Neurodegenerative diseases: an overview of environmental risk factors.
The population of the United States is aging, and an ever-increasing number of Americans are afflicted with neurodegenerative diseases. Because the pathogenesis of many of these diseases remains unknown, we must consider that environmental factors may play a causal role. This review provides an overview of the epidemiologic evidence for environmental etiologies for neurodegenerative diseases such as Alzheimer disease, Parkinson disease, parkinsonian syndromes (multiple system atrophy and progressive supranuclear palsy), and amyotrophic lateral sclerosis. Epidemiologic evidence for an association between environmental agents' exposure and neurodegenerative diseases is not conclusive. However, there are indications that there may be causal links, and the need for more research is obvious.


Beyond the mammography quality standards act: measuring the quality of breast cancer screening programs.
A high-quality screening mammography program should find breast cancer when it exists and when the lesion is small and ensure that suspicious findings receive prompt follow-up. The Mammography Quality Standards Act (MQSA) guidelines related to tracking outcomes are insufficient for assessing quality of care. We used data from a quality improvement project to determine whether screening mammography facilities could show that they met certain quality benchmarks beyond those required by MQSA. Participating facilities provided aggregate data on screening mammography examinations performed in calendar year 2009 and corresponding diagnostic follow-up, including patients lost to follow-up, timing of diagnostic imaging and biopsy, cancer detection rates, and the proportion of cases of cancer detected as minimal and early-stage tumors. Among the 52 participating institutions, the percentage of institutions meeting each benchmark varied from 27% to 83%. Facilities with American College of Surgeons or National Consortium of Breast Centers designation were more likely to meet benchmarks pertaining to cancer detection and early detection, and disproportionate share facilities were less likely to meet benchmarks pertaining to timeliness of care. The results suggest a combination of quality of care issues and incomplete tracking of patients. To accurately measure the quality of the breast cancer screening process, it is critical that there be complete tracking of patients with abnormal screening mammography findings so that results can be interpreted solely in terms of quality of care. The MQSA guidelines for tracking outcomes and measuring quality indicators should be strengthened for better assessment of quality of care.


[Urinary leukotrience E(4) level in children with asthma].
Cysteinyl leukotriene (CysLTs) plays an important role in airway inflammation and remodeling in asthma. Measurement of urinary leukotriene E(4) (LTE(4)) is a sensitive and noninvasive method of assaying total body CysLTs level. This study aimed to evaluate the clinical significance of urinary leukotriene E(4) (LTE(4)) in childhood asthma. Sixty children with acute asthma were randomly divided into montelukast (leukotriene receptor antagonist) treatment and conventional treatment groups (n = 30 each). Urinary LTE(4) levels were measured using ELISA and the airway resistance Rint was assessed by the lung function instrument at the acute and the convalescence phases. Twenty healthy children were used as the control group. Urinary LTE(4) levels in asthmatic children at the acute and the convalescence phases were significantly higher than those in the control group (p<0.01). The urinary LTE(4) levels at the convalescence phase were significantly reduced compared with those at the acute phase in asthmatic children (p<0.01). More significantly decreased urinary LTE(4) levels were noted in the montelukast treatment group than the conventional treatment group at the convalescence phase (p<0.01). In the acute phase, there was no correlation between urinary LTE4 level and Rint in asthmatic children. Urinary LTE(4) level is significantly increased in children with acute asthma. Urinary LTE(4) is a useful marker for the diagnosis of asthma and can be as a predictor of asthma control and marker of susceptibility to treatment with leukotriene receptor antagonists.


Premature termination of the sympathetic chain.
The sympathetic chain serves to distribute visceral efferents and afferents over the entire body. The sympathetic chain courses from the base of the skull to the coccyx and sends branches to distribute along spinal nerves and a number of visceral nerves that distribute to cardiac muscle, smooth muscle and glands. During dissection of the posterior abdominal wall, we identified a rare variation of the sympathetic chain. In this subject, the sympathetic chain failed to send grey rami to the L2-4 spinal nerves and terminated by joining the S1 anterior ramus. Such a variation has only been reported once in the literature in 1895. We provide both schematic and photographic documentation of this variation and propose a number of possible circuits whereby visceral axons can reach their target despite these anatomical barriers.


Characterization of fungal communities in house dust samples collected from central Portugal-a preliminary survey.
House dust is a repository and concentrator of many chemical and biological agents including fungi. Considering that dust acts as a long-term reservoir of airborne fungi and that cumulative exposure is more relevant to potential health problems than single-day or short-term exposure, characterization of fungal communities in dust samples is of paramount importance. In the present study, the fungal composition of Portuguese house dust samples was determined. A total of 28 samples were obtained from vacuum cleaner deposits from households located in central Portugal. DNA was extracted from dust samples and fungal communities were analyzed using a culture-independent polymerase chain reaction (PCR)- denaturing gradient gel electrophoresis (DGGE) approach. Cultural analyses were also performed in order to identify the viable fungi species present in selected samples. Fungal diversity, reported as the number of operational taxonomic units (OTU), varied between 9 and 56 OTU. This analysis of viable fungi showed that Aspergillus was the most abundant genus, followed by Penicillium, Mucor, and Rhizomucor. Trichoderma, Chrysosporium, Fusarium, Rhizopus, and Stachybotrys were found in a limited number of houses. Our results demonstrated that dust is, in fact, home for a diverse and heterogeneous fungal community and that some of the species found are known allergic agents with severe negative impacts on human health.


HER-2 as a Prognostic, Predictive, and Therapeutic Target in Breast Cancer.
BACKGROUND: An expanded understanding of the biology of breast cancer has led to the identification of the HER-2 receptor as an important growth factor. This receptor possesses intrinsic tyrosine kinase activity and has been associated with aggressive biological behavior and poor clinical outcome. METHODS: Data have been reviewed regarding the role of HER-2 expression as a prognostic variable, as a predictive factor for response to chemotherapy and hormonal therapies, and as a directed therapeutic target for breast cancer. RESULTS: Therapy with a humanized monoclonal antibody to HER-2 (trastuzumab) can be effective treatment in some patients with metastatic breast cancer, either given alone or in combination with some chemotherapeutic agents. Cardiac toxicity limits concurrent use with anthracyclines. Clinical trials will further define optimal combination regimens with this agent, and its value in patients with localized or locally advanced stages. CONCLUSIONS: Trastuzumab is a significant addition to the armamentarium against breast cancer. Standardization of the optimal method to evaluate for HER-2 overexpression is necessary to better define its role as a prognostic, predictor, and therapeutic target in this disease.


An optimal test with maximum average power while controlling FDR with application to RNA-seq data.
The recent RNA-seq technology is an attractive method to study gene expression. One of the most important goals in RNA-seq data analysis is to detect genes differentially expressed across treatments. Although several statistical methods have been published, there are no theoretical justifications for whether these methods are optimal or how to search for the optimal test. Furthermore, most proposed tests are designed for testing whether the mean expression levels are exactly the same or not across treatments, whereas sometimes, biologists are interested in detecting genes with expression changes larger than a certain threshold. Another issue with current methods is that the false discovery rate (FDR) control is not well studied. In this manuscript, we propose a test to address all the above issues. Under model assumptions, we derive an optimal test that achieves the maximum of average power among those that control FDR at the same level. We also provide an approximated version, the approximated most average powerful (AMAP) test, for practical implementation. The proposed method allows for testing null hypotheses that are much more general than the ones most previous studies have considered, and it leads to a natural way of controlling the FDR. Through simulation studies, we show that our test has a higher power than other methods, including the widely-used edgeR, DESeq, and baySeq methods, as well as better FDR control than two other FDR control procedures commonly used in practice. For demonstration, we also apply the proposed method to a real RNA-seq dataset obtained from maize.


Effects of ChunDoSunBup Qi-training on growth hormone, insulin-like growth factor-I, and testosterone in young and elderly subjects.
We observed the response of plasma growth hormone (GH), insulin-like growth factor-I (IGF-I) and testosterone (T) to an acute period of ChunDoSunBup (CDSB) Qi-training. Although the basal level of GH was not different between the two groups, after the portion of the training in which the subjects were physically active (the mid-training point), plasma GH levels increased by 7.26 fold (p < 0.05) in the elderly trainees and by 1.66 fold (p < 0.05) in the young. In response to CDSB Qi-training, IGF-I levels in the young increased significantly at mid-training point, but there were no increase in the elderly. Significant correlations existed between GH and IGF-I levels in the young subjects, but not in the elderly. The T level at the mid-training point increased significantly in elderly subjects but not in the young. These results suggest that CDSB Qi-training is a potential method for modulating of the secretion of growth factor in the young and the elderly, but that the elderly IGF-I response does not equal that of the young. In addition, our study suggests CDSB Qi-training may be one mode of therapy applicable to growth factor related disorders such as GH deficiency in children and osteoporosis in the elderly, especially women.


Regulation of dipicolinic acid biosynthesis in sporulating Bacillus cereus. Characterization of enzymic changes and analysis of mutants.
Some of the early enzymes in the lysine-biosynthetic pathway also function for dipicolinic acid synthesis in sporulating Bacillus cereus T. 1. The first enzyme, aspartokinase, loses its sensitivity to feedback inhibition by lysing. This change occurs before the time of dipicolinic acid synthesis but at a time when diaminopimelic acid is required for spore cortex formation. 2. A possible regulatory change at a branch point in the pathway was studied by examining the properties of a key enzyme, dihydrodipicolinic acid reductase. No alteration in the feedback sensitivity or sedimentation rate of this enzyme could be detected during sporulation. 3. Two mutants producing heat-sensitive spores were analysed. Both produced spores that contained decreased amounts of dipicolinic acid. Although neither was a lysine auxotroph, they both had greatly decreased activities of certain lysine-biosynthetic enzymes in sporulating cells. 4. Starvation of cells for calcium also results in the production of spores that are heat-sensitive and contain less dipicolinic acid than the control. A decreased content of one of the lysine-biosynthetic enzymes, dihydrodipicolinic acid synthetase, in calcium-starved cells could account for the lower concentration of dipicolinic acid in the spores.


