Prophylaxis against atrial fibrillation after cardiac surgery: beneficial effect of perioperative metoprolol.
Multiple agents have been investigated to prevent atrial fibrillation (AF) after cardiac surgery. Several studies have investigated the use of β-blockers such as metoprolol or amiodarone with promising results. We aimed to investigate perioperative pharmacologic prophylaxis against AF using metoprolol, and amiodarone in combination with metoprolol. We conducted a prospective, randomised, single-blind, controlled pilot study in patients undergoing elective cardiac surgery. Subjects were randomised pre-operatively to one of three treatment groups: standard therapy (control) or metoprolol (5 mg IV over 5 min on commencement of bypass then 5 mg IV qid for 24h then 25-50 mg tds orally until discharge) or amiodarone (300 mg over 1h starting shortly after the commencement of bypass, then 900 mg over 24h then 400 mg orally tds until discharge) plus metoprolol as above. Patients had ECG monitoring for the occurrence of AF for six days or until discharge. Two hundred and fifteen patients were enrolled. Between-group differences in AF in an intention-to-treat analysis were not significant: control 34% (23-45%), metoprolol 35% (24-46%), combined 22% (12-33%) (p = 0.21). However 87 patients (40%) did not receive the assigned treatment mainly due to side effects, especially bradycardia. The remaining 128 patients were analysed on a per-protocol basis with the overall difference between the three groups bordering on significance: control 34% (23-45%), metoprolol 26% (9-43%), combined 11% (0-23%) (p = 0.06). Logistic regression analysis, correcting for age and gender, was used to separate the individual effects of metoprolol and amiodarone in the presence of metoprolol which showed that compared to control there was a significant effect of metroprolol on AF incidence (O.R. 0.31 (0.10-0.99), p = 0.048) but not of amiodarone (O.R. 0.97 (0.19-5.02), p = 0.97). (1) Perioperative metoprolol but not amiodarone itself in combination with metoprolol is associated with a significant reduction in postoperative AF. (2) Perioperative administration of metoprolol and combination of metoprolol with amiodarone is associated with a high incidence of side effects, especially bradycardia. (3) Further studies are indicated to confirm these preliminary findings but in the meantime it would not be unreasonable to implement the use of perioperative metoprolol for routine prophylaxis of AF.


Effect of low-dose androgen and zinc sulfate on sperm motility and seminal zinc levels in infertile men.
Beneficial effects of zinc therapy in some infertile patients with low seminal zinc concentrations and decreased sperm motility have been reported recently. The effects of zinc therapy, low-dose (5-10 mg/day) androgen therapy, and combination therapy of both zinc and low-dose androgen, on sperm motility and seminal zinc concentration were studied in patients referred to the andrology clinic. Low-dose androgen therapy increased seminal zinc concentrations and sperm motility, only when pretreatment seminal zinc concentrations were low. Furthermore, patients with low seminal zinc concentrations and poor sperm motility showed greater improvement of sperm motility and seminal zinc levels in response to zinc sulfate with fluoxymesterone than did fluoxymesterone alone or zinc sulfate alone, possible due to a synergistic effect of zinc and androgen.


Early specification of GAD67 subventricular derived olfactory interneurons.
Olfactory bulb interneurons are continuously generated in the subventricular zone (SVZ) and migrate along the rostral migratory stream (RMS) into the olfactory bulb (OB) where the majority becomes local GABAergic interneurons. We previously showed that SVZ-derived progenitor cells expressed glutamic acid decarboxylase 65 kDa (GAD65) very early in the migratory pathway. However, only approximately half of OB GABAergic interneurons use GAD65, an equal number express the 67 kDa GAD enzyme. To investigate the differentiation of these GABAergic interneurons we examined their migration in a transgenic mouse expressing green fluorescent protein (GFP) under the control of the GAD67 promoter. In adult, GFP was expressed by a subpopulation of migratory cells in the SVZ and along the RMS. Using Doublecortin (DCX) as a marker of migrating neuroblasts and bromodeoxyuridine (BrdU) incorporation, we show that these GAD67-GFP neurons co-express DCX and incorporate BrdU indicating they are newly born migratory neuroblasts. This is similar to GAD65 transgene expression, and in contrast to dopaminergic interneuron transgene expression which occurs only after cells reach the olfactory bulb. Although the GAD65/67 transgenes are expressed early in migration, there is minimal protein production in the cells prior to reaching the OB. These results suggest that migrating SVZ-derived neuroblasts acquire GABAergic identity prior to reaching their final location in the olfactory bulb.


Argatroban therapy for heparin-induced thrombocytopenia during pregnancy in a woman with hereditary antithrombin deficiency.
A 33-year-old woman developed deep venous thrombosis at 7 gestational weeks (GW). Heparin-induced thrombocytopenia was evident at 9 GW during unfractionated heparin infusion. Immediately, anticoagulation therapies together with antithrombin (AT) infusion were commenced with the use of argatroban from 9 GW, and fondaparinux was substituted for argatroban after 24 GW. The patient had hereditary AT deficiency type I determined by laboratory findings and results of genomic DNA analysis. The pregnancy ended in full-term vaginal delivery of a healthy male without adverse effects of the anticoagulation therapies. This was the first report of a pregnant woman who developed heparin-induced thrombocytopenia caused by heparin therapy for deep venous thrombosis due to AT deficiency.


Trends in atrial fibrillation ablation: have we maximized the current paradigms?
The purpose of this study was to evaluate how atrial fibrillation (AF) ablation has evolved over time with regards to patient characteristics, procedural variables, complications, and outcomes. We evaluated trends over time from 2003 to 2010 in clinical characteristics, procedural variables, complications, and Kaplan-Meier AF-free rates after the initial and final AF ablation in 1,125 patients undergoing 1,504 ablations. Evaluating trends from 2003 to 2010, we found that patients undergoing AF ablation became older (P < 0.0001), had higher CHADS(2) scores (P < 0.0001), and more coronary artery disease (P = 0.021), persistent AF (P < 0.0001), hypertension (P < 0.0001), and previous strokes/transient ischemic attacks (P = 0.005). Procedure times decreased from 256 ± 49 to 122 ± 28 min (P < 0.0005), fluoroscopy times decreased from 134 ± 29 to 56 ± 19 min (P < 0.0005), and major (P = 0.023), minor (P = 0.023), and total complications (P = 0.001) decreased over time. The learning curve to minimize complications was 6 years. For paroxysmal AF, initial ablation AF-free rates improved over time (P = 0.015) but improvement plateaued in recent years. For persistent AF, initial ablation AF-free rates trended toward improvement over time (P = 0.062) but also plateaued in recent years. For long-standing persistent AF (P = 0.995), there was no outcome improvement after initial ablation over time. There was no trend for improved final outcomes (including repeat ablations) over time for paroxysmal, persistent, or long-standing AF (P = 0.150 to P = 0.978). Despite decreased procedural and fluoroscopy times and reduced complication rates, post-ablation freedom from AF has not improved commensurately in recent years. A better understanding of AF initiation and maintenance may be required to devise personalized approaches to AF ablation and further improve outcomes.


Contemporary management of TMJ involvement in JIA patients and its orofacial consequences.
Juvenile idiopathic arthritis is the most common chronic rheumatic condition during childhood. Temporomandibular joint arthritis is frequently asymptomatic. When it takes place during childhood, it may affect condylar growth; therefore, these children are at risk of unfavorable long-term outcomes from the associated joint damage. The etiology is not completely understood, but it is considered as multifactorial with both genetic and environmental factors involved. The standardized examination and imaging protocols serve important purpose to diagnose temporomandibular joint (TMJ) arthritis not only to establish an early interventional strategy but also to assess craniofacial growth and the progression of signs and symptoms in those patients. Although the treatment of juvenile idiopathic arthritis (JIA) has changed dramatically over the last decades due to new therapeutic options, TMJ arthritis still can develop during the course of the disease. In clinical experience, TMJs appear to respond less well to the standard of care used to treat other joints. More individualized approach to the patient's treatment serves as the main goal of personalized medicine. It could be achieved by adopting new methods of medical imaging such as conebeam computer tomography as well as developing reliable biomarkers which may assist with predicting disease type, course, or severity and predicting response to medication. This article provides an overview of current information on orofacial complications in JIA and its management. Based on information provided in this review, more precise diagnosis, proper tools for recognizing people at risk, and more efficient treatment approaches could be implemented. This may lead to more personalized treatment management strategies of TMJ complications of JIA patients.


Portopulmonary hypertension in pediatric patients.
To investigate the clinical presentation, manifestations, and response to therapy of portopulmonary hypertension (PPHTN) in pediatric patients. This study was a retrospective chart review describing the evaluation and course of 7 patients with PPHTN. Causes of portal hypertension (HTN) included biliary atresia (3 cases), cavernous transformation of the portal vein (2 cases), and primary sclerosing cholangitis and cryptogenic cirrhosis (1 case each). The median interval from the diagnosis of portal HTN to PPHTN was 12.1 years. Four patients presented with a new heart murmur, 4 presented with syncope, and 3 presented with dyspnea. Although electrocardiograms (ECGs) and chest x-rays were normal in 3 and 2 patients, respectively, echocardiograms diagnosed pulmonary HTN in all 7 patients. Five patients had cardiac catheterizations; the average mean pulmonary artery pressure was 65 +/- 20 mm Hg. Response to therapy was variable, and 4 patients died. Postmortem lung tissue examination revealed plexiform lesions and pulmonary arteriopathy. Because symptoms are subtle and may be overlooked, pediatric patients with portal HTN who develop a new heart murmur, dyspnea, syncope, or who are being evaluated for liver transplantation require evaluation for PPHTN. ECG and chest x-ray are insensitive screens for PPHTN. An echocardiogram and cardiology evaluation is essential for the diagnosis.


Differences in digital health literacy and future anxiety between health care and other university students in England during the COVID-19 pandemic.
This study investigates university students' digital health literacy and web-based information-seeking behaviours during the early stages of the COVID-19 pandemic in England. It compares undergraduate and postgraduate students in non-health related subjects with health care students, many of whom were preparing for, or working in, frontline roles. The survey was conducted as part of a wider study by the COVID-HL research consortium. A cross-sectional study was conducted among n = 691 university students aged ≥18 years from 25 universities across England using an adapted digital survey developed by COVID-HL. Data were collected regarding sociodemographic characteristics and specific measures drawn from the Future Anxiety Scale and the Digital Health Literacy Instrument (DHLI). These had been adapted for use in an English setting and to the specific context of the COVID-19 pandemic. Other data collected included students' anxiety or worries about the future using the Dark Future Scale as well as behaviours in online information-seeking. Data were analysed using correlations to test for relationships between constructs and also between group comparisons to test for differences between students studying health and non-health related subjects. Across digital health literacy dimensions, there was no significant difference between students studying health-related subjects and other students. Health care students did report greater difficulties in relation to how to behave online. They also relied less on public body sources for information about the pandemic. A significant difference was found between the two student populations in relation to their anxiety about the future with health care students reporting fewer fears about the future. Although digital health literacy is well developed in university students, a significant proportion of students still face difficulties with evaluating online information which may frustrate public health efforts. This could be addressed by ensuring health students' curriculum in particular encompasses digital health literacy.


Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway.
We recently reported that macrophages from aged mice produced less tumor necrosis factor (TNF)-alpha following lipopolysaccharide (LPS) stimulation than macrophages from young animals. This correlated with decreased levels of phosphorylated and total p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs). Here, we went on to determine if age affects other Toll-like (TLR) and non-TLR signaling pathways. We found that LPS- and zymosan-stimulated TNF-alpha and IL-6 production is attenuated in splenic macrophages from aged mice compared to young. Conversely, LPS-stimulated, but not zymosan-stimulated, IL-10 production from the aged group was elevated over that of the young group. In contrast, IL-2-stimulated TNF-alpha and IL-6 production was not affected by age. The age-associated changes did not correlate with alterations in the cell-surface expression of TLR2, TLR4, or IL-2Rbeta. Macrophages from aged mice demonstrated lower p38 MAPK and MAPK-activated protein kinase (APK)-2 activation. Protein expression of p38, but not MAPK-APK-2, was reduced with age. Additionally, nuclear factor (NF)-kappaB activation was significantly decreased in macrophages from aged mice after exposure to LPS, but not IL-2. These data indicate that age-associated macrophage signaling alterations are pathway-specific and suggest that TLR-mediated pathways are impaired with age at the level of MAPK expression.


Division of the spleen cells and popliteal lymph nodes in non-continuous BSA gradient of the bovine serum albumin.
Lymphocytes from the popliteal lymph nodes and the spleen of a rabbit were divided by means of rotating in the gradient of bovine albumin (BSA). Nine fractions were obtained, and the percentage of the T lymphocytes as well as the total number of cells were determined.


Erythrocytapheresis versus phlebotomy in the maintenance treatment of HFE hemochromatosis patients: results from a randomized crossover trial.
Phlebotomy is standard maintenance treatment of patients with hereditary hemochromatosis (HH). Erythrocytapheresis, which selectively removes red blood cells, provides a new, potentially more effective treatment option. Our aim was to evaluate the effectiveness of erythrocytapheresis over phlebotomy for maintenance therapy in patients with HH. We conducted a two-treatment-arms, randomized, crossover clinical trial, involving 46 patients, treated for 1 year with either erythrocytapheresis or phlebotomy to keep the ferritin level at not more than 50 µg/L. After 1 year, patients were switched to the other treatment modality. Primary endpoint was the number of treatment procedures per treatment year. Secondary endpoints were intertreatment intervals, several aspects of health-related quality of life, costs, and patient discomfort as well as preference for one of both treatments. The mean number of required treatment procedures per treatment year was significantly higher using phlebotomy versus erythrocytapheresis (3.3 vs. 1.9; mean difference, 1.4; 95% confidence interval, 1.1-1.7). The median intertreatment time was 2.3 times longer for erythrocytapheresis. There was no significant difference in overall health assessed by SF-36 and EQ-5D, respectively, between both treatments arms. The number of self-reported swollen joints was significantly higher during phlebotomy treatment. The mean treatment costs of one treatment year were 235€ for phlebotomy versus 511€ for erythrocytapheresis. Eighty percent of patients preferred erythrocytapheresis as treatment method. Erythrocytapheresis significantly reduced the number of treatment procedures per treatment year, although the mean treatment costs per year are higher in our health care system. It is the preferred treatment for the majority of patients.


A possible case of myelopathy/tropical spastic paraparesis in an Argentinian woman with human T lymphocyte virus type II.
A case of neurological disease featuring human T lymphocyte virus-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was diagnosed by serological (Western blot) and molecular (polymerase chain reaction) criteria as related to human T lymphocyte virus (HTLV)-II infection. This is, to our knowledge, the first case of this kind found in Argentina and is additional evidence that HAM/TSP solely related to HTLV-II infection occurs in HTLV-I-negative subjects.


Anthropology and affect: a consideration of the idiosyncratic dimension of human behaviour.
In this paper a theoretical perspective is presented in which affect occupies a central position and behaviour is viewed in terms of different degrees of affective expression. Such behaviour is conceptualized in terms of three models: a structural model, a rational model and a psychological model. While the first two models are frequently encountered in the literature, the psychological model has not received explicit formulation, although, as shown here, it is crucial in understanding certain forms of idiosyncratic behaviour that have political and social relevance.


Acute oxidant damage promoted on cancer cells by amitriptyline in comparison with some common chemotherapeutic drugs.
Oxidative therapy is a relatively new anticancer strategy based on the induction of high levels of oxidative stress, achieved by increasing intracellular reactive oxygen species (ROS) and/or by depleting the protective antioxidant machinery of tumor cells. We focused our investigations on the antitumoral potential of amitriptyline in three human tumor cell lines: H460 (lung cancer), HeLa (cervical cancer), and HepG2 (hepatoma); comparing the cytotoxic effect of amitriptyline with three commonly used chemotherapeutic drugs: camptothecin, doxorubicin, and methotrexate. We evaluated apoptosis, ROS production, mitochondrial mass and activity, and antioxidant defenses of tumor cells. Our results show that amitriptyline produces the highest cellular damage, inducing high levels of ROS followed by irreversible serious mitochondrial damage. Interestingly, an unexpected decrease in antioxidant machinery was observed only for amitriptyline. In conclusion, based on the capacity of generating ROS and inhibiting antioxidants in tumor cells, amitriptyline emerges as a promising new drug to be tested for anticancer therapy.


The effect of host plant phenology on reproduction of the milkweed bug, Oncopeltus fasciatus, in tropical Florida.
A field study of the relationship between host plant phenology and the reproductive pattern of the large milkweed bug, Oncopeltus fasciatus, was conducted in south Florida. Since O. fasciatus need seeds of either milkweed or Nerium oleander plants to reproduce, reproduction takes place on only those host plants that are producing seed pods.Two of four major host plants, Asclepias incarnata and Sarcostemma clausa fruit seasonally, producing pods in early autumn and early winter, respectively. The third milkweed host, Asclepias curassavica, produces almost no pods midsummer (although it flowers abundantly) and few pods midwinter. Nerium oleander (Apocynaceae) produces some pods all year but is only used by O. fasciatus in the summer when milkweeds are not producing pods. Correspondingly, reproduction of O. fasciatus has been observed year round, but relatively few females reproduce in midwinter, coinciding with decreased pod production and low temperatures. This pattern is consistent with the hypothesis that a photoperiodic cue of short day lengths under conditions of cool temperatures may cause adult females to enter diapause and delay reproduction in the field.A comparison of plant phenologies and rainfall between 1976, a very dry year, and 1978, a year with normal rainfall, showed that extreme dryness disrupted the seasonal fruiting of the milkweeds and consequently the reproduction of O. fasciatus.


[Ischemic mitral regurgitation: contributions of exercise echocardiography and new therapeutic perspectives].
The ischemic mitral regurgitation is defined by a left ventricular muscle disease affecting the function of normal mitral valve leaflets. This kind of mitral regurgitation is founded in about 20% of the ischemic cardiomyopathy and is attributed to the remodelling of the left ventricular shape. Its development is associated to a significantly worse prognosis. Frequently this ischemic mitral regurgitation will be associated to episode of acute heart failure decompensation. Its diagnosis is sometimes challenging as the degree of regurgitation might be extremely variable and affected by loading conditions. Echocardiography and especially exercise stress echocardiography has been demonstrated as an extremely powerful tool for its diagnosis and the prognostic evaluation. Its treatment should include the pharmacological treatment of the chonic heart failure and we are still waiting data in regard to the prognostic role of surgical mitral valvuloplastie. Works are still ongoing.


Extreme dehydration of plant tissues irreversibly converts the major and variable phyA' into the minor and conserved phyA''.
Effect of dehydration of plant tissues on the two native phenomenological phytochrome A (phyA) pools - major, variable and soluble phyA' and minor, relatively conserved and presumably membrane(protein)-associated phyA'' - was investigated on etiolated seedlings of barley and maize. With the use of in situ low-temperature fluorescence spectroscopy and photochemistry, it was found that even a considerable loss of water (up to 75-85% of the initial fresh weight) by coleoptiles does not bring about noticeable alterations of the spectroscopic and photochemical parameters of phytochrome pointing to a relative stability of the phyA'/phyA'' system in this regard. However, extreme dehydration (loss of weight 90%) of plant tissues including freeze-drying caused dramatic changes of the phytochrome properties - blue shift of the emission maximum and its widening and reduction in the extent of the Pr photoconversion into lumi-R at 85 K and into Pfr at 273 K. Rehydration of the dried tissues did not reverse the spectroscopic changes and did not recover the Pr-->lumi-R phototransformation at 85 K but restored the ability of Pr to photoconvert into Pfr at ambient temperatures. At the same time, the total phytochrome content was not affected by these treatments. These effects were interpreted as an irreversible transformation of phyA' into phyA'' upon extreme loss of water by plant tissues suggesting that water may play a role in stabilizing the conformation of the major and soluble phyA' species. The data also imply that phyA in dry and imbibing seeds is likely represented primarily by its phyA'' isoform.


Plasma vitamin B12 titres as indicators of disease severity and mortality of patients with alcoholic hepatitis.
Patients with alcoholic hepatitis with plasma B12 levels above 800 pg/ml have overt clinical manifestations of liver disease including severe hepatocellular damage. High plasma B12 levels significantly correlate (P less than 0.0001) with standard liver function tests, e.g. bilirubin, cholylglycine, alkaline phosphatase, AST and prothrombin time as an index of the severity of hepatic damage. Decrease in plasma B12 to normal titres implies a decrease in the severity of alcoholic liver disease, whereas increased plasma B12 levels relate to increased severity and mortality.


Behavior therapy for a child with Lesch-Nyhan syndrome.
The behavioural symptoms in a 10-year-old boy with Lesch-Nyhan syndrome were effectively ameliorated by the behavior therapy techniques of systematic desensitization and extinction. Therapy was undertaken in a highly controlled environment. The hypothesis that the self-destructive behaviours in this syndrome were voluntary and maintained through continuous reinforcement was confirmed. Characteristic biting and other maladaptive behaviours were extinguished. Over a period of time it was possible to remove all the physical restraints previously used to prevent the boy injuring himself. During treatment his anxiety, associated with phobic reaction to being unrestrained, was reduced by nitrous oxide. At 1 1/2 years follow-up the boy continues to be symptom-free. He attends a special class at school and is learning to walk with crutches. It is emphasied that a trained and experienced therapist and a controlled environment are essential for the success of this form of behaviour therapy, and the dangers inherent in this method of treatment are discussed.


