Paenibacillus xerothermodurans sp. nov., an extremely dry heat resistant spore forming bacterium isolated from the soil of Cape Canaveral, Florida.
A Gram-stain-positive, motile, endospore-producing, facultative anaerobic bacterial strain, designated ATCC 27380T, was isolated from heat-stressed soil of Cape Canaveral, Florida, USA. Growth was observed at 20-42 °C (optimum, 37 °C), at pH 6.0-10.0 (optimum pH 7.0) and in the presence of 0.5-3 % NaCl (optimum 0.5 %). The cell wall contained meso-diaminopimelic acid as the diagnostic amino acid and the isoprenoid quinone was MK-7. The polar lipids present were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol and one unknown phospholipid. The main fatty acids were iso-C15 : 0 and anteiso-C15 : 0. Phylogenetic analysis based on 16S rRNA gene sequencing affiliated strain ATCC 27380T to the genus Paenibacillus, and showed the highest sequence similarity to Paenibacillus rigui JCM 16352T (97.0 %). The other closely related type strains exhibited 16S rRNA gene sequence similarity values below 95.9 %. The draft genome of ATCC 27380T had a size of 4,361,187 bases, with a G+C content of 51.0 %. The average nucleotide identity and in silico DNA-DNA hybridization values between strain ATCC 27380T and P. rigui JCM 16352T were 72.5% and 18.5 %, respectively, which were below the threshold suggested for species differentiation (96% and 70 %, respectively). The average amino acid identity between strain ATCC 27380T and P. rigui JCM 16352T was 68.72 %, which was above the suggested genus level demarcation of 65 %. Based on phenotypic, genotypic and chemotaxonomic data, strain ATCC 27380T represents a novel species in the genus Paenibacillus, for which the name Paenibacillusxerothermodurans sp. nov. (=DSM 520T=NRRL NRS-1629T=ATCC 27380T) is proposed.


A paradigm for the evaluation and management of spinal coccidioidomycosis.
Coccidioidomycosis is a fungal infection that is endemic to parts of the Southwestern United States. When infection involves the spine, the treatment strategies can be challenging. We have devised a management protocol for spinal coccidioidomycosis based on a review of the literature and our experience. The electronic literature search of National Library of Medicine for publications from 1964 to 2014 was performed using the following keywords: Coccidioidomycosis and spine. The search yielded 24 papers. Treatment strategies were summarized into a treatment protocol. A total of 164 cases of spinal coccidioidomycosis were identified, ranging in age from <10 to >80 years. Males (n = 131) and African-Americans (n = 79) were strikingly over-represented. Medical therapy: Once a diagnosis of spinal coccidioidomycosis is established, antifungal therapy should always be started. Antifungal therapy with amphotericin B or azoles like fluconazole. Medical therapy needs to be continued for many years and sometimes indefinitely to reduce disease recurrence or progression. Surgical management is indicated in cases with mechanical instability, neurologic deficit, medically intractable pain, or progression of infection despite antifungal therapy. This work provides a working protocol involving assessment and reassessment for the management of spinal coccidioidomycosis. Medical management with antifungal agents in some cases can provide satisfactory disease control. However, in patients with mechanical instability, neurologic deficit, medically intractable pain or disease progression disease control may only be achieved with surgical debridement and stabilization.


Robust short-term memory without synaptic learning.
Short-term memory in the brain cannot in general be explained the way long-term memory can--as a gradual modification of synaptic weights--since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings.


Distribution, DNA damage and cytotoxic effects of etoposide in human tumor xenografts in vivo.
Mechanisms of resistance to VP-16 in vivo were studied using sensitive and multidrug resistant human breast tumor (MCF-7) cells, implanted bilaterally in nude mice. Administration of VP-16 (40 mg/kg, i.p.) indicated that there were no significant differences in either accumulation and retention of VP-16 or in the drug-induced bulk DNA damage in sensitive or resistant solid xenografts. Furthermore, under these conditions, no differential cytotoxic response to VP-16 was observed in solid tumors.


Flares After Withdrawal of Biologic Therapies in Juvenile Idiopathic Arthritis: Clinical and Laboratory Correlates of Remission Duration.
To assess the time in remission after discontinuing biologic therapy in patients with juvenile idiopathic arthritis (JIA). We enrolled 135 patients followed in 3 tertiary-care centers. The primary outcome was to assess, once remission was achieved, the time in remission up to the first flare after discontinuing treatment. Mann-Whitney U test, Wilcoxon's signed rank test for paired samples, chi-square tests, and Fisher's exact test were used to compare data. Pearson's and Spearman's correlation tests were used to determine correlation coefficients for different variables. To identify predictors of outcome, Cox regression model and Kaplan-Meier curves were constructed, each one at the mean of entered covariates. The majority of enrolled patients flared after stopping treatment with biologics (102 of 135, 75.6%) after a median followup time in remission off therapy of 6 months (range 3-109 months). A higher probability of maintaining remission after discontinuing treatment was present in systemic-onset disease compared to the rest of the JIA patients (Mantel-Cox χ2 = 8.31, P < 0.004). In analysis limited to children with JIA with polyarticular and oligoarticular disease, patients who received biologics >2 years after achieving remission had a higher probability of maintaining such remission off therapy (mean ± SD 18.64 ± 3.3 months versus 11.51 ± 2.7 months [P < 0.009]; Mantel-Cox χ2 = 9.06, P < 0.002). No other clinical variable was significantly associated with a long-lasting remission. Children with oligoarticular and polyarticular JIA who stop treatment before 2 years from remission have a higher chance of relapsing after biologic withdrawal.


Epigenetic and transcriptional features of the novel human imprinted lncRNA GPR1AS suggest it is a functional ortholog to mouse Zdbf2linc.
Long non-coding RNAs (lncRNAs), transcribed from the intergenic regions of animal genomes, play important roles in key biological processes. In mice, Zdbf2linc was recently identified as an lncRNA isoform of the paternally expressed imprinted Zdbf2 gene. The functional role of Zdbf2linc remains undefined, but it may control parent-of-origin-specific expression of protein-coding neighbors through epigenetic modification in cis, similar to imprinted Nespas, Kcnq1ot1 and Airn lncRNAs. Here, we identified a novel imprinted long-range non-coding RNA, termed GPR1AS, in the human GPR1-ZDBF2 intergenic region. Although GPR1AS contains no human ZDBF2 exons, this lncRNA is transcribed in the antisense orientation from the GPR1 intron to a secondary, differentially methylated region upstream of the ZDBF2 gene (ZDBF2 DMR), similar to mouse Zdbf2linc. Interestingly, GPR1AS/Zdbf2linc is exclusively expressed in human/mouse placenta with paternal-allele-specific expression and maternal-allele-specific promoter methylation (GPR1/Gpr1 DMR). The paternal-allele specific methylation of the secondary ZDBF2 DMR was established in human placentas as well as somatic lineage. Meanwhile, the ZDBF2 gene showed stochastic paternal-allele-specific expression, possibly methylation-independent, in placental tissues. Overall, we demonstrated that epigenetic regulation mechanisms in the imprinted GPR1-GPR1AS-ZDBF2 region were well-conserved between human and mouse genomes without the high sequence conservation of the intergenic lncRNAs. Our findings also suggest that lncRNAs with highly conserved epigenetic and transcriptional regulation across species arose by divergent evolution from a common ancestor, if they do not have identical exon structures.


The effect of fatty-acid autoxidation products on blood coagulation.
Polyunsaturated fatty acids were allowed to autoxidise in air over 4 days. The water soluble oxidation products were extracted at daily intervals and tested for their effect on blood coagulation. After 1 day there was slight acceleration of the recalcification and RVV times, but from 2-4 days the extracts became increasingly inhibitory. The P.T. and P.T.T. were also inhibited. In the thrombin generation test the extracts delayed the appearance of thrombin, but the peak thrombin level was increased and its rate of decay was reduced. When added to phospholipid the extracts altered their coagulant activity. The presence of autoxidation products could account for some of the variable results obtained with different preparations of phospholipids.


Dengue shock syndrome in an infant.
Dengue is a mosquito-borne infection affecting children and adults worldwide. In newborn infants, the dengue virus can cause diseases, especially in infants born to pregnant women hospitalised with dengue or postpartum women with fever. The authors report a case of a term newborn infant who presented with haemodynamic instability and thrombocytopaenia at the age of 7 days, without a history of clinical dengue infection in the mother. The physical examination revealed an afebrile and drowsy infant with a petechial rash all over the body and ecchymosis on both palms and soles. The authors confirmed the diagnosis using the dengue NS1 antigen on the first day of admission. The treatment included fluid management and platelet transfusion. The patient recovered well and was discharged from the hospital on the 10th day of hospitalisation.


Transferable Neural Networks for Enhanced Sampling of Protein Dynamics.
Variational autoencoder frameworks have demonstrated success in reducing complex nonlinear dynamics in molecular simulation to a single nonlinear embedding. In this work, we illustrate how this nonlinear latent embedding can be used as a collective variable for enhanced sampling and present a simple modification that allows us to rapidly perform sampling in multiple related systems. We first demonstrate our method is able to describe the effects of force field changes in capped alanine dipeptide after learning about a model using AMBER99. We further provide a simple extension to variational dynamics encoders that allows the model to be trained in a more efficient manner on larger systems by encoding the outputs of a linear transformation using time-structure based independent component analysis (tICA). Using this technique, we show how such a model trained for one protein, the WW domain, can efficiently be transferred to perform enhanced sampling on a related mutant protein, the GTT mutation. This method shows promise for its ability to rapidly sample related systems using a single transferable collective variable, enabling us to probe the effects of variation in increasingly large systems of biophysical interest.


