Satisfaction with medication in coronary disease treatment: psychometrics of the Treatment Satisfaction Questionnaire for Medication.
to psychometrically test the Brazilian version of the Treatment Satisfaction Questionnaire for Medication - TSQM (version 1.4), regarding ceiling and floor effect, practicability, acceptability, reliability and validity. participants with coronary heart disease (n=190) were recruited from an outpatient cardiology clinic at a university hospital in Southeastern Brazil and interviewed to evaluate their satisfaction with medication using the TSQM (version 1.4) and adherence using the Morisky Self-Reported Measure of Medication Adherence Scale and proportion of adherence. The Ceiling and Floor effect were analyzed considering the 15% worst and best possible TSQM scores; Practicability was assessed by time spent during TSQM interviews; Acceptability by proportion of unanswered items and participants who answered all items; Reliability through the Cronbach's alpha coefficient and Validity through the convergent construct validity between the TSQM and the adherence measures. TSQM was easily applied. Ceiling effect was found in the side effects domain and floor effect in the side effects and global satisfaction domains. Evidence of reliability was close to satisfied in all domains. The convergent construct validity was partially supported. the Brazilian TSQM presents evidence of acceptability and practicability, although its validity was weakly supported and adequate internal consistency was observed for one domain.


Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes.
The differentiation of preadipocyte fibroblasts to adipocytes is a crucial process to many disease states including obesity, cardiovascular, and autoimmune diseases. In Graves' disease, the orbit of the eye can become severely inflamed and infiltrated with T lymphocytes as part of the autoimmune process. The orbital fibroblasts convert to fat-like cells causing the eye to protrude, which is disfiguring and can lead to blindness. Recently, the transcription factor peroxisome proliferator activated receptor (PPAR)-gamma and its natural (15d-PGJ2) and synthetic (thiazolidinedione-type) PPAR-gamma agonists have been shown to be crucial to the in vitro differentiation of preadipocyte fibroblasts to adipocytes. We show herein several novel findings. First, that activated T lymphocytes from Graves' patients drive the differentiation of PPAR-gamma-expressing orbital fibroblasts to adipocytes. Second, this adipogenic differentiation is blocked by nonselective small molecule cyclooxygenase (Cox)-1/Cox-2 inhibitors and by Cox-2 selective inhibitors. Third, activated, but not naïve, human T cells highly express Cox-2 and synthesize prostaglandin D2 and related prostaglandins that are PPAR-gamma ligands. These provocative new findings provide evidence for how activated T lymphocytes, through production of PPAR-gamma ligands, profoundly influence human fibroblast differentiation to adipocytes. They also suggest the possibility that, in addition to the orbit, T lymphocytes influence the deposition of fat in other tissues.


Hpr6 (heme-1 domain protein) regulates the susceptibility of cancer cells to chemotherapeutic drugs.
Cancer cells have varying levels of susceptibility to chemotherapeutic agents, and the proteins that direct drug susceptibility are promising targets for intervention in cancer. Hpr6 (heme-1 domain protein)/PGRMC1 (progesterone receptor membrane component 1) is overexpressed in tumors, and Hpr6 is the human homolog of a budding yeast damage resistance gene called Dap1p. Cells lacking Dap1p are damage-sensitive, and we have found that inhibition of Hpr6 expression by RNA inhibition (RNAi) increases sensitivity of breast cancer cells to chemotherapeutic drugs. Hpr6 is composed largely of a cytochrome b(5)-related heme-1 domain, and we have found that purified Hpr6 binds to heme, similar to its yeast and rodent homologues. We generated an aspartate 120-to-glycine (D120G) mutant of Hpr6 at a highly conserved site in the heme-1 domain and demonstrated that Hpr6-D120G cannot bind to heme. The Hpr6-D120G mutant was named Hpr6(hbd) for heme binding defective. We prepared an adenovirus encoding Hpr6(hbd) and found that adenovirus Hpr6(hbd) increases susceptibility of breast cancer cells to doxorubicin and camptothecin. Our findings support a model in which Hpr6, similar to its yeast homolog, binds to heme and regulates susceptibility to damaging agents.


[Kidney diseases and hypertension].
Renal disease has been recognized as both a cause and a consequence of hypertension. Renal hypertension may be of vascular and nonvascular origin. Generally, the prevalence of hypertension increases with decreasing renal function, including more than 90% of patients with terminal renal failure. However, hypertension is more often found in glomerular than in interstitial disease. The pathomechanisms operative in renal hypertension are sodium retention with concomitant volume expansion, an increase in plasma renin activity or a combination of both factors. While mechanical intervention is usually tried in renovascular hypertension and in the rare cases with "urological" causes, no causal therapy is possible in most cases of renoparenchymal disease. However, as the normalization of blood pressure is the best proved way to stop or at least retard the progression of renoparenchymal disease, pharmacological intervention is mandatory even if the medication sometimes has side effects.


Tetanus toxin and antigenic derivatives. II. Effect of protein and formaldehyde concentration on toxoid formation.
Tetanus toxoid formation was examined under varying conditions. Products of the reaction depended upon the concentration of both formaldehyde and toxin. High concentrations of protein and formaldehyde favored the formation of large polymers, whereas low concentrations yielded smaller polymers and monomer. The monomer had an observed S value of 7.1, whereas the polymers ranged from 10.1S to 110S. The cross-linking between toxin molecules to form toxoid polymers appeared to be random.


The chemical form and spatial variation of metals from sediment of Jemberau mining region of Tasik Chini, Malaysia.
Bauxite and iron ore mining is the major contributor to metal pollution in Tasik Chini, Malaysia. Deforestation of the protected zone of reserve forest exacerbates the problem. The current study is to understand the speciation of metals spatially in sediment to analyse the risk associated in terms of its mobility and bioavailability. The samples of sediment are collected from Sungai Jemberau, Laut Jemberau, and Laut Gumum of Tasik Chini. Four samplings were conducted for a year, by collecting the surface sediment. Sequential extraction method was followed for speciation of sediment and classified it into exchangeable, reducible, Fe-Mn oxides, organic and residual fractions. The results were also analyzed using principal component analysis (PCA) and cluster analysis (CA). The result reveals that Fe, Al, Mn, Zn, and Pb are the primary constituents of sediment contributing to about 98% of residual fraction. Co, Cd, Cr, As, and Ni are found in trace metal concentration and are identified to be mainly released from anthropogenic sources nearby. Although the individual proportion is less than major metals in exchangeable and carbonate fraction, they possess geochemically significant concentration above the permissible limit. More than 70-80% of all its total concentration proportion is hence found in mobile and bioavailable state. These possess toxic and have chronic effects to aquatic life and public health even in trace elemental concentration. Hence, these metals are the most toxic and bioavailable metals pausing risk for aquatic and public health. PCA analysis highlights that the enrichment of heavy metals in bioavailable fraction is mostly contributed from anthropogenic sources. The same results are emphasized by cluster analysis.


A system for preparing and distributing large volumes.
A systein for preparing and distributing 100 liters of distilleddeionized water per day is described. Novel features are an overflow regulator, a " barometer " tube (permitting secondary reservoirs), and a pressure-controlled shutoff valve.


[Research conditions at the preclinical medical, odontological and pharmaceutical fields].
The Danish Medical Research Council has recently published a report (in Danish) entitled "Research Conditions in the Pre-clinical and Dental Institutes of the Health Science Faculties and the Danish University of Pharmaceutical Sciences". According to this report, the Danish educational institutions within health sciences are facing a major generational change among the scientific staff within the coming 5-15 years. It is therefore worrying that young physicians, dentists and pharmacists refrain from choosing a university research career. Possible explanations include more attractive working conditions, salaries, and career possibilities outside universities. The analyses describe a number of problems regarding this matter and outline how the situation might be improved. The Council recommends that to ensure a future optimal staff balance, focus should be placed on recruitment of researchers. It is important that the future scientific staff also includes a substantial number who possess the specific education provided by the faculty. The staff should be made up of a mix of researchers with knowledge about the nature and practice of their specific discipline and researchers with other scientific backgrounds in the health sciences. It is this interplay between the basic and clinical disciplines that must be consolidated in order to meet the future challenges. The interdisciplinary nature of Danish health science has undoubtedly contributed to placing the Danish health care services in the international front line.


A new standard of care: administration of preoperative antibiotics in the operating room.
Surgical site infections increase total hospital expenses and extend the length of hospital stay. Properly administered antibiotics are successful in minimizing postoperative subcutaneous wound infection secondary to perioperative bacterial contamination at the surgical site and are effective in most clean-contaminated surgical procedures. It is imperative that therapeutic levels of antibiotics be present during the time when the wound is open to maximize their effect to prevent the development of surgical wound infections. Only 32 per cent of 97 patients sampled from 1992 to 1994 at the Louisville Veterans Affairs Medical Center were administered preoperative antibiotics within 1 hour prior to surgical incision. Changing the responsibility for preoperative antibiotic administration from ward or holding room nurses to the anesthesiologist in the operating room rendered such antibiotics delivered closer to the induction of anesthesia and subsequent incision. Eighty-eight per cent of 220 patients sampled in 1995 had antibiotics administered within 1 hour of incision. This change in institutional policy of antibiotic administration maximizes the likelihood of appropriate antibiotic tissue levels and thereby their potential efficacy. Routine prophylaxis should be administered as close to the time of induction of anesthesia as possible to provide the best chance for appropriate tissue levels above the minimum inhibitory concentration for potential bacterial contamination.


