualify as minimally invasive markers for early detection of responders. Since the predictive value of plasma sex steroid levels for final maturation of the European eel had not yet been carefully examined, we performed an extensive artificial maturation trial. Farmed silver eels were treated with pituitary extracts and sampled at multiple time intervals. Expression of steroidogenesis-related genes in ovarian tissue of responding and non-responding eels after four weekly injections with pituitary extract was compared using a custom-built microarray and RNAseq. Increased expression of 17β-hsd1 was strongly linked to sexual maturation. Blood plasma levels of sex steroids were measured using ELISAs. We show that a 2.5-fold increase in blood-plasma estradiol level after 4 weekly pituitary extract injections is a strong predictor of final sexual maturation of female European eel.


Differences in Rates of Low Birth Weight among Prefectures in Japan: An Ecological Study Using Government Statistics Data.
The differences in the rates and trends of the overall low birth weight and term low birth weight in recent years are unknown for the Japanese prefectures. In this ecological study, we revealed the rates for each prefecture and investigated the factors affecting the regional differences in these outcomes. Aggregated vital statistics data from 2007 to 2019 were obtained from the Ministry of Health, Labour, and Welfare in Japan. The association between the outcomes and the variables, including the infants' birth characteristics, medical characteristics, and socioeconomic characteristics of the prefectures, were analyzed. An analysis of repeated-measures data was conducted using the data from 2013 and 2018 for each prefecture. The trend for the rates of overall low birth weight and term low birth weight over the years differed among the prefectures. Moreover, the proportions of multiple births and lean (body mass index <18.5 kg/m2) and obese (body mass index ≥25.0 kg/m2) women had a statistically significant positive association with both the overall low birth weight rate and the term low birth weight rate among the prefectures. It was suggested that to resolve the difference in these outcomes among the prefectures, being obese or underweight needs to be addressed in mothers.


Optical properties of ZnO nanostructures.
We present a review of current research on the optical properties of ZnO nanostructures. We provide a brief introduction to different fabrication methods for various ZnO nanostructures and some general guidelines on how fabrication parameters (temperature, vapor-phase versus solution-phase deposition, etc.) affect their properties. A detailed discussion of photoluminescence, both in the UV region and in the visible spectral range, is provided. In addition, different gain (excitonic versus electron hole plasma) and feedback (random lasing versus individual nanostructures functioning as Fabry-Perot resonators) mechanisms for achieving stimulated emission are described. The factors affecting the achievement of stimulated emission are discussed, and the results of time-resolved studies of stimulated emission are summarized. Then, results of nonlinear optical studies, such as second-harmonic generation, are presented. Optical properties of doped ZnO nanostructures are also discussed, along with a concluding outlook for research into the optical properties of ZnO.


RNA-Seq analysis of Phanerochaete sordida YK-624 degrades neonicotinoid pesticide acetamiprid.
Acetamiprid (ACE) belongs to the group of neonicotinoid pesticides, which have become the most widely utilised pesticides around the world in the last two decades. The ability of Phanerochaete sordida YK-624 to degrade ACE under ligninolytic conditions has been demonstrated; however, the functional genes involved in ACE degradation have not been fully elucidated. In the present study, the differentially expressed genes of P. sordida YK-624 under ACE-degrading conditions and in the absence of ACE were elucidated by RNA sequencing (RNA-Seq). Based on the gene ontology enrichment results, the cell wall and cell membrane were significantly affected under ACE-degrading conditions. This result suggested that intracellular degradation of ACE might be mediated by this fungus. In addition, genes in metabolic pathways were the most enriched upregulated differentially expressed genes according to the KEGG pathway analysis. Eleven differentially expressed genes characterised as cytochrome P450s were upregulated, and these genes were determined to be particularly important for ACE degradation by P. sordida YK-624 under ligninolytic conditions.


Therapeutic Efficacy of Nigella Sativa Linn. against Antituberculosis Drug-Induced Hepatic Injury in Wistar Rats.
Antituberculosis drug (ATD)-induced hepatotoxicity is a major impediment for the effective treatment of tuberculosis (TB). All first-line anti-TB medications have adverse effects that interrupt the successful completion of TB treatment. This investigation focuses on the evaluation of the protective role of Nigella sativa (NS) against liver injury caused by ATDs. Female rats were treated with ATDs for 8 weeks (3 d/wk) followed by NS for 8 weeks (3 d/wk). The antioxidant activity of NS was estimated with a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and by analyzing total phenolic contents. Qualitative characterization of active compounds of the plant was done by high-performance liquid chromotography (HPLC). ATD-induced adverse effects were associated with sharp elevation in levels of serum transaminases, albumin, cholesterol, urea, uric acid, creatinine, and blood urea nitrogen (BUN). ATDs significantly increased lipid peroxidation (LPO) and decreased enzyme activities (superoxide dismutase [SOD], catalase [CAT], adenosine triphosphatase [ATPase], and glucose-6-phosphatase [G6Pase]) in liver, indicating oxidative stress. Conjoint treatment with NS could reverse the serological biochemistry and inhibit oxidative stress by suppressing LPO and augmenting antioxidant enzyme activity toward that of the control. Histological studies support the above biochemical findings. Results indicate that NS exerts excellent hepatoprotective abilities and can be used as a supplement to improve patient adherence and reduce interruptions in treatment due to ATD-related liver injury.