Antigenic domains on the peplomer protein of avian infectious bronchitis virus: correlation with biological functions.
Monoclonal antibodies (MAbs) directed against structural proteins of infectious bronchitis virus (IBV) were produced to analyse the antigenic structure of this virus. Competitive binding of enzyme-labelled and unlabelled MAbs to IBV peplomer protein was analysed in an antibody binding assay to test the relatedness of the epitopes defined by the MAbs. Based on the competition groups, eight epitope clusters were defined (S-A to S-H); six of these clusters (S1-A to S1-F) were located on the S1 subunit and two (S2-G and S2-H) on the S2 subunit of the peplomer protein. Epitope clusters S1-A and S1-B overlapped extensively. The biological activities of the MAbs were determined and correlated to the epitope clusters. Monoclonal antibodies directed against epitope clusters S1-A to S1-E and one MAb directed against cluster S2-G moderately to strongly neutralized IBV at titres higher than 2 log10, whereas the remaining MAbs, directed against S1 and S2, neutralized at titres lower than 2 log10. One MAb, directed against cluster S1-D, inhibited the agglutination of chicken erythrocytes.


Abnormal Nuclear Variations in Response to Radiotherapy- As a Tool in Treatment Planning and Assessment of Prognosis.
The treatment approaches for oral squamous cell carcinoma (OSCC) include single management with surgery, radiotherapy, along with chemotherapy or various combinations of these modalities. The estimation of radio sensitivity of individual tumours is essential for planning the optimum radiation schedule for each patient. Assessment of radiation induced histo morphological changes in the nucleus is a known marker of radiosensitivity. The aim of this study was to establish the relationship between nuclear changes with radiation dose and to investigate the prospect of utilizing them as an assay to predict tumour response to radiotherapy in oral cancers. The present study included 50 patients (age range of 30-65yrs) with histopathologically confirmed squamous cell carcinoma of oral mucosa and being treated by radiotherapy alone with a radiation dose schedule of 4, 14, 24 and 60 Gy respectively at 2(nd), 7(th), 12(th) and 30(th) day. From the included patients, smear of the buccal mucosa was collected and was air dried and fixed with methanol. The Nuclear changes of Micronucleus (MN), Nuclear Budding (NB) and Multinucleation (MNU) were evaluated under the bright field microscopy after staining with Giemsa and May-Grunwald's stain. Out of the 50, 37(74%) were males and 13(26%) were females (Ratio 3:1). The mean percentage increase of MN and MNU were found to be statistically significant (p=0.001) when compared with pre-treatment day. Similar findings were seen with NB, except between pretreatment and after 14 Gy (p-0.110). In the present study the measurement of relative increment index done in respect to all nuclear abnormalities show a sustained increase with increasing dosage of radiation. The present study, was undertaken to explore the possibility of establishing a relationship between the frequencies of nuclear abnormalities in patients with oral cancer with applied dosage and duration of radiotherapy. The progressive increase in Micronucleus and Multinucleation indices with increasing dose of radiation proves that these parameters can be used as indicators for assessing the response of tumour for radiotherapy. These parameters can be used as prognostic indicator in oral carcinoma cases undergoing radiotherapy.


Inter-patient variability and impact of proton pump inhibitors on platelet reactivity after prasugrel.
Although there is considerable variability of platelet reactivity among patients treated with clopidogrel, little is known about inter-individual differences and possible role of proton pump inhibitors (PPIs) after prasugrel. We defined the extent of inter-patient variability, and evaluated the impact of PPI interaction in prasugrel-treated patients with acute coronary syndrome (ACS). Between January 2010 and May 2011, 104 prospective, high-risk patients with ACS were recruited into this multicentre, prospective, observational study. Twelve to 24 hours after receiving 60 mg loading dose of prasugrel, light transmission aggregometry (LTA) and whole blood impedance aggregometry (Multiplate) were used to assess platelet activity. Platelet function measurements were repeated during maintenance phase on reduced (5 mg) or on conventional (10 mg) doses of prasugrel. High platelet reactivity (HPR) was defined according to the consensus document of the Working Group on High On-Treatment Platelet Reactivity (LTA:>46%; Multiplate:>47U). Compared to maintenance doses, 60 mg loading dose of prasugrel provided significantly greater platelet reactivity inhibition (p<0.05). There were no significant differences between the conventional and reduced maintenance doses. Notably, a remarkable inter-patient variability was present in platelet reactivity after all doses of prasugrel, and the prevalence of HPR was significantly higher during the maintenance doses (p<0.05). Although median platelet reactivity values were consistently higher when prasugrel was used in combination with PPIs, these differences were not significant (p≥0.17). Despite potent platelet inhibition, inter-patient variability is present after all tested doses of prasugrel. The 60 mg loading dose is superior to conventional and reduced maintenance doses in terms of platelet reactivity inhibition and regarding the prevention of HPR.


Experience of managing complicated diverticulitis of colon: a retrospective case series from South Asian country.
To assess the morbidity and mortality associated with complicated diverticulitis in Pakistan. The retrospective case series was conducted at an urban tertiary care university hospital of Karachi, Pakistan, comprising data from December 1989 to November 2010. International Classification of Diseases codes for diverticular disease and diverticulitis with abscess, fistula, stricture, bowel obstruction and perforation were obtained from the medical record department. SPSS 19 was used for statistical analysis. A total of 60 (1.9%) cases with complicated diverticulitis were located from among 3170 records reviewed. Mean age was 62.7 +/- 13 years with male-to-female ratio being 36:24. In 37 (62%) patients, the diagnosis was established on computed tomography scan of the abdomen, followed by barium enema in 12 (20%) and colonoscopy in 11 (18%). Post-operative morbidity was observed in 24 (40%) and 7 (16%) expired within 28 days of surgery. Post-operative intra-abdominal sepsis, wound dehiscence and incisional hernia were significantly associated with generalised peritonitis (p < 0.05), while admission to intensive care unit was associated with age over 60 years and faecal peritonitis. Post-operative mortality was significantly associated with high American Society of Anaesthesiologists-score III and IV and age above 60 years. Complicated diverticulitis carries significant morbidity and mortality in Pakistani population. Since the trend is on the rise, therefore we propose a prospective multi-centre cohort study to understand the spectrum of disease, management and identification of risk factors to achieve the best possible outcomes in patients with complicated diverticulitis.


Activity of the purified plant ABC transporter NtPDR1 is stimulated by diterpenes and sesquiterpenes involved in constitutive and induced defenses.
Within the plant ATP-binding cassette transporter family, pleiotropic drug resistance (PDR) transporters play essential functions, such as in hormone transport or defense against biotic and abiotic stresses. NtPDR1 from Nicotiana tabacum has been shown to be involved in the constitutive defense against pathogens through the secretion of toxic cyclic diterpenes, such as the antimicrobial substrates cembrene and sclareol from the leaf hairs (trichomes). However, direct evidence of an interaction between NtPDR1 and terpenes is lacking. Here, we stably expressed NtPDR1 in N. tabacum BY-2 suspension cells. NtPDR1 was purified as an active monomer glycosylated at a single site in the third external loop. NtPDR1 reconstitution in proteoliposomes stimulated its basal ATPase activity from 21 to 38 nmol of Pi·mg-1·min-1, and ATPase activity was further stimulated by the NtPDR1 substrates cembrene and sclareol, providing direct evidence of an interaction between NtPDR1 and its two substrates. Interestingly, NtPDR1 was also stimulated by capsidiol, a sesquiterpene produced by N. tabacum upon pathogen attack. We also monitored the transcriptional activity from the NtPDR1 promoter in situ with a reporter gene and found that, although NtPDR1 expression was limited to trichomes under normal conditions, addition of methyl jasmonate, a biotic stress hormone, induced expression in all leaf tissues. This finding indicated that NtPDR1 is involved not only in constitutive but also in induced plant defenses. In conclusion, we provide direct evidence of an interaction between the NtPDR1 transporter and its substrates and that NtPDR1 transports compounds involved in both constitutive (diterpenes) and induced (sesquiterpenes) plant defenses.


Treatment of Cancer-Associated Thrombosis: Beyond HOKUSAI.
Direct oral anticoagulants (DOACs) represent an attractive alternative to low-molecular-weight heparins (LMWHs) for the long-term treatment of cancer-associated thrombosis (CT) since they avoid the burden of daily injections. Analyses in subgroups of cancer patients from large randomized trials suggested that DOACs were at least as effective as vitamin K antagonists, while indirect comparisons suggested that DOACs' efficacy and safety profile were comparable to those of LMWHs. In the randomized controlled HOKUSAI-VTE Cancer study, currently the only completed phase III trial on DOACs in CT patients, edoxaban was shown noninferior to dalteparin on the composite primary endpoint of time to first recurrent venous thromboembolism or major bleeding during the 12 months after randomization. Study results suggest that both agents had comparable benefit/risk ratio in patients with CT. Even though this conclusion was valid from a strict statistical viewpoint, it was potentially misleading when interpreting benefit/risk ratios. Besides the obvious heterogeneity of the study population (e.g., 23% of patients no longer had cancer) and significantly different treatment durations between arms, secondary outcomes for efficacy were in favor of edoxaban for recurrent deep-vein thrombosis but not for recurrent pulmonary embolism, and major bleeding episodes were significantly more frequent in the edoxaban group, with an excess of gastrointestinal (GI) bleeding episodes observed mainly but not only in patients with GI cancers. More research is needed regarding specific patients' profiles, cancer types, and treatment period to better clarify the respective roles of DOACs and LMWHs in CT patients.


Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors.
Tissue microarrays allow high-throughput molecular profiling of cancer specimens by immunohistochemistry. Phenotype information of sections from arrayed biopsies on a multitissue block needs to be representative of full sections, as protein expression varies throughout the entire tumor specimen. To validate the use of tissue microarrays for immunophenotyping, we studied a group of 59 fibroblastic tumors with variable protein expression patterns by immunohistochemistry for Ki-67, p53, and the retinoblastoma protein (pRB). Data on full tissue sections were compared to the results of one, two, and three 0.6-mm core biopsies per tumor on a tissue array. Ki-67 and p53 staining was read as two categories (positive or negative). Concordance for this staining between tissue arrays with triplicate cores per tumor and full sections were 96 and 98%, respectively. For pRB staining was read as three categories (high, moderate, or negative), where concordance was 91%. The use of three cores per tumor resulted in lower numbers of lost cases and lower nonconcordance with standard full sections as compared to one or two cores per tumor. Correlations between phenotypes and clinical outcome were not significantly different between full section and array-based analysis. Triplicate 0.6-mm core biopsies sampled on tissue arrays provide a reliable system for high-throughput expression profiling by immunohistochemistry when compared to standard full sections. Triplicate cores offer a higher rate of assessable cases and a lower rate of nonconcordant readings than one or two cores. Concordance of triplicate cores is high (96 to 98%) for two category distinction and decreases with the complexity of the phenotypes being analyzed (91%).


Evaluation of a Virtual Reality Percutaneous Nephrolithotomy (PCNL) Surgical Simulator.
Percutaneous Nephrolithotomy is the standard surgical procedure used to remove large kidney stones. PCNL procedures have a steep learning curve; a physician needs to complete between 36 and 60 procedures, to achieve clinical proficiency. Marion Surgical K181 is a virtual reality surgical simulator, which emulates the PCNL procedures without compromising the well-being of patients. The simulator uses a VR headset to place a user in a realistic and immersive operating theater, and haptic force-feedback robots to render physical interactions between surgical tools and the virtual patient. The simulator has two modules for two different aspects of PCNL kidney stone removal procedure: kidney access module where the user must insert a needle into the kidney of the patient, and a kidney stone removal module where the user removes the individual stones from the organ. In this paper, we present user trials to validate the face and construct validity of the simulator. The results, based on the data gathered from 4 groups of users independently, indicate that Marion's surgical simulator is a useful tool for teaching and practicing PCNL procedures. The kidney stone removal module of the simulator has proven construct validity by identifying the skill level of different users based on their tool path. We plan to continue evaluating the simulator with a larger sample of users to reinforce our findings.


Effect of NOS inhibitor on forced swim test and neurotransmitters turnover in the mouse brain.
The previous experiments have demonstrated that NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors have antidepressant- and anxiolytic-like activities in rodents. Moreover, chronic treatments with these agents result in down-regulation of beta-adrenoceptors in the brain cortex with a magnitude comparable to clinically effective antidepressants. However, still little is known about the effect of NOS inhibitors on the regulation of neurotransmitter utilization in vivo. The aim of present study was to elucidate the effect of NOS inhibitor at doses active in forced swim test (FST) on dopamine and serotonin turnover in the mouse brain structures. Mice were treated with imipramine (15 mg/kg ip), electroconvulsive shock (ECS) and NOS inhibitor, N(G)-nitro-L-arginine (L-NA) acutely (at doses of 1, 3, 10 mg/kg ip) and chronically (0.3, 1, 3 mg/kg ip). Experiments were carried out 1 h after single and 3 h after chronic (21 days) administration. Metabolism of dopamine and serotonin was investigated using high pressure liquid chromatography (HPLC) with electrochemical detection. The metabolism rate was calculated as a ratio of a metabolite to the parent amine. FST was performed using protocol described previously by Porsolt et al. Now we report that L-NA decreases the level of immobility with potency similar to imipramine. The effect of L-NA was reversed by NOS substrate, L-arginine. L-NA given acutely at doses active in FST did not change the dopamine metabolism rate but it did decrease the serotonin turnover rate in the frontal cortex in a manner similar to imipramine. Thus, it appears that under basal conditions endogenous NO may influence the serotonin turnover, and the acute inhibition of NOS can mimic the effect of imipramine what may result in the antidepressant-like effect in FST. Imipramine given acutely produced massive increase in the level of serotonin in the frontal cortex as well as in the hypothalamus (by 40%, p < 0.01) what was reflected in significant decreases in the metabolism rate. Contrary to acute effect, chronic treatment of L-NA (the most effective dose was 1 mg/kg) produced increase in the dopamine metabolism rate within all investigated structures. In the present study, we demonstrated for the first time that L-NA may alter the neurotransmitter utilization in vivo and the observed effect may be due to adaptational changes in neuronal function.


A Multiple Biomarker Approach in Patients with Cardiac Sarcoidosis.
Sarcoidosis is a systemic granulomatous disease including heart (cardiac sarcoidosis, CS). It has recently been reported that isolated CS, which presenting primarily cardiac symptoms without clinical evidence of sarcoid involvement in other organs. Diagnostic and prognostic biomarkers of CS, especially in isolated CS, have not yet been established.We studied plasma levels of angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI) in consecutive 172 patients with diagnosed sarcoidosis. We compared these markers between non-cardiac sarcoidosis (non-CS, n = 123, 71.5%) and CS patients (n = 49, 28.5%), including non-isolated CS (n = 30, 17.4%) and isolated CS (n = 19, 11.1%). ROC analysis revealed that BNP identified CS with AUC of 0.85 (P < 0.01) in sarcoidosis patients. In addition, ACE and sIL-2R levels were significantly higher in non-isolated CS than in isolated CS (P < 0.05). Furthermore, in the Cox proportional hazard analysis, cTnI, but not ACE, IL2R or BNP, was a predictor of fatal arrhythmia in sarcoidosis patients (HR 2.418, P = 0.003).Higher ACE and sIL2-R are associated with systemic lesions, whereas BNP is a useful marker for detecting cardiac involvement in sarcoidosis patients. cTnI is a predictor of fatal arrhythmia in CS patients. A multiple biomarker approach supports comprehensive management of sarcoidosis.


Unsupervised manifold alignment for single-cell multi-omics data.
Integrating single-cell measurements that capture different properties of the genome is vital to extending our understanding of genome biology. This task is challenging due to the lack of a shared axis across datasets obtained from different types of single-cell experiments. For most such datasets, we lack corresponding information among the cells (samples) and the measurements (features). In this scenario, unsupervised algorithms that are capable of aligning single-cell experiments are critical to learning an in silico co-assay that can help draw correspondences among the cells. Maximum mean discrepancy-based manifold alignment (MMD-MA) is such an unsupervised algorithm. Without requiring correspondence information, it can align single-cell datasets from different modalities in a common shared latent space, showing promising results on simulations and a small-scale single-cell experiment with 61 cells. However, it is essential to explore the applicability of this method to larger single-cell experiments with thousands of cells so that it can be of practical interest to the community. In this paper, we apply MMD-MA to two recent datasets that measure transcriptome and chromatin accessibility in ~2000 single cells. To scale the runtime of MMD-MA to a more substantial number of cells, we extend the original implementation to run on GPUs. We also introduce a method to automatically select one of the user-defined parameters, thus reducing the hyperparameter search space. We demonstrate that the proposed extensions allow MMD-MA to accurately align state-of-the-art single-cell experiments.


Decontamination of multiple casualties who are chemically contaminated: a challenge for acute hospitals.
Patients who have been contaminated by chemical compounds present a number of difficulties to emergency departments, in particular, the risk of secondary contamination of healthcare staff and facilities. The Department of Health in the United Kingdom has provided equipment to decontaminate chemically contaminated casualties who present at emergency departments. The capacity of this equipment is limited, and although both the ambulance and fire services have equipment to cope with mass casualties at the scene of a chemical incident, there is still the possibility that acute hospitals will be overwhelmed by large numbers of self-presenting patients. The risks and potential consequences of this gap in resilience are discussed and a number of possible practical solutions are proposed.


Strategies for correcting the delta F508 CFTR protein-folding defect.
Many human diseases arise as a result of mutations within genes encoding essential proteins. In many cases, the mutations are not so severe as to render the protein biologically inactive. Rather, the mutations oftentimes result in only subtle protein-folding abnormalities. In the case of the CFTR protein, a mutation leading to the loss of a single amino acid is responsible for the diseased state in the majority of individuals with cystic fibrosis. Here the newly synthesized mutant CFTR protein, missing a phenylalanine residue at position 508 (delta F508 CFTR), is unable to transit from the endoplasmic reticulum to the plasma membrane, where it functions as a regulator of chloride transport. All of the available evidence indicate that the newly synthesized delta F508 CFTR protein adopts a slightly altered conformation and therefore is retained at the level of the endoplasmic reticulum, ostensibly by the actions of the cellular quality control system. Because the mutant protein is capable of functioning as a chloride channel, developing ways to elicit its release out of the ER and to the plasma membrane has important clinical implications. Herein, we discuss our recent studies showing that the protein-folding defect associated with the delta F508 CFTR mutation, as well as a number of other temperature-sensitive mutations, can be overcome by strategies designed to influence protein folding inside the cell. Specifically we show that a number of low-molecular-weight compounds, all of which are known to stabilize proteins in their native conformation, are effective in rescuing the folding and/or processing defects associated with different mutations that oftentimes lead to human disease.