Nitrogen Molecule Adsorption on Cationic Tantalum Clusters and Rhodium Clusters and Desorption from Their Nitride Clusters Studied by Thermal Desorption Spectrometry.
Adsorption and desorption of N2 molecules onto cationic Ta and Rh clusters in the gas phase were investigated in the temperature range of 300-1000 K by using thermal desorption spectrometry in combination with density functional theory (DFT) calculations. For Ta6(+), the first N2 molecule was found to adsorb dissociatively, and it remained adsorbed when Ta6(+)N2 was heated to 1000 K. In contrast, the second and the subsequent N2 molecules adsorbed weakly as a molecular form and were released into the gas phase when heated to 600 K. The difference can be explained in terms of the activation barrier between the molecular and dissociative forms. On the other hand, when Ta clusters were generated in the presence of N2 gas by the laser ablation of a Ta rod, isomeric clusters, TanNm(+), having heat resistivity were formed. For Rh6(+), N2 adsorbed molecularly at 300 K and desorbed totally at 450 K. These results were consistent with the DFT calculations, indicating that the dissociative adsorption of N2 is endothermic.


Long-term prognostic impact of the Great East Japan Earthquake in patients with cardiovascular disease - Report from the CHART-2 Study.
We and others have previously reported that the Great East Japan Earthquake (GEJE) caused a significant but transient increase in cardiovascular diseases and deaths in the disaster area. However, it remains to be examined whether the GEJE had a long-term prognostic influence in large-scale cohort studies. This point is important when analyzing the data before and after the GEJE in the cohort studies in the disaster area. We examined 8676 patients registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N=10,219) between 2006 and 2010 and were alive after March 10, 2011. There were 48 GEJE-related deaths, causing a sharp and transient increase in all-cause death within a month after the GEJE. However, after excluding the GEJE-related deaths, the cubic polynomial spline smoothing showed no significant increase in all-cause death, heart failure admission, non-fetal acute myocardial infarction, or non-fetal stroke during the median 3-year follow-up after the GEJE. The extrapolation curves beyond the GEJE, which were obtained by the parametric survival models based on the survival data censored on the GEJE, were not significantly different from the Kaplan-Meier curves estimating the survival functions of deaths and cardiac events during the total follow-up period without considering the impacts of the GEJE. Furthermore, the multivariate Cox proportional hazard model applied to the matched cohort of the baseline data and the data after the GEJE showed no significant differences in the impacts of prognostic factors on all-cause mortality before and after the GEJE. These results indicate that the GEJE had no significant long-term prognostic impact after the earthquake in cardiovascular patients in the disaster area.


Modified sonohysterography immediately after hysteroscopy in the diagnosis of submucous myoma.
To report a new, convenient, inexpensive, office-based examination to evaluate submucous myomas before hysteroscopic myomectomy. Retrospective analysis (Canadian Task Force classification II-2). University-affiliated teaching hospital. One hundred seventy-nine consecutive women. Diagnostic flexible hysteroscopy and transvaginal ultrasonography. Transvaginal ultrasonography was performed immediately after hysteroscopy. The size and depth of invasion of submucous myomas were clearly identified by retained fluid after hysteroscopy. Locations of myomas were as follows: anterior wall, 37 (20.7%); posterior wall, 52 (29.1%); lateral wall, 40 (22.3%); and fundus, 31 (17.3%); and multiple myomas, 19 (10.6%). Myomas with stalk were found in 101 patients (56.4%) and without stalk in 78 (43.6%). The mean myoma diameter was 2.95 +/- 2.12 cm and mean weight was 30.2 +/- 33.6 g. It is important to obtain details as to size and depth of invasion of submucous myomas before hysteroscopic myomectomy. Sonohysterography immediately after hysteroscopy is superior to traditional diagnostic methods.


Multivariate decomposition of trends, inequalities and predictors of skilled birth attendants utilisation in Nigeria (1990-2018): a cross-sectional analysis of change drivers.
Literature has assessed skilled birth attendants (SBAs) utilisation, but little is known about what contributes to the changes in SBA use. Multivariate decomposition analysis was thus applied in this study to examine; levels, trends, inequalities and drivers of changes in SBA utilisation. A cross-sectional analysis of five-waves of NDHS-data (1990, 2003, 2008, 2013, and 2018), collected through similar multistage sampling across the 36 states and the federal-capital-territory of Nigeria. Women of reproductive age (15-49 years), and with at least one birth in the last 5 years preceding each of the surveys. SBA use is the response variable while explanatory variables were classified into; Demographics, Health, Economic and Corporal factors. Chi-square test for trends of proportions across the ordered survey years assessed trends in SBA use. MDA that quantifies and partition predictors effect into endowment and coefficient components evaluated contributors to changes in SBA use. Statistical analysis was carried out at a 95% confidence interval in Stata 16. SBA use increased with significant (p<0.05) linear trends by 12% between 2003 and 2018. The decomposition analysis showed that differences in characteristics (endowment) accounted for 11.5% of the changes while the remaining 88.5% were due to differences in effects (coefficient). SBA utilisation rises by 61% when respondents decided on her health compared to when such decisions were made by the spouse. Utilisation of SBA, however, fell by 88% among women who reside in the states with high rural populations percentage. SBA use remained low in Nigeria, and slowly increase at the rate of <1% yearly. Women health decision-making power contributed most to positive changes. Residing in states with high rural populations has a negative impact on SBA use. Maternal health programmes that strengthen women's health autonomy and capacity building in rural communities should be encouraged.


Preventing the ITU syndrome or how not to torture an ITU patient! Part 2.
Admission to an intensive therapy unit (ITU) has been described as a 'necessary evil' (Barrie-Shevlin 1987), and some of the 'tortures' described in Part I of this article (Dyer 1995) may be an inevitable result of ITU care. This does not mean that the development of the ITU syndrome should be regarded as inevitable. Many potential causes of the syndrome can be avoided or at least ameliorated. Some suggested means of preventing the syndrome include designing ITUs with windows (Keep et al 1980), use of noise reducing materials when building ITUs (Hopkinson 1994, Topf & Davis 1993), using noise level as a criterion when purchasing equipment (Dracup 1988) or using remote telemetry for monitoring (Fisher & Moxham 1984). These would undoubtedly be beneficial but they are not practical propositions for nurses who wish to improve psychological care in the short term. For this reason, this article, concentrates mainly on immediately applicable, relatively cost-free interventions. Methods of preventing the syndrome should begin, whenever possible, before admission and should continue throughout the patients' stay. The main emphasis should be placed on prevention, but early detection and treatment of problems should also be given high priority. If a patient exhibits symptoms of psychological disturbance physical causes should be considered, but at the same time the ITU syndrome should be suspected and attempts made to alleviate possible causes of this. Nurses play a vital role in any attempts to alleviate problems and in 'humanising' the technical ITU environment (Ashworth 1987, Mackellaig 1990).(ABSTRACT TRUNCATED AT 250 WORDS)


Manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, a superoxide dismutase mimetic, reduces disease severity in in vitro and in vivo models for dry-eye disease.
To determine the efficacy of the superoxide dismutase mimetic, manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin (Mn-TM-2-PyP), in vitro in human corneal epithelial (HCE-T) cells and in vivo in a preclinical mouse model for dry-eye disease (DED). In vitro, HCE-T cultures were exposed either to tert-butylhydroperoxide (tBHP) to generate oxidative stress or to hyperosmolar conditions modeling cellular stress during DED. Cells were pre-treated with Mn-TM-2-PyP or vehicle. Mn-TM-2-PyP permeability across stratified HCE-T cells was assayed. In vivo, Mn-TM-2-PyP (0.1% w/v in saline) was delivered topically as eye drops in a desiccating stress/scopolamine model for DED. Preclinical efficacy was compared to untreated, vehicle- and ophthalmic cyclosporine emulsion-treated mice. Mn-TM-2-PyP protected HCE-T cells in a dose-dependent manner against tBHP-induced oxidative stress as determined by calculating the IC50 for tBHP in the resazurin, MTT and lactate dehydrogenase release cell viability assays. Mn-TM-2-PyP did not protect HCE-T cells from hyperosmolar insult. Its permeability coefficient across a barrier of HCE-T cells was 1.1 ± 0.05 × 10-6 cm/s and the mass balance was 62 ± 0.6%. In vivo, topical dosing with Mn-TM-2-PyP resulted in a statistically significant reduction of corneal fluorescein staining, similar to ophthalmic cyclosporine emulsion. Furthermore, Mn-TM-2-PyP significantly reduced leukocyte infiltration into lacrimal glands and prevented degeneration of parenchymal tissue. No protective effect against loss of conjunctival goblet cells was observed. Notably, Mn-TM-2-PyP did not produce ocular toxicity when administered topically. Our data suggest that Mn-TM-2-PyP, a prototypic synthetic metalloporphyrin compound with potent catalytic antioxidant activity, can improve signs of DED in vivo by reducing oxidative stress in corneal epithelial cells.


Late Rectal Toxicity from Image-guided Intensity Modulated Radiotherapy for Prostate Cancer.
Late rectal toxicity (LRT) was retrospectively evaluated in men with prostate cancer treated with image-guided intensity modulated radiotherapy (IG-IMRT). Between May 2008 and December 2009, 47 men with prostate adenocarcinoma were treated with IG-IMRT using in-room computed tomography (CT). The median time to grade 2 LRT was 12 months (range=1-24 months). Two of 3 men who developed grade 2 LRT had received treatment for diabetes, and the other was receiving anticoagulant/antiplatelet therapy (AC therapy). Their rectal wall V70 (the volume of rectal wall receiving 70 Gy) values were 12.6%, 13.0%, and 13.3%. Univariate analysis revealed that V70 of the rectal wall was the only significant risk factor for LRT (p=0.0073). No man with V70 ≤12.0% experienced grade 2 LRT. Strict rectal wall V70 ≤12% dose constraints should be considered when treating prostate cancer patients who are also receiving diabetic or AC therapy.