Wnt/β-Catenin Signaling Activates Expression of the Bone-Related Transcription Factor RUNX2 in Select Human Osteosarcoma Cell Types.
Osteosarcoma is the most common malignant bone tumor in children and adolescents. Metastasis and poor responsiveness to chemotherapy in osteosarcoma correlates with over-expression of the runt-related transcription factor RUNX2, which normally plays a key role in osteogenic lineage commitment, osteoblast differentiation, and bone formation. Furthermore, WNT/β-catenin signaling is over-activated in osteosarcoma and promotes tumor progression. Importantly, the WNT/β-catenin pathway normally activates RUNX2 gene expression during osteogenic lineage commitment. Therefore, we examined whether the WNT/β-catenin pathway controls the tumor-related elevation of RUNX2 expression in osteosarcoma. We analyzed protein levels and nuclear localization of β-catenin and RUNX2 in a panel of human osteosarcoma cell lines (SAOS, MG63, U2OS, HOS, G292, and 143B). In all six cell lines, β-catenin and RUNX2 are expressed to different degrees and localized in the nucleus and/or cytoplasm. SAOS cells have the highest levels of RUNX2 protein that is localized in the nucleus, while MG63 cells have the lowest RUNX2 levels which is mostly localized in the cytoplasm. Levels of β-catenin and RUNX2 protein are enhanced in HOS, G292, and 143B cells after treatment with the GSK3β inhibitor SB216763. Furthermore, small interfering RNA (siRNA)-mediated depletion of β-catenin inhibits RUNX2 expression in G292 cells. Thus, WNT/β-catenin activation is required for RUNX2 expression in at least some osteosarcoma cell types, where RUNX2 is known to promote expression of metastasis related genes. J. Cell. Biochem. 118: 3662-3674, 2017. © 2017 Wiley Periodicals, Inc.


Inhibition of bleomycin-induced pulmonary fibrosis by cobra venom factor.
A single dose of cobra venom factor, a known, potent depletor of serum complement, has recently been reported to be highly effective in inhibiting lung collagen deposition at 7 days after bleomycin treatment. The present study shows that this is associated with suppression of the bleomycin-induced increase in collagen synthesis, down to virtually normal levels. There is also a concomitant reduction in tissue free proline pool size. No significant effects are noted in noncollagenous protein synthetic rates. This inhibitory effect is not seen at 30 days after bleomycin and is correlated with a return to normal levels of serum complement hemolytic activity. These data suggest an important role for complementary activity in the lung's fibrotic response to bleomycin.


Clinical benefit of preserving residual renal function in dialysis patients: an update for clinicians.
Residual renal function (RRF) remains important even after beginning of dialysis. RRF contributes significantly to the overall health and well-being of patients on dialysis. It plays an important role in maintaining fluid balance, phosphorus control, nutrition, and removal of middle molecular uremic toxins and shows inverse relationships with valvular calcification and cardiac hypertrophy in patients on dialysis. RRF may allow for a reduction in the duration of hemodialysis sessions and the need for dietary and fluid restrictions in both patients on peritoneal dialysis and hemodialysis. More importantly, the loss of RRF is a powerful predictor of mortality. This article will review the evidence supporting the importance of RRF on outcome and outline potential strategies that may better preserve RRF in patients on dialysis.


Copper release from chemical root-control baskets in hardwood tree production.
The City of Montreal, Canada, evaluated the environmental impact and usefulness of in-ground copper (Cu)-treated baskets in controlling root growth of hardwood trees in nursery culture. Using baskets planted with 5-yr-old Norway maple (Acer platanoides L.) trees, the amount and temporal pattern of Cu release from the basket surface into soil was determined for two copper formulations: Cu metal powder and Cu(OH)2. Release of both Cu formulations from the basket surface decreased exponentially over time, with Cu concentration at the basket surface dropping to 2% of the initial Cu applied by the end of the second field season. Total Cu content increased significantly in the soil around the baskets (from 7 to 28 mg Cu kg(-1) soil) and in the baskets (from 7 to 50-70 mg Cu kg(-1) soil) over the two years of the study. Three levels of phosphorus application (33, 66, and 100% of the regular nursery rate of 465 kg ha(-1) yr(-1)) did not affect release of Cu from the basket surface. The release of Cu metal at 28 and 105 d in the field was significantly increased by inoculation with the symbiotic arbuscular mycorrhizal fungus (AMF) Glomus intraradices Schenck & Smith; however, AMF inoculation had no affect on Cu(OH)2 release. Trees grown in Cu-treated baskets and inoculated with G. intraradices had similar colonization to non-inoculated trees, suggesting that inoculation was not very effective and that AMF inoculum was already present in the root ball of the trees at planting. After two years, copper basket-grown trees had significantly less root colonization than isolated control trees growing in the open field. This strongly suggests that conditions inside the baskets were not favorable to AMF.


A randomized controlled trial to reduce delay in older adults seeking help for symptoms of acute myocardial infarction.
Older adults with symptoms of acute myocardial infarction (AMI) have longer pre-treatment delay times than their younger counterparts. A 2-group, randomized controlled sample consisted of 115 adults, 65 years of age or older with a self-reported history of coronary artery disease. A pre-test was given to all participants followed by a structured education and counseling intervention to those in the experimental group. Data were re-collected at 3 months. There was a statistically significant increase in knowledge, beliefs, and perceived control without an increase in anxiety in the intervention group. There was no significant difference in attitudes. Older adults at risk for AMI should be targeted for individualized education and counseling in clinics, physician offices, and community centers.


Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion.
OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) is a deubiquitinating enzyme (DUB) that belongs to the ovarian tumor (OTU) domain protease superfamily. Although it has been demonstrated to play important roles in the development of many kinds of cancer, the mechanism of OTUB1 in hepatocellular carcinoma (HCC) is not clear. The aim of this study was to explore the roles of OTUB1 in HCC progression using cell lines and 115 archived HCC samples. In addition, the clinical outcomes were also analyzed with a special focus on OTUB1 expression in HCC samples. In the immunohistochemical study, OTUB1 showed high expression in 60 of the 115 cases (52.2%). The OTUB1 expression level was significantly correlated with many clinicopathological parameters, including TNM stage (P = 0.002), histology stage (P = 0.002), and metastasis/recurrence (P = 0.016). Survival analysis showed that the group with OTUB1 overexpression had significantly shorter overall survival time than the group with OTUB1 downregulation (hazard ratio [HR] = 0.482; confidence interval [CI]: 0.311-0.748; P = 0.001). Multivariate analysis indicated that OTUB1 expression was a significant and independent prognostic parameter (HR = 0.214; CI: 0.126-0.364; P < 0.001) for HCC patients. The ability of HCC cells to undergo proliferation, migration, and invasion was suppressed by disruption of endogenous OTUB1 using short hairpin RNA (shRNA). OTUB1 expression appears to be a new and independent predictor for the prognosis of HCC patients. Overexpression of OTUB1 in HCC could be a novel, effective, and supplementary biomarker for HCC because it plays a vital role in the progression of HCC.


Elevated levels of PDGF alpha receptors in keloid fibroblasts contribute to an enhanced response to PDGF.
Despite a number of studies, the etiology of keloids remains unknown. We have investigated the response of fibroblasts derived from keloid tissue and normal adult skin to platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF). Keloid fibroblasts were more responsive in both chemotactic and mitogenic assays to all three isoforms of PDGF than fibroblasts from normal skin. No enhanced response of the cells to either EGF or FGF was detected. The enhanced PDGF response of keloid fibroblasts appears to be mediated by elevated levels of PDGF alpha receptors, which are 4-5 times higher than those in normal human skin fibroblasts.


Research Advances in Resistance to Platinum-based Chemotherapy in Lung Cancer.
Platinum-based chemotherapy is the the cornerstone of treatment of many cancers. Combinations of platinum drugs with other agents are still the mainstream therapies for non-small cell lung cancer,showing significant effectiveness in an early phase. Along with the treatment,the tumor cells can become resistant to chemotherapy drugs,which affect the efficacy and prognosis. The mechanisms of drug resistance are complicated,including abnormal expressions of membrane proteins,enhanced DNA repair functions,abnormal regulation mechanisms of apoptosis,and enhanced cellular detoxification function. In this article we summarize some of the main mechanisms of platinum resistance in lung cancer cells,with an attempt to identify new potential target analogues or inhibitors and improve the efficacies of the combined use of platinum-based drugs.


Eumycetoma caused by Cladophialophora bantiana successfully treated with itraconazole.
A 57-year-old male presented with dermatosis of the dorsum of the foot consisting of tumefaction, deformity and sinus tract formation. The direct examination of exudates as well as the biopsy tissue, demonstrated the presence of black granules. A dematiaceous fungus was isolated from the lesions and was identified by ribosomal DNA sequencing as Cladophialophora bantiana. This is the second report of this fungus as an etiologic agent of eumycetoma in humans. Clinical and mycologic cure was achieved after 20 months of treatment with itraconazole at a starting dose of 300 mg/day that was tapered during the course of therapy. The patient's isolate had an itraconazole MIC of 0.012 microg/ml.


Key factors for predictable aesthetics in single tooth immediate implantation with provisionalization.
Early implant placement is one treatment option for implant therapy following a single-tooth extraction in the anterior maxilla. In this article some key factors are presented to analyze and follow in an effort to obtain a predictable and acceptable esthetic result. The creation of predictable peri-implant esthetics requires proper preservation of the osseous and soft tissues around the failing teeth, proper 3-D implant placement and proper understanding of the prosthetic management. The surgical technique presented here is characterized by tooth extraction without flap elevation, implant placement in a correct three-dimensional position, simultaneous contour augmentation on the facial aspect with connective tissue grafting combined with heterologous bone chips filled into the implant bone gap.