Efficacy of a herbal mouthwash for management of periodontitis and radiation-induced mucositis - A consolidated report of two randomized controlled clinical trials.
Oral diseases like periodontitis and mucositis often require home care using topical agents in the form of mouthwashes. Many herbal mouthwashes are found to be beneficial; however lack proper scientific evidence to support their use. Study 1 evaluated clinical efficacy of herbal mouthwash in the management of chronic periodontitis in comparison with chlorhexidine mouthwash. Study 2 aimed at assessment of herbal mouthwash in patients of radiation-induced mucosititis. The novel herbal mouthwash used in the present study wa prepared from extracts of five plants namely Emblica Officinalis, Terminalia chebula, Terminalia bellerica, Glycyrrhiza glabra, and Azadirachta indica. 50 periodontitis patients were randomly allocated to two groups. As per allocation, they were instructed to use either herbal mouthwash or chlorhexidine mouthwash twice daily for two weeks after nonsurgical periodontal therapy. Similarly, patients with radiation-induced mucositis were randomly given herbal mouthwash and soda saline mouthwash. Intergroup and intragroup comparisons of continuous variables were conducted using paired and unpaired t-tests. Categorical variables were compared using the chi-square test. Significant reductions in gingival bleeding, plaque accumulation, and pocket depth were noticed in periodontitis patients in both groups. Patients reported acceptable taste, freshness, and satisfaction after the use of herbal mouthwash. The herbal mouthwash group noticed a significant reduction in the severity of radiation-induced mucositis and analgesic requirements. The intensity of pain, dryness of mouth, oral hygiene, and need for the use of antibiotic and antifungal during radiotherapy was not significant among the groups. The results of this preliminary clinical trial support the use of the tested herbal formulation mouthwash as an adjunct in the treatment of periodontitis as well as radiation-induced mucositis. For Study 1: CTRI/2019/10/021574, Study 2: CTRI/2020/04/024851.


Daily level examination indicates that positive affect, but not negative affect, is associated with alcohol and marijuana use among adolescents and young adults.
Although there is growing evidence that alcohol use at the daily level is associated with positive but not negative affect, results are mixed when examining marijuana use and simultaneous alcohol and marijuana (SAM) use (i.e., use with overlapping effects). In addition, less is known about these daily level associations among diverse samples of adolescents and young adults. The present study will address these gaps. Participants (N = 1,006; 57.3% female, 43.1% White, Non-Hispanic, ages 15-25; Mage = 20.0) were part of a study on substance use that consisted of a 3-week ecological momentary assessment (EMA) burst design (eight surveys per week, up to 2×/day) that was repeated quarterly over a 12-month period. Within-person results indicated that on days with elevated positive affect, participants reported consuming more drinks, whereas positive affect was not significant for hours high from marijuana. In addition, on days with elevated negative affect, participants reported fewer hours high from marijuana. No association was found between negative affect and number of drinks. Finally, within-person results indicated that on alcohol or marijuana days with elevated positive affect, individuals were more likely to report SAM use. There was no association found between negative affect and SAM use. Results have implications such that in-the-moment interventions for alcohol and SAM use may be more salient when individuals have higher positive affect than average, whereas such interventions may be more relevant for marijuana use when negative affect is lower compared to average levels. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Five primate species follow the visual gaze of conspecifics.
Individuals from five primate species were tested experimentally for their ability to follow the visual gaze of conspecifics to an outside object. Subjects were from captive social groups of chimpanzees, Pan troglodytes, sooty mangabeys, Cercocebus atys torquatus, rhesus macaques, Macaca mulatta, stumptail macaques, M. arctoides, and pigtail macaques, M. nemestrina. Experimental trials consisted of an experimenter inducing one individual to look at food being displayed, and then observing the reaction of another individual (the subject) that was looking at that individual (not the food). Control trials consisted of an experimenter displaying the food in an identical manner when the subject was alone. Individuals from all species reliably followed the gaze of conspecifics, looking to the food about 80% of the time in experimental trials, compared with about 20% of the time in control trials. Results are discussed in terms of both the proximate mechanisms that might be involved and the adaptive functions that might be served by gaze-following. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.


Enzyme promiscuity, metabolite damage, and metabolite damage control systems of the tricarboxylic acid cycle.
Promiscuous enzymes and spontaneous chemical reactions can convert normal cellular metabolites into noncanonical or damaged metabolites. These damaged metabolites can be a useless drain on metabolism and may be inhibitory and/or reactive, sometimes leading to toxicity. Thus, mechanisms to prevent metabolite damage from occurring (metabolite damage preemption) or to convert damaged metabolites back to physiological forms (metabolite repair) are essential for sustained operation of metabolic networks. Some iconic examples of metabolite damage and its repair or preemption are associated with the tricarboxylic acid (TCA) cycle, and other metabolite damage control systems are likely to exist here due to the inherent promiscuity of TCA cycle enzymes and reactivity of TCA cycle intermediates. Here, we review known metabolite damage reactions and metabolite damage control systems associated with the TCA cycle. This includes a previously unrecognized metabolite damage control system - an oxaloacetate (OAA) enol-keto tautomerase activity that is 'built-in' to the TCA cycle. This activity is required to remove the highly inhibitory enol form of OAA and is likely to be critical for TCA cycle operation. By cataloging these instances, we show that metabolite damage and its repair or preemption is a prevalent feature of the TCA cycle and suggest many more metabolite damage control systems are likely to exist.


Coeliac disease and granulomatous ileocolitis: an association or chance occurrence?
Enteric granulomatous inflammation can be caused by a number of conditions including Crohn's disease, sarcoidosis, enteric infections, chronic granulomatous disease and also by drug reactions. Granulomas have also been described in microscopic colitis associated with certain medications and autoimmune diseases. The association of granulomatous ileocolitis with coeliac disease is not common. We present a case of coeliac disease with granulomatous ileocolitis with follow-up and repeat histology on a gluten-free diet. We discuss the pathological mechanisms leading to the association of granulomatous ileocolitis with coeliac disease as well as other conditions.


Clinical and arteriographic variables predictive of survival in coronary artery disease.
Survival, subsequent myocardial infarction and current anginal status were determined for 90 nearly consecutive patients who underwent coronary arteriography at the Johns Hopkins Hospital between 1960 and 1967. All patients had at least one coronary arterial narrowing equal to or greater than 70 percent; 78 of 90 patients would be candidates for coronary bypass surgery by present criteria. Twenty-nine of the 78 surgically "suitable" patients died of cardiac causes; 7 of 49 survivors sustained an acute myocardial infarction (mean follow-up period 9.9 years). Patients with a 70 percent or greater narrowing proximal to the first septal branch of the left anterior descending coronary artery had a significantly greater mortality compared with patients with equivalent narrowing distal to the first septal branch or with patients without 70 percent or greater narrowing of the left anterior descending artery. The patients with a 70 percent or greater narrowing of the left anterior descending artery who died were those with a significant narrowing in at least one other major coronary artery. Multivariate stepwise discriminate function analysis of all clinical, electrocardiographic (except stress electrocardiographic) and arteriographic variables identified three independent predictors of mortality: (1) the simultaneous occurrence of a narrowing in left anterior descending and right coronary arteries, (2) prior myocardial infarction; and (3) 70 percent or greater narrowing proximal to the first anterior descending septal branch. When stress electrocardiographic findings were included, a "positive" stress electrocardiographic test was also an independent predictor of mortality.


Monitoring of Root Caries Lesions.
The early detection of root caries is essential for the implementation of appropriate preventive therapeutic regimes. Subsequent monitoring of lesions is required to determine the outcomes of such therapies. While much research activity has been seen in the detection and monitoring of enamel caries, this has not been seen in root caries - despite the possibilities for shorter clinical trials due to the more rapid remineralization and arrest of such lesions. The main stay of both clinical practice and research has been the use of visual tactile criteria including, hardness, texture, the presence or absence of cavitation, and color. A range of clinical trials, using high fluoride products of known efficacy, have shown such techniques to be valid. The use of adjunct technologies has been limited in large scale in vivo studies, to devices using electrical resistance measurement (electronic caries monitor, ECM). The use of dyes, laser fluorescence, and advanced imaging such as near infra-red has been described in vitro but few, with the exception of DiagnoDent, have been translated to chair side. Except for ECM, no other technology has been used in the clinical assessments of root caries remineralization and there remains a need to supplement visual tactile techniques for future work.


Gabapentin as a potential option for treatment of sciatica.
Gabapentin has been approved in the United States for the treatment of epilepsy and postherpetic neuralgia. Gabapentin has also demonstrated proven efficacy for the treatment of diabetic peripheral neuropathy and trigeminal neuralgia, although these represent off-label uses of the drug. However, to our knowledge, no data have been published regarding the efficacy of gabapentin for treating sciatica. We describe two patients with sciatica who were successfully treated with gabapentin. The first was a 32-year-old man with severe shooting pain in his left leg that was later diagnosed as sciatica secondary to a fifth lumbar-first sacral intervertebral disk herniation. The patient was treated with acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), narcotics, and muscle relaxants; he reported only limited pain relief with any of these agents or combination of agents. He was then prescribed gabapentin 300 mg once/day; his pain substantially improved, even after the first dose. The drug was titrated gradually up to 900 mg 3 times/day with good results. The patient subsequently underwent a laminectomy and diskectomy on the advice of his neurosurgeon, who assured him that the result would be immediate pain relief. After surgery, the patient continued to experience pain; however, his pain resolved completely after several weeks of receiving gabapentin 600 mg 3 times/day. The second patient was a 68-year-old Caucasian woman with renal insufficiency who experienced severe burning pain and numbness of abrupt onset in the posterior right leg; this was diagnosed as sciatica. The patient had contraindications for NSAID therapy and was intolerant of hydrocodone. Initial therapy with propoxyphene and acetaminophen, self-started by the patient, was ineffective. Gabapentin 100 mg at bedtime was started and then titrated up to 100 mg twice/day with 200 mg at bedtime. The patient's pain improved rapidly, and at follow-up approximately 5 weeks later, she was experiencing good pain control with gabapentin. Gabapentin is widely prescribed for management of peripheral neuropathic pain syndromes. To our knowledge, however, these two case reports are the first to describe sciatica successfully controlled with gabapentin. Because gabapentin has the potential to prevent central sensitization, consideration should be given to prescribing this therapy early in the course of sciatica. Further research using randomized, placebo-controlled trials are needed to validate the benefit of gabapentin in the treatment of sciatica.