Picogram-level quantification of some growth hormones in bovine urine using mixed-solvent bubble-in-drop single drop micro-extraction.
Growth hormones are important biologically active compounds. However, they can cause deleterious effects if not used with care and their use in farmed animals is banned in the European Union. This study presents the development and application of a mixed-solvent "bubble-in-drop single drop micro-extraction" (BID-SDME) method for enrichment of stilbene hormones in bovine urine samples. The hormones are quantified using GC-MS showing good linearity with the coefficient of determination (R(2)) of 0.999 and 0.999 for hexestrol and diethylstilbestrol, respectively, in the concentration range 0.05-10 ng mL(-1). Excellent precision (RSD<10%) and accuracy (using a bovine urine certified reference material) were obtained. The observed detection capability (CCα, or LOD) values were 0.01 ng mL(-1) (hexestrol), 0.03 ng mL(-1) (cis-diethylstilbestrol) and 0.02 ng mL(-1) (trans-diethylstilbestrol), respectively, while the decision limit (CCβ, or LOQ) values were 0.03 ng mL(-1), 0.08 ng mL(-1) and 0.07 ng mL(-1), which are comparable to or better than those reported in literature. Importantly, sample handling is significantly simplified by our method and enrichment values are greatly enhanced. The results show that a 3:1 chloroform/toluene mixture gave the highest extraction efficiency with a drop-bubble ratio of 2:1. We highlight the importance of solvent density on the success of the BID-SDME method.


Synthesis of New Binary Thiazole-Based Heterocycles and Their Molecular Docking Study as COVID-19 Main Protease (Mpro) Inhibitors.
Isolated polynuclear binary heterocyclic compounds containing thiazole building block combined with benzofuran, pyrrole, thiazole, or thiophene via carboxamide and/or secondary amine as a junction are presented. The synthetic strategy of those is based on utilization of 2-chloroacetamido-4-phenylthiazole in the synthesis of binary heterocyclic compounds by cyclocondensation with salicylic aldehyde, acetonitrile derivatives, ammonium thiocyanate, 3-mercaptoacrylonitrile derivatives, and/or 3-mercaptoacrylate derivatives. The prepared binary thiazole-based heterocycles have been studied as protease (Mpro) inhibitors by molecular docking for visualization of their orientation and interactions with COVID-19 units using hydroxychloroquine as a reference molecule.


Energetics of the Electron Transfer Pathways in the Homodimeric Photosynthetic Reaction Center.
Photosynthetic reaction centers from a green sulfur bacterium (GsbRC), the PscA/PscA proteins, and photosystem I (PSI), PsaA/PsaB proteins, share structural similarities. Here, we report the redox potential (Em) values of GsbRC by solving the linear Poisson-Boltzmann equation and considering the protonation states of all titratable sites in the entire GsbRC protein and identify the factors that shift the Em values with respect to PSI. The Em values for one-electron reduction of the accessory (A-1) and adjacent (A0) chlorophylls in GsbRC are 100-250 mV higher than those in PSI, whereas the Em values for the Fe4S4 cluster (FX) are at the same level. The PsaA-Trp697/PsaB-Trp677 pair in PSI, which forms the A1-quinone binding site, is replaced with PscA-Arg638 in GsbRC. PsaB-Asp575 in PSI, which is responsible for the Em difference between A1A and A1B quinones in PSI, is absent in GsbRC. These discrepancies also contribute to the upshift in Em(A-1) and Em(A0) in GsbRC with respect to PSI. It seems likely that the upshifted Em for chlorophylls in GsbRC ultimately originates from the characteristics of the electrostatic environment that corresponds to the A1 site of PSI.


Multivariate analysis of otolith microchemistry can discriminate the source of oil contamination in exposed fish.
The uptake of metals into the aragonite lattice of the fish otolith (ear-bone) has been used for decades as a historical record of exposure to metals in polluted environments. The relative abundance of two metals in particular, Ni and V, are used in forensic chemical analysis of crude oils to assist in confirming its origin. In this study we investigate the potential for metal accumulation in otoliths to act as a biomarker of exposure to crude oil. Using a 33-day static-renewal laboratory trial design, 56 juvenile Lates calcarifer (commonly known as Asian seabass or barramundi) were fed diets enriched with V (20 mg/kg), Ni (500 mg/kg), Fe (500 mg/kg), and two crude oils with distinctly different metals profiles: a heavy fuel oil (1% w/w) and a typical Australian medium crude (1% w/w). Fish exposed to crude oils showed Ba and Al retained in otoliths in a dose-dependent manner, but fish fed V-, Ni- and Fe-enriched diets showed no metal increase in otoliths, indicating that V, Ni and Fe are not incorporated into the otolith of L. calcarifer via dietary exposure. For crude oils, incorporation into otolith for many metals is likely limited due to porphyrin casing reducing their bioavailability. Principal components analysis (PCA) and subsequent linear discriminatory analysis (LDA) of selected otolith metals demonstrated that, even despite large variability in the metal abundances detected in otolith between individuals within the test groups (cv = 1.00), it is possible to discriminate between fish exposed to different crude oils using multivariate analysis of their otolith microchemistry.


Research and action for bridging science and practice in prevention.
There is a well-known gap between science and practice. To address this gap in the areas of Child Maltreatment (CM) and Youth Violence (Y/V), the Division of Violence Prevention (DVP) at the Centers for Disease Control and Prevention (CDC) embarked on a Dissemination/Implementation (D/I) planning project. The project was aimed at identifying better ways to connect research and practice through reviews of the literature as well as through discussions with experts on violence prevention and research utilization. This introductory article sets the stage for the rest of the special issue by defining terms, providing a rationale for the planning project, describing the planning process, and summarizing what is to come in the rest of the issue.


A major rearrangement in the H-2 complex of mouse t haplotypes.
A proportion of wild mice carry a chromosome 17 of which a large part is very different from the standard mouse chromosome 17. The affected region is called the t complex, and the anomalous chromosomal types are the t haplotypes. In combination with various other chromosomes 17, t haplotypes can produce crossover suppression, taillessness, transmission distortion, male sterility and lethality early in development. The various t haplotypes also carry H-2 specificities which are different from those of other mice. This, together with the fact that the lethality genes map to both sides of H-2, suggests that the major histocompatibility complex is contained within the t complex. The lack of recombination between t haplotypes and standard chromosomes 17 may be due to large-scale rearrangements. Genetic data support this idea, in that the tufted gene, the H-2 complex and a group of H-2-related genes appear to be in inverted order in t haplotypes relative to the standard chromosome 17. The mapping of several t-lethal factors close to the H-2-related genes in t haplotypes suggests that breakpoint(s) may be found here. We have now investigated the major histocompatibility complex of t haplotypes by Southern blots using a variety of cloned DNA probes, and find a major rearrangement, specific to the t haplotypes, in the Qa-2,3 region of the complex. This involves the loss of several large homology units, probably including several class I H-2-related genes, and the creation of two possible breakpoints.


Toward 3D imaging of corrosion at the nanoscale: Cross-sectional analysis of in-situ oxidized TEM samples.
Understanding the effect of microstructural features on corrosion behavior will allow for significant improvements to alloy design for harsh environments. Recently, in-situ TEM has been recognized to offer significant data on corrosion behavior at the nanoscale, but in order for the best information to be acquired, a three dimensional view of the oxidation process is needed so that oxide structure and phase can be identified. Described herein is a new method of sample preparation for transmission electron microscopy (TEM) using a focused ion beam (FIB) to cross-section a previously FIB prepared sample. In-situ TEM was used to oxidize a sample using an environmental cell, and this in-situ sample is cross-sectioned to study oxide depth and oxide structure. This technique provides a new method to investigate in-situ TEM samples in 3D.


A cumulative score based on preoperative fibrinogen and the neutrophil-lymphocyte ratio to predict outcomes in resectable gastric cancer.
Recent studies have revealed that preoperative fibrinogen and the neutrophil-lymphocyte ratio (NLR) are associated with poor outcome in gastric cancer (GC). We aimed to evaluate whether the fibrinogen and the NLR score had a consistent prognostic value for resectable GC. We analyzed 1,293 consecutive patients who underwent curative surgery for GC. The F-NLR score was 2 for patients with hyperfibrinogenemia (>400 mg/dL) and elevated NLR (≥5.0), 1 for those with one abnormal index, and 0 for those with no abnormal indices. We found that higher F-NLR scores were associated with larger tumor size, deeper tumor invasion and more lymph node metastasis (all P<0.05). In a multivariate analysis, F-NLR independently predicted postoperative survival (P<0.001). When stratified by tumor-node-metastasis (TNM) stage, the prognostic value of F-NLR was still maintained for stages I-II (P<0.001) and stage III (P=0.003). Of note, F-NLR also effectively stratified overall survival (OS) irrespective of age, adjuvant chemotherapy administration, tumor location and histological grade (all P<0.05). Furthermore, F-NLR and TNM stratified 5-year OS from 61% (F-NLR 0) to 15% (F-NLR 2) and from 92% (stage I) to 37% (stage III), respectively. Utilizing both F-NLR and TNM, 5-year OS ranged from 93% (F-NLR 0, TNM I) to 6% (F-NLR 2, TNM III). The F-NLR score independently predicts outcomes in GC patients after curative surgery. Therefore, it should be implemented in routine clinical practice for identifying more high-risk patients.


Anion selectivity and pumping mechanism of halorhodopsin.
Comparison of the amino acid sequences in the A-B and B-C interhelical loop segments in all bacteriorhodopsins and halorhodopsins has shed light on the anion selectivity and pumping mechanism of halorhodopsin. The nucleotide sequences of two haloopsins from two new halobacterial strains, shark and port, have been determined, and shark halorhodopsin was functionally overexpressed in Halobacterium halobium. Although a series of six amino acid residues (EMPAGH) in the B-C interhelical loop segment was substituted by QMPPGH, all putative charged residues were conserved. It was also shown that His-95 mutants had lower pumping activity in low chloride concentrations. These results further support the hypothesis that His-95 is important in the halorhodopsin function.


Serotypes of non-O157 verocytotoxigenic Escherichia coli isolated from meat in New Zealand.
Verocytotoxigenic Escherichia coli (VTEC) were isolated from meat in New Zealand. They were tested for the presence of virulence factors associated with VTEC and serotyped. Some of the serotypes found were identical to ones reported from other parts of the world, but some serotypes were also found which had not been reported elsewhere. This study confirms the world-wide distribution of these emerging food-borne pathogens.


