Suicidal Risk in Women with Premenstrual Syndrome and Premenstrual Dysphoric Disorder: A Systematic Review and Meta-Analysis.
Purpose: Women with premenstrual dysphoric disorder (PMDD) and premenstrual syndrome (PMS) experience substantial functional impairment and decreased quality of life. While previous research has highlighted a relationship between premenstrual disturbances and suicide risk, no meta-analysis has been conducted to quantitatively assess the findings. Methods: A systematic review and meta-analysis was conducted by searching the literature in three databases (Pubmed, PsycINFO, and EMBASE) on July 15, 2020. Studies that assessed the relationship between suicidality (attempt, ideation, and/or plan) and premenstrual disturbance (PMDD, PMS, and/or premenstrual symptoms) were included. Results: Thirteen studies were included in the qualitative review (n = 10 included in meta-analysis). Results revealed that women with PMDD are almost seven times at higher risk of suicide attempt (OR: 6.97; 95% CI: 2.98-16.29, p < 0.001) and almost four times as likely to exhibit suicidal ideation (OR: 3.95; 95% CI: 2.97-5.24, p < 0.001). Similarly, women with PMS are also at increased risk of suicidal ideation (OR: 10.06; 95% CI: 1.32 to -76.67, p = 0.03), but not for suicide attempt (OR: 1.85; 95% CI: 0.77 to -4.46, p = 0.17). Conclusions: Women with PMDD and PMS are at higher risk of suicidality compared with women without premenstrual disturbances. These findings support routine suicidal risk assessments for women who suffer from moderate-to-severe premenstrual disturbance. Furthermore, psychosocial treatments for women diagnosed with PMS/PMDD should consider and target suicidality to minimize risk and improve well-being.


The Pseudomonas putida HskA hybrid sensor kinase responds to redox signals and contributes to the adaptation of the electron transport chain composition in response to oxygen availability.
Pseudomonas putida has a branched aerobic electron transport that includes five terminal oxidases, each of which has different properties. The relative expression of each oxidase is carefully regulated to assemble the most suitable electron transport chain for the prevailing conditions. The HskA hybrid sensor kinase participates in this control, but the signals to which HskA responds were unknown. Here, the influence of HskA on the mRNA abundance of genes coding for all terminal oxidases and for the bc1 complex was analysed in cells growing under controlled aerobic, semiaerobic or microaerobic conditions. The results indicate that the influence of HskA on the expression of each terminal oxidase and the bc1 complex varies depending on oxygen availability. This effect was more pronounced under aerobic or semiaerobic conditions, but decreased under microaerobic conditions. The expression of hskA was regulated by oxygen availability. We show that HskA autophosphorylation is inhibited by ubiquinone but not by ubiquinol, its reduced derivative. This suggests that HskA could sense the oxidation state of the respiratory ubiquinones, which may be a key factor in HskA activity. Inactivation of hskA reduced growth rate and oxygen consumption, stressing the importance of HskA for the assembly of an efficient electron transport chain.


Functional annotation of colon cancer risk SNPs.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with increased risk for CRC. A molecular understanding of the functional consequences of this genetic variation has been complicated because each GWAS SNP is a surrogate for hundreds of other SNPs, most of which are located in non-coding regions. Here we use genomic and epigenomic information to test the hypothesis that the GWAS SNPs and/or correlated SNPs are in elements that regulate gene expression, and identify 23 promoters and 28 enhancers. Using gene expression data from normal and tumour cells, we identify 66 putative target genes of the risk-associated enhancers (10 of which were also identified by promoter SNPs). Employing CRISPR nucleases, we delete one risk-associated enhancer and identify genes showing altered expression. We suggest that similar studies be performed to characterize all CRC risk-associated enhancers.


Watercress and amphipods Potential chemical defense in a spring stream macrophyte.
We investigated the potential role of defensive chemicals in the avoidance of watercress (Nasturtium officinale) by the cooccurring amphipod,Gammarus pseudolimnaeus at two spring brooks: Carp Creek, Michigan and Squabble Brook, Connecticut. We conducted observations and laboratory experiments on the consumption of watercress, the toxicity of damaged (frozen) watercress, and the toxicity of damage-released secondary chemicals. Field-collected yellowed watercress typically lacked the bite and odor characteristic of green watercress and was consumed byG. pseudolimnaeus. G. pseudolimnaeus strongly preferred yellowed watercress to green watercress despite the higher nitrogen content of the latter (2.7 vs 5.4%), and usually consumed five times more yellowed watercress (>50% of yellowed leaf area vs. <8% of green leaf area presented). Fresh green watercress contained seven times more phenylethyl glucosinolate than yellowed watercress (8.9 mg/g wet vs. 1.2 mg/g). Cell-damaged (frozen) watercress was toxic toG. pseudolimnaeus (48-hr LC50s: ca. 1 g wet/liter), and the primary volatile secondary chemicals released by damage were highly toxic. The predominant glucosinolate hydrolysis product, 2-phenylethyl isothiocyanate had 48-hr LC50s between 0.96 and 3.62 mg/liter, whereas 3-phenylpropionitrile was less toxic, with 48-hr LC50s between 130 and 211 mg/liter. These results suggest that live watercress is chemically defended against consumption. The glucosinolate-myrosinase system, recognized as the principle deterrent system of terrestrial crucifers, is also possessed byN. officinale and may contribute to defense from herbivory by aquatic crustaceans. This system may be just one of many examples of the use of defensive chemicals by stream and lake macrophytes.