Home Blood Pressure Management Intervention in Low- to Middle-Income Countries: Protocol for a Mixed Methods Study.
Control of hypertension in low- and middle-income countries (LMICs) is poor, often less than 10%. A strong body of evidence demonstrates that home blood pressure management lowers blood pressure, and recent guidelines from the National Institute for Clinical Health and Excellence recommends home blood pressure monitoring. However, the preponderance of data on the benefits of home blood pressure management comes from studies in high-income countries. The objective of the study is to examine whether an intervention of home blood pressure management is feasible in LMICs. Home blood pressure management is defined as self-monitoring of blood pressure and self-titration of antihypertensive medications. We will identify barriers and facilitators of home blood pressure management and explore unique contextual factors in LMICs that influence implementation of home blood pressure management. Participants will be recruited from 6 sites from 2015 to 2018. Patients and health care workers will be included. We will use mixed methods including focus groups, interviews, and standardized checklists. When possible, we will adapt materials from prior successful studies so that they are culturally and contextually appropriate. This ongoing study is funded by the World Heart Federation. The information that is obtained will be used to develop a randomized clinical trial of home blood pressure management in LMICs. The data generated from this qualitative study will provide much needed information from patients and health care workers about barriers and facilitators of home blood pressure management and unique contextual factors that might influence implementation of home blood pressure management in LMICs.


Retrospective population-based study of emergency medical services-attended out-of-hospital cardiac arrests in children in Belgium.
This study presents an analysis of clinical data of the circumstances and outcome of paediatric (0-16 years) out-of-hospital cardiac arrests (p-OHCA) in Belgium. This was a retrospective study of a prospective population-based registration of physician-attended [mobile emergency group (MUG)] emergency medical services (EMS) interventions of p-OHCA in Belgium between 2010 and 2012. We identified 365 OHCA in 18 295 paediatric MUG interventions (2%). Cardiopulmonary resuscitation was performed in 260 (71.2%) cases. In 59.2%, a medical problem was presumed to be underlying. In 106 (40.7%) cases, an 'external' cause (e.g. trauma) was the reason for the OHCA. Eventually, 133 children were transported to the emergency department, with return-of-spontaneous-circulation (ROSC) in 42 cases. In the group with initial shockable rhythm (n=13), sustained ROSC was obtained in 69.2%. For those with an initial nonshockable rhythm, the prognosis was much more reserved (13.4% sustained ROSC). This number is in contrast to the high number of children who are transported from scene (51.2%). Importantly, 40.6% of the latter were proclaimed 'dead' during transport. p-OHCA remains rare. Typically, Belgian MUGs each encounter less than two p-OHCA yearly, thus inducing a risk of being insufficiently prepared. Compared with other countries, cardiopulmonary resuscitation was not started in more cases. Even so, in many other cases, children were transported from scene to be proclaimed 'dead' very soon after, pointing to a practice of 'slow code'. This study provides 'real-life' data on p-OHCA in Belgium. As it is based on an administrative registry, it lacks information on individual cases. Large population-based registries are needed to further guide our decision making.


Estimating service demand for respite care among informal carers of people with psychological disabilities in Australia.
To estimate service demand (willingness to seek or use services) for respite care among informal, primary carers of people with a psychological disability and to describe their characteristics. Analysis of data from the household component of the 2009 Survey of Disability Ageing and Carers (n=64,213 persons). In Australia in 2009, 1.0% of people aged 15 years or over (177,900 persons) provided informal, primary care to a co-resident with a psychological disability. One-quarter (27.2%) of these carers reported service demand for respite care, of whom one-third had used respite services in the past three months and four-fifths had an unmet need for any or more respite care. A significantly greater percentages of carers with service demand for respite care spent 40 or more hours per week on caregiving, provided care to a person with profound activity restrictions and reported unmet support needs, compared to carers without service demand. Lack of suitable, available respite care models was a barrier to utilisation. Findings confirm significant service demand for, and under-utilisation of, respite care among mental health carers. Increased coverage of respite services, more flexible service delivery models matched to carers' needs and better integration with other support services are indicated.


Acute Anabolic Response and Muscular Adaptation After Hypertrophy-Style and Strength-Style Resistance Exercise.
Gonzalez, AM. Acute anabolic response and muscular adaptation after hypertrophy-style and strength-style resistance exercise. J Strength Cond Res 30(10): 2959-2964, 2016-Resistance training paradigms are often divided into protocols designed to promote an increase in either hypertrophy or strength. Hypertrophy-style protocols (HYPs) typically involve greater volume (3-6 sets; 8-12 repetitions), moderate intensities (<85% 1 repetition maximum [1RM]), and short rest intervals (30-90 seconds), whereas strength-style protocols (STRs) typically involve higher intensities (≥85% 1RM), low volumes (2-6 sets; ≤6 repetitions), and longer rest intervals (3-5 minutes). However, the literature supporting such classifications is surprisingly sparse in trained individuals, and the distinct classifications of such protocols may be an oversimplification. Thus, the purpose of this review was to examine the acute anabolic responses and training-induced muscular adaptations after HYP and STR styles of resistance exercise in trained individuals. Despite the classification of training paradigms, HYP and STR resistance training routines appear to elicit similar magnitudes of muscle growth, although STR routines appear to be more conducive to increasing strength in resistance-trained individuals. Current evidence suggests that the classification of HYP and STR is an oversimplification, and practitioners are advised to look beyond the classification of resistance exercise protocols when aiming to elicit specific physiological responses.


Albuminuria increases cystatin C excretion: implications for urinary biomarkers.
Low-molecular weight (LMW) proteins, including albumin and novel urinary biomarkers of acute kidney injury (AKI) such as cystatin C and neutrophil gelatinase-associated lipocalin (NGAL), are normally absorbed from the glomerular filtrate by receptor-mediated transport. We evaluated the effect of albuminuria on urinary excretion of novel biomarkers. Sprague-Dawley rats given four injections over 2 days of 5 mg/g body wt/day bovine serum albumin (BSA) in saline were compared with controls given saline alone. Urinary cystatin C, albumin and protein excretion rates were compared prior to treatment (Day -1), after treatment (Day 2) and 4 days later (Day 6). A preliminary assessment of the clinical effect of proteinuria on the filtered urinary biomarkers cystatin C and NGAL was made by comparison with the effect on urinary interleukin-18 (IL-18) that is not absorbed from the glomerular filtrate, in a cohort of intensive care unit patients. BSA induced transient increases in albuminuria, proteinuria and cystatinuria (P < 0.01, P < 0.001 and P < 0.001, respectively). Beyond a threshold 6-fold increase in albuminuria, cystatin C absorption was reduced by competitive inhibition. The excretion rates of all analytes returned to preinjection levels by Day 6. Clinical proteinuria was associated with increasing cystatin C and NGAL concentrations (n = 90, P < 0.0001) but not IL-18 (P = 0.12). Proteinuria may increase the threshold for detection of AKI by increasing the excretion of LMW protein biomarkers.


[Inactivation of enteroviruses in sewage with ozone].
The study of ozone inactivation of enteroviruses in sewage showed the presence in sewage of suspensions of organic origin and bacterial flora to influence the rate of inactivation. The inactivation rate of poliomyelitis virus in sewage free from organic suspension and bacterial flora was significantly higher than that in sewage containing such suspension and bacterial flora. The inactivation rate of enteroviruses was found not to depend upon the protein and salt composition and pH of sewage or strain appurtenance of viruses. The inactivation rate of enteroviruses directly depended upon the dose of ozone and time of contact with it. Differences in the resistance of different types of poliomyelitis virus, ECHO and Coxsackie viruses to the effect of ozone are likely exist. These differences are manifested within the range of relatively small doses of ozone. E. coli is more resistant to ozone than entero-viruses. The results of laboratory studies were used to choose the regimen of sanitation of urban sewage to be used in technological cycles of industrial enterprises.


Design of Core-Shell Quantum Dots-3D WS2 Nanowall Hybrid Nanostructures with High-Performance Bifunctional Sensing Applications.
Transition metal dichalcogenides (TMDCs) have recently attracted a tremendous amount of attention owing to their superior optical and electrical properties as well as the interesting and various nanostructures that are created by different synthesis processes. However, the atomic thickness of TMDCs limits the light absorption and results in the weak performance of optoelectronic devices, such as photodetectors. Here, we demonstrate the approach to increase the surface area of TMDCs by a one-step synthesis process of TMDC nanowalls from WOx into three-dimensional (3D) WS2 nanowalls. By utilizing a rapid heating and rapid cooling process, the formation of 3D nanowalls with a height of approximately 150 nm standing perpendicularly on top of the substrate can be achieved. The combination of core-shell colloidal quantum dots (QDs) with three different emission wavelengths and 3D WS2 nanowalls further improves the performance of WS2-based photodetector devices, including a photocurrent enhancement of 320-470% and shorter response time. The significant results of the core-shell QD-WS2 hybrid devices can be contributed by the high nonradiative energy transfer efficiency between core-shell QDs and the nanostructured material, which is caused by the spectral overlap between the emission of core-shell QDs and the absorption of WS2. Besides, outstanding NO2 gas-sensing performance of core-shell QDs/WS2 devices can be achieved with an extremely low detection limit of 50 ppb and a fast response time of 26.8 s because of local p-n junctions generated by p-type 3D WS2 nanowalls and n-type core-shell CdSe-ZnS QDs. Our work successfully reveals the energy transfer phenomenon in core-shell QD-WS2 hybrid devices and shows great potential in commercial multifunctional sensing applications.


