Mapping of ventricular tachycardia induced by programmed stimulation in canine preparations of myocardial infarction.
To investigate the mechanism of uniform ventricular tachycardia induced by programmed stimulation, we recorded His bundle electrograms and unipolar electrograms from 64 subepicardial, subendocardial, and intramural sites in dogs. Isochronal maps were generated off-line by computer. Two groups of dogs were studied 3 days after occlusion of their left anterior descending coronary arteries; one group underwent reperfusion after 2 to 2.5 hr of occlusion and the other methylprednisolone treatment before permanent occlusion. In the former, subepicardial sequences presented either a pattern suggesting circus movement or a radial pattern in which excitation at intramural sites could precede earliest subepicardial excitation. In the latter preparations, subepicardial excitation patterns consistently suggested circus movement in the subepicardial muscle layer surviving over necrotic tissue. Assuming complete circus movement, the "missed" time interval, measured as the interval left unaccounted for by actual recording of local excitation between ventricular tachycardia cycles, ranged from 3% to 64% of the cycle length of ventricular tachycardia. While surviving subepicardial and intramural layers appeared to be involved in the mechanism of ventricular tachycardia, a late second breakthrough on the right ventricle, in conjunction with fixed-coupled H deflections on the His bundle electrograms, suggested the involvement of the conducting system in propagation of the impulse.


Melanotic neuroectodermal tumor of the epididymis. A case report.
Melanotic neuroectodermal tumors occur very rarely in the epididymis, only eleven cases having been reported to date in the world literature. An additional case is reported which we believe is the first from India.


Overexpression of IL-4 alters the homeostasis in the skin.
IL-4 has been implicated to play an important role in the pathogenesis of many inflammatory diseases including skin diseases such as atopic dermatitis. Because it is not clear which pathologic features of atopic dermatitis are dependent on IL-4, we assessed the consequences of IL-4 overexpression in the skin, using transgenic mice overexpressing IL-4 ubiquitously. Although transgenic mice display no clinical signs of skin inflammation, IL-4 induced a wide spectrum of pathologies including an increased number of mast cells and Langerhans cells in dermis and epidermis, respectively, focal deposition of collagen and a considerably reduced adipocyte layer in the dermis as well as an increased mitotic activity of keratinocytes, reflected in acanthosis and hyperkeratosis. The increase in Langerhans cell number may be explained in part by the substantially reduced Langerhans cell emigration from the epidermis in transgenic mice. The molecular mechanism behind this phenomenon remains to be clarified. Under in vitro culture conditions, Langerhans cells from transgenic mice undergo a maturation process similar to that of Langerhans cells from control mice, and their immunostimulatory capacity is also comparable. In contrast, transgenic Langerhans cells are superior to control Langerhans cells in their antigen-processing capacity. We conclude that the overexpression of IL-4 in the skin is, by itself, not sufficient for the induction of a full-blown atopic dermatitis phenotype, but several changes seen in the skin of transgenic mice mirror the cardinal pathologic manifestations of this disease.


Scaphoid fracture non-union: a systematic review of surgical treatment using bone graft.
This systematic review assesses the quality and outcomes of published articles concerning bone graft surgery for scaphoid fracture non-union. Searches of the CENTRAL, MEDLINE, EMBASE, CINAHL and AMED databases captured 2710 articles. Each article was screened and 144 met our inclusion criteria. Data regarding source, study design, population, intervention, comparator and outcomes were extracted. There were 5464 scaphoid non-union outcomes within the 144 studies. Mean reported union rates for vascularized and non-vascularized bone graft were 84% and 80%, respectively. Avascular necrosis was diagnosed in several ways and, when present, the vascularized bone graft union rate was 74% compared with 62% with non-vascularized bone graft. Reported union rates vary considerably. These differences may be due to patient factors, fracture factors, treatment factors or study design failures or bias. We recommend that future researchers take into account the deficiencies of previous studies and use the suggested minimum data set in future studies. II.


[The sweet secret of dark chocolate].
For centuries dark chocolate has been known for its taste as well as its beneficial effects on health. Mainly polyphenols, a heterogeneous group of molecules, have been associated with antioxidant and immunomodulatory properties. Furthermore they inhibit primary hemostasis and pathways associated with platelet activation and aggregation.


Observation of Quantum Droplets in a Strongly Dipolar Bose Gas.
Quantum fluctuations are the origin of genuine quantum many-body effects, and can be neglected in classical mean-field phenomena. Here, we report on the observation of stable quantum droplets containing ∼800 atoms that are expected to collapse at the mean-field level due to the essentially attractive interaction. By systematic measurements on individual droplets we demonstrate quantitatively that quantum fluctuations mechanically stabilize them against the mean-field collapse. We observe in addition the interference of several droplets indicating that this stable many-body state is phase coherent.


More relevant prediction for in vivo drug interaction of candesartan cilexetil on hepatic bile acid transporter BSEP using sandwich-cultured hepatocytes.
Bile salt export pump (BSEP) plays a major role in biliary secretion of bile salts; therefore, drug-induced cholestasis could occur because of BSEP inhibition by drugs. Drug interaction on hepatic bile canalicular transporters such as BSEP with prodrugs that are rapidly metabolized has not been evaluated well. In the present study, candesartan cilexetil (CIL) was used as a model compound and its inhibitory potential against BSEP was determined in sandwich-cultured human hepatocytes (hSCH) as well as in BSEP-expressing membrane vesicles. CIL exhibited potent BSEP inhibition with an IC50 value of 6.2 µM in the transport assay using membrane vesicles. In contrast, BSEP inhibition by CIL was not observed in hSCH after 120 min exposure. This discordance is possibly explained by metabolic elimination of CIL in hSCH because BSEP inhibition became reversely pronounced under the conditions where CIL metabolism was suppressed by diisopropyl fluorophosphates. The results observed in hSCH are consistent with the fact that liver dysfunction or jaundice occurs with low frequency in clinical use of CIL, which may not be obtained by membrane vesicle study on the effect of CIL on BSEP.


Antimicrobial susceptibility and multilocus sequence typing of Mycoplasma capricolum subsp. capricolum.
Mycoplasma capricolum subsp. capricolum is one of the causative agents of contagious agalactia (CA). Nevertheless, there is still a lack of information about its antimicrobial susceptibility and genetic characteristics. Therefore, the aim of this work was to study the antimicrobial and genetic variability of different Mycoplasma capricolum subsp. capricolum field isolates. For this purpose, the growth inhibition effect of 18 antimicrobials and a multilocus sequence typing (MLST) scheme based on five housekeeping genes (fusA, glpQ, gyrB, lepA and rpoB) were performed on 32 selected field isolates from Italy and Spain.The results showed a wide range of growth inhibitory effects for almost all the antimicrobials studied. Macrolides presented lower efficacy inhibiting Mcc growth than in previous works performed on other CA-causative mycoplasmas. Erythromycin was not able to inhibit the growth of any of the studied strains, contrary to doxycycline, which inhibited the growth of all of them from low concentrations. On the other hand, the study of the concatenated genes revealed a high genetic variability among the different Mcc isolates. Hence, these genetic variations were greater than the ones reported in prior works on other mycoplasma species.


[Method and evaluation of hormone assays in practical obstetrics and gynecology].
Hormone assays are very important in obstetrics and gynecology. Today, I want to talk about how to measure hormones and how to evaluate the data obtained for therapeutic purposes. In humans, there are two mechanisms of control, neural control and endocrine control. Generally speaking, the neural system controls organs directly via various neurotransmitters, while the endocrine system controls organs by hormones transported in the blood. In fact, recent progress in hormone research has shown that this concept should be modified, because some hormones act as neurotransmitters or regulate other cells or even endocrine cells themselves in the same organ. But I shall not go into this. Today's lecture is focused on hormones that are closely related to clinical obstetrics and gynecology. The hormones that are important are those in females, reproduction, and pregnancy, and tumors. First, and most important, is that patients acquire femininity in the physiological and psychological sense by hormones. The hormones closely related to this are estrogens and pituitary hormones. For reproduction, cyclic hormonal change is important. In the reproductive period, women have menstruation and ovulation along with cyclic changes of ovarian and pituitary hormones. After conception, various kinds of hormones, including hCG, HPL and estriol, are secreted from the feto-placental system. These hormones are used clinically as a markers of placental function. Hormones also have important roles in oncology. hCG is an excellent marker of trophoblastic diseases. Endometrial cancer is expected respond to large doses of progestins if they have progesterone receptors. There are three types of hormone assays, biological assays, immunological assays and chemical assays.(ABSTRACT TRUNCATED AT 250 WORDS)


Postoperative function of "free" jejunal transplants for replacement of the cervical esophagus.
The postoperative function of "free" jejunal autotransplants for replacement of the pharyngoesophagus after palliative resection was evaluated in nine patients using clinical assessment, cinefluoroscopy, manometry, and electrical studies. After an initial period of adjustment, all patients swallowed solids and liquids with minimal difficulty, gained weight appropriately and were satisfied with their operations. Cinefluoroscopy and esophageal manometry demonstrated normal function of the intact distal esophagus, which correlated with the absence of reflux symptoms. The grafts were capable of contraction in response to local distension and maintained an intrinsic myoelectrical activity. These results indicate that jejunal autotransplantation may provide excellent palliation with restoration of a near normal swallowing mechanism for patients with large resectable lesions of the pharyngoesophagus. An additional observation was that the instillation of food directly into the gastric antrum caused a change in the motor activity in the transplantd jejunum, indicating physiological hormonal control of intestinal motility.