Evaluation by simulation of clinical trial designs for evaluation of treatment during a viral haemorrhagic fever outbreak.
Viral haemorrhagic fevers are characterized by irregular outbreaks with high mortality rate. Difficulties arise when implementing therapeutic trials in this context. The outbreak duration is hard to predict and can be short compared to delays of trial launch and number of subject needed (NSN) recruitment. Our objectives were to compare, using clinical trial simulation, different trial designs for experimental treatment evaluation in various outbreak scenarios. Four type of designs were compared: fixed or group-sequential, each being single- or two-arm. The primary outcome was 14-day survival rate. For single-arm designs, results were compared to a pre-trial historical survival rate pH. Treatments efficacy was evaluated by one-sided tests of proportion (fixed designs) and Whitehead triangular tests (group-sequential designs) with type-I-error = 0.025. Both survival rates in the control arm pC and survival rate differences Δ (including 0) varied. Three specific cases were considered: "standard" (fixed pC, reaching NSN for fixed designs and maximum sample size NMax for group-sequential designs); "changing with time" (increased pC over time); "stopping of recruitment" (epidemic ends). We calculated the proportion of simulated trials showing treatment efficacy, with K = 93,639 simulated trials to get a type-I-error PI95% of [0.024;0.026]. Under H0 (Δ = 0), for the "standard" case, the type-I-error was maintained regardless of trial designs. For "changing with time" case, when pC > pH, type-I-error was inflated, and when pC < pH it decreased. Wrong conclusions were more often observed for single-arm designs due to an increase of Δ over time. Under H1 (Δ = + 0.2), for the "standard" case, the power was similar between single- and two-arm designs when pC = pH. For "stopping of recruitment" case, single-arm performed better than two-arm designs, and fixed designs reported higher power than group-sequential designs. A web R-Shiny application was developed. At an outbreak beginning, group-sequential two-arm trials should be preferred, as the infected cases number increases allowing to conduct a strong randomized control trial. Group-sequential designs allow early termination of trials in cases of harmful experimental treatment. After the epidemic peak, fixed single-arm design should be preferred, as the cases number decreases but this assumes a high level of confidence on the pre-trial historical survival rate.


Hydrogen Attenuates Myocardial Injury in Rats by Regulating Oxidative Stress and NLRP3 Inflammasome Mediated Pyroptosis.
Purpose: Hydrogen (H2) is an antioxidant with anti-inflammatory and apoptosis functions.This study aimed to estimate the effects of H2 on acute myocardial infarction (AMI) in rats and its association with the inhibition of oxidative stress and cardiomyocyte pyroptosis. Methods: Sixty-four rats were randomly divided into three groups (Sham, AMI, and H2). The left anterior descending coronary artery (LAD) of rats in the AMI and H2 groups was ligated, while rats in the Sham group were threaded without ligation. In addition, 2% H2 was administered by inhalation for 24 h after ligation in the H2 group. Transthoracic echocardiography was performed after H2 inhalation, followed by collection of the serum and cardiac tissue of all rats. Results: H2 inhalation ameliorated the cardiac dysfunction, infarct size and inflammatory cell infiltration caused by AMI. Meanwhile, H2 inhalation reduced the concentration of serum Troponin I (TnI), brain natriuretic peptide (BNP), reactive oxygen species (ROS), cardiac malondialdehyde (MDA), and 8-OHdG. In addition, H2 inhalation inhibited cardiac inflammation and pyroptosis relative proteins expression. Conclusion: H2 effectively promoted heart functions in AMI rats by regulating oxidative stress and pyroptosis.


Alarming downtrend in mechanical thrombectomy rates in African American patients during the COVID-19 pandemic-Insights from STAR.
The coronavirus disease (COVID-19) pandemic has affected stroke care globally. In this study, we aim to evaluate the impact of the current pandemic on racial disparities among stroke patients receiving mechanical thrombectomy (MT). We used the prospectively collected data in the Stroke Thrombectomy and Aneurysm Registry from 12 thrombectomy-capable stroke centers in the US and Europe. We included acute stroke patients who underwent MT between January 2017 and May 2020. We compared baseline features, vascular risk factors, location of occlusion, procedural metrics, complications, and discharge outcomes between patients presenting before (before February 2020) and those who presented during the pandemic (February to May 2020). We identified 2083 stroke patients: of those 235 (11.3%) underwent MT during the COVID-19 pandemic. Compared with pre-pandemic, stroke patients who received MT during the pandemic had longer procedure duration (44 vs 38 min, P=0.006), longer length of hospitalization (6 vs 4 days, P<0.001), and higher in-hospital mortality (18.7% vs 11%, P<0.001). Importantly, there was a lower number of African American patients undergoing MT during the COVID-19 pandemic (609 (32.9%) vs 56 (23.8%); P=0.004). The COVID-19 pandemic has affected the care process for stroke patients receiving MT globally. There is a significant decline in the number of African American patients receiving MT, which mandates further investigation.