[Total intravenous anesthesia in patients with postburn deformations of the face and neck].
Total intravenous anaesthesia was used in 1482 patients with postburn deformations of face and neck. Sodium hydroxybutyrate (SH) stimulating respiration at the expense of activation of cholinergic processes was the principal component of anaesthesia. The following protocols were used: 1) thalamonal-SH-seduxene-analgin, 23 cases; 2) barbiturates-SH-phentanyl-analgin, 182 cases; 3) seduxene-SH-phentanyl, 494 cases; 4) seduxene-SH-calypsol, 293 cases; 5) rogipnol-SH-phentanyl-calypsol, 394 cases; 6) dipidolor-SH-benzodiazepines (or barbiturates), 96 cases. All the operations were smooth, no serious complications were observed.


Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer.
Etiologic factors for pancreatic cancer, the 4th deadliest malignant neoplasm in the United States, include obesity and abnormal glucose metabolism. Calorie restriction (CR) and rapamycin each affect energy metabolism and cell survival pathways via inhibition of mammalian target of rapamycin (mTOR) signaling. By using a Panc02 murine pancreatic cancer cell transplant model in 45 male C57BL/6 mice, we tested the hypothesis that rapamycin mimics the effects of CR on pancreatic tumor growth. A chronic regimen of CR, relative to an ad libitum-fed control diet, produced global metabolic effects such as reduced body weight (20.6 ± 1.6 g vs. 29.3 ± 2.3 g; P < 0.0001), improved glucose responsiveness, and decreased circulating levels of insulin-like growth factor (IGF)-1 (126 ± 8 ng/mL vs. 199 ± 11 ng/mL; P = 0.0006) and leptin (1.14 ± 0.2 ng/mL vs. 5.05 ± 1.2 ng/mL; P = 0.01). In contrast, rapamycin treatment (2.5 mg/kg intraperitoneal every other day, initiated in mice following 20 weeks of ad libitum control diet consumption), relative to control diet, produced no significant change in body weight, IGF-1 or leptin levels, but decreased glucose responsiveness. Pancreatic tumor volume was significantly reduced in the CR group (221 ± 107 mm(3); P < 0.001) and, to a lesser extent, the rapamycin group (374 ± 206 mm(3); P = 0.04) relative to controls (550 ± 147 mm(3)), and this differential inhibition correlated with expression of the proliferation marker Ki-67. Both CR and rapamycin decreased phosphorylation of mTOR, p70/S6K, and S6 ribosomal protein, but only CR decreased phosphorylation of Akt, GSK-3β, extracellular signal regulated kinase/mitogen-activated protein kinase, and STAT3(TYR705). These findings suggest that rapamycin partially mimics the anticancer effects of CR on tumor growth in a murine model of pancreatic cancer.


The formation of the Indo-Pacific montane avifauna.
The processes generating the earth's montane biodiversity remain a matter of debate. Two contrasting hypotheses have been advanced to explain how montane populations form: via direct colonization from other mountains, or, alternatively, via upslope range shifts from adjacent lowland areas. We seek to reconcile these apparently conflicting hypotheses by asking whether a species' ancestral geographic origin determines its mode of mountain colonization. Island-dwelling passerine birds at the faunal crossroads between Eurasia and Australo-Papua provide an ideal study system. We recover the phylogenetic relationships of the region's montane species and reconstruct their ancestral geographic ranges, elevational ranges, and migratory behavior. We also perform genomic population studies of three super-dispersive montane species/clades with broad island distributions. Eurasian-origin species populated archipelagos via direct colonization between mountains. This mode of colonization appears related to ancestral adaptations to cold and seasonal climates, specifically short-distance migration. Australo-Papuan-origin mountain populations, by contrast, evolved from lowland ancestors, and highland distribution mostly precludes their further colonization of island mountains. Our study explains much of the distributional variation within a complex biological system, and provides a synthesis of two seemingly discordant hypotheses for montane community formation.


[Screening tests for early detecting breast cancer in women in Israel--performance rates and patient characteristics].
Screening tests including mammograms for early detection of breast cancer are in the basket of services provided under the National Health Insurance Law. The law also defines the population groups entitled to mammograms, and sets the frequency of the test as once every 2 years. The aim of this study was to examine the screening rates for early detection of breast cancer at the inception of the law, in order to monitor future changes in performance rates, and identify the characteristics of those unlikely to undergo these tests, in order to promote the use of screening tests by them. This study is part of a comprehensive survey examining the effect of the National Health Insurance Law on the Israeli population. The survey, carried out in the summer of 1995, included a sample of 1,400 Israeli residents aged 22 and over. To determine performance rates for clinical breast examinations a subgroup of 515 women aged 30 and over was sampled. To determine performance rates for mammograms, 173 women were aged 50-74 (the entitlement ages under the law), were sampled. 54% of women aged 30+ reported having had at least 1 clinical breast examination during their lifetime, and 56% of women aged 50-74 reported having had a mammogram during the past 2 years. Variables with an independent effect on the likelihood of having had a clinical breast examination by a physician during the past 2 years were: being over the age of 50, having at least 9 years of education, being a veteran resident of Israel (as opposed to a new immigrant), and being Jewish. Variables with an independent effect on the likelihood of having a mammogram during the past 2 years were: being a veteran resident of Israel, and having a high income--which was found to have a borderline effect. The findings of the survey emphasize the importance of changing the behavior patterns of both women and physicians, informing women about their entitlement to the tests, and raising consciousness of the importance of having repeated clinical examinations by a physician, as well as mammograms.


Environmental toxicity of PFCs: an enhanced integrated biomarker assessment and structure-activity analysis.
Perfluorinated chemicals (PFCs) are a group of compounds with varying carbon chains and functional groups. Currently, available toxicity studies of PFCs are limited mainly to dominant species. While many other PFCs are detected in the environment and biota, it is important to extend toxicity studies to different types of PFCs to better assess their environmental and ecological impacts. In the present study, the environmental toxicity of perfluorooctanesulfonate, perfluoroocanoic acid, perfluorononanoic acid, and perfluorodecanoic acid were evaluated in green mussel, Perna viridis, using a new and improved integrated biomarker approach, the enhanced integrated biomarker response (EIBR) system, with biomarkers from multiple biological levels. Structure-activity relationships were also examined based on the biomarker results. The results show that the 4 PFCs have distinct toxicity patterns and the integrative toxicity, in terms of the EIBR value, is governed by the fluorinated chain length. In addition to commonly recognized chain length and functional group effects, several structural factors are also involved in the toxic actions of PFCs, including hydrophobicity and molecular size, and so on. By integrating biomarkers from multiple biological levels with weight-of-evidence, the proposed EIBR provides a new perspective and an ecologically relevant assessment of the environmental toxicity of the pollutants. The results of EIBR and structure-activity analysis are also useful to predict toxic behaviors of other PFCs in the group and facilitate the decision-making process.


Learning-based, automatic 2D-to-3D image and video conversion.
Despite a significant growth in the last few years, the availability of 3D content is still dwarfed by that of its 2D counterpart. To close this gap, many 2D-to-3D image and video conversion methods have been proposed. Methods involving human operators have been most successful but also time-consuming and costly. Automatic methods, which typically make use of a deterministic 3D scene model, have not yet achieved the same level of quality for they rely on assumptions that are often violated in practice. In this paper, we propose a new class of methods that are based on the radically different approach of learning the 2D-to-3D conversion from examples. We develop two types of methods. The first is based on learning a point mapping from local image/video attributes, such as color, spatial position, and, in the case of video, motion at each pixel, to scene-depth at that pixel using a regression type idea. The second method is based on globally estimating the entire depth map of a query image directly from a repository of 3D images ( image+depth pairs or stereopairs) using a nearest-neighbor regression type idea. We demonstrate both the efficacy and the computational efficiency of our methods on numerous 2D images and discuss their drawbacks and benefits. Although far from perfect, our results demonstrate that repositories of 3D content can be used for effective 2D-to-3D image conversion. An extension to video is immediate by enforcing temporal continuity of computed depth maps.


Spindle checkpoint requires Mad1-bound and Mad1-free Mad2.
The spindle checkpoint prevents anaphase from occurring until all chromosomes have attached properly to the mitotic spindle. The checkpoint components Mad1 and Mad2 associate with unattached kinetochores and are probably involved in triggering the checkpoint. We now demonstrate that in Xenopus egg extracts Mad1 and Mad2 form a stable complex, whereas a fraction of Mad2 molecules is not bound to Mad1. The checkpoint establishment and maintenance are lost upon titrating out free Mad2 with an excess of Mad1 or a truncated Mad1 (amino acids 326-718, Mad1C) that contains the Mad2-binding region. Mad1N (amino acids 1-445) that binds kinetochores, but not Mad2, reduces Mad1 and Mad2 at kinetochores and abolishes checkpoint maintenance. Furthermore, the association between Mad2 and Cdc20, the activator for the anaphase-promoting complex, is enhanced under checkpoint-active condition compared with that at metaphase. Immunodepletion analysis shows that the Mad1-free Mad2 protein is unable to bind Cdc20, consistent with the model that kinetochore localization of Mad2 facilitates the formation of Mad2-Cdc20 complex. This study demonstrates that the ratio between Mad1 and Mad2 is critical for maintaining a pool of Mad1-free Mad2 that is necessary for the spindle checkpoint. We propose that Mad2 may become activated and dissociated from Mad1 at kinetochores and is replenished by the pool of Mad1-free Mad2.


Sexual desire and arousal disorders in women.
According to incentive motivation theory, sexual desire is the result of the interplay between a sensitive sexual response system and stimuli that activate the system. From this notion it follows that sexual desire is not a cause but a consequence of sexual arousal. The effects of hormones, somatic disease and medication on sexual arousability are discussed, as well as the influence of psychological factors - such as stimulus meaning, mood and cognition - and relational context on female sexual desire and arousal. At present, much attention is being paid to possible pharmacological treatments for decreased desire and arousal problems, even though desire and arousal seem more strongly associated with psychological and relational factors. Empirical evidence of the effect of psychological treatments for decreased desire and arousal problems in women is scarce. A cognitive-behavioral therapy approach with explicit attention to relational context and a focus on improving arousal and sexual satisfaction has shown to be effective. Knowledge about which treatment elements bring about change is still lacking.