Plasma serpinB1 is related to insulin sensitivity but not pancreatic β-Cell function in non-diabetic adults.
Pancreatic β-cell dysfunction because of reduced β-cell mass and function is a primary determinant in the progression of diabetes. Increase in β-cell mass and compensatory hyperinsulinaemia is frequently associated with insulin-resistant states. Although the humoral factors mediating this compensatory response are unknown, serpinB1, a protease inhibitor, has recently been proposed to be one such factor. In this study, we examine the relationships between plasma serpinB1, insulin sensitivity, and pancreatic β-cell function in non-diabetic individuals. 117 subjects (women, n = 50, men, n = 67; age= 37.6 ± 10.8; BMI=31.1 ± 7.7 kg/m2) underwent an insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) at the NIH Clinical Research Center. Acute insulin response (AIR) and insulin sensitivity index (SI) were obtained from the FSIVGTT with MINMOD analysis. The Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated from fasting insulin and glucose values. Plasma serpinB1 levels were measured using an ELISA assay. Simple linear correlation analyses were performed to evaluate the relationship between serpinB1 and measures of insulin sensitivity and β-cell function. Circulating serpinB1 levels were unrelated to age, sex, race, BMI, or percent body fat. SI but not AIR significantly correlated with circulating serpinB1 levels (r = 0.23, P < 0.05). QUICKI tended to positively correlate with serpinB1 (r = 0.16, P = 0.09). Circulating serpinB1 is directly associated with insulin sensitivity but not β-cell function in non-diabetic adults. Whether this modest association plays a role in insulin sensitivity in humans remains to be clarified.


Zinc deficiency in mild hypertensive patients treated with diuretics.
Mean hair zinc was found to be significantly lower in 20 mild hypertensive patients treated with thiazides for 6-36 months than in 19 mild hypertensive patients who had not been given diuretics for at least six months before study. Mean serum zinc did not differ significantly between the two groups. Chronic diuretic treatment can result in zinc deficiency through enhanced urinary excretion of zinc.


Paramedicine students' perception of preparedness for clinical placement in Australia and New Zealand.
Clinical placement is an essential element of paramedicine education and training as the profession completes the transition from vocational training to a pre-employment, university based model. The objective of this study was to survey pre-employment paramedicine students at Universities in Victoria, Australia and Auckland, New Zealand to measure their self-assessed preparedness for clinical placement. This was a cross-sectional study involving paper-based questionnaires employing a convenience sample of 682 undergraduate paramedicine students (years 1-4) who had completed at least one clinical placement. Student perceptions of preparedness for clinical placement were measured using an adaptation of the 'Preparedness for Hospital Practice' questionnaire. There are significant differences in students' perception of preparedness for clinical placement, which reflects the differences between universities in relation to structure of their paramedicine programs, the timing of clinical education and the number of hours of clinical placement. There needs to be clinical placement agreements between the ambulance services and universities that clearly describe the standards and expected elements of a quality clinical placement. In order to improve the preparedness for placement for paramedicine students, a united approach is required by all stakeholders, including ambulance services, students and universities.


Ethyl glucuronide determination: head hair versus non-head hair.
In previous studies, hair analysis of ethyl glucuronide (EtG), a non-volatile, water-soluble, direct metabolite of ethanol, was shown to be adequate for the detection of social and chronic excessive alcohol consumption. As in some cases scalp hair is not available, the analysis of hair from alternative anatomical sites becomes of interest. In this study, hair samples from head, beard, chest, armpit, stomach, pubis, arms and legs from 32 subjects were analyzed when available, in order to compare the EtG concentrations and to study if the cut-offs used for head hair could be used for non-head hair. EtG was determined by GC/MS in negative chemical ionization mode using EtG-d5 as internal standard, after extraction by solid phase extraction using Oasis MAX columns and pentafluoropropionic anhydride (PFPA) derivatization. The results showed that in the cases of negative findings in head hair (EtG < 7 pg/mg), in 7 out of 12 cases negative results could also be found in non-head hair. The five others were positive, due to a positive EtG finding in pubic hair. In 20 cases of positive EtG results for head hair, in all cases positive results could also be found in non-head hair. In conclusion, although preliminary results indicate a clear trend regarding the accordance between EtG results in head hair and non-head hair, interpretation of non-head hair results remains to be carefully done for pubic hair, for which often higher concentrations have been found.


Patterns of sugar consumption in early infancy.
A study is described in which patterns of sugar consumption in early infancy have been investigated in a rural area in Britain. A representative group of 94 mothers of first babies aged 8-11 months answered questions on the introduction of various foods and drinks containing sugar to their babies' diet. A diet sheet was completed in order to estimate the frequency of sugar consumption on the previous day for both the mother and her child. The findings show that babies received sweet items on an average of 4.3 separate occasions and that 77% of the meals and snacks given to babies contained sugar. The study describes some of the specific ways which sugar is first introduced and concludes that the frequency of sugar consumption is high, even in the 1st year of life.


Revealing the impact of strain in the optical properties of bubbles in monolayer MoSe2.
Strain plays an important role for the optical properties of monolayer transition metal dichalcogenides (TMDCs). Here, we investigate strain effects in a monolayer MoSe2 sample with a large bubble region using μ-Raman, second harmonic generation (SHG), μ-photoluminescence and magneto μ-photoluminescence at low temperature. Remarkably, our results reveal the presence of a non-uniform strain field and the observation of emission peaks at lower energies which are the signatures of exciton and trion quasiparticles red-shifted by strain effects in the bubble region, in agreement with our theoretical predictions. Furthermore, we have observed that the emission in the strained region decreases the trion binding energy and enhances the valley g-factors as compared to non-strained regions. Considering uniform biaxial strain effects within the unit cell of the TMDC monolayer (ML), our first principles calculations predict the observed enhancement of the exciton valley Zeeman effect. In addition, our results suggest that the exciton-trion fine structure plays an important role for the optical properties of strained TMDC ML. In summary, our study provides fundamental insights on the behaviour of excitons and trions in strained monolayer MoSe2 which are particularly relevant to properly characterize and understand the fine structure of excitonic complexes in strained TMDC systems/devices.


Using collaboration networks to identify authorship dependence in meta-analysis results.
Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question and are widely used in many academic fields. Meta-analyzes can also be used to study sources of heterogeneity and bias among results, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological heterogeneity and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyzes, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting for authorship dependence in results.


Effect of Litter Treatment on Campylobacter jejuni in Broilers and on Cecal Microbiota.
Since 2018, when a process hygiene criterion for Campylobacter in broilers at the slaughterhouse was implemented across Europe, efforts to reduce Campylobacter at farm level have increased. Despite numerous studies aiming to reduce Campylobacter colonization in broilers, no efficient control strategy has been identified so far. The present work assessed first the efficacy of a commercial litter treatment to reduce Campylobacter colonization in broilers during two in-vivo trials and second, its impact on cecal microbiota. The treatment does not affect broiler growth and no effect on Campylobacter counts was observed during the in-vivo trials. Nevertheless, cecal microbiota were affected by the treatment. Alpha and beta diversity were significantly different for the control and litter-treated groups on day 35. In addition, several taxa were identified as significantly associated with the different experimental groups. Further work is needed to find a suitable control measure combining different strategies in order to reduce Campylobacter.


[Relationship between awareness of sexually transmitted diseases and condom use by university students: development of an awareness scale for prediction of condom use].
The purpose of this study was 1) to develop a psychological scale for preventing STDs and 2) to examine whether such an awareness scale might be used for predicting condom use by Japanese heterosexual university students. The sample data were collected in January 2006 for our first survey and January 2007 for our second survey. In the first survey, 362 Japanese university students (males = 180, females = 182, mean age = 20.14, SD = 1.41) were asked to answer a questionnaire composed of a face sheet and 20 items during lecture periods. In order to explore the factor structure of these 20 items and confirm the reliability for each factor, Exploratory Factor Analysis (EFA), Step Wise Exploratory Factor Analysis (SEFA) and Reliability Analysis were conducted on the questionnaires. In the second survey, 248 Japanese university students (males = 121, females = 127, mean age = 20.07, SD = 1.50) were asked to answer a questionnaire composed of a face sheet and an STDs Awareness Scale for University Students with 16 items that were newly developed based on the EFA results of the first survey. In order to confirm the structural validity of this scale, Confirmation Factor Analysis (CFA) was conducted on these 16 items. Logistic Regression Analysis was conducted to examine whether the awareness scale might be used in predicting condom use. 1) EFA using the maximum likelihood method with a Promax rotation identified a four-factor solution with 20 items. 2) The results of the SEFA found a four-factor solution with 16 items as the most statistically acceptable model of the scale. 3) Each of the factors demonstrated acceptable internal consistency with Cronbach's alpha reliability values from 0.759 to 0.879. 4) The CFA showed that the structural validity of this scale satisfied the high level of statistical requirements. 5) The results of Logistic Regression Analysis demonstrated that there was a statistically significant partial regression coefficient between the scale and condom use or non-condom use at the last sexual intercourse. The results of the analyses supported the reliability and the structural validity of an STDs Awareness Scale for University Students as a means of assessing Japanese university students' awareness of STDs prevention and also indicated that the scale can be used in predicting students' condom use. Future research with other age groups will be needed to clarify the relationship between models for young people and models for other age groups.


Bacteriorhodopsin mutants containing single tyrosine to phenylalanine substitutions are all active in proton translocation.
To study the possible role of the tyrosine residues in proton translocation by bacteriorhodopsin, we have replaced these residues individually by phenylalanine. The required codon changes were introduced in the bacterioopsin gene by replacement of appropriate restriction fragments by synthetic counterparts containing the desired nucleotide changes. The denatured opsin polypeptides obtained by expression of the mutant genes in Escherichia coli were purified and treated with a mixture of detergents, phospholipids, and retinal in a previously established renaturation procedure. All of the mutant proteins folded to regenerate bacteriorhodopsin-like chromophores. Three mutants with tyrosine to phenylalanine substitutions at positions 57, 83, and 185 regenerated the chromophore more slowly than the wild-type protein, and two of these mutants, Phe-57 and -83, showed slightly blue-shifted chromophores. When reconstituted into liposomes all of the mutant proteins with single Tyr----Phe substitutions pumped protons at rates and levels comparable to those of the wild-type bacteriorhodopsin. We conclude that single substitutions of tyrosine by phenylalanine do not affect folding, retinal binding, or light-dependent proton pumping in bacteriorhodopsin.