[Nitric Oxide(II) in the Biology of Chlorophyta].
NO is a gaseous signaling redox-active molecule that functions in various eukaryotes. However, its synthesis, turnover, and effects in cells are specific in plants in several aspects. Compared with higher plants, the role of NO in Chlorophyta has not been investigated enough. However, some of the mechanisms for controlling the levels of this signaling molecule have been characterized in model green algae. In Chlamydomonas reinhardtii, NO synthesis is carried out by a dual system of nitrate reductase and NO-forming nitrite reductase. Other mechanisms that might produce NO from nitrite are associated with components of the mitochondrial electron-transport chain. In addition, NO formation in some green algae proceeds by an oxidative mechanism similar to that in mammals. The recent discovery of L-arginine-dependent NO synthesis in the colorless alga Polytomella parva suggests the existence of a protein complex with enzyme activities that are similar to animal nitric oxide synthase. This latter finding paves the way for further research into potential members of the NO synthases family in Chlorophyta. Beyond synthesis, the regulatory processes to maintain intracellular NO levels are also an integral part for its function in cells. Members of the truncated hemoglobins family with dioxygenase activity can convert NO to nitrate, as was shown for C. reinhardtii. In addition, the implication of NO reductases in NO scavenging has also been described. Even more intriguing, unlike in animals, the typical NO/cGMP signaling module appears not to be used by green algae. S-nitrosylated glutathione, which is considered the main reservoir for NO, provides NO signals to proteins. In Chlorophyta, protein S-nitrosation is one of the key mechanisms of action of the redox molecule. In this review, we discuss the current state-of-the-art and possible future directions related to the biology of NO in green algae.


Enhancement of crystalline plane orientation in silsesquioxane-containing vaterite particles towards tuning of calcium ion release.
Siloxane-containing vaterite (SiV) particles with spherical- to discoidal-morphologies were selectively prepared by a CO2 gas carbonation process in a methanol-acetone mixed solvent; they are intended for application as osteogenic devices in bone tissue engineering. Moreover, the c/ab-face ratio of vaterite was successfully tuned through the selection of methanol-acetone volume fractions. The solvent increased the supersaturation of CO3 2- ions and accelerated the crystal growth along the ab-axis in the presence of silsesquioxane. The particles released soluble silica species and calcium ions upon soaking in physiological pH buffer solution, which are expected to genetically stimulate osteoblasts to enhance bone reconstruction. An initial calcium ion release from the particles significantly decreased from 3.1 to 1.6 mmol L-1 as the c/ab-face ratio increased, while the composition of the particle and release profiles of soluble silica remained consistent. This demonstrated the possibility of tuning the calcium ion release from SiV particles by controlling the degree of crystalline plane orientation.


A comparison of glycemic parameters and their relationship with C-peptide and Proinsulin levels during partial remission and non-remission periods in children with type 1 diabetes mellitus - a cross-sectional study.
Currently, there is a lack of data relating to glycemic parameters and their relationship with C-peptide (CP) and proinsulin (PI) during the partial remission period (PRP) in type 1 diabetes mellitus (T1D). The aim of this study was to evaluate glycemic parameters in children with T1D who are in the PRP using intermittently scanned continuous glucose monitoring systems (isCGMS) and to investigate any relationships between CP and PI levels. The study included 21 children who were in the PRP and 31 children who were not. A cross-sectional, non-randomized study was performed. Demographic, clinical data were collected and 2 week- isCGMS data were retrieved. The Serum CP showed a positive correlation with time-in-range in the PRP (p:0.03), however PI showed no correlations with glycemic parameters in both periods. The Serum CP and PI levels and the PI:CP ratio were significantly higher in the PRP group than in the non-PRP group. In the non-PRP group, the PI level was below 0.1 pmol/L (which is the detectable limit) in only 2 of the 17 cases as compared with none in the PRP group. Similarly, only 2 of the 17 children in the non-PRP group had CP levels of less than 0.2 nmol / L, although both had detectable PI levels. Overall time-in-range (3. 9-1.0 mmol/L) was significantly high in the PRP group. In contrast, the mean sensor glucose levels, time spent in hyperglycemia, and coefficient of variation levels (32.2vs 40.5%) were significantly lower in the PRP group. Although the mean glucose and time in range during the PRP was better than that in the non-PRP group, the glycemic variability during this period was not as low as expected. While the CP levels showed an association with TIR during the PRP, there was no correlation between PI levels and glycemic parameters. Further studies are needed to determine if PI might prove to be a useful parameter in clinical follow-up.


SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism.
The SIRT1 deacetylase inhibits fat synthesis and stimulates fat oxidation in response to fasting, but the underlying mechanisms remain unclear. Here we report that SREBP-1c, a key lipogenic activator, is an in vivo target of SIRT1. SIRT1 interaction with SREBP-1c was increased during fasting and decreased upon feeding, and consistently, SREBP-1c acetylation levels were decreased during fasting in mouse liver. Acetylated SREBP-1c levels were also increased in HepG2 cells treated with insulin and glucose to mimic feeding conditions, and down-regulation of p300 by siRNA decreased the acetylation. Depletion of hepatic SIRT1 by adenoviral siRNA increased acetylation of SREBP-1c with increased lipogenic gene expression. Tandem mass spectrometry and mutagenesis studies revealed that SREBP-1c is acetylated by p300 at Lys-289 and Lys-309. Mechanistic studies using acetylation-defective mutants showed that SIRT1 deacetylates and inhibits SREBP-1c transactivation by decreasing its stability and its occupancy at the lipogenic genes. Remarkably, SREBP-1c acetylation levels were elevated in diet-induced obese mice, and hepatic overexpression of SIRT1 or treatment with resveratrol, a SIRT1 activator, daily for 1 week decreased acetylated SREBP-1c levels with beneficial functional outcomes. These results demonstrate an intriguing connection between elevated SREBP-1c acetylation and increased lipogenic gene expression, suggesting that abnormally elevated SREBP-1c acetylation increases SREBP-1c lipogenic activity in obese mice. Reducing acetylation of SREBP-1c by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes.


Biphasic cholinergic synaptic transmission controls action potential activity in thalamic reticular nucleus neurons.
Cholinergic neurons in the basal forebrain and the brainstem form extensive projections to a number of thalamic nuclei. Activation of cholinergic afferents during distinct behavioral states can regulate neuronal firing, transmitter release at glutamatergic and GABAergic synapses, and synchrony in thalamic networks, thereby controlling the flow of sensory information. These effects are thought to be mediated by slow and persistent increases in extracellular ACh levels, resulting in the modulation of populations of thalamic neurons over large temporal and spatial scales. However, the synaptic mechanisms underlying cholinergic signaling in the thalamus are not well understood. Here, we demonstrate highly reliable cholinergic transmission in the mouse thalamic reticular nucleus (TRN), a brain structure essential for sensory processing, arousal, and attention. We find that ACh release evoked by low-frequency stimulation leads to biphasic excitatory-inhibitory (E-I) postsynaptic responses, mediated by the activation of postsynaptic α4β2 nicotinic ACh receptors (nAChRs) and M2 muscarinic ACh receptors (mAChRs), respectively. In addition, ACh can bind to mAChRs expressed near cholinergic release sites, resulting in autoinhibition of release. We show that the activation of postsynaptic nAChRs by transmitter release from only a small number of individual axons is sufficient to trigger action potentials in TRN neurons. Furthermore, short trains of cholinergic synaptic inputs can powerfully entrain ongoing TRN neuronal activity. Our study demonstrates fast and precise synaptic E-I signaling mediated by ACh, suggesting novel computational mechanisms for the cholinergic control of neuronal activity in thalamic circuits.


Role of Vitamin D in the Outcome of Ischemic Stroke- A Randomized Controlled Trial.
Vitamin D deficiency has reached epidemic proportions in India with prevalence rates of 70-100% in the general population. Low vitamin D levels are associated with worse outcomes in ischemic strokes. The outcome of stroke after vitamin D replenishment has not been much studied. To compare the stroke outcome between patients receiving vitamin D supplementation and patients without vitamin D supplementation by Scandinavian Stroke Scale (SSS) and thus, to assess the long term outcome of ischemic stroke patients with low vitamin D level by supplementation of vitamin D. This is a non blinded randomized controlled trial conducted in ischemic stroke patients. The patients were divided into two groups (A and B) where Group A received a single dose of 6 lac IU of Cholecalciferol Intramascular (IM) injection and Group B were not given vitamin D. Finally 30 patients in each group were analyzed. SSS was applied to evaluate the stroke severity at the onset and at the follow up after three months in both groups. The difference in SSS was analyzed using SPSS software. Independent t-test was applied and p-value < 0.05 was taken as significant. Mean±SD of vitamin D levels in Group A and Group B were 17.98±3.81ng/ml and 18.44±4.69 ng/ml respectively. Mean±SD of SSS at time of admission and after three months for Group A was 32.50±11.61 and 38.89±8.34; and for Group B 35.82±8.56 and 38.32±7.10. The difference in SSS from time of admission and after three months, in Group A (6.39±4.56) and Group B (2.50±2.20) were analyzed statistically and found to be highly significant (p<0.001). The results showed that there is a significant improvement in the stroke outcome after three months in those patients who were supplemented with vitamin D. Thus screening for vitamin D deficiency in stroke patients is essential and vitamin D replenishment will improve the stroke outcome.


Cancer Cells and M2 Macrophages: Cooperative Invasive Ecosystem Engineers.
Many aspects of cancer can be explained utilizing well-defined ecological principles. Applying these principles to cancer, cancer cells are an invasive species to a healthy organ ecosystem. In their capacity as ecosystem engineers, cancer cells release cytokines that recruit monocytes to the tumor and polarize them to M2-like protumor macrophages. Macrophages, recruited by the cancer cells, act as a secondary invasive species. The ecosystem engineering functions of M2-macrophages in turn support and stimulate cancer cell survival and proliferation. The cooperative ecosystem engineering of both the primary invasive species of the cancer cell and the secondary invasive species of the M2-macrophage thus creates a vicious cycle of tumor promotion. Targeting a specific aspect of this tumor-promoting ecosystem engineering, such as blocking efferocytosis by M2-like macrophages, may improve the response to standard-of-care anticancer therapies. This strategy has the potential to redirect cooperative protumor ecosystem engineering toward an antitumor ecosystem engineering strategy.