When soils become sediments: Large-scale storage of soils in sandpits and lakes and the impact of reduction kinetics on heavy metals and arsenic release to groundwater.
Simulating the storage of aerobic soils under water, the chemical speciation of heavy metals and arsenic was studied over a long-term reduction period. Time-dynamic and redox-discrete measurements in reactors were used to study geochemical changes. Large kinetic differences in the net-complexation quantities of heavy metals with sulfides was observed, and elevated pore water concentrations remained for a prolonged period (>1 year) specifically for As, B, Ba, Co, Mo, and Ni. Arsenic is associated to the iron phases as a co-precipitate or sorbed fraction to Fe-(hydr)oxides, and it is being released into solution as a consequence of the reduction of iron. The composition of dissolved organic matter (DOM) in reducing pore water was monitored, and relative contributions of fulvic, humic and hydrophylic compounds were measured via analytical batch procedures. Quantitative and qualitative shifts in organic compounds occur during reduction; DOM increased up to a factor 10, while fulvic acids become dominant over humic acids which disappear altogether as reduction progresses. Both the hydrophobic and hydrophilic fractions increase and may even become the dominant fraction. Reactive amorphous and crystalline iron phases, as well as dissolved FeII/FeIII speciation, were measured and used as input for the geochemical model to improve predictions for risk assessment to suboxic and anaerobic environments. The release of arsenic is related to readily reducible iron fractions that may be identified by 1 mM CaCl2 extraction procedure. Including DOM concentration shifts and compositional changes during reduction significantly improved model simulations, enabling the prediction of peak concentrations and identification of soils with increased emission risk. Practical methods are suggested to facilitate the practice of environmentally acceptable soil storage under water.


Comparison of throat swabs and sputum specimens for viral nucleic acid detection in 52 cases of novel coronavirus (SARS-Cov-2)-infected pneumonia (COVID-19).
Objectives In December 2019, a novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, China. Laboratory-based diagnostic tests utilized real-time reverse transcriptase polymerase chain reaction (RT-PCR) on throat samples. This study evaluated the diagnostic value to analyzing throat and sputum samples in order to improve accuracy and detection efficiency. Methods Paired specimens of throat swabs and sputum were obtained from 54 cases, and RNA was extracted and tested for 2019-nCoV (equated with SARS-CoV-2) by the RT-PCR assay. Results The positive rates of 2019-nCoV from sputum specimens and throat swabs were 76.9% and 44.2%, respectively. Sputum specimens showed a significantly higher positive rate than throat swabs in detecting viral nucleic acid using the RT-PCR assay (p = 0.001). Conclusions The detection rates of 2019-nCoV from sputum specimens were significantly higher than those from throat swabs. We suggest that sputum would benefit for the detection of 2019-nCoV in patients who produce sputum. The results can facilitate the selection of specimens and increase the accuracy of diagnosis.


Thromboembolic cardiovascular risk among arthritis patients using cyclooxygenase-2-selective inhibitor or nonselective cyclooxygenase inhibitor nonsteroidal anti-inflammatory drugs.
Selective cyclooxygenase (COX)-2 inhibitors have been associated with an increased risk of thromboembolic cardiovascular (CV) events. Prior studies have found that rofecoxib has a destabilizing effect on blood pressure; however, whether this translates to an increased risk of thromboembolic CV events is unknown. The objective of this study was to evaluate risk of thromboembolic CV events among hypertensive and nonhypertensive patients treated with rofecoxib or celecoxib, nonselective nonsteroidal anti-inflammatory drugs (ns-NSAIDs), or no NSAIDs (nonusers). This was a retrospective cohort study of 31,743 adult arthritis patients enrolled in a Blue Cross/Blue Shield health insurance plan in the northeastern United States. The main outcome measure was incident acute myocardial infarction and stroke. A clinically significant channeling effect was observed where selective COX-2 inhibitor users had a more severe CV risk profile. Among normotensive patients, the hazard ratio (HR) of CV events for ns-NSAIDs, rofecoxib, or celecoxib versus nonusers was 0.91 (95% confidence interval, 0.68-1.21), 1.05 (0.61-1.80), and 1.19 (0.86-1.66), respectively. Among hypertensive patients, the risk of CV events for ns-NSAIDs users was not significantly different versus nonusers (HR=1.21; 0.88-1.67). However, rofecoxib was associated with a significant 2-fold increase in CV risk versus nonusers of NSAIDs (HR=2.16; 1.51-3.09), whereas celecoxib was not (HR=1.18; 0.89-1.57). These data support the hypothesis that elevated CV risk is not a drug class effect of selective COX-2 inhibitors. That this effect was specific to hypertensive patients indicates that blood pressure destabilization is likely an important contributing mechanism.


Dystrophin Gene Replacement and Gene Repair Therapy for Duchenne Muscular Dystrophy in 2016: An Interview.
After years of relentless efforts, gene therapy has now begun to deliver its therapeutic promise in several diseases. A number of gene therapy products have received regulatory approval in Europe and Asia. Duchenne muscular dystrophy (DMD) is an X-linked inherited lethal muscle disease. It is caused by mutations in the dystrophin gene. Replacing and/or repairing the mutated dystrophin gene holds great promises to treated DMD at the genetic level. Last several years have evidenced significant developments in preclinical experimentations in murine and canine models of DMD. There has been a strong interest in moving these promising findings to clinical trials. In light of rapid progress in this field, the Parent Project Muscular Dystrophy (PPMD) recently interviewed me on the current status of DMD gene therapy and readiness for clinical trials. Here I summarized the interview with PPMD.


Assessment of the impact of altitude on nasal airflow via expiratory nasal sound spectral analysis.
The aim of the study was to evaluate the effects of high altitude (HA) on the expiratory nasal sound spectra. The design consisted of a prospective analysis. The study group consisted of 24 otorhinolaryngologists and a student (2 females, 23 males) climber of the mountain of Kackar in Rize, a city located in northeastern Turkey. The elevation of the highest peak of the Kackar Mountain is 3,937 m (12,920 ft) and that of mountain plateaus at about 3,000 m (9,800 ft). Nasal sound spectral analysis was performed on 25 subjects at 700 and 3,937 m, respectively. We found that sound intensity (dB) at high frequency (Hf) was below 18.6 dB in the subjects at low altitude, while the results were found to be above 25.1 dB in the subjects at HA during expiration. A correlation was observed between the degree of HA and 'Odiosoft-rhino' findings at Hf intervals of the subjects. At the top of the mountain, the sound intensities at low and medium frequency were observed to be significantly lower than at low altitude (p < 0.05). We concluded that Hf values of HA were significantly higher than at low altitude because of nasal congestion and also narrowing of the cross-sectional area of the nasal airway. Nasal conchal and mucosal congestion affects airflow through the nasal cavity at HA, transforming it from a laminar pattern to turbulent flow. We found significant increases in the sound intensity level at Hf in the sound spectra at HA. Awareness of the impact of HA in nasal airflow is important in the diagnosis and treatment of nasal obstruction symptoms.


Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity.
Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.


Differential sensitivity of normal and chemically transformed epithelial cells to cholera toxin.
We have been studying the regulation of growth by cyclic adenosine 3':5'-monophosphate (cyclic AMP) and other factors in untransformed (K16) and chemically transformed (W8) rat liver epithelial cells. Initially, we found that 8-bromocyclic adenosine 3':5'-monophosphate was a more potent inhibitor of cell replication in K16 than in W8 cells. In addition, the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine (MIX) caused marked growth inhibition in K16 but not in W8 cells. Through the use of cholera toxin (CT) with or without MIX, we elevated intracellular cyclic AMP levels in a quantifiable fashion. With CT alone or combined with MIX, we observed a dose-dependent morphological change in W8 cells, which consisted of extensive "process" formation. K16 morphology was not altered at any concentration of CT +/- MIX tested. K16 cell growth was only marginally inhibited by CT alone, but markedly inhibited by CT plus MIX. W8 cell growth was moderately inhibited by CT alone or combined with MIX. Analysis of cyclic AMP levels revealed that, at all concentrations of CT +/- MIX and at all time periods tested, W8 cells produced significantly more cyclic AMP than K16 cells. It appears that morphological changes and growth inhibition are not necessarily linked and that MIX may inhibit K16 cell replication by means other than its ability to increase intracellular cyclic AMP levels.


Targeted inactivation of GPR26 leads to hyperphagia and adiposity by activating AMPK in the hypothalamus.
G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet-induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation.


"I just don't focus on my needs." The unmet health needs of partner and offspring caregivers of people with dementia: A qualitative study.
Family caregivers of people with dementia have significant unmet health needs. There is a lack of research that differentiates between the needs that are specifically relevant to partner and offspring caregivers. The aim of this study was to examine the health needs of partner and offspring caregivers of older people with dementia, including the barriers they experience in meeting their needs. Semi-structured interviews were conducted with 24 family caregivers of community-dwelling people with dementia. Of these, 12 were partner caregivers (4 men, 8 women) and 12 were offspring caregivers (2 men, 10 women). The interviews were transcribed and analysed using thematic analysis. Five themes were identified within the data. The first theme represents caregivers' overall assessment and perception of their health needs. The remaining four themes represent the most important aspects of caregivers' health needs; mental health, emotional support and social relationships, healthy diet and exercise, and personal time. While these themes were similar for offspring and partner caregivers, the specific needs and barriers within these areas were different. A prominent barrier for partner caregivers was that they had difficulty in acknowledging their needs. Despite this, partner caregivers demonstrated unmet emotional support needs, as they no longer had emotional support from their partner with dementia. They also had an unmet need for time away from the care-giving role, yet they were reluctant to leave the person with dementia. Offspring caregivers' unmet health needs were easily identified and were focused on their unmet mental health needs and feeling socially isolated. These unmet mental health and social support needs were related to their unmet health needs in other areas such as exercise, diet and having time to themselves. Caregivers have significant unmet needs and these are often complex, multidimensional, and they often differ between partner and offspring caregivers. Gaining a more detailed understanding of the needs and barriers that are particularly relevant to either partner or offspring caregivers will assist in the development of interventions that are tailored to the unique needs of caregivers.