Endoscopic hemostasis of gastrointestinal hemorrhage by local application of absolute ethanol: a clinical study.
The procedure of endoscopic hemostasis with topical injection of absolute ethanol has been developed and applied since 1975 for the control of postoperative hemorrhage associated with diathermic polypectomy. Since June 1979, upper gastrointestinal hemorrhages other than varices have also been subjected to this procedure. This method is based on the principle of dehydration and fixation of the tissue with absolute ethanol. In this procedure, the bleeding vasculatures are dehydrated and fixed with consequent vasoconstriction and necrosis of the vascular wall including its endothelial lining, thereby thrombogenesis and hemostasis are facilitated. The troubled blood vessels fixed in vivo are disintegrated and disappeared. Rebleeding from the ulcer has been extremely rare with this method since the necrotized tissue seldom defoliates but often constitutes a part of the white coating and protects the base of ulcer. Treatment by this method has been successful in all 23 cases of upper gastrointestinal hemorrhage associated with endoscopic diathermy, and none has developed rebleeding. The hemostasis has also been successful in 51 cases (72 hemorrhagic lesions) with fresh blood clots adhering to the lesion, exposed blood vessels in the lesion or an actively bleeding lesion out of 126 cases referred for emergency endoscopic examination because of upper gastrointestinal hemorrhage during the 3-year period from June 1979 to May 1982. After hemostasis, however, 3 patients received an elective operation and one patient was also operated due to perforation of the gastric wall. Rebleeding occurred in 3 cases more than a week after the hemostasis; one of these was the above-described operated case of perforation. The rebleeding occurred in stress ulcers following surgery for femoral fracture. The other two were at the terminal stage of malignancy and complicated with DIC respectively. Of the patients treated by this method, 8 died by causes other than gastrointestinal hemorrhage. All the rest of 39 cases attained cure of ulcer by the non-surgical treatment alone.


Depression and associated factors in hospitalized elderly: a cross-sectional study in a Saudi teaching hospital.
Depression in the elderly is a serious and often underdiagnosed psychiatric disorder that has been linked to adverse outcomes in the hospital setting. To determine the prevalence of depression and possible associated factors among hospitalized elderly. An analytical cross-sectional study. Medical and surgical wards of King Abdulaziz University Hospital, Jeddah, Saudi Arabia. The study included 200 consecutively hospitalized patients aged 60 years and older. Participants were evaluated within 48 hours of admission using an interviewer-administered question-naire to provide basic demographic and clinical information. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9) screening method and the Structured Clinical Interview for the Diagnostic and Statistical Manual, Fifth Edition (DSM-5) mood disorder module. According to PHQ-9, 17% and 10.5% of the hospitalized patients were diagnosed with a major depressive disorder and other depressive disorders, respectively. The DSM-5 criteria identified 12% of elderly with major depression. Overall, the number of comorbidities associated with depression was signifi-cantly higher in the major depressive disorder group than in the no depression group (post hoc P=.022). Depression was also associated with female gender, unmarried status, lower income, and polypharmacy. In addition, cardiovascular disease and cancer were the most prevalent medical illnesses associated with depression among hospitalized elderly. Major depressive disorder was prevalent among hospitalized elderly, especially among those with comorbid conditions. Hospital physicians must, therefore, maintain a high index of suspicion to identify early and manage depressive symptoms in these patients. The small size of certain subgroups limits the statistical power to examine for associations of depression with particular conditions.


Regulation of MAP kinase-mediated endothelial dysfunction in hyperglycemia via arginase I and eNOS dysregulation.
Emerging evidence suggests that arginase contributes to endothelial dysfunction in diabetes. Intracellular signaling pathways, which interplay between arginase and eNOS enzyme activity leading to the development of endothelial dysfunction in hyperglycemia are not fully understood. Here, we analyzed the possible involvement of hyperglycemia (HG) induced arginase expression in eNOS protein regulation and activity and also the impact of arginase inhibition on eNOS activity. Furthermore, the roles of p38 MAPK and Erk1/2 phosphorylation in upregulation of arginase expression and eNOS dysregulation in endothelial cells (ECs) under hyperglycemia were evaluated. Protein analysis showed a concurrent increase in arginase I expression and decrease in eNOS expression and phosphorylation at Ser1177 under HG conditions. There was no simultaneous change in phosphorylation of eNOS at Thr495 in HG. Arginase inhibition prevented increased arginase activity, restored impaired NO bioavailability and reduced superoxide anion generation. Inhibition of MAP-kinases demonstrated that, unlike Erk1/2, p38 MAPK is an upstream activator in a signaling cascade leading to increased arginase I in HG conditions. P38 MAPK protein expression and phosphorylation were increased in response to HG. In the presence of a p38 MAPK inhibitor, HG-induced arginase expression was blunted. Although Erk1/2 was activated in HG, increased arginase expression was not blocked by co-treatment with an Erk1/2 inhibitor. Activation of both, p38 MAPK and Erk1/2 in HG, induced a downregulation in eNOS activity. Hence, applying MAPK inhibitors increased eNOS phosphorylation in HG. In conclusion, these findings demonstrate contributions of arginase I in the development of endothelial cell dysfunction under HG conditions via impaired eNOS regulation, which maybe mediated by p38 MAPK.


Differences in Integron Cassette Excision Dynamics Shape a Trade-Off between Evolvability and Genetic Capacitance.
Integrons ensure a rapid and "on demand" response to environmental stresses driving bacterial adaptation. They are able to capture, store, and reorder functional gene cassettes due to site-specific recombination catalyzed by their integrase. Integrons can be either sedentary and chromosomally located or mobile when they are associated with transposons and plasmids. They are respectively called sedentary chromosomal integrons (SCIs) and mobile integrons (MIs). MIs are key players in the dissemination of antibiotic resistance genes. Here, we used in silico and in vivo approaches to study cassette excision dynamics in MIs and SCIs. We show that the orientation of cassette arrays relative to replication influences attC site folding and cassette excision by placing the recombinogenic strands of attC sites on either the leading or lagging strand template. We also demonstrate that stability of attC sites and their propensity to form recombinogenic structures also regulate cassette excision. We observe that cassette excision dynamics driven by these factors differ between MIs and SCIs. Cassettes with high excision rates are more commonly found on MIs, which favors their dissemination relative to SCIs. This is especially true for SCIs carried in the Vibrio genus, where maintenance of large cassette arrays and vertical transmission are crucial to serve as a reservoir of adaptive functions. These results expand the repertoire of known processes regulating integron recombination that were previously established and demonstrate that, in terms of cassette dynamics, a subtle trade-off between evolvability and genetic capacitance has been established in bacteria.IMPORTANCE The integron system confers upon bacteria a rapid adaptation capability in changing environments. Specifically, integrons are involved in the continuous emergence of bacteria resistant to almost all antibiotic treatments. The international situation is critical, and in 2050, the annual number of deaths caused by multiresistant bacteria could reach 10 million, exceeding the incidence of deaths related to cancer. It is crucial to increase our understanding of antibiotic resistance dissemination and therefore integron recombination dynamics to find new approaches to cope with the worldwide problem of multiresistance. Here, we studied the dynamics of recombination and dissemination of gene encoding cassettes carried on integrons. By combining in silico and in vivo analyses, we show that cassette excision is highly regulated by replication and by the intrinsic properties of cassette recombination sites. We also demonstrated differences in the dynamics of cassette recombination between mobile and sedentary chromosomal integrons (MIs and SCIs). For MIs, a high cassette recombination rate is favored and timed to conditions when generating diversity (upon which selection can act) allows for a rapid response to environmental conditions and stresses. In contrast, for SCIs, cassette excisions are less frequent, limiting cassette loss and ensuring a large pool of cassettes. We therefore confirm a role of SCIs as reservoirs of adaptive functions and demonstrate that the remarkable adaptive success of integron recombination system is due to its intricate regulation.


Archaea on human skin.
The recent era of exploring the human microbiome has provided valuable information on microbial inhabitants, beneficials and pathogens. Screening efforts based on DNA sequencing identified thousands of bacterial lineages associated with human skin but provided only incomplete and crude information on Archaea. Here, we report for the first time the quantification and visualization of Archaea from human skin. Based on 16 S rRNA gene copies Archaea comprised up to 4.2% of the prokaryotic skin microbiome. Most of the gene signatures analyzed belonged to the Thaumarchaeota, a group of Archaea we also found in hospitals and clean room facilities. The metabolic potential for ammonia oxidation of the skin-associated Archaea was supported by the successful detection of thaumarchaeal amoA genes in human skin samples. However, the activity and possible interaction with human epithelial cells of these associated Archaea remains an open question. Nevertheless, in this study we provide evidence that Archaea are part of the human skin microbiome and discuss their potential for ammonia turnover on human skin.


Fabrication of monolayers of uniform polymeric particles by inkjet printing of monodisperse emulsions produced by microfluidics.
Emulsion solvent evaporation is a well-established method for generating microparticles from solutions of polymers in volatile organic solvents dispersed in an aqueous medium. Previous work has shown that this approach can also be used to deposit particles by inkjet printing where the particles are formed during the drying of a liquid ink on a substrate. The particle size distribution, however, was very broad. Here we demonstrate that inkjet printing of oil-in-water emulsions produced by microfluidics can generate micron-sized particles with a narrow size distribution (coefficient of variation <6%) and that these particles can self-assemble into ordered arrays with hexagonal packing. The conditions under which drops can be printed with a minimum of break up and coalescence of the oil droplets in the emulsion are explored. Factors affecting the size of the particles and the morphology of the deposit are described. This study uses polystyrene in dichloromethane as a model system, but the approach can be generalized to the production of structured and functional particles.


Effect of replacing dietary vitamin E by sage on performance and meatiness of spent hens, and the oxidative stability of sausages produced from their meat.
A total of 3960 hens (half ISA Warren and half Dekalb White) were housed in 18 compartments with 220 hens each. The effect of replacing dietary vitamin E by sage on productivity, meat yield and oxidative stability of sausages was studied. One third of all animals received either a vitamin E deficient diet (negative control) or diets supplemented with 30 mg/kg α-tocopherylacetate (positive control) or 25 g sage leaves/kg. At slaughter, meat yield was assessed and sausages were produced (n = 12 per treatment). The omission of vitamin E did not impair the oxidative stability of the raw sausage material or the spiced sausages in comparison to the positive control. Sage supplementation improved oxidative stability after 7 m of frozen storage, but not after 1, 4 and 10 m. Spice addition during meat processing had an antioxidant effect regardless of dietary treatment. Diet supplementation of any type did not affect laying performance and sausage meat yield. Feeding antioxidants to spent hens seemed to be not as efficient as in growing chickens, while seasoning with spices during sausage production proved to be a feasible way to delay lipid oxidation.