Comparison of salivary and serum glucose levels in diabetic patients.
Diabetes mellitus is a noncommunicable disease with a rising prevalence worldwide and in developing countries. The most commonly used diagnostic biofluid for detection of glucose levels is blood, but sample collection is an invasive and painful procedure. Thus, there arises a need for a noninvasive and painless technique to detect glucose levels. The objectives of the present study were to estimate the glucose levels of saliva, to assess if any significant correlation existed between the serum and salivary glucose levels, and to correlate salivary glucose levels with regard to duration of diabetes, age, and gender. In the present study, serum and salivary glucose levels of 200 subjects (100 diabetic subjects and 100 nondiabetic subjects) were estimated by glucose oxidase method. Glycosylated hemoglobin levels were also measured in randomly selected 40 diabetic subjects. The findings of present study revealed a significant correlation between salivary and serum glucose levels in both diabetic and nondiabetic subjects. No significant relationship was observed between salivary glucose levels and gender or age in both diabetics and nondiabetics and between salivary glucose levels and duration of diabetes in diabetics. On the basis of the findings, it was concluded that salivary glucose levels could serve as a potentially noninvasive adjunct to monitor glycemic control in diabetic patients.


Alpha-helix stabilization within a peptide dendrimer.
The alpha-helical second generation peptide dendrimer of sequence (AcAMEA)(4)(KKLME)(2)KMKLA is more stable than the corresponding linear peptide AcAMEAAKLMEAMKLA toward pH-induced unfolding and temperature-induced intermolecular aggregation. The effect is interpreted in terms of an alpha-helix spanning across two successive branching points of the dendrimer. This stabilization effect is unprecedented and opens the way to folded dendritic analogues of proteins using natural amino acids only.


Overconfidence in an objective anticipatory motor task.
Overconfidence can place humans in hazardous situations, and yet it has been observed in a variety of cognitive tasks in which participants have to rate their own performance. We demonstrate here that overconfidence can be revealed in a natural and objective visuo-motor task. Participants were asked to press a key in synchrony with a predictable visual event and were rewarded if they succeeded and sometimes penalized if they were too quick or too slow. If they had used their own motor uncertainty in anticipating the timing of the visual stimulus, they would have maximized their gain. However, they instead displayed an overconfidence in the sense that they underestimated the magnitude of their uncertainty and the cost of their error. Therefore, overconfidence is not limited to subjective ratings in cognitive tasks, but rather appears to be a general characteristic of human decision making.


Untargeted analysis to monitor metabolic changes of garlic along heat treatment by LC-QTOF MS/MS.
Black garlic is increasing its popularity in cuisine around the world; however, scant information exists on the composition of this processed product. In this study, polar compounds in fresh garlic and in samples taken at different times during the heat treatment process to obtain black garlic have been characterized by liquid chromatography coupled to tandem mass spectrometry in high resolution mode. Ninety-five compounds (mainly amino acids and metabolites, organosulfur compounds, and saccharides and derivatives) were tentatively identified in all the analysed samples and classified as a function of the family they belong to. Statistical analysis of the results allowed establishing that the major changes in garlic occur during the first days of treatment, and they mainly affect to the three representative families. The main pathways involved in the synthesis of the compounds affected by heat treatment, and their evolution during the process were studied.


Purification and characterization of an alkaline serine endopeptidase from a feather-degrading Xanthomonas maltophilia strain.
A keratinolytic Xanthomonas maltophilia strain (POA-1), cultured on feather meal broth, using keratin as its sole source of carbon and nitrogen, secretes several extracellular peptidases. The major serine peptidase was purified to homogeneity by a five-step procedure. Its purity was evaluated by capillary zone electrophoresis. This enzyme has a molecular mass of 36 kDa, an optimum pH of 9.0, and an optimum temperature of 60 degrees C. The inhibitory profile using protease inhibitors shows that this enzyme is a serine endopeptidase. Besides keratin, the enzyme is active upon the substrates azokeratin, azocasein, and the following fluorogenic peptide substrates: Abz-Leu-Gly-Met-Ile-Ser-Leu-Met-Lys-Arg-Pro-Gln-EDDnp, Abz-Lys-Leu-Cys(SBzl)-Gly-Pro-Lys-Gln-EDDnp, and Abz-Lys-Pro-Cys(SBzl)-Phe-Ser-Lys-Gln-EDDnp.


The cyto-linker and scaffolding protein "plectin" mis-localization leads to softening of cancer cells.
Discovering tools to prevent cancer progression requires understanding the fundamental differences between normal and cancer cells. More than a decade ago, atomic force microscopy (AFM) revealed cancer cells' softer body compared to their healthy counterparts. Here, we investigated the mechanism underlying the softening of cancerous cells in comparison with their healthy counterparts based on AFM high resolution stiffness tomography and 3D confocal microscopy. We showed microtubules (MTs) network in invasive ductal carcinoma cell cytoskeleton is basally located and segmented for around 400 nm from the cell periphery. Additionally, the cytoskeleton scaffolding protein plectin exhibits a mis-localization from the cytoplasm to the surface of cells in the carcinoma which justifies the dissociation of the MT network from the cell's cortex. Furthermore, the assessment of MTs' persistence length using a worm-like-chain (WLC) model in high resolution AFM images showed lower persistence length of the single MTs in ductal carcinoma compared to that in the normal state. Overall, these tuned mechanics support the invasive cells to ascertain more flexibility under compressive forces in small deformations. These data provide new insights into the structural origins of cancer aids in progression.


Ketanserin in combination with beta-adrenergic receptor blocking agents in the treatment of essential hypertension.
The antihypertensive properties of ketanserin, a 5-HT2 receptor antagonist, was investigated in combination with beta-adrenoceptor blockade. Ketanserin was given 40 mg twice daily to 10 hypertensive patients during 4 weeks in a double-blind placebo-controlled trial. Ketanserin significantly reduced supine and erect blood pressure compared to double-blind placebo, while no changes in heart rate were seen. When the blood pressure was assessed during 24 h at steady state conditions, the blood pressure reduction was maximal 1-2 h after tablet intake, corresponding to peak plasma concentrations of ketanserin. The blood pressure remained significantly reduced until next tablet intake (12 h). At steady state, on a 40 mg twice daily regimen, Css was 41.6 +/- 4.22, 36.9 +/- 5.19 and 39.8 +/- 4.81 ng/ml, Cmax 102.4 +/- 15.64 ng/ml and tmax 1.6 +/- 0.32 h. A slight sedation was observed in six patients. This side effect occurred 1-2 h after tablet intake and tended to subside with continued treatment.


Bovine leptospirosis: Prevalence, associated risk factors for infection and their cause-effect relation.
Leptospirosis is a cosmopolitan infectious disease that causes severe reproductive disorders in cattle, especially those related to abortion. This disease has rodents as main reservoirs; however, cattle are responsible for maintenance of the disease. Thus, the aim of this study was to identify the factors associated with infection and cause-effect relation of leptospirosis in dairy herds from Southern of Brazil. Serum samples of 1242 cows were collected from herds classified as of medium and high density, and tested by microscopic agglutination test (MAT). These farms were located in the West part of Santa Catarina State (Brazil). A total of 80 cows (6.44%) were considered positives for the infection with titration of 1:100. Using a multivariate analysis, we identified two factors associated to bovine leptospirosis: dog access to pastures (p < 0.001) and feed exposure to rodents (p = 0.05). Cause-effect analysis demonstrated that the occurrence of reproductive disorders was significantly (p = 0.01) linked to leptospirosis. Thus, we conclude that leptospirosis is prevalent in dairy cattle in the west part of Santa Catarina state, as well as the access of dogs to pastures and contact of rodents with feed increase the chance of cattle infection by Leptospira spp.


Time-series transcriptome comparison reveals the gene regulation network under salt stress in soybean (Glycine max) roots.
Soil salinity is a primary factor limiting soybean (Glycine max) productivity. Breeding soybean for tolerance to high salt conditions is therefore critical for increasing yield. To explore the molecular mechanism of soybean responses to salt stress, we performed a comparative transcriptome time-series analysis of root samples collected from two soybean cultivars with contrasting salt sensitivity. The salt-tolerant cultivar 'Qi Huang No.34' (QH34) showed more differential expression of genes than the salt-sensitive cultivar 'Dong Nong No.50' (DN50). We identified 17,477 genes responsive to salt stress, of which 6644 exhibited distinct expression differences between the two soybean cultivars. We constructed the corresponding co-expression network and performed Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The results suggested that phytohormone signaling, oxidoreduction, phenylpropanoid biosynthesis, the mitogen-activated protein kinase pathway and ribosome metabolism may play crucial roles in response to salt stress. Our comparative analysis offers a comprehensive understanding of the genes involved in responding to salt stress and maintaining cell homeostasis in soybean. The regulatory gene networks constructed here also provide valuable molecular resources for future functional studies and breeding of soybean with improved tolerance to salinity.


Clinical and operative findings of choledochal cysts in neonates and infants differ from those in older children.
Significant differences in the clinical and pathological presentation of choledochal cysts between infants and older children have been noted. We developed a new management strategy according to these differences. Between 1990 and 2001, we managed 34 cases of type I choledochal cyst. Nineteen patients were more than 1 year old. Fifteen patients underwent surgery before the age of 1 year, and eight before the age of 2 months. One patient was diagnosed prenatally. All patients underwent choledochal cyst excision and hepaticojejunostomy. Symptoms and signs, and findings from physical examination, laboratory tests, and pathology were recorded and analysed. Follow-up periods ranged from 6 months to 11 years. Eight cases who were less than 1 year old suffered from painless jaundice, and choledochal cysts in this group usually ended as a blind pouch. Their cystic amylase and lipase concentrations were within normal limits. Biliary cirrhosis was diagnosed by liver biopsy in three of these patients. In contrast, 17 of the 19 patients who were more than 1 year old had abdominal pain, and 15 of their cysts were connected to the pancreatic duct. Cystic amylase and lipase concentrations were often elevated. All patients had an excellent outcome. Diseases with different pathogeneses may cause different clinical manifestations and pathology of choledochal cysts in infants and older children. Some patients develop biliary cirrhosis in the early months of life. Our findings show that it is safe and imperative to treat neonates and infants with choledochal cysts as soon as possible, as delayed surgery may cause severe complications.