Predictors for early readmission in acute pancreatitis (AP) in the United States (US) - A nationwide population based study.
Population based data on the burden and patterns of acute pancreatitis (AP) early readmissions (≤30-days) are limited. 2013 Nationwide Readmission Database (NRD) was queried. AP etiology was determined using associated diagnoses codes. Proportion, reasons for readmission, and associated costs were evaluated. Multivariate logistic regression analysis was performed to identify independent predictors for 30-day readmission. After exclusions, we identified 178,541 patients with primary diagnosis of AP (mean age 53 ± 17 years, 51% male). 13.7% were readmitted ≤30 days [7.1% in acute biliary pancreatitis (ABP) patients with index cholecystectomy (CCY), 16.3% in ABP patients without CCY, and 14.3% in non-biliary AP patients (p < 0.0001)]. Reasons for readmission included AP, chronic pancreatitis, Pseudocyst/walled off necrosis, biliary tract disease, smoldering symptoms and others. On multivariate analysis male gender, comorbidity status (≥3), non-biliary etiology, organ failure, Pseudocyst/walled off necrosis complications, and patients discharged to extended care facilities were associated with increased risk of readmission. ABP patients with index CCY had a significantly lower risk of early unplanned readmission (odds ratio 0.45, p < 0.0001) but ABP patients with index ERCP did not (p = 0.96). About 1 in 7 AP patients had a 30-day readmission after index hospitalization and about half of these were related to AP. Our data confirms the higher risk of readmission in alcohol and idiopathic AP and a lower risk in ABP. Risk of early unplanned readmission is significantly lower in ABP patients who underwent CCY and not ERCP during index hospitalization. Cholecystectomy should be performed in all ABP patients as per recommended guidelines.


Functional disassociation of the central and peripheral fatty acid amide signaling systems.
Fatty acid amides (FAAs) constitute a large class of endogenous signaling lipids that modulate several physiological processes, including pain, feeding, blood pressure, sleep, and inflammation. Although FAAs have been proposed to evoke their behavioral effects through both central and peripheral mechanisms, these distinct signaling pathways have remained experimentally challenging to separate. Here, we report a transgenic mouse model in which the central and peripheral FAA systems have been functionally uncoupled. Mice were generated that express the principle FAA-degrading enzyme FAA hydrolase (FAAH) specifically in the nervous system (FAAH-NS mice) by crossing FAAH(-/-) mice with transgenic mice that express FAAH under the neural specific enolase promoter. FAAH-NS mice were found to possess wild-type levels of FAAs in the brain and spinal cord, but significantly elevated concentrations of these lipid transmitters in peripheral tissues. This anatomically restricted biochemical phenotype correlated with a reversion of the reduced pain sensitivity of FAAH(-/-) mice, consistent with the FAA anandamide producing this effect by acting on cannabinoid receptors in the nervous system. Interestingly, however, FAAH-NS mice still exhibited an antiinflammatory phenotype similar in magnitude to FAAH(-/-) mice, indicating that this activity, which was not blocked by cannabinoid receptor antagonists, was mediated by peripherally elevated FAAs. These data suggest that the central and peripheral FAA signaling systems regulate discrete behavioral processes and may be targeted for distinct therapeutic gain.


Aerobic Vaginitis Caused by Enterococcus Faecalis - Clinical Features and Treatment.
Aerobic vaginitis is an imbalance of the vaginal flora and the main characteristic is an abnormal vaginal flora that contains aerobic and intestinal pathogens with varying degrees of vaginal inflammation. The frequency of AV varies from 12% to 23.7% in symptomatic women who are not pregnant and 4 to 8% during pregnancy and has an increased risk for sexually transmitted diseases (STI). The causative agents of AV are: Enterococcus faecalis (E. faecalis), Esherichia coli, group B streptococcus and Staphylococcus aureus. The aim of this review was to present the most important features of aerobic vaginitis regarding description of this frequent clinical problems within population in Bosnia and Herzegovina and also worlfwide. Author analized aerobic vaginitis based on scientific literature by searching published papers in important indexed databases. The most frequently isolated AV pathogen is E. faecalis in about 31%. New works indicate the presence of the HPV 16 gene and genome in E. faecalis in the biopsied material of cervical cancer, as well as the ability that HPV 16 genes can be translated and transcribed in these bacteria, and that the HPV gene can form viral particles in these bacteria leads to certain connection that can be a risk factor in the progression of cervical lesions to cancer. A decrease in the number of lactobacilli in the vaginal secretion reduces the defense ability and changes the pH value of the vaginal environment, which favors the development of bacterial inflammation. AV positive for E. faecalis leads to a change in the pH value of the vaginal environment above 5, and the increased pH value of the vaginal environment in HPV positive women can be an association for cervical intraepithelial lesion (CIN). A dominant pathogen in AV such as E. faecalis can reduce the protective effect of lactobacilli by causing inflammation, as well as an increase in IL-6, IL-8 and TNF, increasing the risk of HPV 16 infection resulting in CIN and cervical cancer. In cervical cancer research, the presence of genes and genomes (except E1) of human papillomavirus (HPV) type 16 was found in bacteria such as: E. faecalis and Staphylococcus aureus from cervical cancer biopsies. Intensive treatment of AV could be a very important factor in preventing the onset of precancerous lesions and cervical cancer. The recommended treatment of AV includes a combination of therapy such as: antibacterial (antiseptic and antibiotic), hormonal, non-steroidal anti-inflammatory and/or probiotics, which can be prescribed in the form of local or systemic therapy. There is no generally accepted clinical strategy for the treatment of AV caused by E. faecalis. Most authors suggest that therapy be based on microscopic or microbiological findings using a topical antibiotic for the infectious agent, a topical steroid to reduce inflammation, and estrogen to treat atrophy.


Neutrophils and their role in the aetiopathogenesis of type 1 and type 2 diabetes.
Multiple and complex aetiological processes underlie diabetes mellitus, which invariably result in the development of hyperglycaemia. Although there are two prevalent distinct forms of the disease, that is, type 1 and type 2 diabetes, accumulating evidence indicates that these syndromes share more aetiopathological mechanisms than originally thought. This compels a rethinking of the approaches to prevent and treat the different manifestations of what eventually becomes a hyperglycaemic state. This review aims to address the involvement of neutrophils, the most abundant type of granulocytes involved in the initiation of the acute phase of inflammation, in the aetiopathogenesis of diabetes mellitus, with a focus on type 1 and type 2 diabetes. We review the evidence that neutrophils are the first leucocytes to react to and accumulate inside target tissues of diabetes, such as the pancreas and insulin-sensitive tissues. We then review available data on the role of neutrophils and their functional alteration, with a focus on NETosis, in the progression towards clinical disease. Finally, we review potential approaches as secondary and adjunctive treatments to limit neutrophil-mediated damage in the prevention of the progression of subclinical disease to clinical hyperglycaemia.


Sensitivity of routine system for reporting patient safety incidents in an NHS hospital: retrospective patient case note review.
To evaluate the performance of a routine incident reporting system in identifying patient safety incidents. Two stage retrospective review of patients' case notes and analysis of data submitted to the routine incident reporting system on the same patients. A large NHS hospital in England. 1006 hospital admissions between January and May 2004: surgery (n=311), general medicine (n=251), elderly care (n=184), orthopaedics (n=131), urology (n=61), and three other specialties (n=68). Proportion of admissions with at least one patient safety incident; proportion and type of patient safety incidents missed by routine incident reporting and case note review methods. 324 patient safety incidents were identified in 230/1006 admissions (22.9%; 95% confidence interval 20.3% to 25.5%). 270 (83%) patient safety incidents were identified by case note review only, 21 (7%) by the routine reporting system only, and 33 (10%) by both methods. 110 admissions (10.9%; 9.0% to 12.8%) had at least one patient safety incident resulting in patient harm, all of which were detected by the case note review and six (5%) by the reporting system. The routine incident reporting system may be poor at identifying patient safety incidents, particularly those resulting in harm. Structured case note review may have a useful role in surveillance of routine incident reporting and associated quality improvement programmes.


Nitric oxide signaling participates in norepinephrine-induced activity of neuronal intracellular survival pathways.
Much evidence has gathered that nitric oxide (NO) signaling, via cGMP-dependent mechanisms, may activate pro-survival pathways in hippocampal neurons and inhibit apoptosis. Past research has revealed that the enhancement of monoaminergic neurotransmission via exercise or treatment with antidepressant medications leads to an enhanced expression of brain-derived neurotrophic factor (BDNF). In isolated hippocampal neurons, norepinephrine (NE) application also increases the immunoreactivity of BDNF and several pro-survival signaling molecules. The data herein support the possibility that NO signaling plays an important role in enhancing neurotrophin expression and activation of the pro-survival phosphatidylinositol 3' kinase (PI-3K) pathway stimulated by NE. In isolated hippocampal neurons, the NO donor, sodium nitroprusside, increases BDNF, PI-3K, and phospho-ERK1 immunoreactivity. Specific inhibitors of the NO system suggest that NE-induced increases in hippocampal BDNF and the PI-3K pathway, but not stimulation of the MAPK pathway, depend upon NO signaling. In addition, inhibiting cGMP suggest that the effects of NE on BDNF immunoreactivity and Akt phosphorylation are also cGMP-dependent. Finally, the application of l-NAME to hippocampal neurons increases cell death. This is the first study of its kind demonstrating the involvement of NE-induced pro-survival signaling in three distinct signaling pathways: PI-3K, MAPK, and NO/cGMP. Possible mechanisms are discussed in light of the results.


Parallel replica dynamics simulations of reactions in shock compressed liquid benzene.
The study of the long-term evolution of slow chemical reactions is challenging because quantum-based reactive molecular dynamics simulation times are typically limited to hundreds of picoseconds. Here, the extended Lagrangian Born-Oppenheimer molecular dynamics formalism is used in conjunction with parallel replica dynamics to obtain an accurate tool to describe the long-term chemical dynamics of shock-compressed benzene. Langevin dynamics has been employed at different temperatures to calculate the first reaction times in liquid benzene at pressures and temperatures consistent with its unreacted Hugoniot. Our coupled engine runs for times on the order of nanoseconds (one to two orders of magnitude longer than traditional techniques) and is capable of detecting reactions that are characterized by rates significantly slower than we could study before. At lower pressures and temperatures, we mainly observe Diels-Alder metastable reactions, whereas at higher pressures and temperatures we observe stable polymerization reactions.