Flood risk assessments at different spatial scales.
Managing flood risk, i.e. both the hazard and the potential consequences, is an important aspect of adapting to global change and has gained much traction in recent decades. As a result, a priori flood risk assessments have become an important part of flood management practices. Many methodologies have been set up, ranging from global risk assessments for the world as a whole, to local assessments for a particular stretch of a river/coast or small town. Most assessment frameworks generally follow a similar approach, but there are also notable differences between assessments at different spatial scales. This review article examines these differences, for instance those related to the methodology, use of assessments and uncertainties. From this review, future research needs are identified in order to improve flood risk assessments at different scales. At global/continental scale, there is a clear need for harmonised information on flood defences to improve assessments. Furthermore, inclusions of indirect economic effects at the macro-/meso-scale would give a better indication of the total effects of catastrophic flooding. At the meso-/micro-scale, there is an urgent need to improve our understanding of the effects of flooding on critical infrastructures, given their importance to society, the economy, emergency management and reconstruction. An overarching theme at all scales is the validation of flood risk assessments, which is often limited. More detailed post-disaster information would allow for improved calibration, validation and thus performance of flood risk models. Lastly, the link between spatial scales also deserves attention, for instance up- or downscaling methodologies.


Two-dimensional 1H/13C heteronuclear chemical shift correlation spectroscopy of lipid bilayers.
Using solid-state magic angle spinning nuclear magnetic resonance (NMR) techniques, we have obtained two-dimensional (2D), 1H/13C chemical shift-correlated spectra of liquid crystalline 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) bilayers in 30 wt% PO4/D2O buffer. Linewidths in both the 13C and the 1H dimensions were less than 0.3 ppm wide. The 2D spectrum consists of chemical shift correlations between all resolvable, directly bonded 13C-1H pairs and exhibits considerably greater spectral dispersion than either ID 1H or 13C MAS spectra. This approach promises to be an important tool in structural studies of biological membranes.


Fetal mesenchymal stem cells derived from human umbilical cord sustain primitive characteristics during extensive expansion.
Stem cells of fetal origin lie between embryonic and adult stem cells in terms of potentiality. Because of the ethical controversy surrounding embryonic stem cells and the relatively inferior quality of adult stem cells, the use of fetal stem cells would be an attractive option in future therapeutic applications. Here, we have investigated primitive characteristics of human umbilical-cord-derived fetal mesenchymal stem cells (UC fMSCs) during extensive expansion. We have successfully isolated and cultured UC fMSCs from all UC samples, but with two early fungal contaminations. UC fMSCs proliferated without significant evidence of morphological changes, and the average cumulative population-doubling level was over 25 for about 3 months. UC fMSCs showed the positive expression of several CD markers, known to be related to MSCs, including CD73 (SH-3, 4), CD90 (Thy-1), CD105 (SH-2), CD117 (c-kit), and CD166 (ALCAM). They demonstrated primitive properties throughout the expansion period: multilineage differentiation potentials examined by functional assays, a variety of pluripotent stem cell markers including Nanog, Oct-4, Sox-2, Rex-1, SSEA-3, SSEA-4, Tra-1-60, and Tra-1-81, minimal evidence of senescence as shown by beta-galactosidase staining, and the consistent expression of telomerase activity. These results suggest that UC fMSCs have more primitive properties than adult MSCs, which might make them a useful source of MSCs for clinical applications.


Exposing human primary dermal fibroblasts to particulate matter induces changes associated with skin aging.
With a large proportion of the world's population living in areas where air quality does not meet current WHO guidelines, combined with the knowledge that pollutants can interact with human skin, it is now of even greater importance that the effects of air pollutant exposure on human skin be investigated. To evaluate the damaging effects of a known component of air pollution (particulate matter) on human primary dermal fibroblasts. These studies were undertaken by exposing primary human dermal fibroblasts to different concentrations of particulate matter and analyzing the effects over time using resazurin reduction assays. Immunofluorescence microscopy was used to determine if particulate matter caused activation of the aryl hydrocarbon receptor, and phosphorylation of histone H2AX, a known marker of double-strand DNA breaks. Dot blotting was also used to analyze expression changes in secreted MMP-1, MMP-3, and TGFβ. Particulate matter was found to dose-dependently increase cellular viability, activate the aryl hydrocarbon receptor, increase double-strand DNA breaks, and increase the expression of MMP-1, MMP-3, and TGFβ. With the potential of air pollutants such as particulate matter to not only modulate the expression of proteins implicated in skin aging, but also affect cells at a genetic level, brings a pressing need for further investigation so protective strategies can be implemented.


Sensitive fluorimetric method for the determination of putrescine, spermidine and spermine by high-performance liquid chromatography and its application to human blood.
A fast and sensitive method for the determination of putrescine, spermidine and spermine by high-performance liquid chromatography is described. These compounds are converted to their fluorescent dansyl derivatives and are separated by a reversed-phase chromatographic system (Micropak CH-10) with water and acetonitrile as mobile phase. The sensitivity of the method is 30 pmoles. The application of the method to the determination of polyamines in blood is described. It was found that most of the polyamines circulating in blood are localized in the erythrocytes, their content in normal human blood being spermidine 14.1 +/- 3.1, and spermine 8.4 +/- 2.8 nmoles/ml packed erythrocytes. The polyamine level in serum is less than 0.1 nmole/ml. The polyamine content of the erythrocytes from patients with malignant neoplasms was significantly elevated.


Production of insulin resistance by hyperinsulinaemia in man.
It has been proposed that hyperinsulinaemia may cause or exacerbate insulin resistance. The present studies were undertaken to test this hypothesis in man. Glucose utilization, glucose production, and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations (approximately 80 and approximately 1700 mU/l), and monocyte and adipocyte insulin binding were measured in normal volunteers on two occasions: once after 40 h of hyperinsulinaemia (25-35 mU/l) produced by infusion of insulin and once after infusion of saline (75 mmol/l; plasma insulin approximately 10 mU/l). After 40 h of hyperinsulinaemia, glucose utilization and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations were both slightly, but significantly, reduced compared with values observed after the infusion of saline (p less than 0.05), whereas glucose production rates were unaffected. Monocyte and adipocyte binding were also unaffected. These results indicate that hyperinsulinaemia of the magnitude observed in insulin resistant states, such as obesity, can produce insulin resistance in man. Assuming that human insulin sensitive tissues possess spare insulin receptors and that monocyte and adipocyte insulin binding accurately reflect insulin binding in insulin-sensitive tissues, the decreased maximal responses to insulin and the lack of change in insulin binding suggest that this insulin resistance occurred at a post-binding site.


Usefulness of beta radiation for de novo and in-stent restenotic lesions in saphenous vein grafts.
Following successful angioplasty of 49 saphenous vein graft lesions, a novel, self-centering phosphorus-32 solid foil beta source encapsulated within a dual-balloon membrane was used to deliver 20 Gy 1 mm into the vessel wall. Clinical and angiographic recurrence rates at 12 months were low, especially in de novo lesions.


Complementary/Integrative Medicine Treatment and Prevention of Youth Psychosis.
The rationale for CIM treatments in youth psychoses is to optimize treatment by targeting symptoms not resolved by antipsychotics, such as negative symptoms (major drivers of disability). Adjunctive omega-3 fatty acids (ω-3 FA) or N-acetyl cystine (NAC usage for > 24-week) can potentially reduce negative symptoms and improve function. ω-3 FA or exercise may prevent progression to psychosis in youth (in prodromal stage). Weekly 90-minute moderate to vigorous physical activity or aerobic exercise can reduce positive and negative symptoms. Awaiting better research, CIM agents are also recommended because they are devoid of any serious side-effects.


A review of the effects of memantine on clinical progression in Alzheimer's disease.
As Alzheimer's disease (AD) progresses, patients become increasingly dependent on others, placing a substantial impact on the daily lives of patients and caregivers. A treatment that slows clinical progression is a realistic and meaningful therapeutic goal for patients and caregivers. If given early, such a treatment would be expected to maximise any potential benefit. Memantine has shown clinical benefits in the key domains of AD, both as monotherapy and in combination with a cholinesterase inhibitor (ChEI). Memantine now has a considerable database of published studies and is associated with benefits in aspects of behaviour, cognition and communication, and on clinical progression. The results of these clinical studies are reviewed. Short-term clinical studies (≤28 weeks) have shown that memantine reduces clinical worsening and has also demonstrated positive effects in aspects of cognition--language, memory, praxis, functional communication--and in activities of daily living. Furthermore, memantine has been shown to reduce the rate of emergence of troublesome behaviour in patients with AD who were asymptomatic at baseline. Long-term follow-up studies (>1 year) have shown that the benefits of memantine are sustained and increase over time, and that memantine can delay nursing home placement in patients with AD. These findings provide evidence for the benefits of memantine, either alone or in combination with a ChEI, in slowing clinical progression in AD, and indicate that early treatment initiation may maximise clinical success. The benefits of memantine increase over time, allowing patients to remain independent for longer, alleviating caregiver burden and delaying institutionalisation.


Reproductive traits of the dwarf gobies Pandaka trimaculata and Pandaka lidwilli in the western Pacific Ocean: histological evidence from one of the smallest fishes in the world.
Gobies are generally small fishes which play important roles in estuarine ecosystems, yet little attention has been paid to their life-history traits in the western Pacific region. In the present study, the reproductive traits of the dwarf gobies Pandaka trimaculata and Pandaka lidwilli were explored by examining their populations in a subtropical estuary on Okinawa-jima Island, Japan, over 15 months. The Okinawan populations of both species shared similar reproductive traits. Pandaka trimaculata and P. lidwilli exhibited early female maturation at minimum sizes of 8.8 and 9.4 mm standard length (SL), respectively, which indicate that populations of the Pandaka species in the subtropical region represent some of the smallest fishes in the world. Nonetheless, they also had high relative body sizes at maturity relative to the attained asymptotic SLs, ranging from 75.8% to 80.4%, which suggests that their populations are vulnerable to negative impacts. Both the species also had prolonged spawning periods, extending from February to November (P. trimaculata) and from January to October (P. lidwilli), indicating that these local populations have a high potential for maintenance and resilience. Their spawning periods, sizes at maturity and fecundities varied among seasons and latitudes, possibly because of low water temperatures affecting the relative allocation of energy to growth and reproduction. Such plasticity of life-history traits in these small fishes indicates that they would be suitable models for understanding the evolution of life-history strategies and monitoring the responses of organisms to climate change.


The relevance of molecular biomarkers in cervical cancer patients treated with radiotherapy.
Radiotherapy (RT) plays an integral role in the combined-modality management of cervical cancer. Various molecular mechanisms have been implicated in the adaptive cellular response to RT. Identification of these molecular processes may permit the prediction of treatment outcome and enhanced radiation-induced cancer cell killing through tailoring of the management approach, and/or the employment of selective inhibitors of these pathways. PubMed was searched for studies presenting biomarkers of cervical cancer radioresistance validated in patient studies or in laboratory experimentation. Several biomarkers of cervical cancer radioresistance are validated by patient survival or recurrence data. These biomarkers fall into categories of biological function including hypoxia, cell proliferation, cell-cell adhesion, and evasion of apoptosis. Additional radioresistance biomarkers have been identified in exploratory experiments. Biomarkers of radioresistance in cervical cancer may allow molecular profiling of individual tumors, leading to tailored therapies and better prognostication and prediction of outcomes.