A community-based exercise programme in COPD self-management: two years follow-up of the COPE-II study.
It is still unknown how best to maintain effects of exercise programmes in COPD in the long-term. We present the long-term effects of a community-based exercise programme incorporated in a self-management programme, compared to a self-management programme only in patients with COPD. All included patients participated in four self-management sessions. Additionally, patients in the intervention group participated in an 11-month community-based exercise programme led by physiotherapists. Patients trained three times/week for six months and two times/week during the subsequent five months. To encourage a behavioural change towards exercise, one of these weekly training sessions was home-based (unsupervised). No formal exercise training was offered to intervention patients in the second year. The intervention was assigned to 80 patients, and the control condition to 79 patients. 82.5% and 78.5% of the intervention and control group, respectively, completed 24 months follow-up. Modified intention-to-treat analyses were performed. Although statistically significant after 12 months (35.1 m (95%CI: 8.4-61.8)), the between-group difference on maximal exercise capacity was not statistically significant after 24 months (12.2 m (95%CI: -16.6 to 41.0). Nevertheless, the between-group difference in daily physical activity was maintained after 24 months (1193 steps/day (95%CI: 203-2182)). A beneficial effect was also found on CRQ dyspnoea score but not on other CRQ domains, CCQ and HADS. Our intervention was effective in achieving a behavioural change reflected by a sustained increase in daily physical activity, not accompanied by a sustained increase in maximal exercise capacity after two years of follow-up (ISRCTN81447311).


Stromal differences in salivary gland tumors of a common histopathogenesis but with different biological behavior: a study with picrosirius red and polarizing microscopy.
Salivary gland neoplasms - pleomorphic adenoma, polymorphous low-grade adenocarcinoma, and adenoid cystic carcinoma - share a common histogenetic trait, but differ markedly in their biological properties. The objective of the study was to assess the polarization colors of picrosirius red-stained stromal collagen fibers in these salivary gland neoplasms to evaluate their possible role in the histopathogenesis of the tumors and to evaluate the potential usefulness of this approach as a diagnostic tool. Ten cases of each tumor type and 10 cases of mucous extravasation phenomenon (control) were examined using picrosirius red staining and polarizing microscopy. In each case, at least 50 thin ( approximately 0.8 microm) and 50 thick (1.6-2.4 microm) collagen fibers were counted and classified as green-yellow or yellow-orange, the mean percentage was calculated and statistical differences analyzed by one-way ANOVA. Results showed a similar thin fiber distribution in all tumor types and controls (82-88% green-yellow, 12-18% yellow-orange, p>0.05). Thick fibers showed a different distribution in polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma (approximately 50% green-yellow) compared to pleomorphic adenoma and mucous extravasation phenomenon (approximately 13% green-yellow) (p=0.001). Thick fiber distribution was similar in polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma (p>0.05). We conclude that with picrosirius red staining and polarizing microscopy, stromal collagen fibers differ significantly in pleomorphic adenoma from those in polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma, but not from mucous extravasation phenomenon. Similarity between polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma may indicate that these tumor types represent a single entity with a broad spectrum of biological behavior.


Development of cyclosporine A nanosuspension: cytotoxicity and permeability on Caco-2 cell lines.
Cyclosporine A is a calcineurin inhibitor and is usually used as an immunosuppressant medication. The main purpose of this study is to develop nanosuspension of polypeptide cyclosporine A by using the wet milling method for oral administration. Cell culture studies were also performed with human intestinal Caco-2 cell lines. Hydroxypropyl methylcellulose and sodium dodecyl sulfate were used as stabilizers in nanosuspension. In vitro characterization studies such as Fourier-transform infrared analysis and morphological imaging with scanning electron microscopy have been carried out with obtained cyclosporine A nanosuspension. The particle size, particle size distribution, and zeta potential values of the nanosuspension were measured approximately 400 nm, 0.4, and -25 mV, respectively. The solubility of cyclosporine A was increased 4.5 times in nanosuspension compared to the coarse cyclosporine A powder. As a result of cytotoxicity studies conducted with different concentrations, it was decided to conduct permeability studies at a dose equivalent to 150 µg/mL cyclosporine A. Permeation studies have shown that the nanosuspension increases cyclosporine A transport by 5 and 1.5 times, respectively, compared to coarse powder and commercial product.


Impact of spatial dimension on structural ordering in metallic glass.
Metallic glasses (MGs) have so far attracted considerable attention for their applications as bulk materials. However, new physics and applications often emerge by dimensional reduction from three dimensions (3D) to two dimensions (2D). Here, we study, by molecular dynamics simulations, how the liquid-to-glass transition of a binary Cu_{50}Zr_{50} MG is affected by spatial dimensionality. We find clear evidence that crystal-like structural ordering controls both dynamic heterogeneity and slow dynamics, and thus plays a crucial role in the formation of the 2DMG. Although the 2DMG reproduces the dynamical behaviors of its 3D counterpart by considering Mermin-Wagner-type fluctuations specific to 2D, this atomic-scale structural mechanism is essentially different from that for the 3DMG in which icosahedral clusters incompatible with crystallographic symmetry play a key role in glassy behaviors. Our finding provides a structural mechanism for the formation of 2DMGs, which cannot be inferred from the knowledge of 3DMGs. The results suggest a structural basis for the glass transition in 2DMG and provide possible explanations for some previous experimental observations in ultrathin film MGs.


The effect of physico-chemical treatment in reducing Listeria monocytogenes biofilms on lettuce leaf surfaces.
The purpose of this research was to characterize Listeria monocytogenes from several environmental and clinical sources and assess the efficacy of single and combined physico-chemical treatments in reducing biofilm on lettuce leaves. PCR analysis of L. monocytogenes isolates collected from different clinical (10 strains) and environmental sources (12 strains) was used to look for the presence of one Listeria-specific gene and five virulence genes. Biofilms of L. monocytogenes were developed on lettuce leaves over 24 h. A 5-min ultrasound and a 300-ppm sodium hypochlorite (NaOCl) wash resulted in similar reductions in cell numbers of 0.82 log CFU cm-2. For chlorine dioxide (ClO2) at 60 ppm, the cell numbers were reduced by ∼5.45 log CFU cm-2. A combined treatment of 5 min of ultrasound plus 300 ppm NaOCl or 40 ppm ClO2, provided maximal efficacy, reducing the number of L. monocytogenes on the lettuce surface to non-detectable levels. Therefore, ClO2 has the potential to replace NaOCl for the disinfection of food products in the food industry.


Alpha-synuclein transgenic mice exhibit reduced anxiety-like behaviour.
Up to 40% of Parkinson's disease patients suffer from anxiety, but little is known about the mechanisms involved. We used the elevated plus maze and open field test to evaluate groups of young adult mice expressing different levels of alpha-synuclein, including mice transgenic for human alpha-synuclein with the A53T mutation. Compared to alpha-synuclein knock-out mice and wild-type controls, alpha-synuclein A53T transgenic mice exhibited reduced anxiety-like behaviour by spending markedly greater amounts of time on the maze open arms and by a higher proportion of entries to the open arms. In the open field, transgenic mice showed a trend towards reduced locomotor habituation and increased thigmotaxis. These results indicate a possible role for alpha-synuclein in anxiety-like behaviours.


Becoming a Mentor: The Impact of Training and the Experience of Mentoring University Students on the Autism Spectrum.
While it is widely recognised that the number of young adults diagnosed with Autism Spectrum Disoders (ASD) is increasing, there is currently limited understanding of effective support for the transition to adulthood. One approach gaining increasing attention in the university sector is specialised peer mentoring. The aim of this inductive study was to understand the impact of peer mentor training on seven student mentors working with university students with an ASD. Kirkpatrick's model framed a mixed methods evaluation of the mentors' training and description of their experience. Overall, the training was well received by the mentors, who reported on average a 29% increase in their ASD knowledge following the training. Results from the semi-structured interviews conducted three months after the training, found that mentors felt that the general ASD knowledge they gained as part of their training had been essential to their role. The mentors described how their overall experience had been positive and reported that the training and support provided to them was pivotal to their ability to succeed in as peer mentors to students with ASD. This study provides feedback in support of specialist peer-mentoring programs for university students and can inform recommendations for future programs and research.


The dynamics of singlet fission in crystalline tetracene and covalent analogs.
Singlet fission (SF) is a spin-allowed process in which an excited singlet state spontaneously splits into a pair of triplet excitons. This relaxation pathway is of interest as a mechanism for increasing the efficiency of photovoltaic solar cells, since ionization of the triplets could produce two charge carriers per absorbed photon. In this Account, we summarize our recent work on trying to understand how SF occurs using both covalent and noncovalent assemblies of tetracene. We first give a brief overview of the SF process and discuss why tetracene, where the singlet and triplet pair energies are nearly degenerate, is a particularly useful molecule for studying this process. Then we describe our experiments, beginning with the study of phenylene-linked tetracene dimers as covalent analogs for the crystal form, where SF is known to be very efficient. We found that only 2-3% of the initially excited singlets underwent SF in these dimers. These results motivated us to study crystalline tetracene in more detail. Transient absorption and photoluminescence experiments on polycrystalline thin films provided evidence for a delocalized singlet exciton that decays with a complicated temperature-dependence, but we were unable to unambiguously identify the signature of the triplet pair formed by SF. Then, using ultrathin single crystals, we observed quantum beats in the delayed fluorescence arising from recombination of spin-coherent triplet pairs. Analyzing these quantum beats revealed that SF proceeds through a direct one-step process occurring within 200 ps at room temperature. The product of this reaction is a pair of unperturbed triplets that have negligible interaction with each other. Looking at the overall SF process in tetracene, remaining issues that need to be clarified include the role of exciton diffusion, the temperature dependence of the SF rate, and how to use insights gained from the solid-state studies to generate design principles for high-efficiency covalent systems. Our experiments provide a good illustration of why the polyacenes, and tetracene in particular, play an important role as systems for the study of SF.