Improvement of a p(65)+Be neutron beam for therapy at Cyclone, Louvain-la-Neuve.
The variable energy cyclotron of the Catholic University of Louvain is used to produce intense neutron beams for neutron therapy purposes. As a first step, neutrons were produced by bombarding a Be target with 50 MeV deuterons; at present they are produced by 65 MeV protons. This paper describes the improvements to the target system. A new (17 mm) Be target together with the old (10 mm) Be target are inserted in a movable support which allows the production of neutrons either by 65 MeV protons or by 50 MeV deuterons. Both targets can be removed for proton beam therapy. The dosimetric characteristics of the p(65)+Be and d(50)+Be neutron beams are compared: dose rate, gamma-contribution, depth dose and room activation.


Vivax and falciparum malaria seen at an Indian service hospital.
The cases of 740 adult males with vivax and/or falciparum malaria managed in a military hospital in north-eastern India during the period from June 1978 to March 1981 were analysed. Four hundred and nine (55.3%) were infected with Plasmodium falciparum, 237 (32.0%) with P. vivax and the remaining 94 (12.7%) with both P. vivax and P. falciparum. The majority of cases were chloroquine sensitive and did not pose diagnostic or therapeutic problems. Of 381 patients subjected to an extended field test, 82 (21.5%) exhibited a variable degree of chloroquine resistance. Cerebral and haemopoietic involvement were the commonest of the pernicious syndromes observed in 92 (12.4%) patients. Atypical presentations, variable chloroquine resistance and presentation with complications call for timely recognition and institution of a specific supportive therapeutic regime.


[Dietary survey and biochemical study of blood and urine among Yi and Han nationality farmers in low prevalent district of hypertension].
This paper reports the dietary investigation (55 persons) and nutrient biochemical analysis of blood and urine (173 persons) among Yi and Han nationality farmers with low incidence of hypertension in Weinin, Guizhou. The results suggest that the three main nutrients as protein, fat and carbohydrate had no uniform relationship to the blood pressure, but high potassium and low sodium diet was intimately correlated to the low incidence of hypertension. The Na/K ratio of dietary intake and urine was more closely related to blood pressure. The relationship between calcium and blood pressure was quite complicated. The appropriate ratio of calcium and magnesium intake may be significant in the prevention and treatment of hypertension. It also indicates some intrinsic connection between lipid metabolism and blood pressure, while the degree of smoking is definitely correlated to blood pressure.


Effects of early and late diabetic neuropathy on sciatic nerve block duration and neurotoxicity in Zucker diabetic fatty rats.
The neuropathy of type II diabetes mellitus (DM) is increasing in prevalence worldwide. We aimed to test the hypothesis that in a rodent model of type II DM, neuropathy would lead to increased neurotoxicity and block duration after lidocaine-induced sciatic nerve block when compared with control animals. Experiments were carried out in Zucker diabetic fatty rats aged 10 weeks (early diabetic) or 18 weeks (late diabetic, with or without insulin 3 units per day), and age-matched healthy controls. Left sciatic nerve block was performed using 0.2 ml lidocaine 2%. Nerve conduction velocity (NCV) and F-wave latency were used to quantify nerve function before, and 1 week after nerve block, after which sciatic nerves were used for neurohistopathology. Early diabetic animals did not show increased signs of nerve dysfunction after nerve block. In late diabetic animals without insulin vs control animals, NCV was 34.8 (5.0) vs 41.1 (4.1) ms s(-1) (P<0.01), and F-wave latency was 7.7 (0.5) vs 7.0 (0.2) ms (P<0.01), respectively. Motor nerve block duration was prolonged in late diabetic animals, but neurotoxicity was not. Late diabetic animals receiving insulin showed intermediate results. In a rodent type II DM model, nerves have increased sensitivity for short-acting local anaesthetics without adjuvants in vivo, as evidenced by prolonged block duration. This sensitivity appears to increase with the progression of neuropathy. Our results do not support the hypothesis that neuropathy due to type II DM increases the risk of nerve injury after nerve block.


Exercise-related QT interval shortening with a peaked T wave in a healthy boy with a family history of sudden cardiac death.
An asymptomatic 15-year-old boy, who had a family history of sudden cardiac death, was referred for screening for cardiac disease. The 12-lead electrocardiogram at rest showed a short QT/QTc(Bazett)/QTc(Fredericia) interval of 320/388/364 ms, but the intervals were further shortened to 200/339/284 ms after the treadmill test concomitant with appearance of a peaked T wave. Other conventional cardiac examinations were normal, but effective refractory period was less than 180 ms in both ventricles, and double ventricular extrastimulation reproducibly induced nonsustained polymorphic ventricular tachycardia. Intravenous administration of epinephrine also induced a short QT interval and a peaked T wave, and a hump was manifested on the T wave of the first postpacing beat with a longer preceding R-R interval. Furthermore, a couple of premature ventricular complexes originated from a similar timing as the hump. Genetic analysis did not show the mutation in KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, SCN5A genes but revealed single nucleotide polymorphism (C5457T) in SCN5A gene.