The 2G2 antibody recognizes an acidic 110-kDa human mitochondrial protein.
Using fluorescence microscopy, the mouse monoclonal antibody 2G2 was found to label mitochondria in human cells, as assessed by double staining with either Rhodamine 123 or a polyclonal antibody to mitochondrial matrix HSP-60 proteins. No reactivity to the 2G2 antibody was detected in cells from mouse, rat and chicken. Immunoblotting analysis demonstrated that the 2G2 antigen corresponds to a human protein with a relative mobility of 110kDa and an approximate isoelectric point of 6.5 that co-partitions with HSP-60 proteins during isolation of mitochondria from HeLa cells. Close examination of the 2G2 staining pattern in HeLa and Fanconi's anaemia cells revealed differences in the morphology and organization of mitochondria in these two cell types. In HeLa cells, mitochondria appear as individual tubular compartments of variable length and are closely associated with vimentin filaments, particularly at the periphery of the nucleus. In Fanconi's anaemia cells, mitochondria have a filamentous shape and form an interconnected cytoplasmic reticulum running in parallel with both vimentin filaments and microtubules. After stabilization with aldehyde- or alcohol-based fixation protocols that optimize the preservation of cytoskeletal components, the epitope targeted by the 2G2 antibody may serve as a valuable marker in the investigation of relationships between mitochondria and other cellular structures in human cells.


Drug-induced gambling disorder: A not so rare but underreported condition.
The widespread use of dopaminergic agents for the treatment of Parkinson's disease has revealed the presence of gambling disorder (GD) as an uncommon, but serious, adverse reaction to these agents. We describe the main characteristics of drug-induced GD reports received by the Spanish Pharmacovigilance System during the period from 1983 to 2016. Fifteen reports of GD have been identified. Dopaminergic agonists, especially pramipexole, are the main drugs involved in inducing GD. Physicians prescribing these drugs should warn patients and families about this disorder. Knowledge of this disorder will encourage early diagnosis, treatment, and reporting of this clinically and socially relevant disorder.


Pelvic Floor Biometric Changes Assessed by 4D Translabial Ultrassound in Women With Vulvodynia Submitted to Physical Therapy: A Pilot Study of a Randomized Controlled Trial.
Vulvodynia is a disabling condition in which pelvic floor muscles' (PFM) hypertonicity plays an important role. To evaluate biometric changes in PFM in women with vulvodynia undergoing kinesiotherapy treatment protocol (KTP). A single-blinded randomized controlled trial of 57 women with vulvodynia randomly assigned to either KTP + amitriptyline or amitriptyline alone (controls) for treatment. Four-dimensional translabial ultrasound assessed PFM regarding symphysis-levator distance at rest, anorectal angle at rest, excursion of the levator plate angle, and levator hiatal narrowing. Volunteers underwent a vaginal examination for a cotton swab test (CST), fulfillment of Friedrich criteria score and PFM power of contraction, and completed a diary of sexual pain and frequency of vaginal intercourse. Outcomes were assessed at baseline and after 8 weeks of treatment. Primary outcomes were differences in biometric parameters assessed by four-dimensional translabial ultrasound after treatment, between groups. Secondary outcomes were changes in clinical variables (CST, Friedrich criteria, PFM power of contraction, frequency of intercourse, and intensity of sexual pain) between groups and correlation analysis between biometric parameters and clinical variables. Only the KTP group had statistically significant changes in biometric parameters after treatment (symphysis-levator distance: 0.22 ± 0.2, 95% CI = 0.1-0.4, P = .008; levator hiatal narrowing: -0.33 ± 0.2, 95% CI = -1 to -0.2, P = .04). Comparisons between groups showed that symphysis-levator distance (0.3, 95% CI = 0.2-0.6, P = .005) and excursion of levator plate angle (4.9, 95% CI = -0.4 to 10.1, P = .02) improved significantly after KTP treatment. Clinical variables showed greater improvement in the group treated with KTP for CST (difference of -3.7, 95% CI = -7 to -0.4, P = .01), Friedrich criteria (difference of -1.9, 95% CI = -3.2 to -0.6, P = .003), PFM power of contraction (0.3, 95% CI = 0.1-0.6, P = .05) and intensity of sexual pain (reduction of 1.7, 95% CI = -3.1 to -0.2, P = .01). Some clinical and biometric variables correlated positively, for example, frequency of vaginal intercourse and anorectal angle (P = .04; r = 0.25), or inversely, for example, pain intensity at CST and anorectal angle (P = .004, r = -0.31). This study provides evidence on efficiency of a physical therapy protocol for improvement of symptoms of vulvodynia and hypertonicity changes. This pilot study suggests that KTP for women with vulvodynia promoted significant changes in PFM biometric measures, consistent with alterations in hypertonicity and clinical improvement. Bardin MG, Giraldo PC, Martinho N. Pelvic Floor Biometric Changes Assessed by 4D Translabial Ultrassound in Women With Vulvodynia Submitted to Physical Therapy: A Pilot Study of a Randomized Controlled Trial. J Sex Med 2020;17:2236-2246.


Human malignant tumours of the breast, as compared to their respective normal tissue, have elevated expression of the Harvey ras oncogene.
Analysis of expression of Harvey-ras related oncogenes in human malignant breast tumours and in their respective normal tissue has revealed a significant elevation of Harvey-ras transcripts in malignant as compared to normal tissue. In contrast, the sis oncogene is not expressed significantly in either type of malignant or normal tissue. These results suggest that Harvey-ras oncogene may be specifically activated in the development of human malignant breast tumours.


Psychological stress in heart failure: a potentially actionable disease modifier.
Psychological stress is common in patients with heart failure, due in part to the complexities of effective disease self-management and progressively worsening functional limitations, including frequent symptom exacerbations and hospitalizations. Emerging evidence suggests that heart failure patients who experience higher levels of stress may have a more burdensome disease course, with diminished quality of life and increased risk for adverse events, and that multiple behavioral and pathophysiological pathways are involved. Furthermore, the reduced quality of life associated with heart failure can serve as a life stressor for many patients. The purpose of this review is to summarize the current state of the science concerning psychological stress in patients with heart failure and to discuss potential pathways responsible for the observed effects. Key knowledge gaps are also outlined, including the need to understand patterns of exposure to various heart failure-related and daily life stressors and their associated effects on heart failure symptoms and pathophysiology, to identify patient subgroups at increased risk for stress exposure and disease-related consequences, and the effect of stress specifically for patients who have heart failure with preserved ejection fraction. Stress is a potentially modifiable factor, and addressing these gaps and advancing the science of stress in heart failure is likely to yield important insights about actionable pathways for improving patient quality of life and outcomes.


Seed priming with NaCl helps to improve tissue tolerance, potassium retention ability of plants, and protects the photosynthetic ability in two different legumes, chickpea and lentil, under salt stress.
Seed priming with NaCl mimicked the conditions of natural priming to improve the tissue tolerance nature of sensitive legumes, which helps to maintain survivability and yield in mildly saline areas. Seed priming with NaCl is a seed invigoration technique that helps to improve plant growth by altering Na+ and K+ content under salt stress. Legumes are overall sensitive to salt and salinity hampers their growth and yield. Therefore, a priming (50 mM NaCl) experiment was performed with two different legume members [Cicer arietinum cv. Anuradha and Lens culinaris cv. Ranjan] and different morpho-physiological, biochemical responses at 50 mM, 100 mM, and 150 mM NaCl and molecular responses at 150 mM NaCl were studied in hydroponically grown nonprimed and primed members. Similarly, a pot experiment was performed at 80 mM Na+, to check the yield. Tissue Na+ and K+ content suggested NaCl-priming did not significantly alter the accumulation of Na+ among nonprimed and primed members but retained more K+ in cells, thus maintaining a lower cellular Na+/K+ ratio. Low osmolyte content (e.g., proline) in primed members suggested priming could minimize their overall osmolytic requirement. Altogether, these implied tissue tolerance (TT) nature might have improved in case of NaCl-priming as was also reflected by a better TT score (LC50 value). An improved TT nature enabled the primed plants to maintain a significantly higher photosynthetic rate through better stomatal conductance. Along with this, a higher level of chlorophyll content and competent functioning of the photosynthetic subunits improved photosynthetic performance that ensured yield under stress. Overall, this study explores the potential of NaCl-priming and creates possibilities for considerably sensitive members; those in their nonprimed forms have no prospect in mildly saline agriculture.


Molecular characterization and evaluation of plant litter-associated fungi from the spring 'grazing corridor' of a sheep herd vulnerable to alveld disease.
This study sample and identify species of fungi on withered vegetation in the spring 'grazing corridor' from infields to Narthecium bogs for a sheep herd almost chronically vulnerable to phototoxic disease. Hepatogen photosensitizing disorders like alveld attack grazing sheep, especially lambs, in various parts of the world. It has been hypothesized that saponin metabolites in the monocotyledonous plant Narthecium ossifragum causes the disorder in Norway, however, this has not been verified. Thus, the search for other causal agents or saponin cofactors (the cofactor hypothesis) has been intensified, and endophytic poisonous fungi associated with dead N. ossifragum leaves and grasses are among the prime suspects. The fungal diversity was targeted by obtaining axenic cultures from surface-sterilized plant material, with subsequent DNA isolation, PCR, and sequencing of the ITS nrDNA region. The taxonomic affinities of the obtained sequences were thereafter explored by similarity searches against the public access sequence database EMBL/GenBank/DDBJ. Among the spectrum of identified taxa were representatives of Cladosporium, Fusarium, Penicillium, and Trichoderma, all of which are well known as potential producers of toxins. A possible involvement of these toxic species in the etiology of alveld is evaluated and discussed.