[Role of social-hygienic factors and psychophysiological characteristics in human aging].
Influences of the environmental factors and psycho-physiological characteristics on human organism's viability have been studied. The role of life conditions in their combined action and interaction in forming middle age pathology has been elucidated. The age-dependent dynamic of indices of cardiovascular, nervous-muscular and respiratory systems has been received. So, the dynamic of cardiovascular system (CVS) changes is rather variable, both in men and in women. The maximum rate of CVS activity decline was found at 50-59 years in men and at 60-69 years in women. In the long-living individuals, regressive processes of weakening of major systems functioning at a level of an entire organism's viability maintenance develop uniformly. The emotional disposition has been shown to contribute greatly to health and longevity. In conclusion, to reduce behavioural and environment risk factors especially at critical age periods of human life is the main goal of prophylactic measures against premature aging.


A pool-adjacent-violators type algorithm for non-parametric estimation of current status data with dependent censoring.
A likelihood based approach to obtaining non-parametric estimates of the failure time distribution is developed for the copula based model of Wang et al. (Lifetime Data Anal 18:434-445, 2012) for current status data under dependent observation. Maximization of the likelihood involves a generalized pool-adjacent violators algorithm. The estimator coincides with the standard non-parametric maximum likelihood estimate under an independence model. Confidence intervals for the estimator are constructed based on a smoothed bootstrap. It is also shown that the non-parametric failure distribution is only identifiable if the copula linking the observation and failure time distributions is fully-specified. The method is illustrated on a previously analyzed tumorigenicity dataset.


Photoinduced chitosan-PEG hydrogels with long-term antibacterial properties.
Photochemical processes offer the possibility of preparing functional hydrogels under green conditions that are compatible with both synthetic and natural polymers. In this study, chitosan-based poly(ethylene) glycol (PEG) were successfully synthesized under light irradiation in aqueous medium. Kinetic studies under irradiation showed that less than 2 min were necessary to obtain fully cross-linked networks. Thermomechanical analyses and swelling experiments indicated that introduction of chitosan overall weakens the hydrogel network but can create domains of higher thermal stability than the PEG-alone structure. The resulting chitosan-PEG hydrogels demonstrated a tremendous inhibition (100%) of bacterial growth (Escherichia coli and Staphylococcus aureus). After 6 months' ageing, one of the hydrogels preserved a high antifouling activity against Escherichia coli. This interesting result, which could be correlated with the network features, demonstrates the strong potential of these photochemical methods to obtain robust bio-functional materials.


Structure of the Janus-faced C2B domain of rabphilin.
C2 domains are widespread protein modules that often occur as tandem repeats in many membrane-trafficking proteins such as synaptotagmin and rabphilin. The first and second C2 domains (C2A and C2B, respectively) have a high degree of homology but also specific differences. The structure of the C2A domain of synaptotagmin I has been extensively studied but little is known about the C2B domains. We have used NMR spectroscopy to determine the solution structure of the C2B domain of rabphilin. The overall structure of the C2B domain is very similar to that of other C2 domains, with a rigid beta-sandwich core and loops at the top (where Ca2+ binds) and the bottom. Surprisingly, a relatively long alpha-helix is inserted at the bottom of the domain and is conserved in all C2B domains. Our results, together with the Ca(2+)-independent interactions observed for C2B domains, indicate that these domains have a Janus-faced nature, with a Ca(2+)-binding top surface and a Ca(2+)-independent bottom surface.


Influence of different surface finishing protocols on the wear behavior of a lithium disilicate glass-ceramic.
This study aims to evaluate the effect of different finishing protocols on the wear behavior of a lithium disilicate glass-ceramic. Specimens were produced from lithium disilicate glass-ceramic prefabricated CAD/CAM blocks and divided into three groups, according to the surface treatment (n = 8): control; polishing; glaze. Ceramic specimens were subjected to wear test using a dual-axis chewing simulator. A 49 N load was applied in the axial direction combined with a lateral movement (1 mm path) using a lithium disilicate glass-ceramic spherical piston for a total of 106 cycles. Qualitative analysis of the wear surface was performed using an optical microscope. Quantitative analysis of surface roughness and volume loss was performed using a confocal microscope and a 3D-image editing software, respectively. Surface roughness and volume loss data were analyzed using Friedman's non-parametric statistical test for repeated measures and the Student-Newman-Keuls test (α = 0.050). There were statistical differences for surface roughness and volume loss of lithium disilicate glass-ceramic specimens in the different experimental conditions (P˂0.001). Control and polishing groups showed similar surface roughness and volume loss values for all testing times. Glaze group had greater wear volume after 103, 104 and 105 cycles. After 106 cycles, surface roughness and volume loss were similar among groups. For the piston, surface roughness was similar over time and among groups. A distinct wear behavior was found for glazed glass-ceramic specimens in comparison to control and polished specimens. The end of the simulation, the surface roughness and volume loss was similar for the groups.


Paederus Dermatitis: A Case Series.
Vorderman (1901) was the first to record blisters caused by beetles in medical literature. Blister beetle dermatitis is a cutaneous condition caused by the toxins released by blister beetles. The vesicant chemical in the body fluids of these insects causes an acute irritant contact dermatitis characterized by erythematovesicular lesions associated with burning sensation on exposed parts of the body. The aim of this study was to investigate the morphological patterns of blister beetle dermatitis. We conducted a 1-year (January-December 2014) prospective study of the clinical presentation of Paederus dermatitis noticed in urban and semiurban areas close to paddy fields in the Cauvery Basin, Mysuru, Karnataka. All patients with Paederus dermatitis attending the outpatient department of Department of Dermatology were recruited in the study with a total of 37 patients. Diagnosis was made on detailed history regarding onset of lesions, symptoms, as well as thorough clinical examination of the lesions. The peak time of presentation was June-September, the monsoon season in this part of India. The average duration of lesions at the time of presentation was 2-5 days. All patients had a history of burning and itchy sensation at night followed by full blown lesions the next morning, with the face, neck, and arms being the most common sites. Patients were predominantly males with the age range of 13-55 years. The most common presentations were linear erythematous plaques and erythematovesicles with a "burnt" appearance and a gray necrotic centre. "Kissing" lesions and periorbital involvement were seen in 5 and 6 patients, respectively. Species identification of the Paederus beetles was not done. Paederus dermatitis occurs in tropical regions. Awareness about the morphological patterns of the condition will prevent misdiagnosis. Simple preventive measures can be undertaken based on the behavioral pattern of this nocturnal beetle.


COVID-19 may have increased global support for universal health coverage: multi-country observational study.
The multiple risks generated by the COVID-19 pandemic intensified the debate about healthcare access and coverage. Whether the burden of disease caused by the coronavirus outbreak changed public opinion about healthcare provision remains unclear. In this study, it was specifically examined if the pandemic changed support for governmental intervention in healthcare as a proxy to support for universal health coverage (UHC). It also examined which psychological factors related to the socioeconomic interdependence exposed by the pandemic may be associated with a potential change. Online survey data was collected over 18 months (from March 2020 to August 2021) across 73 countries, containing various social attitudes and risk perceptions related to COVID-19. This was a convenience sample composed of voluntary participants (N = 3,176; age 18 years and above). The results show that support for government intervention in healthcare increased across geographical regions, age groups, and gender groups (an average increase of 39%), more than the support for government intervention in other social welfare issues. Factors related to socioeconomic interdependence predicted increased support for government intervention in healthcare, namely, social solidarity (ß = 0.14, p < 0.0001), and risk to economic livelihood (ß = 0.09, p < 0.0001). Trust in the government to deal with COVID-19 decreased over time, and this negative trajectory predicted a demand for better future government intervention in healthcare (ß = -0.10, p = 0.0003). The COVID-19 pandemic may have been a potential turning point in the global public support for UHC, as evidenced by a higher level of consensus that governments should be guarantors of healthcare.


Delayed Urinary Symptoms Induced by Ketamine.
One of the side-effects of ketamine abuse is genito-urinary damage. This report describes a case of a former ketamine user who presented with urinary symptoms associated with ketamine years after stopping consumption. This was a 26-year-old male with a history of ketamine abuse. He started treatment for alcohol dependence at age 19. He smoked marijuana daily and denied any other drug use. During the follow-up, urinary symptoms were evidenced (dysuria, frequency, urgency, incontinence, nocturia, hematuria, and suprapubic pain). Urinary symptoms started two years ago and worsened over time. The patient was referred to a urologist. A cystoscopy revealed lesions compatible with interstitial cystitis like the ones that appear in some ketamine abusers. Given the medical history, the urologist asked him about ketamine consumption and the patient declared a daily use of 50 milligrams intranasally from age 15 to age 17. Given these findings, not reported previously in the medical literature, future research should follow up patients who at some point in their life made an abusive consumption of ketamine in order to understand the pathogenesis and to be able to intervene before clinical disease manifests itself.