Saphenous vein graft disease, pathophysiology, prevention, and treatment. A review of the literature.
The saphenous vein remains the most frequently used conduit for coronary artery bypass grafting, despite reported unsatisfactory long-term patency rates. Understanding the pathophysiology of vein graft failure and attempting to improve its longevity has been a significant area of research for more than three decades. This article aims to review the current understanding of the pathophysiology and potential new intervention strategies. A search of three databases: MEDLINE, Web of Science, and Cochrane Library, was undertaken for the terms "pathophysiology," "prevention," and "treatment" plus the term "vein graft failure." Saphenous graft failure is commonly the consequence of four different pathophysiological mechanisms, early acute thrombosis, vascular inflammation, intimal hyperplasia, and late accelerated atherosclerosis. Different methods have been proposed to inhibit or attenuate these pathological processes including modified surgical technique, topical pretreatment, external graft support, and postoperative pharmacological interventions. Once graft failure occurs, the available treatments are either surgical reintervention, angioplasty, or conservative medical management reserved for patients not eligible for either procedure. Despite the extensive amount of research performed, the pathophysiology of saphenous vein graft is still not completely understood. Surgical and pharmacological interventions have improved early patency and different strategies for prevention seem to offer some hope in improving long-term patency.


Dynamic Control of a Multistate Chiral Supramolecular Polymer in Water.
Natural systems transfer chiral information across multiple length scales through dynamic supramolecular interaction to accomplish various functions. Inspired by nature, many exquisite artificial supramolecular systems have been developed, in which controlling the supramolecular chirality holds the key to completing specific tasks. However, to achieve precise and non-invasive control and modulation of chirality in these systems remains challenging. As a non-invasive stimulus, light can be used to remotely control the chirality with high spatiotemporal precision. In contrast to common molecular switches, a synthetic molecular motor can act as a multistate chiroptical switch with unidirectional rotation, offering major potential to regulate more complex functions. Here, we present a light-driven molecular motor-based supramolecular polymer, in which the intrinsic chirality is transferred to the nanofibers, and the rotation of molecular motors governs the chirality and morphology of the supramolecular polymer. The resulting supramolecular polymer also exhibits light-controlled multistate aggregation-induced emission. These findings present a photochemically tunable multistate dynamic supramolecular system in water and pave the way for developing molecular motor-driven chiroptical materials.


Body-Earth Mover's Distance: A Matching-Based Approach for Sleep Posture Recognition.
Sleep posture is a key component in sleep quality assessment and pressure ulcer prevention. Currently, body pressure analysis has been a popular method for sleep posture recognition. In this paper, a matching-based approach, Body-Earth Mover's Distance (BEMD), for sleep posture recognition is proposed. BEMD treats pressure images as weighted 2D shapes, and combines EMD and Euclidean distance for similarity measure. Compared with existing work, sleep posture recognition is achieved with posture similarity rather than multiple features for specific postures. A pilot study is performed with 14 persons for six different postures. The experimental results show that the proposed BEMD can achieve 91.21% accuracy, which outperforms the previous method with an improvement of 8.01%.


Mycoplasma pneumoniae-associated Hepatitis without Lung Involvement.
Mycoplasma pneumoniae (M. pneumoniae) is a major cause of community acquired respiratory infections. And it also causes a number of extrapulmonary manifestations including cardiovascular, dermatological, musculoskeletal, and hematological systems. But, acute hepatitis without lung involvement is rare in adults. Here, we report a case of 32-year-old man who presented with fever, chilling, myalgia, and headache. Biochemical analysis showed severely impaired liver function and leukopenia. Laboratory tests and liver biopsy demonstrated a hepatocellular pattern of M. pneumoniae-associated acute hepatitis. Clinical symptoms and laboratory parameters are improved rapidly under treatment with macrolide. Therefore, We recommend that phsycians should consider a possibility of M. pneumoniae infection in acute hepatitis without lung and extrapulmonary involvement, when other more frequent causes have been excluded.


PPInterFinder--a mining tool for extracting causal relations on human proteins from literature.
One of the most common and challenging problem in biomedical text mining is to mine protein-protein interactions (PPIs) from MEDLINE abstracts and full-text research articles because PPIs play a major role in understanding the various biological processes and the impact of proteins in diseases. We implemented, PPInterFinder--a web-based text mining tool to extract human PPIs from biomedical literature. PPInterFinder uses relation keyword co-occurrences with protein names to extract information on PPIs from MEDLINE abstracts and consists of three phases. First, it identifies the relation keyword using a parser with Tregex and a relation keyword dictionary. Next, it automatically identifies the candidate PPI pairs with a set of rules related to PPI recognition. Finally, it extracts the relations by matching the sentence with a set of 11 specific patterns based on the syntactic nature of PPI pair. We find that PPInterFinder is capable of predicting PPIs with the accuracy of 66.05% on AIMED corpus and outperforms most of the existing systems. DATABASE URL: http://www.biomining-bu.in/ppinterfinder/


[Effect of preparation technique on in vitro release mechanism of huperzine A microspheres].
To investigate the effect of preparation technique on in vitro release mechanism of huperzine A-PLGA microspheres. Huperzine A-PLGA microspheres were prepared by two kinds of O/O emulsion solvent evaporation method (method A and B). In vitro release mechanism was explained by release profile, degradation rate and swelling rate of microspheres in vitro. The microspheres morphology and drug distribution within microspheres were observed in order to explain further the drug release mechanism. The encapsulation efficiency of huperzine A microspheres prepared by method A and B was 47.60% and 83.50% respectively. Microspheres prepared by method A could sustain release for 35 days with nearly no initial burst release. The release profile fitted well to zero order equation and drug release mainly through degradation and diffusion mechanism. Huperzine A microspheres prepared by method B could sustain release for 21 days with some evidence of initial burst release. The release profile fitted well to the Higuchi equation and drug release was mainly through diffusion mechanism. Huperzine A microspheres prepared by method A had more desirable release profile.


Inverse agonist up-regulates the constitutively active D3.49(164)Q mutant of the rat mu-opioid receptor by stabilizing the structure and blocking constitutive internalization and down-regulation.
We demonstrated previously that D3.49(164) mutations resulted in constitutive activation of the rat mu-opioid receptor and abolished receptor expression unless cells were pretreated with naloxone, an inverse agonist. In this study, we investigated the properties of the D3.49(164)Q mutant and the mechanisms underlying the effect of naloxone. Naloxone pretreatment up-regulated [(3)H]diprenorphine binding and protein expression of the D3.49(164)Q mutant in a time- and dose-dependent manner without affecting its mRNA level. After naloxone removal, binding and protein expression of the mutant declined with time with no effect on its mRNA level. Naloxone methiodide (a quaternary ammonium analog) caused a maximal up-regulation about 50% of the naloxone effect, indicating that naloxone acts extracellularly and intracellularly. Expression of the mutant was enhanced by inverse agonists, a neutral antagonist, and agonists, with inverse agonists being most effective. In membranes, the mutant was structurally less stable than the wild type upon incubation at 37 degrees C, and naloxone and [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin stabilized the mutant. Coexpression of the dominant-negative mutants GRK2-K220R, arrestin-2(319-418), dynamin I-K44A, rab5A-N133I or rab7-N125I partially prevented the decline in binding of the mutant after naloxone removal. Chloroquine or proteasome inhibitor I reduced the down-regulation of the mutant. These results indicate that the D3.49(164)Q mutant is constitutively internalized via G protein coupled-receptor kinase-, arrestin-2-, dynamin-, rab5-, and rab7-dependent pathways and probably trafficked through early and late endosomes into lysosomes and degraded by lysosomes and proteasomes. Naloxone up-regulates the D3.49(164)Q mutant by stabilizing the mutant protein and blocking its constitutive internalization and down-regulation. To the best of our knowledge, this represents the first comprehensive analysis of the mechanisms involved in up-regulation of constitutively active mutants by an inverse agonist.


Blood Pressure and Stroke: A Review of Sex- and Ethnic/Racial-Specific Attributes to the Epidemiology, Pathophysiology, and Management of Raised Blood Pressure.
Raised blood pressure (BP) is the leading cause of death and disability worldwide, and its particular strong association with stroke is well established. Although systolic BP increases with age in both sexes, raised BP is more prevalent in males in early adulthood, overtaken by females at middle age, consistently across all ethnicities/races. However, there are clear regional differences on when females overtake males. Higher BP among males is observed until the seventh decade of life in high-income countries, compared with almost 3 decades earlier in low- and middle-income countries. Females and males tend to have different cardiovascular disease risk profiles, and many lifestyles also influence BP and cardiovascular disease in a sex-specific manner. Although no hypertension guidelines distinguish between sexes in BP thresholds to define or treat hypertension, observational evidence suggests that in terms of stroke risk, females would benefit from lower BP thresholds to the magnitude of 10 to 20 mm Hg. More randomized evidence is needed to determine if females have greater cardiovascular benefits from lowering BP and whether optimal BP is lower in females. Since 1990, the number of people with hypertension worldwide has doubled, with most of the increase occurring in low- and-middle-income countries where the greatest population growth was also seen. Sub-Saharan Africa, Oceania, and South Asia have the lowest detection, treatment, and control rates. High BP has a more significant effect on the burden of stroke among Black and Asian individuals than Whites, possibly attributable to differences in lifestyle, socioeconomic status, and health system resources. Although pharmacological therapy is recommended differently in local guidelines, recommendations on lifestyle modification are often very similar (salt restriction, increased potassium intake, reducing weight and alcohol, smoking cessation). This overall enhanced understanding of the sex- and ethnic/racial-specific attributes to BP motivates further scientific discovery to develop more effective prevention and treatment strategies to prevent stroke in high-risk populations.