Reproductive health challenges of male and female street beggars and use of reproductive health services by female street beggars in Ife-Ijesa, Nigeria.
The aims of the study were to investigate the reproductive health challenges in Nigeria of male and female street beggars and the use of reproductive health services by female street beggars. The study had a cross-sectional descriptive design. An interviewer-administered questionnaire, designed by the authors, was used to elicit information from 100 male and female street beggars recruited over a 4 week period in Ife-Ijesa zone, south-western Nigeria. Information was obtained about male and female participants' reproductive health challenges (symptoms and issues) and female participants' use of reproductive health services. More than a third of participants were aged ≥60 years (37%), 57% were men, 82% were from the Hausa tribe and 92% were Muslims. The main reasons given for street begging were poverty (30%) and physical handicap (66%). Although most of the street beggars were aware of the availability of reproductive health services (81%) and where to access them (89%), only a small proportion of female street beggars had given birth in hospital (9.3%) and family planning services (32.6%). Street beggars are a poor and vulnerable group with reproductive health challenges. They have difficulty accessing reproductive health services because of physical disabilities and related low socioeconomic status.


Therapeutic Efficacy of a New Procedure for Male Urinary Incontinence Combining a Suburethral Polypropylene Mesh and Cardiovascular Patch.
Stress urinary incontinence (SUI) in men is a complication secondary to prostatectomy or resulting from neurological lesions. This study presents our experiences with male suburethral slings over the past decade. In this study, we considered patients who presented with SUI and were diagnosed with an intrinsic sphincteric deficiency due to postprostatectomy incontinence (PPI) or other causes (non-PPI). Patients who underwent the suburethral sling procedure using a polypropylene mesh and a cardiovascular patch were retrospectively included. An urodynamic study was performed before and after the operation. Global response assessment (GRA) and SUI grading were used for surgical outcome. The revision rate and the infection rate were also evaluated. A total 31 patients were enrolled in this study; the mean patient age was 59.5±18.9 years, and the mean follow-up period was 36.9±29.4 months. Fourteen patients comprised the non-PPI group and 17 were in the PPI group. The preoperative SUI of all patients were categorized as a moderate to severe problem according to the SUI grade, with a mean score of 2.32±0.48 before the operation and 0.48±0.57 after the operation. With a mean score of 2.35±0.71, GRA showed that the patients were satisfied with the treatment. After the sling procedure, 4 patients (13%) reported a mild improvement, 12 (38.7%) a moderate improvement, while 15 (48.4%) reported an excellent improvement. Six patients (19.4%), including 5 from the non-PPI group (35.7%) and 1 (5.9%) from the PPI group (P=0.037), underwent sling removal because of infection. The male suburethral sling procedure using a polypropylene mesh and a cardiovascular patch is a safe, efficacious, and inexpensive surgical procedure for PPI. In cases of neurological incontinence, however, the higher infection rate in non-PPI patients means that they should be carefully managed.


A new theta-type thermosensitive replicon from Lactococcus lactis as an integration vector for Enterococcus faecalis.
We isolated a replication thermosensitive mutant of the theta-type lactococcal pUCL22 replicon. An improved version of this thermosensitive replicon was obtained by fusioning the replication repA gene with the downstream repB gene. The resulting plasmid was named pUCB3522Ts. It is highly instable at 42 degrees C in Enterococcus faecalis. Integration into the chromosome via homologous recombination was monitored using the npr gene of E. faecalis JH2-2 as a target. A 513 bp PCR amplification product from an internal region of this npr gene was cloned into pUCB3522Ts. Integration of this construction into the JH2-2 npr gene was selected by shift temperature, from 30 degrees C to 42 degrees C. 85% of the analysed clones showed integration into the npr gene, demonstrating the practicality of this thermosensitive replicon as a genetic integrative tool for E. faecalis.


High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.
For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.


Achievements in workplace neutron dosimetry in the last decade: lessons learned from the EVIDOS project.
The availability of active neutron personal dosemeters has made real time monitoring of neutron doses possible. This has obvious benefits, but is only of any real assistance if the dose assessments made are of sufficient accuracy and reliability. Preliminary assessments of the performance of active neutron dosemeters can be made in calibration facilities, but these can never replicate the conditions under which the dosemeter is used in the workplace. Consequently, it is necessary to assess their performance in the workplace, which requires the field in the workplace to be fully characterised in terms of the energy and direction dependence of the fluence. This paper presents an overview of developments in workplace neutron dosimetry but concentrates on the outcomes of the EVIDOS project, which has made significant advances in the characterisation of workplace fields and the analysis of dosemeter responses in those fields.


Towards stimulated Raman scattering spectro-microscopy across the entire Raman active region using a multiple-plate continuum.
Stimulated Raman scattering (SRS) has attracted increasing attention in bio-imaging because of the ability toward background-free molecular-specific acquisitions without fluorescence labeling. Nevertheless, the corresponding sensitivity and specificity remain far behind those of fluorescence techniques. Here, we demonstrate SRS spectro-microscopy driven by a multiple-plate continuum (MPC), whose octave-spanning bandwidth (600-1300 nm) and high spectral energy density (∼1 nJ/cm-1) enable spectroscopic interrogation across the entire Raman active region (0-4000 cm-1), SRS imaging of a Drosophila brain, and electronic pre-resonance (EPR) detection of a fluorescent dye. We envision that utilizing MPC light source will substantially enhance the sensitivity and specificity of SRS by implementing EPR mode and spectral multiplexing via accessing three or more coherent wavelengths.


Effects of Cisplatin-Loaded Niosomal Nanoparticleson BT-20 Human Breast Carcinoma Cells
Breast cancer is the fifth most common cause of death among women worldwide. Resistance to cisplatin is a main challenge in its treatment. Our present aim was to prepare nanoniosomated cisplatin and examine its efficacy in vitro using the BT-20 cell line. Niosome nanoparticles containing cisplatin were prepared by reverse-phase evaporation and characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), spectrophotometry and MTT assay. The size and zeta potential of the nanodrug were estimated as 489.3 ± 23.66 nm and 23.4 ± 2.1 mV, respectively. Drug encapsuies confirmed appropriate retention of particles. Nanoparticles also increased the cytotoxic effects of cisplatin by 1.5 times compared to the standard drug. Findings of our study suggest that niosome nanoparticles are good carriers for cisplatin delivery to breast cancer cells.


Magnetic structures and physical properties of Tm3Cu4Ge4 and Tm3Cu4Sn4.
Tm(3)Cu(4)Ge(4) crystallizes in the orthorhombic Gd(3)Cu(4)Ge(4)-type crystal structure (space group Immm) whereas Tm(3)Cu(4)Sn(4) crystallizes in a distorted variant of this structure (monoclinic space group C2/m). The compounds were studied by means of neutron diffraction, specific heat, electrical resistivity and magnetic measurements. Analysis of experimental data revealed the presence of an antiferromagnetic order below 2.8 K in both compounds. In Tm(3)Cu(4)Ge(4) the magnetic unit cell is doubled in respect to the crystal unit cell and the magnetic structure can be described by a propagation vector k = [0, 1/2, 0]. A larger magnetic unit cell was found in Tm(3)Cu(4)Sn(4), given by a propagation vector k = [1/2, 1/2, 0] (for simplicity the orthorhombic description is used for both the germanide and the stannide). Close to 2 K, in each compound an incommensurate antiferromagnetic order develops. This low-temperature magnetic phase is characterized by a propagation vector k = [1/4, 0, k(z)], where k(z) is close to 0.49 and 0.47 in Tm(3)Cu(4)Ge(4) and Tm(3)Cu(4)Sn(4), respectively. The antiferromagnetic phase transitions are clearly seen in the bulk magnetic and specific heat data of both compounds.


Osmotic pressure: resisting or promoting DNA ejection from phage?
Recent in vitro experiments have shown that DNA ejection from bacteriophage can be partially stopped by surrounding osmotic pressure when ejected DNA is digested by DNase I in the course of ejection. In this work, we argue by a combination of experimental techniques (osmotic suppression without DNase I monitored by UV absorbance, pulse-field electrophoresis, and cryo-transmission electron microscopy visualization) and simple scaling modeling that intact genome (i.e., undigested) ejection in a crowded environment is, on the contrary, enhanced or eventually complete with the help of a pulling force resulting from DNA condensation induced by the osmotic stress itself. This demonstrates that in vivo, the osmotically stressed cell cytoplasm will promote phage DNA ejection rather than resist it. The further addition of DNA-binding proteins under crowding conditions is shown to enhance the extent of ejection. We also found some optimal crowding conditions for which DNA content remaining in the capsid upon ejection is maximum, which correlates well with the optimal conditions of maximum DNA packaging efficiency into viral capsids observed almost 20 years ago. Biological consequences of this finding are discussed.


Thyroid disease in patients with idiopathic thrombocytopenia: a cohort study.
To estimate the prevalence of the association between thyroid disease and idiopathic thrombocytopenia (ITP), and to examine the effect of treatment of the thyroid condition on platelet count. Retrospective cohort study performed in a tertiary care center setting. All patients who were diagnosed with ITP by a single provider at the Cleveland Clinic Hematology/Oncology Department between 1988 and 2005 were included. Among the 98 patients, thyroid function tests were available in 80 patients. Of these, 16 (20%) had abnormal thyroid function: 6 had hyperthyroidism and 10 had hypothyroidism. The median interval from the onset of the thyroid or hematological condition (whichever came first) was 84 months (range: 25-612). The autoimmune nature of the thyroid disease was proven in 12 cases (75%). Three patients showed a transient increase in the platelet count after restoring the euthyroid state; however, durable improvement of thrombocytopenia was not encountered. The prevalence of hypothyroidism in patients with ITP is higher than in the general population. Based on this observation, routine assessment of thyroid function should be done in patients with ITP. The long-term course of ITP was not influenced by the treatment of the thyroid condition.