Early and midterm results of aortic aneurysm treatment in patients with challenging anatomy using the Aorfix endograft: single-center experience.
Since the introduction of the first commercial endofraft to treat the abdominal aortic aneurysm in the early 1990s, there has been a continuous improvement and technology evolution making feasible to treat successfully highly complex AAA with endovascular repair. We have performed EVAR therapy in highly complex aorto-iliac aneurysm using the Aorfix(®) stent-graft system from 2009 to 2011. A retrospective review to our clinical experience was performed, comparing two groups of patients: 1. Challenging anatomy group treated with Aorfix Endograft. 2. Standard anatomy group was integrated by EVAR procedures performed in patients with aortic angulation less than 75°or non-tortuos iliac vessels. In 96.5-97% of cases a bifurcated endograft was implanted with clinical and technical succes . After 1 year follow up in most cases and at least 6 months follow up in all the series we saw successful results, with aneurysmal sac reduction or stability, 2 type II endoleaks related to lumbar arteries with sac stability and no AAA-related complications were finded in the complex anatomy group. The 30 days, early-midterm and 12 months results for challenging anatomy group are identical to those finded in standard anatomy and consistent with published data, showing the performance of this endograft system in tortuous anatomies. These early results are quite promising, this particular graft, in its labeled use, is providing an excellent platform to EVAR therapy in challenging anatomies, off label to other devices currently avaliable; however, further studies are needed to evaluate the long-term results.


AKT/GSK3 signaling pathway and schizophrenia.
Schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathways in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathway in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al. in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK-3β in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal and non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally, different transcription factors related to schizophrenia will be reviewed to see how hypo-activity of AKT signaling pathway may impact such transcriptional mechanisms.


Bisphenol A and phthalates in utero and in childhood: association with child BMI z-score and adiposity.
To assess the relationship between in utero and concurrent child urinary exposures to bisphenol A (BPA) and phthalates with BMI z-score, waist circumference, and sum of triceps and subscapular skinfold thickness in Mexican children. Among participants (N=249) from the Early Life Exposure in Mexico to ENvironmental Toxicants study, we evaluated associations between maternal third trimester and concurrent urinary BPA and individual and summed phthalates metabolites (∑Di(2-ethylhexyl phthalate), ∑high molecular weight, ∑low molecular weight) with measures of weight status and adiposity in children aged 8-14 years. Linear regressions with specific-gravity corrected and natural log-transformed urinary concentrations were estimated, adjusting for covariates. Effect modification by sex was explored. Prenatal urinary exposure to monobenzyl phthalate (MBzP) was inversely associated with child's BMI z-score (β=-0.21, 95%CI: -0.41, -0.02) and child urinary exposure to mono(2-ethylhexyl)phthalate (MEHP) was inversely associated with waist circumference (β=-1.85, 95%CI: -3.36, -0.35) and sum of skinfold thicknesses (β=-2.08, 95%CI: -3.80, -0.37) after adjusting for confounders. In the childhood exposure period, sex modified the relationships with BPA, MEHP, MBzP, monoethyl phthalate (MEP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP). In girls, increased BPA exposure was positively associated with sum of skinfold thickness (β=3.47, 95%CI: 0.05, 6.40) while increased MEHP was inversely associated with sum of skinfold thicknesses in boys (β=-2.95, 95%CI: -5.08, -0.82); these results remained in sensitivity analyses after excluding children who had initiated pubertal development (Tanner stage >1 for pubic hair). We did not observe relationships between summed phthalates metabolites at any exposure period with outcome measures. Our results identified associations between urinary BPA and phthalates metabolites with measures of weight status and adiposity that differed by timing of exposure, sex, and pubertal status. Additional studies are needed to explore how associations may differ between those who are pre- and post-pubertal.


Phase II Study of Pemetrexed as a Salvage Chemotherapy for Thymidylate Synthase-Low Squamous Cell Lung Cancer.
Squamous cell carcinomas (SqCC) of the lung often express high levels of thymidylate synthase (TS), which is associated with primary resistance to pemetrexed. We explored the efficacy of pemetrexed in a selected population of patients with lung SqCC with low TS expression. In this single-arm phase II trial, we enrolled 32 previously-treated patients with advanced lung SqCC exhibiting low immunohistochemical staining for TS (i.e., in 10% or less of tumor cells). The primary endpoint was 12-week progression-free survival (PFS) rate. Of 32 patients, eight patients (25%) had an Eastern Cooperative Oncology Group performance status of 2, and seven patients (22%) had previously received three or more lines of chemotherapy. The disease control rate from pemetrexed treatment was 30%, and no objective response was observed. The 12-week PFS rate was 24.5% (95% confidence interval [CI], 13.0 to 46.1). Median PFS was 1.3 months (95% CI, 1.3 to 2.7), and median overall survival was 11.8 months (95% CI, 8.1 to not applicable). Most of adverse events were grade 1 or 2. Pemetrexed demonstrated modest activity as a salvage chemotherapy in patients with advanced lung SqCC with low TS expression, although its toxicity was generally manageable.