Fracture resistance of endodontically treated teeth restored with ceramic inlays and different base materials.
This study evaluated the fracture resistance of endodontically treated teeth restored with different base materials and mesioocclusal-distal (MOD) ceramic inlays. Fifty mandibular molars were assigned into five groups (n=10 per group). Group1 (control) comprised intact molar teeth without any treatment. Teeth in other groups were subjected to root canal treatment and restored with MOD ceramic inlays on different base materials. In Group 2, base material was zinc phosphate cement; Group 3's was glass ionomer cement; Group 4's was composite resin, and Group 5's was composite resin reinforced with fiber. Finally, a continuous occlusal load was applied until fracture occurred. Mean fracture resistance of Group 1 (3,027 N) was significantly higher than the other groups (890, 1,070, 1,670, 1,226 N respectively). Fracture resistance of Group 4 was statistically comparable with Group 5 and significantly higher than Groups 2 and 3 (p<0.05; Tukey's HSD). Use of different base materials under ceramic inlay restorations could affect the fracture resistance of endodontically treated teeth.


A pilot study on a step-feeding anoxic/oxic activated sludge system.
A four stage pilot plant of step-feed biological nutrient removal (BNR) was employed to investigate reactor performance and process stability. The results obtained showed that step-feed BNR is efficient and cost-effective for nitrogen and carbonaceous removal from municipal wastewater. The total average removal efficiencies of COD, NH3-N, TN and TP could reach as high as 89.5, 97.8, 73 and 75%, respectively, with 50% of return activated sludge (RAS), 9 h of hydraulic retention time (HRT) and 20 d of sludge retention time (SRT). Step-feed BNR is an alternative and effective technology of nutrient removal for municipal wastewater treatment.


Increased Risk of Osteoporotic Fracture in Postgastrectomy Gastric Cancer Survivors Compared With Matched Controls: A Nationwide Cohort Study in Korea.
Gastrectomy can lead to bone loss. Previous studies have suggested that there is an increased risk of fracture in gastric cancer survivors. However, these studies were performed without proper control groups. Therefore, we used Korean national health insurance data to compare the fracture risk in gastric cancer survivors who received gastrectomy to that of the general population. A total of 133,179 gastric cancer survivors were included and matched to noncancer controls using 1:1 propensity score matching. Cox proportional hazards regression analysis was used to determine the relative risk of fracture between the gastric cancer survivors and matched controls. We also examined the factors associated with fracture in gastric cancer survivors. Compared with the matched controls, gastric cancer survivors had an elevated risk of osteoporotic fracture (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.53-1.70), which was most prominent in patients who underwent total gastrectomy (HR 2.18, 95% CI 1.96-2.44) and adjuvant chemotherapy (HR 2.01, 95% CI 1.81-2.23). In multivariate analysis, anemia was significantly associated with increased fracture risk (aHR 1.34, 95% CI 1.13-1.59), while decrease in weight >5% was not (aHR 1.06, 95% CI 0.89-1.25). Gastric cancer survivors who underwent gastrectomy had an increased osteoporotic fracture risk than did matched controls. Total gastrectomy, adjuvant chemotherapy, and anemia were associated with an even higher risk in these patients. Additional studies are needed to establish optimal strategies, such as screening for osteoporosis and preventive interventions, that will reduce fracture risk in this population.


Golgin-84 is a rab1 binding partner involved in Golgi structure.
Members of the golgin family of coiled-coil proteins have been implicated in the tethering of vesicles to Golgi membranes and cisternal membranes to each other. Many also bind to rab GTPases. Golgin-84 is a membrane-anchored golgin that we now show binds preferentially to the GTP form of the rab1 GTPase. It is also present throughout the Golgi stack by immuno-EM. Antibodies to golgin-84 inhibit stacking of cisternal membranes in a cell-free assay for Golgi reassembly, whereas the cytoplasmic domain of golgin-84 stimulates stacking and increases the length of re-assembled stacks. Transient expression of golgin-84 in NRK cells helps prevent the disassembly of the Golgi apparatus normally triggered by treatment with brefeldin A. Together these data suggest that golgin-84 is involved in generating and maintaining the architecture of the Golgi apparatus.


Location of Aryl Sulfatase in Conidia and Young Mycelia of Neurospora crassa.
Aryl sulfatase (arylsulfate sulfohydrolase, EC 22.214.171.124) was found to have multiple locations in Neurospora conidia. Some enzyme activity remained in the supernatant when a spore suspension was centrifuged or filtered. Part of the cell-bound activity could be detected by adding the assay ingredients to a suspension of intact spores (patent enzyme), and additional activity was only detectable when the spores were first treated to destroy their permeability barriers (cryptic enzyme). Such treatments include: disruption with an X-press, brief rinsing with chloroform or acetone, incubation at 60 C for 5 min, and incubation with phenethyl alcohol, nystatin, or ascosin. Part of the patent aryl sulfatase was inactivated by briefly acid treating the intact spores (no loss of conidial viability). This enzyme was considered to have a cell surface location. Some enzyme was acid-resistant in intact spores, but all of the enzyme was acid-sensitive in spores whose permeability barriers had been disrupted. The pH dependence, kinetic properties, and p-nitrophenyl sulfate uptake were investigated in acid-treated conidia. No aryl sulfatase was detected in ascospores. Young mycelia contained more aryl sulfatase than did conidia, but little, if any, was secreted into the growth medium. Cryptic activity was demonstrated in young mycelia by brief chloroform treatment or by rinsing the cells with 0.1 m acetate buffer. Enzyme activity in young mycelia was completely labile to acid treatment, as was cell viability.


Protective Buffering and Individual and Relational Adjustment Following Hematopoietic Stem Cell Transplantation: A Dyadic Daily-Diary Study.
Supportive communication (e.g., protective buffering, PB) may impact individual and relational adjustment in patients following hematopoietic stem cell transplantation (HSCT) and their caregivers. Previous studies revealed that PB (i.e., hiding one's concerns and denying one's worries) has mixed effects, namely it is beneficial, costly or unrelated to dyadic adjustment. This study aimed to verify these findings by addressing some unresolved issues, i.e., examining (1) both individual and relational as well as both positive and negative indicators of adjustment, (2) the effect of within-dyad congruence (i.e., complementarity/similarity) in PB, and (3) within-dyad causal associations between PB and adjustment. Two hundred patients (following first autologous or allogeneic HSCT) and their caregivers independently completed measures of daily PB, relationship satisfaction, relationship stress, and positive affect (PA) and negative affect (NA) for 28 consecutive evenings after discharge of patients. For both patients and caregivers, the results showed a same-day association between daily PB and individual (positive and negative) and relational (positive and negative) adjustment indicators showing the advantage of PB. In terms of the dyad congruence, complementarity (one partner high and the other low) in daily PB was related to higher same-day relationship satisfaction for both patients and caregivers and lower same-day relationship stress in caregivers. The benefits from similarity (both patient and caregiver high or low in PB) had delayed effects, although only in patients. As far as the causal associations were concerned, day-to-day changes in PB preceded changes in daily adjustment. In caregivers, reverse causality was found, i.e., changes in adjustment predicted next-day changes in support. Contrary to previous studies, daily PB has a rather beneficial effect in dyads following HSCT. Patients seemed to have benefited the most from the similarity in daily PB fluctuation, while caregivers profited from complementarity. Causal associations between PB and adjustment within-dyad were also different. The findings may add to a better understanding of PB-adjustment relationship in dyads facing HSCT.


Quality of diabetes care and coronary heart disease absolute risk in patients with type 2 diabetes mellitus in Australian general practice.
To examine the quality of diabetes care and prevention of cardiovascular disease (CVD) in Australian general practice patients with type 2 diabetes and to investigate its relationship with coronary heart disease absolute risk (CHDAR). A total of 3286 patient records were extracted from registers of patients with type 2 diabetes held by 16 divisions of general practice (250 practices) across Australia for the year 2002. CHDAR was estimated using the United Kingdom Prospective Diabetes Study algorithm with higher CHDAR set at a 10 year risk of >15%. Multivariate multilevel logistic regression investigated the association between CHDAR and diabetes care. 47.9% of diabetic patient records had glycosylated haemoglobin (HbA1c) >7%, 87.6% had total cholesterol >or=4.0 mmol/l, and 73.8% had blood pressure (BP) >or=130/85 mm Hg. 57.6% of patients were at a higher CHDAR, 76.8% of whom were not on lipid modifying medication and 66.2% were not on antihypertensive medication. After adjusting for clustering at the general practice level and age, lipid modifying medication was negatively related to CHDAR (odds ratio (OR) 0.84) and total cholesterol. Antihypertensive medication was positively related to systolic BP but negatively related to CHDAR (OR 0.88). Referral to ophthalmologists/optometrists and attendance at other health professionals were not related to CHDAR. At the time of the study the diabetes and CVD preventive care in Australian general practice was suboptimal, even after a number of national initiatives. The Australian Pharmaceutical Benefits Scheme (PBS) guidelines need to be modified to improve CVD preventive care in patients with type 2 diabetes.


Long-Term Effect of Sirolimus on Serum Vascular Endothelial Growth Factor D Levels in Patients With Lymphangioleiomyomatosis.
Sirolimus reduces serum levels of vascular endothelial growth factor D (VEGF-D); the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas; and stabilizes lung function in patients with lymphangioleiomyomatosis (LAM). To determine whether reductions in VEGF-D levels are sustained over time, as well as parallel changes in lung function and lymphatic disease, we evaluated 25 patients with LAM and measured VEGF-D levels, lung function, and extent of lymphatic disease before and during sirolimus therapy. Treatment with sirolimus stabilized FEV1 and diffusion capacity for carbon monoxide (Dlco) over a period of 4.5 ± 1.6 years, caused resolution of lymphatic disease, and reduced the size of angiomyolipomas and VEGF-D levels (3,720 ± 3,020 pg/mL to 945 ± 591 pg/mL; P < .0001). Yearly changes in FEV1 % predicted and Dlco % predicted were reduced from -7.4% ± 1.4% to -0.3% ± 0.5% (P < .001) and -6.4% ± 0.9% to -0.4% ± 0.5% (P < .001), respectively. Lower VEGF-D levels correlated with sirolimus therapy (P < .001), but no significant relationship was observed between reduction in VEGF-D levels and FEV1 and Dlco during sirolimus therapy. The magnitude of VEGF-D decline was not related to the effect on lung function. Patients with lymphatic disease had higher serum VEGF-D levels, a greater reduction in VEGF-D levels, and better long-term sustained improvement in lung function during sirolimus therapy than did those without lymphatic disease. Sirolimus therapy stabilizes lung function over many years of therapy while producing a sustained reduction in VEGF-D levels in patients with elevated levels preceding therapy. An association was not demonstrated between the magnitude of VEGF-D decline and the beneficial effect of sirolimus on lung function. Persistent improvement in lung function was observed in patients with lymphatic disease.


Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations.
BACKGROUND Uterine fibroids are the most common gynecologic tumors in women of reproductive age yet the etiology and pathogenesis of these lesions remain poorly understood. Age, African ancestry, nulliparity and obesity have been identified as predisposing factors for uterine fibroids. Symptomatic tumors can cause excessive uterine bleeding, bladder dysfunction and pelvic pain, as well as associated reproductive disorders such as infertility, miscarriage and other adverse pregnancy outcomes. Currently, there are limited noninvasive therapies for fibroids and no early intervention or prevention strategies are readily available. This review summarizes the advances in basic, applied and translational uterine fibroid research, in addition to current and proposed approaches to clinical management as presented at the 'Advances in Uterine Leiomyoma Research: 3rd NIH International Congress'. Congress recommendations and a review of the fibroid literature are also reported. METHODS This review is a report of meeting proceedings, the resulting recommendations and a literature review of the subject. RESULTS The research data presented highlights the complexity of uterine fibroids and the convergence of ethnicity, race, genetics, epigenetics and environmental factors, including lifestyle and possible socioeconomic parameters on disease manifestation. The data presented suggest it is likely that the majority of women with uterine fibroids will have normal pregnancy outcomes; however, additional research is warranted. As an alternative to surgery, an effective long-term medical treatment for uterine fibroids should reduce heavy uterine bleeding and fibroid/uterine volume without excessive side effects. This goal has not been achieved and current treatments reduce symptoms only temporarily; however, a multi-disciplined approach to understanding the molecular origins and pathogenesis of uterine fibroids, as presented in this report, makes our quest for identifying novel targets for noninvasive, possibly nonsystemic and effective long-term treatment very promising. CONCLUSIONS The Congress facilitated the exchange of scientific information among members of the uterine leiomyoma research and health-care communities. While advances in research have deepened our knowledge of the pathobiology of fibroids, their etiology still remains incompletely understood. Further needs exist for determination of risk factors and initiation of preventive measures for fibroids, in addition to continued development of new medical and minimally invasive options for treatment.


Integration of single nucleotide variants and whole-genome DNA methylation profiles for classification of rheumatoid arthritis cases from controls.
This study evaluated the use of multiomics data for classification accuracy of rheumatoid arthritis (RA). Three approaches were used and compared in terms of prediction accuracy: (1) whole-genome prediction (WGP) using SNP marker information only, (2) whole-methylome prediction (WMP) using methylation profiles only, and (3) whole-genome/methylome prediction (WGMP) with combining both omics layers. The number of SNP and of methylation sites varied in each scenario, with either 1, 10, or 50% of these preselected based on four approaches: randomly, evenly spaced, lowest p value (genome-wide association or epigenome-wide association study), and estimated effect size using a Bayesian ridge regression (BRR) model. To remove effects of high levels of pairwise linkage disequilibrium (LD), SNPs were also preselected with an LD-pruning method. Five Bayesian regression models were studied for classification, including BRR, Bayes-A, Bayes-B, Bayes-C, and the Bayesian LASSO. Adjusting methylation profiles for cellular heterogeneity within whole blood samples had a detrimental effect on the classification ability of the models. Overall, WGMP using Bayes-B model has the best performance. In particular, selecting SNPs based on LD-pruning with 1% of the methylation sites selected based on BRR included in the model, and fitting the most significant SNP as a fixed effect was the best method for predicting disease risk with a classification accuracy of 0.975. Our results showed that multiomics data can be used to effectively predict the risk of RA and identify cases in early stages to prevent or alter disease progression via appropriate interventions.


Long-term statin therapy improves oncological outcome after radical gastrectomy for stage II and III gastric cancer.
Although several epidemiological studies have indicated that statins may have antitumor properties, the effect of statins on patient survival after curative resection of gastric cancer is unknown. The aim of the present study was to determine whether statin use could improve long-term outcomes after radical gastrectomy. PATIENS AND METHODS: We conducted a matched case-control study of 65 statin users and 176 non-users who underwent radical gastrectomy for stage II and III gastric cancer from January 2006 to December 2009. No significant differences were found in recurrence-free survival (RFS) or overall survival (OS) between statin users and non-users. However, subgroup analysis showed that patients who used statins for more than six months had more favorable outcomes than non-users or those who used statins for less than six months [adjusted hazard ratio of death (non-users as reference); statin use <6 months: 2.405, 95% confidence interval (CI)=1.056-5.477 and statin use >6 months: 0.168, 95% CI=0.032-0.881, p=0.006]. Statin use did not improve RFS or OS after curative resection of stage II or III gastric cancer in the overall study population. However, statin use of more than six months was associated with increased survival.


Overall survival based on oncologist density in the United States: A retrospective cohort study.
Medically underserved areas (MUA) or health professional shortage areas (HPSA) designations are based on primary care health services availability. These designations are used in recruiting international medical graduates (IMGs) trained in primary care or subspecialty (e.g., oncology) to areas of need. Whether the MUA/HPSA designation correlates with Oncologist Density (OD) and supports IMG oncologists' recruitment to areas of need is unknown. We evaluated the concordance of OD with the designation of MUAs/HPSAs and evaluated the impact of OD and MUA/HPSA status on overall survival. We conducted a retrospective cohort study of patients diagnosed with hematological malignancies or metastatic solid tumors in 2011 from the Surveillance Epidemiology and End Results (SEER) database. SEER was linked to the American Medical Association Masterfile to calculate OD, defined as the number of oncologists per 100,000 population at the county level. We calculated the proportion of counties with MUA or HPSA designation for each OD category. Overall survival was estimated using the Kaplan-Meier method and compared between the OD category using a log-rank test. We identified 68,699 adult patients with hematologic malignancies or metastatic solid cancers in 609 counties. The proportion of MUA/HPSA designation was similar across counties categorized by OD (93.2%, 95.4%, 90.3%, and 91.7% in counties with <2.9, 2.9-6.5, 6.5-8.4 and >8.4 oncologists per 100K population, p = 0.7). Patients' median survival in counties with the lowest OD was significantly lower compared to counties with the highest OD (8 vs. 11 months, p<0.0001). The difference remained statistically significant in multivariate and subgroup analysis. MUA/HPSA status was not associated with survival (HR 1.03, 95%CI 0.97-1.09, p = 0.3). MUA/HPSA designation based on primary care services is not concordant with OD. Patients in counties with lower OD correlated with inferior survival. Federal programs designed to recruit physicians in high-need areas should consider the availability of health care services beyond primary care.


Paraphyly and cryptic diversity unveils unexpected challenges in the "naked lichens" (Calvitimela, Lecanoromycetes, Ascomycota).
Molecular phylogenetics has revolutionized the taxonomy of crustose lichens and revealed an extensive amount of cryptic diversity. Resolving the relationships between genera in the crustose lichen family Tephromelataceae has proven difficult and the taxon limits within the genus Calvitimela are only partly understood. In this study, we tested the monophyly of Calvitimela and investigated phylogenetic relationships at different taxonomic levels using an integrative taxonomic approach. We performed a global sampling of all species currently assigned to Calvitimela and conducted additional sampling of C. melaleuca sensu lato across Norway. We included 108 specimens and produced more than 300 sequences from five different loci (ITS, LSU, MCM7, mtSSU, TEF1-α). We inferred phylogenetic relationships and estimated divergence times in Calvitimela. Moreover, we analyzed chemical and morphological characters to test their diagnostic values in the genus. Our molecular phylogenetic results show evolutionarily old and deeply divergent lineages in Calvitimela. The morphological characters are overlapping between divergent subgenera within this genus. Chemical characters, however, are largely informative at the level of subgenera, but are often homoplastic at the species level. The subgenus Calvitimela is found to include four distinct genetic lineages. Detailed morphological examinations of C. melaleuca s. lat. reveal differences between taxa previously assumed to be morphologically cryptic. Furthermore, young evolutionary ages and signs of gene tree discordance indicate a recent divergence and possibly incomplete lineage sorting in the subgenus Calvitimela. Phylogenetic analysis and morphological observations revealed that C. austrochilensis and C. uniseptata are extraneous to Calvitimela (Tephromelataceae). We also found molecular evidence supporting C. septentrionalis being sister to C. cuprea. In the subgenus Severidea, one new grouping is recovered as a highly supported sister to C. aglaea. Lastly, two fertile specimens were found to be phylogenetically nested within the sorediate species C. cuprea. We discuss the need for an updated classification of Calvitimela and the evolution of cryptic species. Through generic circumscription and species delimitation we propose a practical taxonomy of Calvitimela.


A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.
Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.