[Fibronectins (review)].
The most important studies on fibronectins (FN) carried out within the recent 5-7 years are reviewed. The FN localization in cells and tissues is considered and various functions of FN are discussed. Characterization of chemical structure, physical parameters and properties of the glycoprotein are briefly considered. Complex-formation ability of FN is discussed.


Purification and partial characterization of a cellular inhibitor of the interferon-induced protein kinase of Mr 68,000 from influenza virus-infected cells.
A number of eukaryotic viruses have evolved mechanisms to downregulate activity of the interferon-induced, double-stranded RNA-activated protein kinase (referred to as P68 based on its Mr of 68,000 in human cells). This control is essential because once activated, the P68 kinase phosphorylates its natural substrate, the alpha subunit of the eukaryotic protein synthesis initiation factor 2 (eIF-2), limiting functional eukaryotic protein synthesis initiation factor 2 available for protein synthesis initiation. We have previously shown that influenza virus encoded a specific mechanism to repress the autophosphorylation and activity of P68. Using in vitro assays for P68 inhibition, we now have purified, to near homogeneity, the P68 repressor from influenza virus-infected cells. The purified product inhibited both the autophosphorylation of P68 as well as phosphorylation of the alpha subunit of eukaryotic protein synthesis initiation factor 2 by the kinase. We tested for both protease and phosphatase activity but found neither activity associated with the purified inhibitor. Surprisingly we found the purified repressor, which had an apparent Mr of approximately 58,000, was a cellular and not a viral-encoded protein. Possible mechanisms by which influenza virus activates this cellular regulator of the protein kinase, thereby minimizing potential antiviral effects of interferon, are discussed.


Caregivers' Perspectives on the Impact of Cannabidiol (CBD) Treatment for Dravet and Lennox-Gastaut Syndromes: A Multinational Qualitative Study.
To increase understanding of the impact of cannabidiol (CBD) on outcomes beyond seizure control among individuals with Dravet syndrome or Lennox-Gastaut syndrome. Qualitative interviews were conducted with caregivers of individuals with Dravet syndrome or Lennox-Gastaut syndrome treated with plant-derived, highly purified CBD medicine (Epidiolex in the USA; Epidyolex in Europe; 100 mg/mL oral solution). Symptoms and impacts of Dravet syndrome and Lennox-Gastaut syndrome on individuals were explored, as were the effects of CBD. Data were analyzed using thematic analysis. Twenty-one caregivers of individuals with Dravet syndrome (n = 14) and Lennox-Gastaut syndrome (n = 7) aged 4-22 years participated. Health-related quality of life improvements associated with CBD included cognitive function, communication, behavior, mobility, and participation in daily activities. Seizure frequency reduction was commonly reported (n = 12), resulting in caregivers having greater freedom and family life being less disrupted. Adverse events were reported by 10 caregivers. In addition to reduced seizure frequency, CBD may have a wide range of beneficial effects beyond seizure control that warrant further investigation.


Nucleosome core particles of calf thymus, Tetrahymena, and the reconstituted hybrid. Their structure reflects the nature of the histone octamer.
The circular dichroism spectra and the thermal denaturation profiles of the nucleosome core particles isolated by micrococcal nuclease digestion from nuclei of calf thymus and the protozoan Tetrahymena pyriformis were compared with those of the homogeneous and hybrid core particles reconstituted from calf core DNA and either calf or Tetrahymena histone octamer. The core DNA was obtained from the calf core particle, and both the histone octamers were reconstituted from the acid-extracted four core histones of calf thymus or Tetrahymena, whose amino acid sequences show the largest differences hitherto known. The reconstituted homogeneous core particle was identical in both the physical properties with the isolated calf core particle, showing that the correct reconstitution was achieved. The circular dichroism spectra of the calf and Tetrahymena core particles and the hybrid core particle showed no essential differences, indicating that the three core particles have the same overall structure. The derivative thermal-denaturation profiles, however, clearly differed; the calf core particle showed two melting transitions at 60 degrees C and 72 degrees C, while the Tetrahymena and hybrid core particles showed the same three transitions at 48-50 degrees C, 60-61 degrees C, and 72 degrees C. Thus, the thermal denaturation properties of nucleosome core particles do not reflect the nature of DNA, but rather that of the histone octamer bound to the DNA. We conclude that the Tetrahymena histones are more weakly bound to the DNA than the calf thymus histones in the same overall structure of nucleosomes.


Co-incident insertion enables high efficiency genome engineering in mouse embryonic stem cells.
CRISPR/Cas9 nucleases have enabled powerful, new genome editing capabilities; however, the preponderance of non-homologous end joining (NHEJ) mediated repair events over homology directed repair (HDR) in most cell types limits the ability to engineer precise changes in mammalian genomes. Here, we increase the efficiency of isolating precise HDR-mediated events in mouse embryonic stem (ES) cells by more than 20-fold through the use of co-incidental insertion (COIN) of independent donor DNA sequences. Analysis of on:off-target frequencies at the Lef1 gene revealed that bi-allelic insertion of a PGK-Neo cassette occurred more frequently than expected. Using various selection cassettes targeting multiple loci, we show that the insertion of a selectable marker at one control site frequently coincided with an insertion at an unlinked, independently targeted site, suggesting enrichment of a sub-population of HDR-proficient cells. When individual cell events were tracked using flow cytometry and fluorescent protein markers, individual cells frequently performed either a homology-dependent insertion event or a homology-independent event, but rarely both types of insertions in a single cell. Thus, when HDR-dependent selection donors are used, COIN enriches for HDR-proficient cells among heterogeneous cell populations. When combined with a self-excising selection cassette, COIN provides highly efficient and scarless genome editing.


Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets.
Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. To identify genetic alterations with potential clinical implications in NMIBC. Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p<0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio=3.14, 95% confidence interval: 1.51-6.51, p=0.002). Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests.


Transition in the dynamics of a diffusive running sandpile.
A running sandpile is shown to undergo a dynamical transition as diffusion is increased from zero. The transition takes place after the local diffusion has become so large as to erase the local inhomogeneities, caused by the intermittent rain of sand, before they can trigger avalanche activity. The system then undergoes an abrupt change with the self-similar structure of the dynamics being replaced with quasiperiodic, near system-size transport events. These results may have significant implications for many of the driven physical systems for which self-organized criticality based dynamical models have been proposed.


Surveillance of congenital rubella and the immunity status to rubella in the Jerusalem area.
A retrospective study on the incidence of congenital rubella (CR) in the past 10 years in the Jerusalem area was conducted. After the 1972 epidemic, which resulted in 48 cases of congenital rubella, few sporadic cases of CR appeared each year, and in the 1978-79 period the number of CR cases was relatively small. Immunity to rubella in different categories of population (children 3 months to 18 years, college students, nurses in pediatric, newborn and intensive care units, student nurses, and women of childbearing age) was determined by hemolysis in gel (HIG) and hemagglutination inhibition (HI) methods. Susceptibility was defined as an absence of antibody at a dilution of 1:16 in HI, and hemolysis of less than 7 mm in the HIG test. Compared with previous studies on the incidence of antibodies to rubella in women of childbearing age, a mild decrease in the percentage of sero-negative women was found.


The occurrence and allergising potential of airborne pollen in West Bengal, India.
A continuous 2-year volumetric aerobiological survey was conducted in Berhampore town, a centrally located and representative part of West Bengal, India. The aim of the study was to assess the allergising potential of airborne pollen grains of West Bengal. A total of 31 pollen types were identified of which Poaceae (grasses) pollen showed maximum frequency, followed by Cyperaceae, Cassia sp., Acacia auriculiformis, etc. The seasonal periodicities of the pollen types and their relationship to meteorological conditions were investigated. It was found that the pollen concentration is positively correlated with temperature and negatively correlated with rainfall and relative humidity. Clinical investigations by skin prick test were carried out to detect allergenicity of pollen types. Eighteen common airborne pollen types induced positive responses of which pollen extracts of Saccharum officinarum (grass), Azadirachta indica, Cocos nucifera, Phoenix sylvestris, Cyperus rotundus and Eucalyptus citriodora showed strongest sensitising potential. This result is consistent with previous investigations in different parts of West Bengal.


Unraveling genes and pathways influenced by H-prune PDE overexpression: a model to study cellular motility.
H-prune, a new cyclic nucleotide phosphodiesterase, binds to nm23-H1, a metastasis suppressor protein. The overexpression of h-prune in the MDA-MB-435 breast carcinoma cell line causes a substantial decrease of cAMP, and an increase in cellular motility. This latest effect is correlated both to the h-prune phosphodiesterase activity and to the interaction between h-prune and nm23-H1 proteins. Understanding the molecular changes in tumor cells with an increased level of expression of h-prune might shed light on motility processes, which are the driving forces of the cells to move away from the primary tumor and to become metastatic. This report overview genes and pathways influenced by h-prune overexpression in a conventional breast cancer cellular model.


Hand Perfusion in Patients with Physiological or Pathological Allen's Tests.
The Allen test (AT) is a widely used clinical tool for the preoperative assessment of sufficient dual vessel hand perfusion although the impact of a pathological AT on tissue perfusion of the hand is not entirely clear. This study reveals perfusion changes of the hand in patients with pathological and physiological AT after terminating the dual blood supply. Patients were distributed into 2 groups (physiological and pathological AT) that each contained 25 members. Perfusion of the thumb, middle, and small fingers was measured with a laser Doppler based ("oxygen-to-see" [O2C]) device. A steady state was measured and also values at 1, 3, 5, and 10 minutes after radial occlusion were measured. In patients with a physiological AT, only 1 out of 18 values differed significantly from the steady state measurements after 10 minutes, whereas patients with a pathological AT showed significant alterations in 8 out of 18 values. Oxygen saturation of the superficial and deep tissues appeared to be significantly worse in patients with a pathological AT. Patients with a pathological AT suffered significantly more from the loss of dual hand perfusion than patients with a physiological AT. Patients with a pathological AT need more time to compensate for the altered perfusion pattern.