The metabolism and hormonal activity of some ring-C aromatic steroids.
The metabolism and steroid hormonal activity of the ring-C aromatic steroid 20 alpha,21-dihydroxy-17 beta-methyl-18-norpregna-4,8,11,13-tetraen-3-one (20 alpha,21-diol) was studied in rats and mice. The excretion of metabolites following intraperitoneal administration was monitored using tritium-labelled steroid. Of the total radioactivity, 15% was excreted in the urine after 2 days. Biliary excretion was rapid, with 80% of radioactivity collected over 12 h, while 67% was excreted in the faeces after 3 days. The metabolites isolated from bile and urine are conjugates, predominantly glucuronides, while only 5% of the dose was excreted as free unchanged steroid. The aglycones of the main metabolites from bile were identified as unchanged 20 alpha,21-diol and the two steroids 3 alpha,20 alpha,21-trihydroxy-17 beta-methyl-18-nor-5 alpha-pregna-8,11,13-triene and 3 beta, 20 alpha,21-trihydroxy-17 beta-methyl-18-nor-5 alpha-pregna-8,11,13-triene which resulted from reduction of the 4-ene-3-ketone system. Liver glycogen deposition, used as a measure of glucocorticoid activity, was induced in mice by 20 alpha,21-diol but not by its epimer the corresponding 20 beta,21-diol. Only the 20 alpha,21-diol was found to antagonise glycogen deposition when given simultaneously with cortisol. In adrenalectomised rats, the 20 alpha,21-diol produced a significant decrease in urinary Na+ excretion and increased K+ excretion. An equimolar dose of the 20 alpha,21-diol and deoxycorticosterone acetate gave a urinary excretion Na+/K+ ratio which reflected the combined mineralocorticoid effect of each steroid. The 20 beta, 21-diol produced no change in the urinary Na+/K+ ratio.


Lignin containing cellulose nanofibers (LCNFs): Lignin content-morphology-rheology relationships.
This study aims to investigate the relationship between lignin content, morphology, and rheology of lignin containing cellulose nanofibers (LCNFs). The morphology and rheology of LCNFs were dominated by lignin content. Lignin content had two-sides on mechanical fibrillation. At high lignin content (23.79 %), reduced efficiency of defibrillation resulted in large LCNFs connecting with lignin patches. LCNF suspensions exhibited low viscosity, weak gel behavior due to infirm fibril network. Small yield stress of 1.14 Pa suggested that fibril network was easily disrupted. At residual lignin of 6.52 %, fibril bundles were sensitive to defibrillation, producing long and flexible LCNFs with high capacity of entanglement. The entangled fibril network had high viscosity and strong gel like behavior. Creep compliance of 0.09 Pa-1 and large yield stress of 4.25 Pa indicated excellent resistance to deformation. The desired rheology can be tailored by lignin content, providing practical guidance on novel rheology-dependent LCNF based materials.


Role of Calcium Signaling in B Cell Activation and Biology.
Increase in intracellular levels of calcium ions (Ca2+) is one of the key triggering signals for the development of B cell response to the antigen. The diverse Ca2+ signals finely controlled by multiple factors participate in the regulation of gene expression, B cell development, and effector functions. B cell receptor (BCR)-initiated Ca2+ mobilization is sourced from two pathways: one is the release of Ca2+ from the intracellular stores, endoplasmic reticulum (ER), and other is the prolonged influx of extracellular Ca2+ induced by depleting the stores via store-operated calcium entry (SOCE) and calcium release-activated calcium (CRAC) channels. The identification of stromal interaction molecule 1(STIM1), the ER Ca2+ sensor, and Orai1, a key subunit of the CRAC channel pore, has now provided the tools to understand the mode of Ca2+ influx regulation and physiological relevance. Herein, we discuss our current understanding of the molecular mechanisms underlying BCR-triggered Ca2+ signaling as well as its contribution to the B cell biological processes and diseases.


Quillaja brasiliensis saponin-based nanoparticulate adjuvants are capable of triggering early immune responses.
Commercially available saponins are extracted from Quillaja saponaria barks, being Quil A® the most widely used. Nanoparticulate immunostimulating complexes (ISCOMs or ISCOMATRIX) formulated with these, are able to stimulate strong humoral and cellular immune responses. Recently, we formulated novel ISCOMs replacing QuilA® by QB-90 (IQB-90), a Quillaja brasiliensis leaf-extracted saponin fraction, and reported that IQB-90 improved antigen uptake, and induced systemic and mucosal antibody production, and T-cell responses. However, its mechanism of action remains unclear. In this study we provide a deeper insight into the immune stimulatory properties of QB-90 and ISCOMATRIX-like based on this fraction (IMXQB-90). We show herein that, when used as a viral vaccine adjuvant, QB-90 promotes an "immunocompetent environment". In addition, QB-90 and IMXQB-90 induce immune-cells recruitment at draining-lymph nodes and spleen. Subsequently, we prove that QB-90 or IMXQB-90 stimulated dendritic cells secret IL-1β by mechanisms involving Caspase-1/11 and MyD88 pathways, implying canonical inflammasome activation. Finally, both formulations induce a change in the expression of cytokines and chemokines coding genes, many of which are up-regulated. Findings reported here provide important insights into the molecular and cellular mechanisms underlying the adjuvant activity of Q. brasiliensis leaf-saponins and its respective nanoparticles.


Multi-level Drivers of Disparities in Hispanic Cesarean Delivery Rates in US-Mexico Border States.
Hispanic women living along the US-Mexico border have higher cesarean delivery rates than non-Hispanic white women, African American women, and other Hispanic women in the USA. Their rates also exceed those of other Hispanic women in states that border Mexico and non-Hispanic white women along the border. Our objective was to determine the causes of the disparities in border Hispanic cesarean rates. Using the 2015 birth certificate file and other sources, we performed a twofold Oaxaca-Blinder decomposition analysis of the disparities in low-risk primary and repeat cesarean rates between Hispanic and non-Hispanic white women in the US-Mexico border counties and Hispanic women residing in nonborder counties of border states. Rates of low-risk primary cesarean among border Hispanic, nonborder Hispanic, and border non-Hispanic white women were 21.1%, 15.0%, and 16.5%, respectively. Higher Hispanic concentration in county of residence, a larger proportion of for-profit hospital beds, and greater poverty accounted for 24.7%, 22.1%, and 11.1% of the border-nonborder Hispanic difference, respectively. No other variable explained more than 5% of the difference. Higher Hispanic concentration, more for-profit beds, less attendance by an MD, higher BMI, and greater poverty explained 60.6%, 42.4%, 42.4%, 27.4%, and 21.3%, respectively, of the Hispanic-non-Hispanic white difference. Hispanic concentration and for-profit beds were also important explanatory variables for low-risk repeat cesareans. Efforts to address potentially unnecessary cesareans among Hispanic women on the border should recognize that community demographic and health delivery system characteristics are more influential than maternal medical risk factors.


Preparation of ethylenediaminephosphoramidates of nucleotides and derivatization with fluorescein isothiocyanate.
Fluorescence post-labeling of nucleotides is a potentially useful technique for the detection of trace amounts of damaged DNA (DNA adducts). Towards this goal, we have studied a derivatization procedure starting with the four major 5'-deoxynucleotides as model compounds. The 5'-phosphate group was first labeled with ethylenediamine via a phosphorimidazolide intermediate in methanol with an organic-soluble carbodiimide. The resulting ethylenediaminephosphoramidate products were reacted in turn with fluorescein isothiocyanate. The reaction sequence has been characterised at all stages by high-performance liquid chromatography.


IFNgamma sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway.
Resistance of tumors to cytotoxic therapy may be due to disrupted apoptosis programs and remains a major obstacle in cancer treatment. Here, we report that IFNgamma sensitizes resistant tumor cells with absent or low caspase-8 expression for apoptosis induced by death-inducing ligands or cytotoxic drugs by upregulating caspase-8 through a Stat1/IRF1 dependent pathway. Combined treatment using IFNgamma with TRAIL, APO1, TNFalpha or cytotoxic drugs cooperated to trigger apoptosis in various resistant tumor cell lines derived from Ewing tumor, neuroblastoma or medulloblastoma, while single agents exerted only a minimal effect. Importantly, IFNgamma induced caspase-8 expression also in cells with inactivation of the caspase-8 gene by hypermethylation, although no direct effect of IFNgamma on the methylation status of regulatory sequences of the caspase-8 gene was found. IFNgamma-mediated facilitation of apoptosis was inhibited by the caspase-8 specific inhibitor zIETD.fmk or in caspase-8 mutant Jurkat cells implying a prominent role of caspase-8 in mediating sensitization by IFNgamma. Upregulation of caspase-8 and sensitization for apoptosis by IFNgamma was blocked by overexpression of dominant-negative mutants of Stat1 or in Stat1-deficient U3A cells, while complementation of Stat1-deficient U3A cells with wild-type Stat1 restored the IFNgamma effect. Moreover, ectopic expression of IRF1 induced caspase-8 expression thereby sensitizing cells for TRAIL-, APO1- or doxorubicin-induced apoptosis. These findings provide evidence that the Stat1/IRF1 pathway is involved in induction of caspase-8 expression and apoptosis initiated by IFNgamma and indicate that IFNgamma might be an effective strategy to sensitize various resistant tumor cells with deficient caspase-8 expression for chemotherapy- or death receptor-induced apoptosis.


Canine visceral leishmaniasis: diagnostic approaches based on polymerase chain reaction employing different biological samples.
The accurate diagnosis of canine visceral leishmaniasis (CanL) is essential for visceral leishmaniasis control. To this end, DNA detection on different biological samples has been employed. In this study, we report the use of polymerase chain reaction (PCR) assay on samples such as buffy coat, bone marrow, intact skin and cutaneous ulcers fragments, and lymph node aspirate collected from 430 dogs to determine the suitable biological sample for use in CanL diagnosis. The PCR results were correlated with clinical status and other tests previously performed. Leishmania chagasi DNA was detected in 14.6% (n = 63) of the dogs investigated, regardless of the sample analyzed. Our results showed that symptomatic cases were easily diagnosed when compared to asymptomatic animals; however, the PCR proved to be very useful for Leishmania DNA detection, mainly in lymph node aspirate (41; 9.6%), irrespective of the clinical status of the dog. The finding that the lymph node aspirate produced high positivity rates and the fact that this specimen was obtained by noninvasive methods highlight its use in epidemiological survey by PCR for CanL diagnosis.


Effects of caffeine, vitamin D, and other nutrients on quantitative phalangeal bone ultrasound in postmenopausal women.
We investigated the controversial effects of coffee and other nutrients on bone mass. In a study of 93 healthy postmenopausal women (mean +/- standard deviation: 57.3 +/- 7.1 y old and 8.9 +/- 7.5 y since menopause) selected on the basis of not having changed their eating habits since premenopause, not smoking, not exercising, not receiving hormone-replacement therapy, and having a weight in the range of 70% to 130% of their ideal weights, amplitude-dependent speed of sound (Ad-SOS) was determined by quantitative bone ultrasound, and a prospective 7-d diet survey evaluated the intake of caffeine and nutrients involved in calcium metabolism. Women were stratified according to their caffeine, calcium, and vitamin D intakes and ratios of calcium to phosphorus and to protein. Ad-SOS differed only with vitamin D intake and was greater in the group taking at leasst 400 IU/d (P < 0.0001). In simple and multiple regression analyses, the only significant variable that affected Ad-SOS and nutrient intake was vitamin D (P < 0.0001). Phalangeal bone Ad-SOS was influenced only by the intake of vitamin D, not of caffeine or other nutrients. This lack of effect of caffeine and protein may be related to good nutritional intake or the low levels of caffeine consumed.