NMR studies of the structure and dynamics of membrane-bound bacteriophage Pf1 coat protein.
Filamentous bacteriophage coat protein undergoes a remarkable structural transition during the viral assembly process as it is transferred from the membrane environment of the cell, where it spans the phospholipid bilayer, to the newly extruded virus particles. Nuclear magnetic resonance (NMR) studies show the membrane-bound form of the 46-residue Pf1 coat protein to be surprisingly complex with five distinct regions. The secondary structure consists of a long hydrophobic helix (residues 19 to 42) that spans the bilayer and a short amphipathic helix (residues 6 to 13) parallel to the plane of the bilayer. The NH2-terminus (residues 1 to 5), the COOH-terminus (residues 43 to 46), and residues 14 to 18 connecting the two helices are mobile. By comparing the structure and dynamics of the membrane-bound coat protein with that of the viral form as determined by NMR and neutron diffraction, essential features of assembly process can be identified.


Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION 2 randomized 12-month trial including 6-month extension.
To compare the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) over 12 months of treatment in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs (OADs). EDITION 2 (NCT01499095) was a randomized, 6-month, multicentre, open-label, two-arm, phase IIIa study investigating once-daily Gla-300 versus Gla-100, plus OADs (excluding sulphonylureas), with a 6-month safety extension. Similar numbers of participants in each group completed 12 months of treatment [Gla-300, 315 participants (78%); Gla-100, 314 participants (77%)]. The reduction in glycated haemoglobin was maintained for 12 months with both treatments: least squares (LS) mean (standard error) change from baseline -0.55 (0.06)% for Gla-300 and -0.50 (0.06)% for Gla-100; LS mean difference -0.06 [95% confidence interval (CI) -0.22 to 0.10)%]. A significant relative reduction of 37% in the annualized rate of nocturnal confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemia was observed with Gla-300 compared with Gla-100: rate ratio 0.63 [(95% CI 0.42-0.96); p = 0.031], and fewer participants experienced ≥1 event [relative risk 0.84 (95% CI 0.71-0.99)]. Severe hypoglycaemia was infrequent. Weight gain was significantly lower with Gla-300 than Gla-100 [LS mean difference -0.7 (95% CI -1.3 to -0.2) kg; p = 0.009]. Both treatments were well tolerated with a similar pattern of adverse events (incidence of 69 and 60% in the Gla-300 and Gla-100 groups). In people with type 2 diabetes treated with Gla-300 or Gla-100, and non-sulphonylurea OADs, glycaemic control was sustained over 12 months, with less nocturnal hypoglycaemia in the Gla-300 group.


Update on management of stable chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a major chronic debilitating condition with significant impact on quality of life, symptoms, comorbidity, health care utilization and longevity. The main pathophysiological hallmark of COPD is expiratory flow limitation which impairs the ability of respiratory system to adequately and properly ventilate. To be able to prognosticate and manage patients with COPD, various societies have developed classifications of disease severity. Current classification schemes combine three elements that include lung function, patient reported symptoms (shortness of breath) and frequency of exacerbations. Global Initiative for Obstructive Lung Disease (GOLD), an international guideline for diagnosis and management of COPD, started using this approach since the 2011 revision. Management according to this scheme has been developed and is in use. Comprehensive COPD management is multifaceted. It includes pharmacologic management, patient education, smoking cessation, influenza and pneumococcal vaccinations, depression and anxiety management, pulmonary rehabilitation, and if indicated, home oxygen therapy. The following chapter will review management recommendations currently in use for stable COPD. We intend to make the chapter to the point and practical and avoid an exhaustive review of the literature.


Chaperone-mediated autophagy controls the turnover of E3 ubiquitin ligase MARCHF5 and regulates mitochondrial dynamics.
As a highly dynamic organelle, mitochondria undergo constant fission and fusion to change their morphology and function, coping with various stress conditions. Loss of the balance between fission and fusion leads to impaired mitochondria function, which plays a critical role in the pathogenesis of Parkinson disease (PD). Yet the mechanisms behind mitochondria dynamics regulation remain to be fully illustrated. Chaperone-mediated autophagy (CMA) is a lysosome-dependent process that selectively degrades proteins to maintain cellular proteostasis. In this study, we demonstrated that MARCHF5, an E3 ubiquitin ligase required for mitochondria fission, is a CMA substrate. MARCHF5 interacted with key CMA regulators and was degraded by lysosomes. Severe oxidative stress compromised CMA activity and stabilized MARCHF5, which facilitated DNM1L translocation and led to excessive fission. Increase of CMA activity promoted MARCHF5 turnover, attenuated DNM1L translocation, and reduced mitochondria fragmentation, which alleviated mitochondrial dysfunction under oxidative stress. Furthermore, we showed that conditional expression of LAMP2A, the key CMA regulator, in dopaminergic (DA) neurons helped maintain mitochondria morphology and protected DA neuronal viability in a rodent PD model. Our work uncovers a critical role of CMA in maintaining proper mitochondria dynamics, and loss of this regulatory control may occur in PD and underlie its pathogenic process.Abbreviations: CMA: chaperone-mediated autophagy; DA: dopaminergic; DNM1L: dynamin 1 like; FCCP: carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; HSPA8: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; MARCHF5: membrane-associated ring-CH-type finger 5; MMP: mitochondria membrane potential; OCR: oxygen consumption rate; 6-OHDA: 6-hydroxydopamine; PD: Parkinson disease; SNc: substantia nigra pars compacta; TEM: transmission electron microscopy; TH: tyrosine hydroxylase; TMRE: tetramethylrhodamine ethyl ester perchlorate; WT: wild type.


Predicting the Impact of Temperature Change on the Future Distribution of Maize Stem Borers and Their Natural Enemies along East African Mountain Gradients Using Phenology Models.
Lepidopteran stem borers are among the most important pests of maize in East Africa. The objective of the present study was to predict the impact of temperature change on the distribution and abundance of the crambid Chilo partellus, the noctuid Busseola fusca, and their larval parasitoids Cotesia flavipes and Cotesia sesamiae at local scale along Kilimanjaro and Taita Hills gradients in Tanzania and Kenya, respectively. Temperature-dependent phenology models of pests and parasitoids were used in a geographic information system for mapping. The three risk indices namely establishment, generation, and activity indices were computed using current temperature data record from local weather stations and future (i.e., 2055) climatic condition based on downscaled climate change data from the AFRICLIM database. The calculations were carried out using index interpolator, a sub-module of the Insect Life Cycle Modeling (ILCYM) software. Thin plate algorithm was used for interpolation of the indices. Our study confirmed that temperature was a key factor explaining the distribution of stem borers and their natural enemies but other climatic factors and factors related to the top-down regulation of pests by parasitoids (host-parasitoid synchrony) also played a role. Results based on temperature only indicated a worsening of stem borer impact on maize production along the two East African mountain gradients studied. This was attributed to three main changes occurring simultaneously: (1) range expansion of the lowland species C. partellus in areas above 1200 m.a.s.l.; (2) increase of the number of pest generations across all altitudes, thus by 2055 damage by both pests will increase in the most productive maize zones of both transects; (3) disruption of the geographical distribution of pests and their larval parasitoids will cause an improvement of biological control at altitude below 1200 m.a.s.l. and a deterioration above 1200 m.a.s.l. The predicted increase in pest activity will significantly increase maize yield losses in all agro-ecological zones across both transects but to a much greater extent in lower areas.


Proteomic signature of the murine intervertebral disc.
Low back pain is the most common musculoskeletal problem and the single most common cause of disability, often attributed to degeneration of the intervertebral disc. Lack of effective treatment is directly related to our limited understanding of the pathways responsible for maintaining disc health. While transcriptional analysis has permitted initial insights into the biology of the intervertebral disc, complete proteomic characterization is required. We therefore employed liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) protein/peptide separation and mass spectrometric analyses to characterize the protein content of intervertebral discs from skeletally mature wild-type mice. A total of 1360 proteins were identified and categorized using PANTHER. Identified proteins were primarily intracellular/plasma membrane (35%), organelle (30%), macromolecular complex (10%), extracellular region (9%). Molecular function categorization resulted in three distinct categories: catalytic activity (33%), binding (molecule interactions) (29%), and structural activity (13%). To validate our list, we confirmed the presence of 14 of 20 previously identified IVD-associated markers, including matrix proteins, transcriptional regulators, and secreted proteins. Immunohistochemical analysis confirmed distinct localization patterns of select protein with the intervertebral disc. Characterization of the protein composition of healthy intervertebral disc tissue is an important first step in identifying cellular processes and pathways disrupted during aging or disease progression.


Analysis of bacterial communities and characterization of antimicrobial strains from cave microbiota.
In this study for the first-time microbial communities in the caves located in the mountain range of Hindu Kush were evaluated. The samples were analyzed using culture-independent (16S rRNA gene amplicon sequencing) and culture-dependent methods. The amplicon sequencing results revealed a broad taxonomic diversity, including 21 phyla and 20 candidate phyla. Proteobacteria were dominant in both caves, followed by Bacteroidetes, Actinobacteria, Firmicutes, Verrucomicrobia, Planctomycetes, and the archaeal phylum Euryarchaeota. Representative operational taxonomic units from Koat Maqbari Ghaar and Smasse-Rawo Ghaar were grouped into 235 and 445 different genera, respectively. Comparative analysis of the cultured bacterial isolates revealed distinct bacterial taxonomic profiles in the studied caves dominated by Proteobacteria in Koat Maqbari Ghaar and Firmicutes in Smasse-Rawo Ghaar. Majority of those isolates were associated with the genera Pseudomonas and Bacillus. Thirty strains among the identified isolates from both caves showed antimicrobial activity. Overall, the present study gave insight into the great bacterial taxonomic diversity and antimicrobial potential of the isolates from the previously uncharacterized caves located in the world's highest mountains range in the Indian sub-continent.