Variability in Health Care Quality Measurement among Studies Using Service Provision Assessment Data from Low- and Middle-Income Countries: A Systematic Review.
Quality of care is essential for improving health outcomes, but heterogeneity in theoretical frameworks and metrics can limit studies' generalizability and comparability. This research aimed to compare definitions of care quality across research articles that incorporate data from Service Provision Assessment (SPA) surveys. Following Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, we used a keyword search in PubMed. Each author reviewed abstracts, then full texts, for inclusion criteria, and peer-reviewed publications of empirical analysis using SPA data. The search yielded 3,250 unique abstracts, and 34 publications were included in the final analysis. We extracted details on the SPA dataset(s) used, theoretical framework applied, and how care quality was operationalized. The 34 included articles used SPA data from 14 surveys in nine countries (all in sub-Saharan Africa plus Haiti). One-third of these articles (n = 13) included no theoretical or conceptual framework for care quality. Among those articles referencing a framework, the most common was the Donabedian model (n = 7). Studies operationalized quality constructs in extremely different ways. Few articles included outcomes as a quality construct, and the operationalization of structure varied widely. A key asset of SPA surveys, owing to the standardized structure and use of harmonized data collection instruments, is the potential for cross-survey comparisons. However, this is limited by the lack of a common framework for measuring and reporting quality in the existing literature using SPA data. Service Provision Assessment surveys offer unique and valuable insights, and a common framework and approach would substantially strengthen the body of knowledge on quality of care in low-resource settings.


The Changing Global Epidemiology of Re-emerging Human Monkeypox Virus Infection: A Systematic Review.
Human monkeypox virus (MPVX) infection represents an emerging zoonotic disease caused by an orthopoxvirus, resulting in a condition reminiscent of smallpox. More recent developments have witnessed a notable surge in global MPVX outbreaks, eliciting significant concerns. We aimed to investigate the epidemiological factors of the emerging human monkeypox virus infection, including the number of suspected, confirmed, and fatal cases, as well as the risk factors for contracting monkeypox infection. We performed a systematic review of peer-reviewed literature by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic database search (PubMed, Wiley Online Library, and Science Direct) was undertaken. For monkeypox-related studies, we included 25 peer-reviewed articles from 2018 and 2022, and data were extracted on the current evidence on the cases and the risk factors for MPVX infection, to develop public health advisories. Our reports show a rapid rise of MPVX cases in the highly endemic African regions after the 1970s, spread to other countries, and an increase in the median age from young children to young adults. The cessation of smallpox vaccination might have been one of the factors responsible for these findings. As of 2022, the genomic sequences of ten MPVX strains associated with the recent countrywide outbreak have been determined. While the West African Clade has been primarily implicated in the recent viral surge, data were insufficient to determine which mutation contributed to increased transmissibility. In the Democratic Republic of the Congo (DRC), sleeping on the floor was significantly associated with contracting MPVX, while eating or processing of animal foods was not a significant risk factor. In the United States, cleaning the cages and bedding of sick animals, touching infected animals, and daily exposure to sick animals were associated with an increased probability of contracting the MPVX infection. Recent global outbreaks and the rising incidence of MPVX infections among young adults in the endemic zones might be a result of the cessation of the smallpox vaccine. The increased risk associated with exposure to sick animals or sleeping on the floor suggests high infectivity from animal excretions. Increasing awareness, strict surveillance, and contact tracing can help contain global outbreaks. The ring vaccination approach for exposed individuals is another potential disease containment strategy. Future studies should investigate measures for rapid laboratory diagnosis, maintaining lab safety, and transmissibility.


Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms.
The mammalian pyruvate dehydrogenase complex (PDC) plays central and strategic roles in the control of the use of glucose-linked substrates as sources of oxidative energy or as precursors in the biosynthesis of fatty acids. The activity of this mitochondrial complex is regulated by the continuous operation of competing pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) reactions. The resulting interconversion cycle determines the fraction of active (nonphosphorylated) pyruvate dehydrogenase (E1) component. Tissue-specific and metabolic state-specific control is achieved by the selective expression and distinct regulatory properties of at least four PDK isozymes and two PDP isozymes. The PDK isoforms are members of a family of serine kinases that are not structurally related to cytoplasmic Ser/Thr/Tyr kinases. The catalytic subunits of the PDP isoforms are Mg2+-dependent members of the phosphatase 2C family that has binuclear metal-binding sites within the active site. The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex. One or more of their three lipoyl domains (two in E2) selectively bind each PDK and PDP1. These adaptive interactions predominantly influence the catalytic efficiencies and effector control of these regulatory enzymes. When fatty acids are the preferred source of acetyl-CoA and NADH, feedback inactivation of PDC is accomplished by the activity of certain kinase isoforms being stimulated upon preferentially binding a lipoyl domain containing a reductively acetylated lipoyl group. PDC activity is increased in Ca2+-sensitive tissues by elevating PDP1 activity via the Ca2+-dependent binding of PDP1 to a lipoyl domain of E2. During starvation, the irrecoverable loss of glucose carbons is restricted by minimizing PDC activity due to high kinase activity that results from the overexpression of specific kinase isoforms. Overexpression of the same PDK isoforms deleteriously hinders glucose consumption in unregulated diabetes.


MicroRNA-590-5p regulates proliferation and invasion in human hepatocellular carcinoma cells by targeting TGF-β RII.
MicroRNAs (miRNAs) are regulatory small non-coding RNAs that can regulate gene expression by binding to gene elements, such as the gene promotor 5'UTR, mainly in the 3'UTR of mRNA. One miRNA targets many mRNAs, which can be regulated by many miRNAs, leading to a complex metabolic network. In our study, we found that the expression level of miR-590-5p is higher in the human hepatocellular carcinoma cell line HepG2 than in the normal hepatocellular cell line L02. Downregulation of miR-590-5p inhibited proliferation and invasion of hepatocellular carcinoma cells (HCCs). We also showed that expression of TGF-beta RII, which has been regarded as a regulator of tumor proliferation, invasion, and migration in hepatocellular carcinoma, is regulated by miRNA-590-5p. In addition, miR-590-5p downregulated the expression of TGF-beta RII by targeting the 3'UTR of mRNA. We also found that downregulation of miR-590-5p was associated with an elevation of TGF-beta RII and inhibition of proliferation and invasion in HepG2 cells. Furthermore, overexpression of miR-590-5p was associated with upregulation of TGF-beta RII and could promote proliferation and invasion in L02 cells. In conclusion, we determined that TGF-beta RII is a novel target of miRNA-590-5p. Thus, the role of TGF-beta RII in regulating proliferation and invasion of human HCCs is controlled by miR-590-5p. In other words, miR-590-5p promotes proliferation and invasion in human HCCs by directly targeting TGF-beta RII.


Host plant associations in Western Palaearctic Longitarsus flea beetles (Chrysomelidae, Galerucinae, Alticini): a preliminary phylogenetic assessment.
Longitarsus Latreille (Chrysomelidae, Galerucinae, Alticini) is a very large genus of phytophagous insects, with more than 700 species distributed in all zoogeographical regions. Patterns of host use have been a central topic in phytophagous insect research. In this study a first assessment is provided to test the hypothesis that host-plant association is phylogenetically conserved in Western Palaearctic Longitarsus species. Maximum Likelihood and Bayesian Inference methods were used to infer a phylogeny based on DNA sequence data from two mitochondrial genes from 52 Longitarsus species from the Western Palaearctic. In agreement with the host phylogenetic conservatism hypothesis, a strict association between most of the recovered clades and specific plant families was found, except for species associated with Boraginaceae. Low phylogenetic resolution at deep nodes limited the evaluation of whether closely related Longitarsus clades are associated with the same plant family or to closely related plant families.


Development of an x-ray detector by polycrystalline diamond and its application in Z-pinch x-ray detection.
Large-grain-sized polycrystalline diamond films are fabricated by electron assisted chemical vapor deposition. A pure SP3 carbon bond in the cubic lattice structure is confirmed by Raman spectrum analysis. The grain size is on the order of several hundreds of μm or larger. Interlaced-finger electrodes are imprinted onto a 6 × 6 mm2 × 500 µm film to fabricate the x-ray detector. The width of every finger is 25 µm, and the distance between nearby fingers is 25 μm. Strong x ray irradiates when a pulsed current flows through a double-layer nested tungsten wire array in the Z-pinch. This diamond detector now works as one of the main x-ray detectors for the Z-pinch device. The diamond detector is calibrated using a plastic scintillator. The comparison between the signal measured by these two methods confirms that the large-grain-sized polycrystalline diamond is a good candidate for the detection of nanosecond pulsed x ray.


Activation of Ca2+-dependent currents in dorsal root ganglion neurons by metabotropic glutamate receptors and cyclic ADP-ribose precursors.
Cultured dorsal root ganglion neurons were voltage clamped at -90 mV to study the effects of intracellular application of nicotinamide adenine dinucleotide (betaNAD+), intracellular flash photolysis of caged 3',5'-cyclic guanosine monophosphate (cGMP), and metabotropic glutamate receptor activation. The activation of metabotropic glutamate receptors evoked inward Ca2+-dependent currents in most cells. This was mimicked both by intracellular flash photolysis of the caged axial isomer of cGMP [P-1-(2-nitrophenyl)ethyl cGMP] and intracellular application of betaNAD+. Whole cell Ca2+-activated inward currents were used as a physiological index of raised intracellular Ca2+ levels. Extracellular application of 10 microM glutamate evoked the activation of Ca2+-dependent inward currents, thus reflecting a rise in intracellular Ca2+ levels. Similar inward currents were also activated after isolation of metabotropic glutamate receptor activation by application of 10 microM glutamate in the presence of 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione and 20 microM dizocilpine maleate (MK 801), or by extracellular application of 10 microM trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid. Intracellular photorelease of cGMP, from its caged axial isomer, in the presence of betaNAD+ was also able to evoke similar Ca2+-dependent inward currents. Intracellular application of betaNAD+ alone produced a concentration-dependent effect on inward current activity. Responses to both metabotropic glutamate receptor activation and cGMP were suppressed by intracellular ryanodine, chelation of intracellular Ca2+ by bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid, and depletion of intracellular Ca2+ stores, but were insensitive to the removal of extracellular Ca2+. Therefore both cGMP, possibly via a mechanism that involves betaNAD+ and/or cyclic ADP-ribose, and glutamate can mobilize intracellular Ca2+ from ryanodine-sensitive stores in sensory neurons.