Central nystagmus and its interaction with optokinetic and reversive postoptokinetic forms of nystagmus.
Interaction of central nystagmus (CN) with optokinetic (OKN) and reversive postoptokinetic (RPN) forms of nystagmus was studied in chronic experiments on rabbits. During interaction of CN with OKN or RPN not in the same direction, the latter are inhibited and CN is manifested during the next 5 sec. The reverse process is observed after a cessation of electrical stimulation. If CN coincides in direction with OKN and RPN, the period from the beginning of electrical stimulation until establishment of regular resultant nystagmus is considerably shortened. Furthermore, the period from the moment of cessation of electrical stimulation until establishment of regular OKN and RPN also is shortened.


What holds paper together: nanometre scale exploration of bonding between paper fibres.
Paper, a man-made material that has been used for hundreds of years, is a network of natural cellulosic fibres. To a large extent, it is the strength of bonding between these individual fibres that controls the strength of paper. Using atomic force microscopy, we explore here the mechanical properties of individual fibre-fibre bonds on the nanometre scale. A single fibre-fibre bond is loaded with a calibrated cantilever statically and dynamically until the bond breaks. Besides the calculation of the total energy input, time dependent processes such as creep and relaxation are studied. Through the nanometre scale investigation of the formerly bonded area, we show that fibrils or fibril bundles play a crucial role in fibre-fibre bonding because they act as bridging elements. With this knowledge, new fabrication routes can be deduced to increase the strength of an ancient product that is in fact an overlooked high-tech material.


Ganoderma lucidum polysaccharide peptide alleviates hyperuricemia by regulating adenosine deaminase and urate transporters.
Hyperuricemia (HUA) affects human health and is involved in the pathogenesis of common chronic diseases. Previous studies showed that Ganoderma lucidum extract lowered HUA in animals. However, the active ingredient and pharmacological mechanism of Ganoderma lucidum extract in the improvement of HUA are unknown. The purpose of this study was to determine the anti-HUA efficacy and related mechanism of Ganoderma lucidum polysaccharide peptide (GLPP) using a potassium oxonate (PO)-induced mouse model and an adenosine-induced cell model. The experimental results showed that blood uric acid (UA) was decreased up to 40.6% by GLPP in HUA mice in a dose-dependent manner. Additionally, GLPP significantly reduced UA production by inhibiting the hepatic and blood adenosine deaminase (ADA) activity and increased UA excretion by decreasing the expression of glucose transporter 9 (GLUT9) and increasing the expression of organic anion transporter 1 (OAT1) in kidney. The adenosine-induced cell model showed that the inhibitory effect of GLPP on ADA activity may be the main reason for the alleviation of HUA by GLPP. Furthermore, PO-induced renal histopathological damage was also alleviated by GLPP in a dose-dependent manner. The experimental results in this study indicated that GLPP exerted anti-HUA effects via regulating the UA production and excretion, suggesting that GLPP could be developed into a therapeutic agent for HUA.


Guidance of pharmacotherapy in a complex psychiatric case by CYP450 DNA typing.
To illustrate the utility of CYP450 genotyping to guide clinical psychopharmacological treatment decisions and minimize or avoid harmful and costly adverse drug reactions (ADRs). DNA was extracted from a whole blood sample from the case study subject and tested for CYP450 gene polymorphisms in the CLIA certified Laboratory of Personalized Health at Genomas, Inc. Clinical data were obtained from patient records and clinician observations. We present a case in which the ascertainment of multiple CYP450 isoenzyme deficiencies resulted in a dramatic change in psychotropic treatment approach. Shortly after making these adjustments, the patient saw a significant improvement in most of her debilitating psychiatric symptoms. In complex cases, CYP450 DNA testing can guide pharmacotherapy by exposing innate hepatic metabolic deficiencies as a result of DNA polymorphism. In such cases, clinicians can favor treatments that target functional isoenzyme pathways rather than deficient or null pathways thus leading to decreased risk of ADRs and improved patient response.


Xenohormesis: sensing the chemical cues of other species.
Many plant molecules interact with and modulate key regulators of mammalian physiology in ways that are beneficial to health, but why? We propose that heterotrophs (animals and fungi) are able to sense chemical cues synthesized by plants and other autotrophs in response to stress. These cues provide advance warning about deteriorating environmental conditions, allowing the heterotrophs to prepare for adversity while conditions are still favorable.


The role of vitamin D in asthma.
Vitamin D metabolites are important immune-modulatory hormones and are able to suppress Th2-mediated allergic airway disease. Some genetic factors that may contribute to asthma are regulated by vitamin D, such as vitamin D receptor (VDR), human leukocyte antigen genes (HLA), human Toll-like receptors (TLR), matrix metalloproteinases (MMPs), a disintegrin and metalloprotein-33 (ADAM-33), and poly(ADP-ribosyl) polymerase- 1 (PARP-1). Vitamin D has also been implicated in asthma through its effects on the obesity, bacillus Calmettee Guérin (BCG) vaccination and high vitamin D level, vitamin D supplement, checkpoint protein kinase 1 (Chk1), plasminogen activator inhibitor-1 (PAI-1) and gamma delta T cells (gdT). Vitamin D plays a role in asthma and exerts its action through either genomic and/or non-genomic ways.


Lipoxins and lipoxin analogs in asthma.
The pathobiology of asthma is characterized by production of eicosanoids, a diverse family of bioactive fatty acids that play important roles in regulating airway inflammation and reactivity. Lipoxins (LXs) are products of arachidonic acid metabolism that are distinct from leukotrienes (LTs) and prostaglandins (PGs) in structure and function. Unlike the pro-inflammatory PGs and LTs, LXs display counter-regulatory actions. Cell-type specific biological actions have been uncovered for LXs and LX stable analogs that promote resolution of acute inflammatory responses. At least two classes of receptors, CysLT1 receptors and LXA4 receptors (named ALX), can interact with LXA4 and LXA4 analogs to mediate their biological actions. LXs are generated during asthma and LXA4 signaling blocks asthmatic responses in humans and experimental model systems. Of interest, respiratory diseases of increased severity, such as aspirin-intolerant asthma, cystic fibrosis and steroid-dependent, severe asthma, display defective generation of these protective lipid signals. Together, these findings indicate a pivotal role for LXs in mediating airway homeostasis.


5-Methyl-4-(5-methyl-3-oxo-2-phenyl-2,3-di-hydro-1H-pyrazol-4-yl)-2-phenyl-1H-pyrazol-3(2H)-one.
The title compound, C20H18N4O2, known as bis-pyrazolone, was crystallized from dimethyl sulfoxide. The structure has ortho-rhom-bic (Pbca) symmetry at 150 K, and displays both intra- and inter-molecular hydrogen bonding through C-H⋯O and N-H⋯O contacts, respectively. None of the phenyl and pyrazolone rings in the mol-ecule are coplanar. The dihedral angle between the pyrazolone rings is 66.18 (5)°.


Temporal trends in postoperative and ventilator-associated pneumonia in the United States.
To determine change in rates of postoperative pneumonia and ventilator-associated pneumonia among patients hospitalized in the United States during 2009-2019. Retrospective cohort study. Patients hospitalized for major surgical procedures, acute myocardial infarction, heart failure, and pneumonia. We conducted a retrospective review of data from the Medicare Patient Safety Monitoring System, a chart-abstraction-derived database including 21 adverse-event measures among patients hospitalized in the United States. Changes in observed and risk-adjusted rates of postoperative pneumonia and ventilator-associated pneumonia were derived. Among 58,618 patients undergoing major surgical procedures between 2009 and 2019, the observed rate of postoperative pneumonia from 2009-2011 was 1.9% and decreased to 1.3% during 2017-2019. The adjusted annual risk each year, compared to the prior year, was 0.94 (95% CI, 0.92-0.96). Among 4,007 patients hospitalized for any of these 4 conditions at risk for ventilator-associated pneumonia during 2009-2019, we did not detect a significant change in observed or adjusted rates. Observed rates clustered around 10%, and adjusted annual risk compared to the prior year was 0.99 (95% CI, 0.95-1.02). During 2009-2019, the rate of postoperative pneumonia decreased statistically and clinically significantly in among patients hospitalized for major surgical procedures in the United States, but rates of ventilator-associated pneumonia among patients hospitalized for major surgical procedures, acute myocardial infarction, heart failure, and pneumonia did not change.


An RNA motif advances transcription by preventing Rho-dependent termination.
The transcription termination factor Rho associates with most nascent bacterial RNAs as they emerge from RNA polymerase. However, pharmacological inhibition of Rho derepresses only a small fraction of these transcripts. What, then, determines the specificity of Rho-dependent transcription termination? We now report the identification of a Rho-antagonizing RNA element (RARE) that hinders Rho-dependent transcription termination. We establish that RARE traps Rho in an inactive complex but does not prevent Rho binding to its recruitment sites. Although translating ribosomes normally block Rho access to an mRNA, inefficient translation of an open reading frame in the leader region of the Salmonella mgtCBR operon actually enables transcription of its associated coding region by favoring an RNA conformation that sequesters RARE. The discovery of an RNA element that inactivates Rho signifies that the specificity of nucleic-acid binding proteins is defined not only by the sequences that recruit these proteins but also by sequences that antagonize their activity.


A Retrospective Review of Mercaptopurine Metabolism Reveals High Rate of Patients With Suboptimal Metabolites Successfully Corrected With Allopurinol.
Skewed drug metabolism of 6-mercaptopurine (6-MP) can jeopardize antileukemic effects and result in toxicities during the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Allopurinol can alter 6-MP metabolism to maximize therapeutic effects while reducing toxicities. Over 75% of our patients with acute lymphoblastic leukemia or lymphoblastic lymphoma experienced a 6-MP-related toxicity. Review of metabolite date a showed 6-methylmercaptopurine nucleotide levels were >10,000 in 55% of the cohort, suggesting 6-MP shunting. Allopurinol was initiated in 12 of 23 shunters with resolution of toxicities. We propose an algorithm to incorporate allopurinol into chemotherapy regimens for patients with inappropriate 6-MP metabolism.


Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Discharge of patients who have taken an overdose of opioids.
A short cut review was carried out to establish whether patients with no recurrence of symptoms one hour after receiving naloxone for an opioid overdose can safely be discharged. Altogether 195 papers were found using the reported search, of which five presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.