Inhibition of IL-10 production by maternal antibodies against Group B Streptococcus GAPDH confers immunity to offspring by favoring neutrophil recruitment.
Group B Streptococcus (GBS) is the leading cause of neonatal pneumonia, septicemia, and meningitis. We have previously shown that in adult mice GBS glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an extracellular virulence factor that induces production of the immunosuppressive cytokine interleukin-10 (IL-10) by the host early upon bacterial infection. Here, we investigate whether immunity to neonatal GBS infection could be achieved through maternal vaccination against bacterial GAPDH. Female BALB/c mice were immunized with rGAPDH and the progeny was infected with a lethal inoculum of GBS strains. Neonatal mice born from mothers immunized with rGAPDH were protected against infection with GBS strains, including the ST-17 highly virulent clone. A similar protective effect was observed in newborns passively immunized with anti-rGAPDH IgG antibodies, or F(ab')(2) fragments, indicating that protection achieved with rGAPDH vaccination is independent of opsonophagocytic killing of bacteria. Protection against lethal GBS infection through rGAPDH maternal vaccination was due to neutralization of IL-10 production soon after infection. Consequently, IL-10 deficient (IL-10(-/-)) mice pups were as resistant to GBS infection as pups born from vaccinated mothers. We observed that protection was correlated with increased neutrophil trafficking to infected organs. Thus, anti-rGAPDH or anti-IL-10R treatment of mice pups before GBS infection resulted in increased neutrophil numbers and lower bacterial load in infected organs, as compared to newborn mice treated with the respective control antibodies. We showed that mothers immunized with rGAPDH produce neutralizing antibodies that are sufficient to decrease IL-10 production and induce neutrophil recruitment into infected tissues in newborn mice. These results uncover a novel mechanism for GBS virulence in a neonatal host that could be neutralized by vaccination or immunotherapy. As GBS GAPDH is a structurally conserved enzyme that is metabolically essential for bacterial growth in media containing glucose as the sole carbon source (i.e., the blood), this protein constitutes a powerful candidate for the development of a human vaccine against this pathogen.


Association between 1,25-dihydroxyvitamin D and left atrial diameter in pre-dialysis chronic kidney disease patients .
To investigate the correlation between serum 1,25-dihydroxyvitamin D (1,25D) levels and left atrial diameter (LAD) using echocardiography in pre-dialysis chronic kidney disease (CKD). From an initial population of 487 patients (109 met the exclusion criteria), a total of 378 patients with CKD stage 3a - 5 who had not undergone dialysis or kidney transplantation were included in the study. The relationship between serum 1,25D levels and LAD was examined. Moreover, factors that impacted LAD were extracted through stepwise multiple regression analyses. Serum 1,25D levels correlated negatively with LAD, left ventricular end-diastolic diameter, interventricular septum thickness, end-diastolic volume, stroke volume, left ventricular mass index (LVMI), and E/e'. Stepwise multiple regression analyses revealed there was a significant relationship between serum 1,25D levels and LAD (regression coefficient = -0.070, p = 0.001). In the stratified analysis, serum 1,25D levels were associated with LAD in the LVMI < 125 g/m2 (regression coefficient = -0.067, p = 0.038) and ejection fraction (EF) ≥ 60% groups (regression coefficient = -0.080, p = 0.004). Serum 1,25D levels were independently associated with LAD in CKD patients; however, the association was not significant in patients with an EF < 60% and LVMI > 125 g/m2.


Analysis of HLA-class-II-encoded antigen-processing genes TAP1 and TAP2 in primary biliary cirrhosis.
The search for genes involved in the aetiology of primary biliary cirrhosis (PBC) has centred on the major histocompatibility complex (MHC) on chromosome 6. Genotyping studies have confirmed an association with HLA class II allele DR8. We investigated polymorphisms in two newly identified genes (TAP1 and TAP2) situated close to the DR locus and thought to encode membrane transporter molecules involved in endogenous antigen processing. Genomic DNA extracted from PBC patients was compared with local healthy controls. TAP1 was analysed by amplification refractory mutation system (ARMS) PCR, and two alleles (A and B) were identified. In 126 PBC patients and 116 controls, allele frequencies were (A:B) 81:19% and 79:21%, respectively (NS). TAP2 analysis was by PCR followed by Bfal restriction digest, and again two alleles (A and B) were identified. Their frequencies in 109 PBC patients and 96 controls were (A:B) 76:24% and 73:27%, respectively (NS). No TAP1-TAP2 haplotype was associated with PBC. TAP allele frequencies were estimated within the DR8 subgroups (22 PBC, 14 controls). B allele frequency for TAP1 was increased in both DR8-positive PBC patients and controls compared with DR8-negative patients and controls (41% vs. 14% in PBC; 43% vs. 18% in controls), but no disease association was found. However, the increased frequency of TAP1B in DR8-positive subjects (42% DR8-positive vs. 16% DR8-negative, p < 0.001) indicates linkage disequilibrium between these two loci.


A dataset of formulation compositions for self-emulsifying drug delivery systems.
Self-emulsifying drug delivery systems (SEDDS) are a well-established formulation strategy for improving the oral bioavailability of poorly water-soluble drugs. Traditional development of these formulations relies heavily on empirical observation to assess drug and excipient compatibility, as well as to select and optimize the formulation compositions. The aim of this work was to leverage previously developed SEDDS in the literature to construct a comprehensive SEDDS dataset that can be used to gain insights and advance data-driven approaches to formulation development. A dataset comprised of 668 unique SEDDS formulations encompassing 20 poorly water-soluble drugs was curated. While there are still opportunities to enhance the quality and quantity of data on SEDDS, this research lays the groundwork to potentially simplify the SEDDS formulation development process.