Close contact restriction periods for patients who have received iodine-131 therapy for differentiated thyroid cancer.
Patients treated with radionuclide therapy usually require restrictions on certain activities for a period of time following treatment to optimise protection of the public and ensure the legal dose limit is not exceeded. Software may be used to calculate necessary restriction periods for an individual based on longitudinal dose rate measurements from the time of radiopharmaceutical administration. A spreadsheet program has been used for this purpose in Australian hospitals for the last two decades. However, this spreadsheet has a limitation in that it uses an approximation in the calculation of dose from a contact pattern, which affects the calculated restriction period. A computer program called Dorn was developed that provides the same functionality as the spreadsheet but without this approximation. Proffered radiation safety advice from Dorn and the spreadsheet were compared. Advice from the spreadsheet and Dorn were compared for 55 patients who underwent iodine-131 therapy for differentiated thyroid cancer. The restriction periods for caring for infants, close contact with children and sleeping with a partner were typically about 13 h longer in Dorn than in the spreadsheet, but in some cases were over a week shorter or a month longer. If the Dorn program is used clinically in place of the spreadsheet, some patients will enjoy shorter restriction periods and the therapy provider can be more confident in their compliance with regulatory requirements and best practice. Dorn is freely available fromhttps://doi.org/jg5f.


[Determination of fipronil and its metabolites in eggs and egg products with gas chromatography-negative chemical ionization-mass spectrometry].
A method was established for the determination of fipronil and its metabolites in eggs and egg products with gas chromatography-negative chemical ionization-mass spectrometry (GC-NCI-MS). The targets were extracted from samples with acetonitrile, and followed by a simple cleanup step known as dispersive solid-phase extraction QuEChERS. The extracts were determined by GC-NCI-MS, and quantified by external standard method with matrix correction standard curves. The recoveries were in the range of 87.0% to 99.3% at four spiked levels (0.1, 2.0, 4.0 and 20.0 μg/kg), and all RSDs were not more than 12.7% for the four analytes. The linearity of the method was good between 0.005 and 0.10 mg/L, and all LOQs were less than 0.10 μg/kg. So this method can be used to determine the residues of fipronil and its metabolites in eggs and egg products.


HPV Vaccinations in Lublin Region, Poland.
Secondary prophylaxis of cervical cancer consisting in cytology screening tests, despite its effectiveness, does not achieve the desired results. For several years, primary prophylaxis has been available in the form of protective vaccinations. At present, two vaccine preparations are available on the market, and studies conducted on these preparations confirm their almost 100% effectiveness in the prevention of types of HPV present in the vaccine. Analysis of the programmes of protective vaccinations against HPV carried out during the period 2008-2013 in the Lublin Region. The material used in the study was data obtained from the relevant organs of the territorial self-government concerning programmes of vaccinations against HPV, demographic data pertaining to girls aged 10-18 living in the Lublin Region, as well as data published by the National Institute of Public Health - National Institute of Hygiene (NIZP-PZH). The method applied in the study was analysis of records. During the period 2008-2013, in the Lublin Region a total of 5,496 girls were vaccinated within the health programmes. The mean immunization coverage in Lublin is 50%, and in Radzyń Podlaski 59%. The percentage contribution of vaccinations guaranteed free by the local authorities, with relation to the total number of vaccinations performed in the Lublin Region, was from 60 to 77%. The units of territorial self-government allocated the amount of PLN 5,125,359 for the performance of projects associated with execution of free vaccinations. Among the total number of girls vaccinated against HPV, a considerable percentage were those vaccinated within the prophylactic programmes carried out by the units of territorial self-government. The programmes of free protective vaccinations against HPV began in 4 cities in the Lublin Region, and are continued only in two (Lublin and Radzyń Podlaski). Long-term observation of girls subjected to vaccinations from the aspect of maintenance of the immune response after vaccination should become an important element of performance of health programmes concerning vaccinations against HPV. Among the total number of girls vaccinated against HPV, those vaccinated within prophylactic programmes carried out by territorial self-government units made up a considerable percentage. Programmes of free preventive vaccinations against HPV began in 4 cities in the Lublin Region, but are continued in only 2. Long-term observation of girls subjected to vaccinations from the aspect of duration of maintaining immunity after vaccination should become an important element of the performance of health programmes concerning vaccinations against HPV.


'Catastrophic' Thrombosis in a Young Patient With Acute Myeloid Leukemia Presenting Early in the COVID-19 Pandemic - A Case Report.
We present the case of a 19-year-old male patient diagnosed concomitantly with extensive thromboses (including two intra-cardiac masses and Budd-Chiari syndrome), as well as acute myeloid leukemia. This necessitated prompt deployment of a monitoring and treatment strategy which included twice-daily blood count assessment, multiple platelet transfusions and anti-coagulation therapy with dose-adjustment per blood count during both induction and consolidation chemotherapy. Multiple factors are believed to contribute to the development of thrombosis in acute leukemia such as diffuse intravascular coagulation, cytokine release and chemotherapy. Our patient presented early on in the COVID-19 pandemic, delaying his seeking out medical treatment and we suspect this to have contributed to his 'catastrophic' thrombotic presentation. Well-structured guidelines to help clinicians manage these patients are lacking, and most data are from retrospective analyses or case reports. Our patient continued full-dose anticoagulant therapy until successfully undergoing allogeneic stem cell transplant. The thrombi eventually diminished in size, and the patient was not diagnosed with any further thrombotic events. Our case highlights the feasibility of intensive monitoring and provision of platelet transfusion as necessary in order to safely administer low molecular weight heparin from the outset of chemotherapy.


Progressive development of the osteoblast phenotype during differentiation of osteoprogenitor cells derived from fetal rat calvaria: model for in vitro bone formation.
Osteoblasts are the primary cells responsible for bone formation and are thought to originate from mesenchymal osteoprogenitor cells within skeletal tissues. To elucidate the osteoblastic differentiation process, fetal rat calvariae (FRC) were enzymatically digested and fractionated to provide an osteoprogenitor-enriched cell population. The third fraction of cells from the five sequential digestions tested showed a significant osteogenic response to dexamethasone (Dex), a well-known differentiation hormone, which was demonstrated by high alkaline phosphatase activity early in culture and enhanced calcium deposition and bone nodule formation in late stage cultures. These data indicate that fraction three contains a large number of osteoprogenitor cells. During the osteoblastic differentiation of the third fraction of FRC cells, the formation of collagen cross-links (pyridinoline and deoxypyridinoline) was time-dependently accelerated with the accumulation of collagens, which coincided with an onset of mineralization of the cultures, i.e., calcium deposition and bone nodule formation. Moreover, noncollagenous matrix proteins, bone sialoprotein and osteocalcin, were also increased at both mRNA and protein level in Dex-treated cultures with advancing culture periods. Further examination for mRNA expression of bone morphogenetic proteins (BMPs) and TGF-beta1 revealed a notable elevation in BMP-6 mRNA expression on days 3 and 10, and no significant change in TGF-beta1 expression. These observations suggested that the progressive formation of collagen cross-links, production of noncollagenous proteins, and up regulation of BMP-6 mRNA play an important role in the osteoblastic differentiation process of osteoprogenitor cells isolated from FRC. This culture system provides us a suitable model for in vitro bone formation.


[Spasmus nutans. A re-emergent pathology?].
The authors report two cases of spasmus nutans (a clinical syndrome peculiar to infancy the complete form of which is characterised by nystagmus, rhythmic head movements and wryneck) in two extra-EEC infants. The following elements were present in both patients: scarce exposure to light, early introduction of whole cow's milk, rachitic stigmata, dark skin, poor socio-economic conditions and rapid and complete remission of symptoms following daily exposure to sunlight. It is important to distinguish spasmus nutans, a completely benign and self-restricting disease, from potentially severe conditions which may appear with similar symptoms. It should be expected that this clinical condition will become more frequent in view of the considerable increase in the size of the non-EEC population.


Antigenic epitopes in the hemagglutinin of Qinghai-type influenza H5N1 virus.
The highly pathogenic avian influenza H5N1 viruses have become widespread and evolved into several clades. In our previous studies, the antigenic sites of the H5 hemagglutinin (HA) were characterized by selection and sequencing of escape mutants. In the present studies we analyzed the antigenic epitopes recognized by monoclonal antibodies against avian influenza A/Duck/Novosibirsk/56/05 (H5N1) virus isolated in western Siberia and belonging to subclade 2.2 of the H5N1 viruses. The analysis revealed several antigenically relevant positions of amino acid residues in the globular head of the HA not encountered earlier in the escape mutants of the H5 subtype. The newly recognized positions (113, 117, 118, 120, and 123, mature H5 numbering) are concentrated in an area adjacent to the region described in earlier studies as corresponding to site B in H3 HA, but extending far beyond this area. The amino acid positions recognized by the monoclonal antibodies against A/Duck/Novosibirsk/56/05 (H5N1) virus differ from the positions recognized by the monoclonal antibodies against H5N2 influenza viruses. The data suggest that the evolution of the HA of H5 avian influenza viruses is associated not only with the changes of antigenic epitopes recognized by antibodies, but also with a change in the dominance of the immunogenicity of different sites in the HA.


Factors affecting metabolic activity of the intestinal microflora.
1. The metabolic activity of the gastrointestinal microflora can be modified by numerous factors derived from the host, the host's environment, and the flora itself. 2. Marked differences exist in microbial composition and metabolism of the gut floras of different species of animal, and in the degree of colonization of the various regions of the gut. 3. The microbial flora changes with age, particularly in early infancy, and developmental changes in in vivo metabolism attributable to the gut flora have been noted for methylmercury. 4. Gastrointestinal disease can have a profound effect on microbial colonization and metabolism in the upper regions of the human gut. In particular, hypochlorhydria can lead to elevation in bacterial numbers, and nitrite and nitrosamine concentrations in gastric juice. 5. Environmental factors such as drugs (particularly antibiotics), diet, and xenobiotics can modify microbial metabolism and toxicity of foreign compounds. In some cases exposure to xenobiotics (e.g., cyclamate, rutin) results in metabolic adaptation and increased biotransformation of the foreign compound. 6. By their fermentation of dietary residues and endogenous carbohydrates, the gut bacteria produce acids which can lower lumenal pH and, in turn, modify bacterial enzyme activities. However, the changes in activity appear to be enzyme specific, some increasing with pH and others being inversely related to pH of incubation.