Hydrothermal Synthesis of a Magnesium Vanadate-Functionalized Reduced Graphene Oxide Nanocomposite for an Efficient Photocatalytic Hydrogen Production.
Herein, we reported the fabrication of a magnesium vanadate-reduced graphene oxide (Mg3V2O8-rGO) composite. Further, the structural morphology of the as-prepared Mg3V2O8-rGO composite was studied by scanning electron microscopy. Powder X-ray diffraction and energy-dispersive X-ray spectroscopy techniques were also adopted to check the phase purity and elemental composition of the prepared Mg3V2O8-rGO composite. Mg3V2O8-rGO possesses a band gap of 2.98 eV, which prompted us to explore its photocatalytic activity for hydrogen (H2) evolution reaction. The Mg3V2O8-rGO composite demonstrated the generation of a reasonable amount of H2 evolution (97.45 μmol g-1), which is relatively higher than that of pristine Mg3V2O8 (17.45 μmol g-1). This may be attributed to the presence of synergism between Mg3V2O8 and rGO. In addition, Mg3V2O8-rGO also showed good stability and suggested its potential application for photocatalytic H2 evolution applications. So far, no report is available on the use of Mg3V2O8-rGO as a photocatalyst for H2 evolution. We propose the potential role of the Mg3V2O8-rGO composite for photocatalytic H2 evolution applications.


Emerging role of miRNA in prostate cancer: A future era of diagnostic and therapeutics.
Prostate cancer (PCa) is the most common cancer in men (20%) and is responsible for 6.8% (1/5) of all cancer-related deaths in men around the world. The development and spread of prostate cancer are driven by a wide variety of genomic changes and extensive epigenetic events. Because of this, the MicroRNA (miRNA) and associated molecular mechanisms involved in PCa genesis and aggressive were only partially identified until today. The miRNAs are a newly discovered category of regulatorsthat have recently been recognized to have a significant role in regulating numerous elements of cancer mechanisms, such as proliferation, differentiation, metabolism, and apoptosis. The miRNAs are a type of small (22-24 nucleotides), non-coding, endogenous, single-stranded RNA and work as potent gene regulators. Various types of cancer, including PCa, have found evidence that miRNA genes, which are often located in cancer-related genetic regions or fragile locations, have a role in the primary steps of tumorigenesis, either as oncogenes or tumorsuppressors. To explain the link between miRNAs and their function in the initiation and advancement of PCa, we conducted a preliminary assessment. The purpose of this research was to enhance our understanding of the connection between miRNA expression profiles and PCa by elucidating the fundamental processes of miRNA expression and the target genes.


Impact of glycogen synthase kinase-3ß inhibition on rats' temporomandibular joint collagen-induced rheumatoid arthritis with correlation to miRNA-155/miRNA-24 expression.
The current study considered assessing the role of miRNA-155 and miRNA-24 in collagen-induced rheumatoid arthritis (RA) in rats' temporomandibular joint (TMJ). Their role in histological aggressiveness of the disease and therapy response to glycogen synthase kinase (GSK) inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) will be studied. Rats were randomly distributed to four groups (8 rats/group): group I negative control, group II collagen-induced rheumatoid arthritis (CIA), group III Control+TDZD-8 treated group, and group IV CIA+TDZD-8 treated group. Then were euthanized 42 days after the start of the experiment. H&E staining, Masson trichrome staining, and immunohistochemical antibodies against S100 were performed. qRT-PCR of miRNA-155 and miRNA-24 were done for frozen synovial tissues. Histological analysis showed that the most affected structure in induced rheumatoid arthritis of TMJ is the articular disc, condylar head, and subchondral bone. Combined treatment with TDZD-8 improved histological status in the joint. Masson's trichrome (MTC) histochemical staining revealed disarrangement of collagen fibers and adherence between the articular disc and condylar cartilage. Meanwhile, the morphology and collagen composition of the disc and condyle in CIA+ TDZD-8 were similar to those of healthy tissues. Immunohistochemical analysis for S100A4 revealed increased immunoreactivity staining in the CIA group. The immunoreactivity was significantly decreased in CIA+ TDZD-8 treated group. TDZD-8 significantly decreased the levels of miRNA-155 and miRNA-24 in synovial tissue. Our results reveal for the first-time correlation of miRNA-155 and miRNA-24 that might be implicated in the onset of TMJ RA. Consequently, the treatment of CIA with GSK inhibitor (TDZD-8) yields encouraging results. We predicted the TDZD-8 might protect against CIA by suppressing miRNA-155, miRNA-24, and S100A4 protein levels.


2-Aryl and 2-heteroaryl indoles from 1-alkynes and o-iodotrifluoroacetanilide through a domino copper-catalyzed coupling-cyclization process.
[reaction: see text] A general method for the synthesis of 2-aryl and 2-heteroaryl indoles from aryl iodides and 1-alkynes through a domino copper-catalyzed process is reported. The best results have been obtained with [Cu(phen)(PPh(3))(2)]NO(3) in the presence of K(3)PO(4) in toluene or dioxane at 110 degrees C. 2-Aryl and 2-heteroaryl indoles can also be isolated in good yields by using catalysts derived from CuI and PPh(3) in dioxane at 110 degrees C.


Pretreatment method for hypochlorite decon water before GC analysis of HD, VX, and GD.
Active chlorine decontaminants like hypochlorite are used to destroy chemical warfare agents (CWAs) such as HD, VX and GD due to the former's strong oxidation capacity and high nucleophilicity. In this paper, experiments were performed to identify the main factors affecting agent recovery from decon water. Based on the results, a method to recover residual CWAs from hypochlorite decon water before quantitative determination by GC was developed. The results showed that the extraction solvent was a critical determinant of high CWA recovery. Dichloromethane was more suitable than petroleum either, especially for samples containing GD or low residual CWAs. For VX-containing samples, the use of an alkali solution improved VX recovery. Neutralization was also important for a high CWA recovery, especially for samples with low CWA concentrations and/or strong decontaminant reactivity. The use of 15% sodium sulfite as the neutralization solution gave the best results for hypochlorite decon water. When the optimized conditions of simultaneous sodium sulfite neutralization and dichloromethane extraction were used, the recovery of HD, VX and GD in hypochlorite decon water was greater than 85% at a concentration range of 20 mg/L to 10,000 mg/L.


Endothelial changes of hypertensive rat mesenteric arteries.
The mesenteric arteries of hypertensive rats with bilaterally constricted renal arteries were observed by light, scanning electron and transmission electron microscopy. In the early stage of hypertensive arterial lesions, many leukocytes adhered to the endothelial surface, and large or small and polygonal endothelial cells were irregularly arranged. Sporadically brightened and atrophied endothelial cells were distributed on the injured surface. These atrophied cells were transmission electron microscopically confirmed to have undergone coagulation necrosis. In the surrounding of the atrophied cells were observed opened endothelial cell junctions and enlarged intercellular spaces to which many leukocytes and platelets adhered. Because of loosening of connection with neighboring cells, atrophied endothelial cells became solitary or being denuded. Opened endothelial cell junctions were also observed between the uninjured endothelial cells as well as in areas penetrated by leukocytic pseudopods. Where light microscopy disclosed the deposition of a large amount of fibrinoid substance in the intima and media, scanning electron microscopy showed opened endothelial cell junctions and denudation of endothelial cells. From the results of the present experimental study, it was suggested that in the genesis of the hypertensive rat arterial lesions, the degeneration, necrosis and denudation of endothelial cells, opened endothelial cell junctions between these cells, and insudation of blood plasma through the opened junctions or denuded areas might play important roles.


Genetic Susceptibility to Multiple Sclerosis: The Role of FOXP3 Gene Polymorphism.
It is well recognized that both genetic and environmental factors play an important role in the pathogenesis of multiple sclerosis (MS). Immune pathogenesis of MS focuses on pathogenic CD4+ T lymphocytes. CD4+CD25+ regulatory T cells have suppressive function in this cell group. FOXP3 (forkhead boxP3) transcription factor is a key structure in the development and function of regulatory cells. Functional alterations in FOXP3 gene expression have been observed in various autoimmune diseases. We screened a non-synonymous coding single nucleotide polymorphism (exon +2710 C/T) (rs2232369) of human FOXP3 gene in 148 MS patients (118 with Relapsing Remitting MS, 30 with Secondary Progressive MS) and 102 age- and sex-matched healthy controls. The association of polymorphisms with susceptibility, and course of the disease was evaluated. We could not detect any single nucleotide polymorphism in MS patients, however, polymorphic allele was detected in 3% of the control group. Consequently, a genetic association between the FOXP3 gene polymorphism and MS was not revealed. The distribution of this polymorphism has not been screened in any other MS populations before. Although we could not succeed to find any association between susceptibility to MS and screened FOXP3 gene polymorphisms, we suggest that this particular polymorphism is not appropriate for these kind of studies in the future.