Iron metabolism in pathogenic bacteria.
The ability of pathogens to obtain iron from transferrins, ferritin, hemoglobin, and other iron-containing proteins of their host is central to whether they live or die. To combat invading bacteria, animals go into an iron-withholding mode and also use a protein (Nramp1) to generate reactive oxygen species in an attempt to kill the pathogens. Some invading bacteria respond by producing specific iron chelators-siderophores-that remove the iron from the host sources. Other bacteria rely on direct contact with host iron proteins, either abstracting the iron at their surface or, as with heme, taking it up into the cytoplasm. The expression of a large number of genes (>40 in some cases) is directly controlled by the prevailing intracellular concentration of Fe(II) via its complexing to a regulatory protein (the Fur protein or equivalent). In this way, the biochemistry of the bacterial cell can accommodate the challenges from the host. Agents that interfere with bacterial iron metabolism may prove extremely valuable for chemotherapy of diseases.


Di-μ-thio-cyanato-κN:S;κS:N-bis-({2-morpholino-N-[1-(2-pyrid-yl)ethyl-idene]ethanamine-κN,N',N''}(thio-cyanato-κN)cadmium).
In the title complex, [Cd(2)(NCS)(4)(C(13)H(19)N(3)O)(2)], the two Cd(II) ions are bridged by a pair of thio-cyanate N:S-bridging ligands around an inversion center. One terminal thio-cyanate N atom and one N,N',N''-tridentate Schiff base ligand complete a distorted CdN(5)S octa-hedral geometry about each Cd(II) atom. In the crystal, the Schiff base aromatic rings of adjacent mol-ecules are arranged above each other into infinite chains along the a axis with alternate centroid-centroid separations of 3.5299 (13) and 3.7857 (13) Å.


Hypertension 2008, refining our treatment.
Clinical studies continue to modify our approach to the older hypertensive patient. The pathophysiology of hypertension is now better understood from data derived from ambulatory blood pressure monitoring, the assessment of central arterial pressure and of vascular stiffness. This is altering both the ways we assess, monitor, and treat our older hypertensive patients as well as our choice of pharmacological agents. New data have confirmed the importance of treating the very elderly patient's blood pressure and of modifying the increasing incidence of atrial fibrillation. Resistant hypertension is frequently the result of excessive aldosterone production, a situation easily treated. Several investigators have raised the question of the prehypertensive state and of possible therapy.


Effect of different experimental conditions on lipogenesis and substrate oxidation in isolated adipocytes from fattening Holstein steers.
The present study was undertaken to provide further information on lipogenesis in isolated adipocytes from the subcutaneous adipose tissue of fattening steers. The main aims were to compare different incubation media and to clarify the effects of fetal bovine serum (FBS) on lipogenesis and substrate oxidation rate in the adipocytes. The isolated adipocytes were prepared by the collagenase digestion technique. The changes in cellularity, the incorporation rates of acetate or glucose into lipid molecules, and the oxidation rates to CO2 both in fresh and preincubated adipocytes were measured in different media. It was shown that FBS increased significantly both lipogenesis and the oxidation rates of glucose or acetate in the fresh adipocytes but insulin did not. In isolated adipocytes preincubated for 24 and 48 h, the cellularity, the incorporation rate of glucose into lipid molecules, and the oxidation rates of glucose or acetate to CO2 were not different to those in fresh adipocytes, but the incorporation rate of acetate into lipid molecules was significantly lower.


Metabolomic Response of Equine Skeletal Muscle to Acute Fatiguing Exercise and Training.
The athletic horse, despite being over 50% muscle mass, remains understudied with regard to the effects of exercise and training on skeletal muscle metabolism. To begin to address this knowledge gap, we employed an untargeted metabolomics approach to characterize the exercise-induced and fitness-related changes in the skeletal muscle of eight unconditioned Standardbred horses (four male, four female) before and after a 12-week training period. Before training, unconditioned horses showed a high degree of individual variation in the skeletal muscle metabolome, resulting in very few differences basally and at 3 and 24 h after acute fatiguing exercise. Training did not alter body composition but did improve maximal aerobic and running capacities (p < 0.05), and significantly altered the skeletal muscle metabolome (p < 0.05, q < 0.1). While sex independently influenced body composition and distance run following training (p < 0.05), sex did not affect the skeletal muscle metabolome. Exercise-induced metabolomic alterations (p < 0.05, q < 0.1) largely centered on the branched-chain amino acids (BCAA), xenobiotics, and a variety of lipid and nucleotide-related metabolites, particularly in the conditioned state. Further, training increased (p < 0.05, q < 0.1) the relative abundance of almost every identified lipid species, and this was accompanied by increased plasma BCAAs (p < 0.0005), phenylalanine (p = 0.01), and tyrosine (p < 0.02). Acute exercise in the conditioned state decreased (p < 0.05, q < 0.1) the relative abundance of almost all lipid-related species in skeletal muscle by 24 h post-exercise, whereas plasma amino acids remained unaltered. These changes occurred alongside increased muscle gene expression (p < 0.05) related to lipid uptake (Cd36) and lipid (Cpt1b) and BCAA (Bckdk) utilization. This work suggests that metabolites related to amino acid, lipid, nucleotide and xenobiotic metabolism play pivotal roles in the response of equine skeletal muscle to vigorous exercise and training. Use of these and future data sets could be used to track the impact of training and fitness on equine health and may lead to novel predictors and/or diagnostic biomarkers.