Asymmetry and non-adiabaticity in fragmentation of disulfide bonds upon electron capture.
Although it has been generally assumed that electron attachment to disulfide derivatives leads to a systematic and significant activation of the S-S bond, we show, by using [CH(3)SSX] (X = CH(3), NH(2), OH, F) derivatives as model compounds, that this is the case only when the X substituents have low electronegativity. Through the use of MP2, QCI and CASPT2 molecular orbital (MO) methods, we elucidate, for the first time, the mechanisms that lead to unimolecular fragmentation of disulfide derivatives after electron attachment. Our theoretical scrutiny indicates that these mechanisms are more intricate than assumed in previous studies. The most stable products, from a thermodynamic viewpoint, correspond to the release of neutral molecules; CH(4), NH(3), H(2)O, and HF. However, the barriers to reach these products depend strongly on the electronegativity of the X substituents. Only for very electronegative substituents, such as OH or F, the loss of H(2)O or HF is the most favorable process, and likely the only one observed. This is possible because of two concomitant factors, 1) the extra electron for [CH(3)SSX](-) (X = OH, F) occupies a sigma*(S-X) MO, which favors the cleavage of the S-X bond, and 2) the activation barriers associated with the hydrogen transfer process to produce H(2)O and HF are rather low. Only when the substituents are less electronegative (X = H, CH(3), NH(2)) the extra electron is located in a sigma*(S-S) orbital and the cleavage of the disulfide bridge becomes the most favorable process. The intimate mechanism associated with the S-S bond dissociation process also depends strongly on the nature of the substituent. For X = H or CH(3) the process is strictly adiabatic, while for X = NH(2) it proceeds through a conical intersection (CI) associated with the charge reorganization necessary to obtain, from a molecular anion with the extra electron delocalized in a sigma*(S-S) antibonding orbital, two fragments with the proper charge localization.


[New drugs in the treatment of leprosy].
Two groups of patients were chosen for this treatment; the first group of 14 patients was treated with a daily dose of 600 mg. of Rifampicine and the second group with Rifampicine associated with Isoprodian (1-2 tablets). In the first group clinical and bacteriological improvement was apparent. This was parallel in bacteriological and morphological index. Two patients became negative in nasal mucous. Tolerance was good and number of leprosy reactions 65%. In the second group clinical improvement was good in general but one case that presented a continuous polyneuritis and hepatic intolerance. Bacteriological results were lightly lower than the first group and the number of leprosy reactions 85%. This treatment is considered inferior to the sulfons, which is very expensive. A longer period of time will be needed to appriase results.


Sonography of affected and unaffected shoulders in hemiplegic patients: analysis of the relationship between sonographic imaging data and clinical variables.
To explore the relationship between a number of clinically relevant variables and sonographic imaging data in respect to the level of impairment experienced in the affected and unaffected shoulders of hemiplegic stroke patients. Fifty-one hemiplegic stroke patients (32 males, 19 females; 29 right-sided hemiplegics, 22 left-sided hemiplegics) participated in this study. A musculoskeletal radiologist conducted a sonographic exam on both the affected and unaffected shoulders of all patients and two physicians classified the severity of the injury on a six-point rating scale. Clinical variables including age, sex, duration of injury, spasticity and muscle power of the hemiplegic side, and level of functional activity of the shoulder were assessed. The sonographic rating scores of hemiplegic shoulders were positively correlated with age (p<0.01) and negatively correlated with level of muscle spasticity (p<0.05). The sonographic rating scores of unaffected shoulders were positively correlated with duration of injury (p<0.01). Affected shoulders received sonographic rating scores that reflected significantly more impairment than those of unaffected shoulders (p<0.001), and pre-morbid handedness did not affect the relationship between impairment rating and shoulder injury status. Hemiplegic stroke influences not only affected shoulders, but also unaffected sides. Proper management of spasticity, enhancement of motor recovery, and avoidance of unaffected shoulder overuse should be considered to prevent shoulder problems following strokes which result in hemiplegia.


Acinetobacter baumannii virulence is enhanced in Galleria mellonella following biofilm adaptation.
The opportunistic nosocomial pathogen Acinetobacter baumannii is responsible for a growing number of infections; however, few of its potential virulence factors have been identified, and how this organism causes infection remains largely unknown. Bacterial biofilms are often an important component in infection and persistence but there is no conclusive evidence to link biofilm formation with virulence and severity of infection in Acinetobacter. To investigate this link, several clinical isolates were assessed in biofilm culture models and were tested for virulence in the insect model Galleria mellonella. In both systems, the profiles showed significant differences between strains, but no correlation was observed between virulence and the ability to form biofilms. In contrast, A. baumannii cells from a biofilm produced higher mortality rates than an equivalent number of planktonic cells. Relative to planktonic cells, A. baumannii biofilm cultures also showed reduced sensitivity to antibiotics normally used in the treatment of A. baumannii, especially colistin. This model, therefore, provides a suitable system to investigate the link between biofilm growth and various factors influencing virulence during A. baumannii infection.


Bisphenol A induced neuronal apoptosis and enhanced autophagy in vitro through Nrf2/HO-1 and Akt/mTOR pathways.
Bisphenol A (BPA) was traditionally used in epoxy resins and polycarbonate plastics, but it was found to be harmful to human health due to its endocrine-disrupting effects. It can affect various biological functions of human beings and interfere with brain development. However, the neurotoxic mechanisms of BPA on brain development and associated neurodegeneration remain poorly understood. Here, we reported that BPA (100, 250, 500 μM) inhibited cell viability of neural cells PC12, SH-SY5Y and caused dose-dependent cell death. In addition, BPA exposure increased intracellular reactive oxygen species (ROS) and mitochondrial ROS (mtROS) levels, decreased mitochondrial membrane potential, reduced the expression of cytochrome c oxidase IV (COX4), downregulated Bcl-2, and initiated apoptosis. Moreover, BPA treatment resulted in the accumulation of intracellular acidic vacuoles and increased the autophagy marker LC3 II to LC3 I ratio. Furthermore, BPA exposure inhibited Nrf2/ HO-1 and AKT/mTOR pathways and mediated cellular oxidative stress, apoptosis, and excessive autophagy, leading to neuronal degeneration. The interactions between oxidative stress, autophagy, and apoptosis during BPA-induced neurotoxicity remain unclear and require further in vivo confirmation.


Evaluation of the Epigenetic Demethylation of NRF2, a Master Transcription Factor for Antioxidant Enzymes, in Colorectal Cancer.
Epigenetic changes in CpG islands of the promoter regions of homeostasis-related genes, including nuclear factor erythroid 2-related factor 2 (NRF2), have been shown to hold a significant role in the development of colorectal cancer. Therefore, we aimed to examine the DNA demethylation pattern of the NRF2 promoter region in cancerous lesions from patients with colorectal cancer and the association of methylation status with clinicopathological features in the Iranian population. In this cross-sectional study, 114 colorectal tissue samples were collected. These samples included: 34 tumour tissue samples, 60 precancerous polyps, and 20 normal tissue samples. The promoter methylation status of the NRF2 gene was examined using methylation-specific PCR. Additionally, the relationship between the methylation status and the clinicopathological features was investigated. The frequency of NRF2 demethylation in the tumour samples was significantly higher compared to the polyp tissues (p= 0.003) and normal tissue (p= 0.009), indicating that cancerous colorectal tissues exhibit increased demethylation of the NRF2 promoter. After examining the demethylation status of tissue samples, the clinicopathological features were compared to the demethylation results. No significant association was found between NRF2 promoter demethylation and the clinicopathological features of patient samples. Our findings suggest that the epigenetic modifications leading to NRF2 demethylation found in colorectal tumour samples may contribute to cancer progression from precancerous polyps to cancerous lesions.


Pericardial interstitial cell senescence responsible for pericardial structural remodeling in idiopathic and postsurgical constrictive pericarditis.
Idiopathic and postsurgical constrictive pericarditis is characterized by pericardial structural remodeling that involves fibrosis, calcification, and inflammation. This study aimed to determine whether cell senescence was responsible for pericardial structural remodeling. Pericardial interstitial cells derived from patients with idiopathic or postsurgical pericarditis (pericarditis cells) were harvested. Timing of senescence and differences in telomere length were compared between age- and sex-matched controls (nonpericarditis cells). Pericardial interstitial cells derived from normal pericardia were serially passaged until senescence (senescent cells). Apoptosis, collagen matrix, calcium deposition, chemoattractant properties, gene expression profiles, and paracrine effects of senescent cells were compared with nonsenescent cells of passage 2 (nonsenescent cells). Pericarditis cells displayed senescent changes, including short telomere length, large flattened cell sizes, positive staining for senescence-associated β-galactosidase, and limited growth capacity. These senescent cells were resistant to apoptosis, produced more collagen matrix, deposited more calcium, and attracted more monocytes/lymphocytes than the nonsenescent cells. A cluster of genes involved in extracellular matrix deposition (connective tissue growth factor, fibronectin, collagen type I, collagen type III, and tissue inhibitors of metalloproteinase-1), calcium deposition (osteopontin, bone sialoprotein, osteonectin, and matrix Gla protein), and inflammatory cell recruitment (interleukin-6, chemoattractant protein-1, and tumor necrosis factor-α) were upregulated in senescent cells, whereas extracellular matrix-degrading enzyme (metalloproteinase-1 and metalloproteinase-3) was downregulated. Furthermore, senescent cells had the ability to promote the proliferation, differentiation, and senescence of neighboring cells. These findings suggest that senescent cells have characteristics promoting pericardial structural remodeling, but further work is needed to establish causation.


Superoxide anion production and superoxide dismutase and catalase activities in Coxiella burnetii.
Coxiella burnetii was examined for superoxide anion (O2-) production and superoxide dismutase and catalase activities. The organism generated O2- at pH 4.5 but not at pH 7.4. The rickettsia displayed superoxide dismutase activity distinguishable from that of the host cell (L-929 mouse fibroblast). Catalase activity was maximal at pH 7.0 and diminished at pH 4.5. These enzymes may account, in part, for the ability of this obligate intracellular parasite to survive within phagocytes.