Implementing 'self-help friendliness' in German hospitals: a longitudinal study.
In Germany, the term 'self-help friendliness' (SHF) describes a strategy to institutionalize co-operation of healthcare institutions with mutual aid or self-help groups of chronically ill patients. After a short explanation of the SHF concept and its development, we will present findings from a longitudinal study on the implementation of SHF in three German hospitals. Specifically, we wanted to know (i) to what degree SHF had been put into practice after the initial development phase in the pilot hospitals, (ii) whether it was possible to maintain the level of implementation of SHF in the course of at least 1 year and (iii) which opinions exist about the inclusion of SHF criteria in quality management systems. With only minor restrictions, the findings provide support for the usefulness, practicability, sustainability and transferability of SHF. Limitations of our empirical study are the small number of hospitals, the above average motivation of their staff, the small response rate in the staff-survey and the inability to get enough data from members of self-help groups. The research instrument for measuring SHF was adequate and fulfils the most important scientific quality criteria in a German context. We conclude that the implementation of SHF leads to more patient-centredness in healthcare institutions and thus improves satisfaction, self-management, coping and health literacy of patients. SHF is considered as an adequate approach for reorienting healthcare institutions in the sense of the Ottawa Charta, and particularly suitable for health promoting hospitals.


Spatial patterns of plastic debris along Estuarine shorelines.
The human population generates vast quantities of waste material. Macro (>1 mm) and microscopic (<1 mm) fragments of plastic debris represent a substantial contamination problem. Here, we test hypotheses about the influence of wind and depositional regime on spatial patterns of micro- and macro-plastic debris within the Tamar Estuary, UK. Debris was identified to the type of polymer using Fourier-transform infrared spectroscopy (FT-IR) and categorized according to density. In terms of abundance, microplastic accounted for 65% of debris recorded and mainly comprised polyvinylchloride, polyester, and polyamide. Generally, there were greater quantities of plastic at downwind sites. For macroplastic, there were clear patterns of distribution for less dense items, while for microplastic debris, clear patterns were for denser material. Small particles of sediment and plastic are both likely to settle slowly from the water-column and are likely to be transported by the flow of water and be deposited in areas where the movements of water are slower. There was, however, no relationship between the abundance of microplastic and the proportion of clay in sediments from the strandline. These results illustrate how FT-IR spectroscopy can be used to identify the different types of plastic and in this case was used to indicate spatial patterns, demonstrating habitats that are downwind acting as potential sinks for the accumulation of debris.


[Cases of three patients undergoing chemotherapy for gastric cancer who developed Trousseau's syndrome].
Trousseau's syndrome involves unexplained thrombotic events along with malignancy. We report the cases of 3 patients undergoing chemotherapy for gastric cancer in whom Trousseau's syndrome occurred. Case 1 involved a 43-year-old woman undergoing S-1/cisplatin( CDDP) combination therapy as first-line chemotherapy for type 4 remnant gastric cancer( cT4bN2M1P1/stage IV) who experienced left hemiplegia. Cerebral hemorrhage of the right parietal lobe was diagnosed by computed tomography( CT), and thrombosis from the upper sagittal sinus to the right sinus sigmoideus was diagnosed by magnetic resonance venography( MRV). Case 2 involved a 59-year-old man undergoing S-1/irinotecan (CPT-11) combination therapy as second-line chemotherapy for type 3 gastric cancer( cT3N1M0H1/stage IV) who experienced ataxic, stuttering, and left membrum inferius paralysis. Multiple cerebral infarction of the right parietal lobe was diagnosed by magnetic resonance imaging (MRI). Case 3 involved a 67-year-old woman undergoing S-1/CDDP combination therapy as preoperative chemotherapy for type 3 gastric cancer( cT4aN1M0/stage IIIA) who experienced right cerebellum incontinentia, nystagmus, and right facioplegia. Multiple cerebral infarction of the right cerebellum and pedunculus cerebellaris medius was diagnosed by MRI. An anticoagulant was administered orally for stroke, and chemotherapy for gastric cancer was resumed after activities of daily living( ADL) improved in all 3 patients. Recurrent stroke was not diagnosed in any of the 3 patients. Patients with malignancy often exhibit hypercoagulability associated with cancer. Accordingly, periodic blood tests for coagulation should be performed and dehydration should be prevented to prevent strokes in cancer patients.


Design of Phosphonated Imidazolium-Based Ionic Liquids Grafted on γ-Alumina: Potential Model for Hybrid Membranes.
Imidazolium bromide-based ionic liquids bearing phosphonyl groups on the cationic part were synthesized and grafted on γ-alumina (γ-Al₂O₃) powders. These powders were prepared as companion samples of conventional mesoporous γ-alumina membranes, in order to favor a possible transfer of the results to supported membrane materials, which could be used for CO₂ separation applications. Effective grafting was demonstrated using energy dispersive X-ray spectrometry (EDX), N₂ adsorption measurements, fourier transform infrared spectroscopy (FTIR), and special attention was paid to (31)P and (13)C solid state nuclear magnetic resonance spectroscopy (NMR).


Trace element fluxes during the "Anthropocene" in a large South American industrial and port area (Santos and São Vicente estuarine system, SE, Brazil).
The worldwide evidence of human activities on the environment led the scientific community to recognize a new geologic time unit known as the "Anthropocene." Since the twentieth century, urbanization and industrialization needs driven by population and economic growth have impacted several ecosystems including the estuaries. To assess the contamination, provenance, and fluxes of trace elements (As, Cr, Cu, Ni, Pb, Sc, V, and Zn) over the last century, a geochemical and chemometric technique was employed in sediment cores of an industrial and port region of international importance, the Santos and São Vicente Estuarine System (SSVES). The results indicated low contamination, with the highest enrichment factors (EFs) for Cu (EF = 3.1), Pb (EF = 2.7), Zn (EF = 2.4), and As (EF = 2.3) found next to the harbor area. The Pre-industrial records confirm the relatively high concentrations of As and its naturally enriched occurrence on the Brazilian shelf. Sediment accumulation rates and trace element fluxes showed a general increase over the years, since the early 1960s, associated with the "Great Acceleration" of the mid-twentieth century. These alterations are human-induced and include urbanization and industrialization. Nonetheless, as the contents and enrichment of trace elements indicate that the region is not severely polluted, we hypothesize that the contamination in the SSVES is likely related to the drainage and erosion of the urbanized adjacent area, rather than direct disposal of inorganic contaminants from the industrial activity.


The use of remote monitoring of cardiac implantable devices during the COVID-19 pandemic: an EHRA physician survey.
It is unclear to what extent the COVID-19 pandemic has influenced the use of remote monitoring (RM) of cardiac implantable electronic devices (CIEDs). The present physician-based European Heart Rhythm Association (EHRA) survey aimed to assess the influence of the COVID-19 pandemic on RM of CIEDs among EHRA members and how it changed the current practice. The survey comprised 27 questions focusing on RM use before and during the pandemic. Questions focused on the impact of COVID-19 on the frequency of in-office visits, data filtering, reasons for initiating in-person visits, underutilization of RM during COVID-19, and RM reimbursement. A total of 160 participants from 28 countries completed the survey. Compared to the pre-pandemic period, there was a significant increase in the use of RM in patients with pacemakers (PMs) and implantable loop recorders (ILRs) during the COVID-19 pandemic (PM 24.2 vs. 39.9%, P = 0.002; ILRs 61.5 vs. 73.5%, P = 0.028), while there was a trend towards higher utilization of RM for cardiac resynchronization therapy-pacemaker (CRT-P) devices during the pandemic (44.5 vs. 55%, P = 0.063). The use of RM with implantable cardioverter-defibrillators (ICDs) and CRT-defibrillator (CRT-D) did not significantly change during the pandemic (ICD 65.2 vs. 69.6%, P = 0.408; CRT-D 65.2 vs. 68.8%, P = 0.513). The frequency of in-office visits was significantly lower during the pandemic (P < 0.001). Nearly two-thirds of participants (57 out of 87 respondents), established new RM connections for CIEDs implanted before the pandemic with 33.3% (n = 29) delivering RM transmitters to the patient's home address, and the remaining 32.1% (n = 28) activating RM connections during an in-office visit. The results of this survey suggest that the crisis caused by COVID-19 has led to a significant increase in the use of RM of CIEDs.


Acute abdominal pain in systemic lupus erythematosus: focus on lupus enteritis (gastrointestinal vasculitis).
To determine the causes of acute abdominal pain in systemic lupus erythematosus (SLE) and to compare the clinical and laboratory data, especially antiphospholipid antibodies and the SLE Disease Activity Index (SLEDAI), between lupus enteritis (gastrointestinal vasculitis) and acute abdominal pain without lupus enteritis in patients with SLE. A retrospective study was carried out for all patients admitted with SLE from 1993 to March 2001. The SLEDAI and laboratory data were collected at the time of diagnosis of SLE and at the time of acute abdominal pain. Lupus enteritis (gastrointestinal vasculitis) was diagnosed by clinical investigation and abdominal computed tomographic findings. Chart review identified 175 patients (20 male, 155 female) who had been admitted with SLE. Of these patients, 38 (22%) presented with acute abdominal pain. Lupus enteritis was the most common cause of acute abdominal pain. Patients were divided into three groups: group 1: lupus enteritis (n=17), group 2: acute abdominal pain without lupus enteritis (n=21), and group 3: SLE without acute abdominal pain (n=137). There was no difference in age and sex among the three groups. Antiphospholipid, anti-RNP, anti-Sm, anti-Ro, and anti-La antibodies did not differ among the three groups. There was no difference in the SLEDAI at the time of diagnosis and at the time of acute abdominal pain between groups 1 and 2. Complement, erythrocyte sedimentation rate, C reactive protein, and anti-dsDNA measured at the time of acute abdominal pain did not differ between groups 1 and 2. A drop in the white blood cell count at the time of abdominal pain was more prominent in group 1 than group 2. In lupus enteritis, the jejunum and ileum were the sites most commonly affected. Rectal involvement was rare. Even though four patients relapsed, all the patients with lupus enteritis, including those who relapsed, responded well to corticosteroid. Lupus enteritis is the most common cause of acute abdominal pain in SLE. All patients with lupus enteritis responded well to a high dose of a corticosteroid without surgical intervention. The SLEDAI and laboratory data, except leucopenia, do not correlate with the occurrence of lupus enteritis.