Effects of beta-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome.
Although anemia is frequently found in congestive heart failure (CHF), little is known about the effect of its correction with erythropoietin (EPO) on cardiac structure and function. The present study examines in patients with advanced CHF, chronic renal insufficiency, and anemia the effects of beta-EPO on left ventricular (LV) systolic diameter and volume (LVSD and LVSV), LV diastolic diameter and volume (LVDD and LVDV), LV mass, LV ejection fraction (LVEF), pulmonary artery pressure (PAP), and B-type natriuretic peptide (BNP) levels. Fifty-one consecutive subjects affected with advanced CHF and anemia were studied. We performed a randomized double-blind controlled study of correction of anemia with subcutaneous EPO for 4 months (group A, 26 patients) using saline as the placebo in the control group (group B, 25 patients). We then maintained the EPO treatment in the treated group for another 8 months. Both groups received oral iron throughout the total 12-month period. Echocardiographic evaluation, BNP levels, and hematological parameters are reported at 4 and 12 months. The patients in group A during the double-blind phase (4 months) demonstrated an increase in LVEF and mild reduction in LVSD and LVSV with respect to baseline and to group B with no differences in PAP, LVDD, and LVDV. Over the 12-month period, the hemoglobin increased from 10.40.6 to 12.4 +/- 0.8 g/dL (P < .01) in group A but did not change in group B. Compared with group B, group A had lower LVDD, LVSD, LVDV, LVSV, LV mass, PAP, and BNP and higher LVEF. The serum creatinine and creatinine clearance remained unchanged in the 2 groups. In anemic patients with CHF, correction of anemia with EPO and oral iron over 1 year lead to an improvement in LV systolic function, LV remodeling, BNP levels, and PAP compared with a control group in which only oral iron was used.


Imaging Neuroinflammation - from Bench to Bedside.
Neuroinflammation plays a central role in a variety of neurological diseases, including stroke, multiple sclerosis, Alzheimer's disease, and malignant CNS neoplasms, among many other. Different cell types and molecular mediators participate in a cascade of events in the brain that is ultimately aimed at control, regeneration and repair, but leads to damage of brain tissue under pathological conditions. Non-invasive molecular imaging of key players in the inflammation cascade holds promise for identification and quantification of the disease process before it is too late for effective therapeutic intervention. In this review, we focus on molecular imaging techniques that target inflammatory cells and molecules that are of interest in neuroinflammation, especially those with high translational potential. Over the past decade, a plethora of molecular imaging agents have been developed and tested in animal models of (neuro)inflammation, and a few have been translated from bench to bedside. The most promising imaging techniques to visualize neuroinflammation include MRI, positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging methods. These techniques enable us to image adhesion molecules to visualize endothelial cell activation, assess leukocyte functions such as oxidative stress, granule release, and phagocytosis, and label a variety of inflammatory cells for cell tracking experiments. In addition, several cell types and their activation can be specifically targeted in vivo, and consequences of neuroinflammation such as neuronal death and demyelination can be quantified. As we continue to make progress in utilizing molecular imaging technology to study and understand neuroinflammation, increasing efforts and investment should be made to bring more of these novel imaging agents from the "bench to bedside."


The effect of topology of chitosan biomaterials on the differentiation and proliferation of neural stem cells.
Neural stem cells (NSCs) are capable of self-renewal and differentiation into three principle central nervous system cell types under specific local microenvironments. Chitosan films (Chi-F), chitosan porous scaffolds (Chi-PS) and chitosan multimicrotubule conduits (Chi-MC) were used to investigate their effects on the differentiation and proliferation of NSCs isolated from the cortices of fetal rats. In the presence of 10% fetal bovine serum most NSCs cultured on Chi-F differentiated into astrocytes, NSCs cultured on Chi-MC showed a significant increase in neuronal differentiation, while Chi-PS somewhat promoted NSCs to differentiate into neurons. However, in serum-free medium with 20 ng ml(-1) basic fibroblast growth factor NSCs cultured on Chi-F showed the greatest proliferation, NSCs cultured on Chi-MC showed moderate cell proliferation, but NSCs cultured on Chi-PS exhibited the least cell proliferation. These observations indicate that chitosan topology can play an important role in regulating differentiation and proliferation of NSCs and raise the possibility of the utilization of chitosan in various structural biomaterials in neural tissue engineering.


Review: Roles for astrocytes in epilepsy: insights from malformations of cortical development.
Malformations of cortical development (MCDs), such as cortical dysplasia and tuberous sclerosis complex, are common causes of intractable epilepsy, especially in paediatric patients. Recently, mounting evidence points to a common pathology of these disorders. Hyperactivation of mammalian target of rapamycin (mTOR) has been proposed as a central mechanism in most, if not all, MCDs. The transition from mTOR hyperactivation and cellular abnormalities to large-scale functional changes and seizure is, however, not fully understood. In this article we set out to review currently available information regarding MCD pathology, focusing on glial cells - especially astrocytes - and their interactions with the brain vascular system. A large body of evidence points to these elements as potential targets in MCD. Here, we attempt to provide a review of this evidence and propose some hypotheses regarding the possible chain of events linking primary glial dysfunction and epilepsy. We focus on extracellular matrix remodelling, blood-brain barrier leakage and failure of astrocyte-dependent removal of extracellular debris. We posit that the failure of these systems results in a chronically pro-inflammatory environment, maintaining local astrocytes in a state of gliosis, with increased susceptibility to seizures as a consequence.


Arthritis and hepatitis.
Arthritis has a fascinating relationship with hepatitis of diverse origins. Either condition can predominate and the correct diagnosis may be elusive, especially in the early stages. Humoral autoimmune mechanisms appear to serve as a bridge connecting the two target organs, whether the syndromes are caused by viral infections or unspecified etiologies. Maintaining a keen awareness of and being able to recognize the clinical arthritis-hepatitis syndromes are critical, enabling the physician to establish accurate diagnoses, to prescribe the correct therapies, and to predict outcomes.


Isometric Handgrip as an Adjunct for Blood Pressure Control: a Primer for Clinicians.
Considered a global health crisis by the World Health Organization, hypertension (HTN) is the leading risk factor for death and disability. The majority of treated patients do not attain evidence-based clinical targets, which increases the risk of potentially fatal complications. HTN is the most common chronic condition seen in primary care; thus, implementing therapies that lower and maintain BP to within-target ranges is of tremendous public health importance. Isometric handgrip (IHG) training is a simple intervention endorsed by the American Heart Association as a potential adjuvant BP-lowering treatment. With larger reductions noted in HTN patients, IHG training may be especially beneficial for those who (a) have difficulties continuing or increasing drug-based treatment; (b) are unable to attain BP control despite optimal treatment; (c) have pre-HTN or low-risk stage I mild HTN; and (d) wish to avoid medications or have less pill burden. IHG training is not routinely prescribed in clinical practice. To shift this paradigm, we focus on (1) the challenges of current HTN management strategies; (2) the effect of IHG training; (3) IHG prescription; (4) characterizing the population for whom it works best; (5) clinical relevance; and (6) important next steps to foster broader implementation by clinical practitioners.


Rates and predictors of switching to tenofovir alafenamide-containing ART in a nationwide cohort.
Tenofovir alafenamide (TAF)-containing combinations were introduced in Switzerland after October 2016 and are recommended over tenofovir disoproxil fumarate (TDF) in patients with osteoporosis or impaired renal function. We included all participants of the Swiss HIV Cohort Study on TDF-containing antiretroviral therapy with follow-up visits after January 2016. We determined the proportion of switches from TDF to TAF overall, and among patients with risk factors for TDF toxicity, including osteoporosis, impaired renal function or marked proteinuria. We used multivariable logistic regression to explore predictors of switching from TDF to TAF. We included 5'012 patients, of whom 652 (13.0%) had risk factors for TDF toxicity. A switch from TDF to TAF was undertaken in 2'796 (55.8%) individuals overall, and in 465 (71.3%) with risk factors. Predictors of switching to TAF were male sex (adjusted odds ratio 1.27, 95% confidence interval 1.07-1.50), age > 50 years (1.43, 1.23-1.66) and the presence of risk factors for TDF toxicity (2.21, 1.77-2.75). In contrast, patients with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-pill regimen (0.11, 0.09-0.13), those treated in non-tertiary care centers (0.56, 0.46-0.70), as well as those with CD4 cell counts below 500/μL (0.77, 0.66-0.90) and with chronic hepatitis C infection (0.66, 0.54-0.80) were most likely to stay on TDF. Over 50% of patients on TDF-containing therapy, including the majority of patients at risk for TDF toxicity, were switched to TAF within two years of its introduction in Switzerland. Individuals on NNRTI-based single-pill regimens were most likely to remain on TDF.


Multivariate analysis of independent roles of socioeconomic status, occupational physical activity, reproductive factors, and postmenopausal hormonal therapy in risk of breast cancer.
This case-control study assesses the independent roles of reproductive history, postmenopausal hormonal therapy (HT), socioeconomic status (SES), and occupational physical activity on the risk of breast cancer (BC). Odds ratios (OR) were estimated from conditional logistic multivariate regression model in a data set of 19,253 Finnish women diagnosed with BC between 1994 and 2013 and 96,265 age-matched population controls. Both pre- and postmenopausal white-collar workers had significantly increased risk of ductal and lobular BC as compared to manual workers. Moderate occupational physical activity reduced risk of lobular BC by 14%. There was a transient increase in the risk of BC observed after each birth followed by a protective effect starting some years after the delivery. As the number of children increased, the short-term excess risk was lower and protective effect was observed earlier. Continuous estrogen-progestin therapy (EPT) significantly increased the risk of both ductal and lobular BC and the magnitude of risk was directly proportional to duration of use (OR for 5+ years of use 2.26, 95% confidence interval 2.12-2.42). Monthly EPT for 5+ years increased the risk (OR 1.32, 95% CI 1.20-1.45). Users of estradiol plus levonorgestrel intrauterine system devices showed ORs of 1.56 (95% CI 1.45-1.69) and 2.18 (95% CI 1.81-2.64) for ductal and lobular BC, respectively. This study concludes that pregnancy has a dual effect on BC risk, with a transient increase in risk followed by a long-term protective effect. The SES and HT have a large effect on BC risk while occupational physical activity has only a small independent effect.