Varicella-zoster virus infection triggers formation of an interleukin-1β (IL-1β)-processing inflammasome complex.
Innate cellular immunity is the immediate host response against pathogens, and activation of innate immunity also modulates the induction of adaptive immunity. The nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular receptors that recognize conserved patterns associated with intracellular pathogens, but information about their role in the host defense against DNA viruses is limited. Here we report that varicella-zoster virus (VZV), an alphaherpesvirus that is the causative agent of varicella and herpes zoster, induces formation of the NLRP3 inflammasome and the associated processing of the proinflammatory cytokine IL-1β by activated caspase-1 in infected cells. NLRP3 inflammasome formation was induced in VZV-infected human THP-1 cells, which are a transformed monocyte cell line, primary lung fibroblasts, and melanoma cells. Absent in melanoma gene-2 (AIM2) is an interferon-inducible protein that can form an alternative inflammasome complex with caspase-1 in virus-infected cells. Experiments in VZV-infected melanoma cells showed that NLRP3 protein recruits the adaptor protein ASC and caspase-1 to form an NLRP3 inflammasome complex independent of AIM2 protein and in the absence of free radical reactive oxygen species release. NLRP3 was also expressed extensively in infected skin xenografts in the severe combined immunodeficiency mouse model of VZV pathogenesis in vivo. We conclude that NLRP3 inflammasome formation is an innate cellular response to infection with this common pathogenic human herpesvirus.


Functional characterization of the cleavage specificity of the sapovirus chymotrypsin-like protease.
Sapovirus is a positive-stranded RNA virus with a translational strategy based on processing of a polyprotein precursor by a chymotrypsin-like protease. So far, the molecular mechanisms regulating cleavage specificity of the viral protease are poorly understood. In this study, the catalytic activities and substrate specificities of the predicted forms of the viral protease, the 3C-like protease (NS6) and the 3CD-like protease-polymerase (NS6-7), were examined in vitro. The purified NS6 and NS6-7 were able to cleave synthetic peptides (15 to 17 residues) displaying the cleavage sites of the sapovirus polyprotein, both NS6 and NS6-7 proteins being active forms of the viral protease. High-performance liquid chromatography and subsequent mass spectrometry analysis of digested products showed a specific trans cleavage of peptides bearing Gln-Gly, Gln-Ala, Glu-Gly, Glu-Pro, or Glu-Lys at the scissile bond. In contrast, peptides bearing Glu-Ala or Gln-Asp at the scissile bond (NS4-NS5 and NS5-NS6, or NS6-NS7 junctions, respectively) were resistant to trans cleavage by NS6 or NS6-7 proteins, whereas cis cleavage of the Glu-Ala scissile bond of the NS5-NS6 junction was evidenced. Interestingly, the presence of a Phe at position P4 overruled the resistance to trans cleavage of the Glu-Ala junction (NS5-NS6), whereas substitutions at the P1 and P2' positions altered the cleavage efficiency. The differential cleavage observed is supported by a model of the substrate-binding site of the sapovirus protease, indicating that the P4, P1, and P2' positions in the substrate modulate the cleavage specificity and efficiency of the sapovirus chymotrypsin-like protease.


A novel approach for assigning levels to monkey and human lumbosacral spinal cord based on ventral horn morphology.
Proper identification of spinal cord levels is crucial for clinical-pathological and imaging studies in humans, but can be a challenge given technical limitations. We have previously demonstrated in non-primate models that the contours of the spinal ventral horn are determined by the position of motoneuron pools. These positions are preserved within and among individuals and can be used to identify lumbosacral spinal levels. Here we tested the hypothesis that this approach can be extended to identify monkey and human spinal levels. In 7 rhesus monkeys, we retrogradely labeled motoneuron pools that represent rostral, middle and caudal landmarks of the lumbosacral enlargement. We then aligned the lumbosacral enlargements among animals using absolute length, segmental level or a relative scale based upon rostral and caudal landmarks. Inter-animal matching of labeled motoneurons across the lumbosacral enlargement was most precise when using internal landmarks. We then reconstructed 3 human lumbosacral spinal cords, and aligned these based upon homologous internal landmarks. Changes in shape of the ventral horn were consistent among human subjects using this relative scale, despite marked differences in absolute length or age. These data suggest that the relative position of spinal motoneuron pools is conserved across species, including primates. Therefore, in clinical-pathological or imaging studies in humans, one can assign spinal cord levels to even single sections by matching ventral horn shape to standardized series.


Paraffin (kerosene)* poisoning in under-five children: a problem of developing countries.
Although developed countries have largely eliminated the problem of paraffin ingestion in young children, many developing countries have not. Paraffin, used as a home energy source, particularly in rural area, accounts for a significant percent of paediatric poisoning and can lead to serious health problems, complications and death. This paper presents a review done by a nurse clinician concerned about the number of paediatric poisonings she saw in the hospital in one developing country, Botswana. The first stage of solving the problem is presented in which she established the extent and epidemiology of the issue. Suggestions for its solution are also discussed. It is hoped that this can serve both to increase awareness in developing countries of the dangers of paraffin poisoning and serve as a model for nurse clinicians and researchers in developing countries.


Carbon catabolite repression of phenol degradation in Pseudomonas putida is mediated by the inhibition of the activator protein PhlR.
Enzymes involved in (methyl)phenol degradation of Pseudomonas putida H are encoded by the catabolic operon (phlA-L) on plasmid pPGH1. Transcription of this operon by the sigma54 (RpoN)-containing RNA polymerase is positively controlled by the gene product of the divergently transcribed phlR in response to the availability of the respective substrate. Additionally, phenol degradation is subject to carbon catabolite repression induced by organic acids (e.g., succinate, lactate, and acetate) or carbohydrates (e.g., glucose and gluconate). Analysis of lacZ fusion to the catabolic promoter and quantified primer extension experiments indicate that carbon catabolite repression also occurs at the transcriptional level of the catabolic operon. In this study, it is furthermore shown that carbon catabolite repression is a negative control. Titration of the postulated negative controlling factor was exclusively observed when extra copies of functional phlR gene were present in the cell. We therefore conclude that PhlR is the target and that carbon catabolite repression of phenol degradation occurs by interfering with the activating function of PhlR.


[Drug therapy of patients with emotionally unstable personality].
Most patients with borderline personality disorders are treated with psychotropic medication. There are, however, no clear clinical guidelines concerning optimal treatment of the disorder. This article reviews the data on the efficacy of treatment with different classes of psychopharmacological drugs. The emphasis is on clinical trials published after 1981, as most placebo-controlled double-blind studies have been done in the last two decades. Furthermore, studies conducted before 1980 are more difficult to interpret because of changes in clinical diagnostic criteria. Neuroleptics have been studied most extensively followed by antidepressants. Neuroleptics have a modest, but broad therapeutic effect on symptoms in all domains. Doses are lower than those used for treating schizophrenia. Antidepressants have a more inconsistent effect. Tricyclics have been the least successful, whereas irreversible MAO inhibitors and selective serotonin reuptake inhibitors (SSRIs) have been effective in treating mood symptoms and impulsivity. Lithium has a possible effect in diminishing anger and suicidal symptoms. As there is no "drug of choice" for the treatment of borderline personality disorder, a more rational clinical approach might be to treat different symptom clusters (cognitive/schizotypal, affective, impulsive) rather than the disorder itself. Finally, some practical guidelines for drug treatment of the disorder are proposed.


The mechanism of selective molecular capture in carbon nanotube networks.
Recently, air pollution issues have drawn significant attention to the development of efficient air filters, and one of the most promising materials for this purpose is nanofibers. We explore here the mechanism of selective molecular capture of volatile organic compounds in carbon nanotube networks by performing atomistic simulations. The results are discussed with respect to the two key parameters that define the performance of nanofiltration, i.e. the capture efficiency and flow resistance, which demonstrate the advantages of carbon nanotube networks with high surface-to-volume ratio and atomistically smooth surfaces. We also reveal the important roles of interfacial adhesion and diffusion that govern selective gas transport through the network.


Topologically Enclosed Aluminum Voids as Plasmonic Nanostructures.
Recent advances in the ability to synthesize metallic nanoparticles with tailored geometries have led to a revolution in the field of plasmonics. However, studies of the important complementary system, an inverted nanostructure, have so far been limited to two-dimensional sphere-segment voids or holes. Here we reveal the localized surface plasmon resonances (LSPRs) of nanovoids that are topologically enclosed in three-dimensions: an "anti-nanoparticle". We combine this topology with the favorable plasmonic properties of aluminum to observe strongly localized field enhancements with LSPR energies in the extreme UV range, well beyond those accessible with noble metals or yet achieved with aluminum. We demonstrate the resonance tunability by tailoring the shape and size of the nanovoids, which are truncated octahedra in the 10-20 nm range. This system is pristine: the nanovoid cavity is free from any oxide or supporting substrate that would affect the LSPRs. We exploit this to infer LSPRs of pure, sub-20-nm Al nanoparticles, which have yet to be synthesized. Access to this extreme UV range will allow applications in LSPR-enhanced UV photoemission spectroscopy and photoionization.


Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours.
Stromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC. Nitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro-in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo. The delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy. The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.


Preliminary studies on antigenic variation of poliovirus using neutralizing monoclonal antibodies.
Cross-neutralization assays were done using 85 strains of poliovirus type 1 with five groups of monoclonal antibodies. These strains were classified into 10 subgroups which had marked differences in antigenicity. Subgroups P1-2 (28%) and P1-5 (43%) were dominant and have been epidemic in China in recent years. These two subgroups were antigenically different from the Sabin-1 strain, but according to their responses to one group of monoclonal antibodies they had antigenic epitopes in common with the Mahoney and Brunhilde strains. Similarly, 91 strains of type 3 poliovirus were classified into six subgroups with another five groups of monoclonal antibodies. The results showed that strain P3/Yunnan/2/84, which was isolated from cases of poliomyelitis in a local epidemic in the Yunnan province of China in 1984, and strain P3/Finland/23127/84, which was isolated in Finland in 1984, were both antigenically different from the Sabin-3 strain and the reference virulent strain.