Hybrid Nanoparticles as Drug Carriers for Controlled Chemotherapy of Cancer.
Rapid developments in materials science and biological mechanisms have greatly boosted the research discoveries of new drug delivery systems. In the past few decades, hundreds of nanoparticle-based drug carriers have been reported almost on a daily basis, in which new materials, structures, and mechanisms are proposed and evaluated. Standing out among the drug carriers, the hybrid nanoparticle systems offer a great opportunity for the optimization and improvement of conventional chemotherapy. By combining several features of functional components, these hybrid nanoparticles have shown excellent promises of improved biosafety, biocompatibility, multifunctionality, biodegradability, and so forth. In this Personal Account, we highlight the recent research advances of some representative hybrid nanoparticles as drug delivery systems and discuss their design strategies and responsive mechanisms for controlled drug delivery.


Effect of thyroid hormone on mitochondrial properties and oxidative stress in cells from patients with mtDNA defects.
Mitochondrial (mt)DNA mutations contribute to various disease states characterized by low ATP production. In contrast, thyroid hormone [3,3',5-triiodothyronine (T(3))] induces mitochondrial biogenesis and enhances ATP generation within cells. To evaluate the role of T(3)-mediated mitochondrial biogenesis in patients with mtDNA mutations, three fibroblast cell lines with mtDNA mutations were evaluated, including two patients with Leigh's syndrome and one with hypertrophic cardiomyopathy. Compared with control cells, patient fibroblasts displayed similar levels of mitochondrial mass, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), mitochondrial transcription factor A (Tfam), and uncoupling protein 2 (UCP2) protein expression. However, patient cells exhibited a 1.6-fold elevation in ROS production, a 1.7-fold elevation in cytoplasmic Ca2+ levels, a 1.2-fold elevation in mitochondrial membrane potential, and 30% less complex V activity compared with control cells. Patient cells also displayed 20-25% reductions in both cytochrome c oxidase (COX) activity and MnSOD protein levels compared with control cells. After T(3) treatment of patient cells, ROS production was decreased by 40%, cytoplasmic Ca2+ was reduced by 20%, COX activity was increased by 1.3-fold, and ATP levels were elevated by 1.6-fold, despite the absence of a change in mitochondrial mass. There were no significant alterations in the protein expression of PGC-1alpha, Tfam, or UCP2 in either T(3)-treated patient or control cells. However, T(3) restored the mitochondrial membrane potential, complex V activity, and levels of MnSOD to normal values in patient cells and elevated MnSOD levels by 21% in control cells. These results suggest that T(3) acts to reduce cellular oxidative stress, which may help attenuate ROS-mediated damage, along with improving mitochondrial function and energy status in cells with mtDNA defects.


Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions?
To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration-time curve during the dose interval at steady state (AUCτ,ss) for glimepiride in combination with rosuvastatin than those for glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism.


G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype.
GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-α and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-α and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.


[Animal experiment studies on the damage caused by barium sulfate].
An experimental study is reported on different injections of barium sulfate into peritoneal cavity of 10 dogs and intravasal. All experimental animals died. The experiments show that barium sulfate causes not only local reaction but the most important is it's general deleterious effect. There results macro- and microembolies yet another adverse effect which is not widely appreciated. Barium sulfate medium only may be considered non toxic as long as staying in the gastrointestinal tract.


Denaturation mapping of R factor deoxyribonucleic acid.
The R factor NR1 consists of two components: a resistance transfer factor which harbors the tetracycline resistance genes (RTF-TC) and the r-determinants component which harbors the other drug resistance genes. Using partial denaturation mapping it is possible to distinguish the RTF-TC region from the r-determinants region of the composite R factor NR1 DNA which has a contour length of 37 mum and a density of 1.712 g/ml. The r-determinants region was a relatively undenatured 8.5-mum segment of the molecule when the deoxyribonucleic acid was partially denatured at pH 10.7. An RTF-TC genetic segregant of NR1 which had lost the r-determinants component had a contour length of 28.7 mum and a density of 1.710 g/ml. Characterization of an RTF-TC using partial denaturation mapping at pH 10.7 confirmed that the relatively undenatured 8.5-mum r-determinants segment of the composite R factor had been deleted. Circular, transitioned NR1 DNA molecules (1.716 to 1.718 g/ml), whose contour lengths were consistent with an RTF-TC plus an integral number of tandem copies of r-determinants, were also characterized by denaturation mapping. The relatively undenatured region in these molecules had a length equal to an integral number of copies of r-determinants and was located at the same site in the partially denatured RTF-TC as the single copy of r-determinants in the 37-mum composite NR1. This indicates that there is a unique integration site for r-determinants in the RTF-TC component. The R factor UCR122, a TC deletion mutant of NR1, was also characterized by denaturation mapping. The translocation of the TC resistance gene(s) on the denaturation map permitted the alignment of the denaturation map with the heteroduplex map of Sharp et al. (u073). Linear and circular monomeric and presumed multimeric r-determinants DNA molecules (p = 1.718 g/ml) were partially denatured at a higher pH (11.10). The r-determinants multimers showed a repeating 8.3-mum (monomeric) partial denaturation pattern indicating a head-to-tail arrangement of monomers in these poly-r-determinant molecules.


[Retinal ganglion cell layer and visual function in patients with progressive external ophthalmoplegia caused by common mtDNA deletion].
Mitochondrial (mt) disorders are metabolic conditions with multiorgan involvement, which often cause neuroophtalmological symptoms. The aim of the study was to investigate the relation between progressive external ophthalmoplegia (PEO), visual pathway and mitochondrial DNA (mtDNA) mutations in patients younger than 55 years of age. Five female patients (35 to 53 years of age) with mithochondrial disease were investigated. Automated threshold perimetry (Octopus G2 test), scanning laser polarimetry (GDx-VCC and GDx-ECC) and Fourier-domain optical coherence tomography (RTVue-100 OCT) were used in addition to detailed ophthalmological examination and evaluation of visually evoked potentials (VEP). Frequent mutations of the mtDNA were investigated in the patients' blood and muscle samples. PEO of various severity levels was found in all patients, using clinical tests. Genetic testing showed "common deletion" of mtDNA in all cases. For both eyes of 4 patients functional and structural ophthalmic tests had normal results. In one patient decreased visual acuity, reduced retinal nerve fiber layer thickness and prolonged L3 VEP latency time were found without optic disc damage and visual field deterioration. In 4 of our 5 patients with PEO due to common deletion of mtDNA retinal ganglion cells and visual function remained normal for a long period of life.


[Laryngeal disease. Endoscopic characterization of 1493 procedures based on age].
Based on international epidemiology, some laryngeal diseases could be more frequent at certain ages. The objective was to describe endoscopic findings in patients through distinct decades of age in a laryngoscopy facility. retrospective and descriptive study; clinical and endoscopic records were collected from 1493 procedures performed between 2009 and 2015, and organized in five groups of age for analysis. Differences among them were analyzed by chi squared and ANOVA. 70% of patients reported dysphonia as a main symptom; 24% of subjects were referred with cancer diagnosis and just 7% of them, showed findings related to malignancy; on the other hand, cancer suspicion increased in direct proportion with age (p < 0.0001); inespecific inflammation and other benign endoscopic manifestations (e.g. vocal fold paralysis, subglotic stenosis and nodules) represented 80% of the whole findings; 14% of the procedures were reported as normal. Glottic and supraglottic structures were the two regions affected by malignancy; this finding was directly related to advanced age, particularly in patients of 70 years of age or older. Finally, subglottic stenosis was observed in patients younger than 50 years of age (p < 0.0001). Causes of laryngeal diseases are different in individuals according to their age. Carcinoma was more prevalent in adults of 70 years of age or older. Benign causes were secondary to inflammatory and functional conditions.


Parallel compensatory and pathological events associated with tau pathology in middle aged individuals with Down syndrome.
Aged individuals with Down syndrome (DS) develop senile plaques and neurofibrillary tangles consistent with Alzheimer disease (AD). Prior to or in parallel with AD pathology, compensatory growth responses may occur. Immunohistochemistry and confocal microscopy studies in the hippocampus from 15 individuals ranging in age from 5 months to 67 years compared markers of normal and abnormal tau accumulation (phosphorylated tau [AT8, MC-1], tau-1, N-terminal tau) with the extent and location of neuronal growth marker immunoreactivity (BDNF, GAP-43, MAP-2). In middle age (30-40 years), prior to entorhinal neuron loss, the earliest tau accumulation occurred in the outer molecular layer (OML), which was consistent with both pathological and compensatory fetal tau expression. These events were followed at a later age, associated with entorhinal neuron loss, by an increase in GAP-43. Hilar neurons exhibiting a sprouting morphology were also noted. Age-dependent observations in the DS brain in the current study parallel hippocampal compensatory responses described in entorhinal cortex lesion studies in rodents. Thus, compensatory growth responses may occur in DS prior to extensive AD pathology and may be one mechanism underlying observations in PET studies of hypermetabolism in the entorhinal cortex of individuals with DS.


Low-dosage methotrexate for treatment and maintenance of remission in patients with inflammatory bowel disease.
A literature search was conducted to examine the safety and effectiveness of low-dosage methotrexate for treatment and maintenance of remission in patients with inflammatory bowel disease. Nine published articles indicated that for patients with Crohn's disease, oral or intramuscular methotrexate 20-25 mg/week is safe and effective to induce remission, followed by a lower dosage to maintain remission. In addition, methotrexate allows for corticosteroid dosage reduction. Therapy may be continued until the disease flares or adverse events occur. Evidence is insufficient to support methotrexate as treatment for ulcerative colitis.