Childhood injury: a current perspective.
The majority of childhood injuries requiring admission are due to traffic-related injury, falls, and burns. Many of these injuries are preventable. In the case of the unpreventable, unintentional injury, the natural history of the injury and outcome can be altered by adherence to established safety standards. New standards also need to be set. There is definitely room for improvement in vehicular restraint systems for the smaller and younger passengers. It is known that wearing bicycle helmets, using safety belts, securing firearms in the home, and controlling hot water heater temperature levels will prevent or lessen injury in children. This information is being promulgated to communities by activities such as the National SAFE KIDS Campaign, a program of Children's National Medical Center sponsored by Johnson & Johnson Family of Companies and the National Safety Council. This campaign emphasizes important aspects of childhood injury: scope, causes, and prevention. Questions about the most devastating of childhood injuries, child abuse and assault related to violent crime, are more complex and the answers elusive. The study of patterns of injury in children highlights the need to implement new strategies aimed at prevention. At the same time, valuable information is obtained about specific injuries and responses seen in children that set them apart from adults.


Using the right drug: a treatment algorithm for regular supraventricular tachycardias.
Despite the recent advent of and the successful results from catheter ablation, pharmacological therapy is still used by most clinicians as the first line therapy in patients with regular supraventricular tachycardias. Before prescribing an antiarrhythmic agent, documentation of the arrhythmia using a 12-lead electrocardiogram (ECG) is necessary to identify the type of tachycardia. The ECG diagnosis is based on the presence and polarity of the P wave, the P to QRS relationship, the presence of QRS alternation and the effect of bundle branch block on tachycardia rate. Most regular supraventricular tachycardias use the atrioventricular node either passively, as in atrial tachycardias or flutter, or actively, as paroxysmal junctional tachycardias. The Sicilian Gambit approach attempted to introduce some rationale in the choice of an antiarrhythmic agent, taking into account tachycardia mechanism, by defining the critical components of the tachycardia and the vulnerable parameter, i.e. the component that may readily be affected by an appropriate antiarrhythmic agent. For this approach, an electrophysiological study is particularly useful. The most common regular paroxysmal supraventricular tachycardias include atrioventricular nodal re-entrant tachycardias and atrioventricular re-entrant tachycardias which use an overt or concealed accessory atrioventricular connection (Kent bundle) or atriofascicular connection (Mahaim). For acute termination of paroxysmal junctional tachycardia, intravenous adenosine is the drug of choice. For the prevention of the tachycardia attacks in atrioventricular nodal re-entrant tachycardia, the agents with a depressive effect on the antegrade slow pathway, such as calcium channel blockers or beta-blockers, are likely to be effective. If they fail, sodium channel blockers (propafenone or flecainide) may be indicated. In tachycardias involving accessory connections, agents that affect fast channel dependent tissue (propafenone, flecainide, cibenzoline, disopyramide or hydroquinidine) are effective. Potassium current blockers, such as sotalol or amiodarone, represent an alternative therapy. In atrial tachycardias, the use of propafenone, flecainide or sotalol constitute a logical choice. In drug-resistant cases, amiodarone is the most potent agent. Radiofrequency ablation of the slow atrioventricular nodal pathway, of an accessory connection or of an atrial focus, is indicated in drug-resistant or drug-intolerant patients and is increasingly offered as an alternative therapy.


Novel protein folds and their nonsequential structural analogs.
Newly determined protein structures are classified to belong to a new fold, if the structures are sufficiently dissimilar from all other so far known protein structures. To analyze structural similarities of proteins, structure alignment tools are used. We demonstrate that the usage of nonsequential structure alignment tools, which neglect the polypeptide chain connectivity, can yield structure alignments with significant similarities between proteins of known three-dimensional structure and newly determined protein structures that possess a new fold. The recently introduced protein structure alignment tool, GANGSTA, is specialized to perform nonsequential alignments with proper assignment of the secondary structure types by focusing on helices and strands only. In the new version, GANGSTA+, the underlying algorithms were completely redesigned, yielding enhanced quality of structure alignments, offering alignment against a larger database of protein structures, and being more efficient. We applied DaliLite, TM-align, and GANGSTA+ on three protein crystal structures considered to be novel folds. Applying GANGSTA+ to these novel folds, we find proteins in the ASTRAL40 database, which possess significant structural similarities, albeit the alignments are nonsequential and in some cases involve secondary structure elements aligned in reverse orientation. A web server is available at http://agknapp.chemie.fu-berlin.de/gplus for pairwise alignment, visualization, and database comparison.


Local advocacy for the medically indigent: strategies and accomplishments in one county.
Because no national health program assures entitlement to basic services, advocates must cope with barriers to access on the local level. The authors report several strategies that a community-based coalition has used to improve indigent care in one county. Research strategies have involved short-term investigations of barriers to needed services. Political strategies have attempted to improve the county government's administrative procedures and financial support of services for the poor. Legal strategies have involved the participation of attorneys who represent clients unable to receive care. Although such advocacy efforts do not guarantee access, they can substantially improve the availability of local services.


Age-related normative changes in phasic orthostatic blood pressure in a large population study: findings from The Irish Longitudinal Study on Ageing (TILDA).
In this report, we provide the first normative reference data and prevalence estimates of impaired orthostatic blood pressure (BP) stabilization, initial orthostatic hypotension, and orthostatic hypotension based on beat-to-beat blood pressure methods in a population-representative sample. Participants were recruited from a nationally representative cohort study (≥50 years). Beat-to-beat systolic BP, diastolic BP, and heart rate records were analyzed among those who underwent an active stand test (n=4475). Normograms were estimated by use of generalized additive models for location, shape, and scale with Box-Cox power exponential distribution. Prevalence estimates of impaired BP stabilization, initial orthostatic hypotension, and orthostatic hypotension are reported. Orthostatic BP responses in adults aged 50 to 59 years stabilized within 30 seconds of standing, with older groups taking 30 seconds or longer. The total prevalence of impaired BP stabilization was 15.6% (95% confidence interval [CI], 14.1%-17.1%), increasing with age to 41.2% (95% CI, 30.0%-52.4%) in people ≥80 years old. Initial orthostatic hypotension occurred in 32.9% (95% CI, 31.2%-34.6%) of the population aged ≥50 years, with no age gradient evident. The prevalence of orthostatic hypotension was 6.9% (95% CI, 5.9%-7.8%) in the total population, increasing to 18.5% (95% CI, 9.0%-28.0%) in those aged ≥80 years old. Significant age-related differences exist in the time course of postural BP responses, with abnormal responses taking longer than 30 seconds to stabilize. Impaired BP stabilization is more common as we age, affecting more than two-fifths of the population aged ≥80 years, and may play a future role in the management of falls and syncope.


Anti-Inflammatory, Anticholinesterase, and Antioxidant Potential of Scopoletin Isolated from Canarium patentinervium Miq. (Burseraceae Kunth).
Bioassay guided fractionation of an ethanol extract of leaves of Canarium patentinervium Miq. (Burseraceae Kunth.) led to the isolation of scopoletin. The structure of this coumarin was elucidated based on spectroscopic methods including nuclear magnetic resonance (NMR-1D and 2D) and mass spectrometry. Scopoletin inhibited the enzymatic activity of 5-lipoxygenase and acetyl cholinesterase with an IC50 equal to 1.76 ± 0.01 μ M and 0.27 ± 0.02 mM, respectively, and confronted oxidation in the ABTS, DPPH, FRAP, and β -carotene bleaching assay with EC50 values equal to 5.62 ± 0.03 μ M, 0.19 ± 0.01 mM, 0.25 ± 0.03 mM and 0.65 ± 0.07 mM, respectively. Given the aforementioned evidence, it is tempting to speculate that scopoletin represents an exciting scaffold from which to develop leads for treatment of neurodegenerative diseases.


Cerebral activation patterns related to initiation and inhibition of hand movement.
Sequential ordering of purposeful movements includes distinct transitions between muscle contraction and relaxation. To explore cerebral activation patterns underlying such movement initiation and inhibition, we applied functional magnetic resonance imaging to test the effects of (1) ballistic movement (dominated by initiation), (2) movement with stepwise interruption (dominated by inhibition) and (3) smooth movements. Right-hand movements were performed by 21 healthy participants. In the basal ganglia, ballistic movements evoked putamen activation, indicating its specific contribution to initiation. Stepwise interrupted movement induced increased activation of the caudate nucleus, globus pallidus and subthalamic nucleus whereas, at the cortical level, supplementary motor area activation increased. This indicates a specific basal ganglia-thalamocortical circuit involved in motor inhibition.


Association of the OPRM1 A118G polymorphism and Pavlovian-to-instrumental transfer: Clinical relevance for alcohol dependence.
Pavlovian-to-instrumental transfer (PIT) quantifies the extent to which a stimulus that has been associated with reward or punishment alters operant behaviour. In alcohol dependence (AD), the PIT effect serves as a paradigmatic model of cue-induced relapse. Preclinical studies have suggested a critical role of the opioid system in modulating Pavlovian-instrumental interactions. The A118G polymorphism of the OPRM1 gene affects opioid receptor availability and function. Furthermore, this polymorphism interacts with cue-induced approach behaviour and is a potential biomarker for pharmacological treatment response in AD. In this study, we tested whether the OPRM1 polymorphism is associated with the PIT effect and relapse in AD. Using a PIT task, we examined three independent samples: young healthy subjects (N = 161), detoxified alcohol-dependent patients (N = 186) and age-matched healthy controls (N = 105). We used data from a larger study designed to assess the role of learning mechanisms in the development and maintenance of AD. Subjects were genotyped for the A118G (rs1799971) polymorphism of the OPRM1 gene. Relapse was assessed after three months. In all three samples, participants with the minor OPRM1 G-Allele (G+ carriers) showed increased expression of the PIT effect in the absence of learning differences. Relapse was not associated with the OPRM1 polymorphism. Instead, G+ carriers displaying increased PIT effects were particularly prone to relapse. These results support a role for the opioid system in incentive salience motivation. Furthermore, they inform a mechanistic model of aberrant salience processing and are in line with the pharmacological potential of opioid receptor targets in the treatment of AD.