Differential sensitivity of insulin- and adaptive-regulation-induced system A activation to microtubular function in skeletal muscle.
1. Insulin and adaptive regulation are known to stimulate system A amino acid transport activity in skeletal muscle. The present study was designed to investigate whether activation of system A in muscle is a consequence of processes which rely on microtubule or microfilament function. To that end, extensor digitorum longus (EDL) muscles were incubated in the presence of colchicine and cytochalasin D, well-known inhibitors of microtubule and microfilament activity respectively. 2. Basal alpha-(methyl)aminoisobutyric acid (MeAIB) uptake decreased after incubation with 5 microM-colchicine in a time-dependent manner. In keeping with this, adaptive regulation of MeAIB uptake caused by prolonged incubation in the absence of amino acids was substantially decreased in the presence of colchicine. 3. Under these conditions, stimulation of MeAIB uptake by insulin was unaltered in muscle in the presence of colchicine. This contrasted with the insulin-induced stimulation of MeAIB uptake by isolated rat hepatocytes, which was markedly decreased by colchicine. 4. Cytochalasin D, an agent that disrupts microfilaments, did not inhibit basal or insulin-stimulated MeAIB uptake by the incubated muscle. 5. Neither colchicine nor cytochalasin D modified the stimulatory effect of insulin on 3-O-methylglucose uptake by EDL muscle. 6. We conclude that up-regulation of system A by synthesis of new carriers depends on the integrity of microtubular function both in skeletal muscle and in hepatocytes. Microtubules might play a role in the movement of system A-containing vesicles from the Golgi network to the plasma membrane.


[Outline on the phylogenetic history of Metazoa aging phenomenon (to the study of number of dominating pseudo-scientific concepts in biology of aging)].
Natural selection is just one of the factors determining genome evolution of Metazoa. But it's not a domineering one along with non-adaptive processes: horizontal gene transfer and input of egoistic genetic elements. That's why in phylogenesis (1) there are more genes of first Metazoa lost than new ones acquired; (2) the appearance of new genes among Metazoa branches is a very rare occasion; (3) genetically Metazoa is a homogeneous group of species with similar set of cellular mechanisms which was established in the course of evolution. The genome of first Metazoa turned to be so successful that evolution connected with organism amplification didn't demand radical changes in the genetic repertoire but it demanded changes in DNA sites regulating genes work. These facts along with the fact of existence of species of Metazoa with negligible aging overturn the core theories of aging biology which consider this or that cellular mechanism to be the initiating factor of organism's aging as sets of cellular mechanisms in aging and non-aging Metazoa forms are practically identical. That's why the basis of aging biology is in essence a collection of theories and dogmas that have never been proved but which are still in use and which have since long ago turned into a dangerous myth standing in the way of progress. If we are interested in progress of biogerontology a number of domineering pseudo scientific dogmas must be revisited. The matter of conservatism in this issue is inappropriate.


Cat- or dog-induced immediate and late asthmatic responses before and after immunotherapy.
To assess the effect of specific immunotherapy (IT) on the immediate and late asthmatic responses induced by cat or dog extract bronchial provocation testing, we studied seven cat-sensitive and six dog-sensitive subjects with asthma. Among the cat-sensitive subjects, two of three subjects displaying only an immediate asthmatic response before IT lost the response after 3 months of IT with cat extract, whereas only one of four subjects with the dual (immediate and late) asthmatic responses had ablation of such responses (no significance for the one-tailed test). Three subjects had worsening of the immediate response after IT. Among dog-sensitive subjects with asthma, three of five subjects with only an immediate response demonstrated an ablation of the immediate response, whereas the one subject who was the only subject with a dual response before IT lost the dual response after dog-extract IT (p value of 0.005 on one-tailed test). Immediate systemic side effects, including one episode of anaphylaxis, occurred on seven occasions of 326 injections with cat extract compared to only one episode of rhinitis of 289 injections with dog extract.


Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone.
This 24-week, randomized, multicentre, open-label, parallel-group clinical trial compared efficacy and safety of repaglinide monotherapy, rosiglitazone monotherapy, and combination therapy (repaglinide plus rosiglitazone) in Type 2 diabetes after unsatisfactory response to sulphonylurea or metformin monotherapy. Enrolled patients (n = 252) were adults having Type 2 diabetes for at least 1 year, with HbA(1c) values > 7.0% after previous monotherapy (sulphonylurea or metformin, >/= 50% maximal dose). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, rosiglitazone, or repaglinide/rosiglitazone. Study treatments were initiated with a 12-week dose optimization period (doses optimized according to labelling), followed by a 12-week maintenance period. Efficacy endpoints were changes in HbA(1c) values (primary) or fasting plasma glucose values (secondary). Baseline HbA(1c) values were comparable (9.3% for repaglinide, 9.0% for rosiglitazone, 9.1% for combination). Mean changes in HbA(1c) values at the end of treatment were greater for repaglinide/rosiglitazone therapy (-1.43%) than for repaglinide (-0.17%) or rosiglitazone (-0.56%) monotherapy. Reductions of fasting plasma glucose values were also greater for combination therapy (-5.2 mmol/l, -94 mg/dl) than for repaglinide monotherapy (-3.0 mmol/l, -54 mg/dl) or rosiglitazone monotherapy (-3.7 mmol/l, -67 mg/dl). Minor hypoglycaemic events occurred in 9% of combination therapy patients, vs. 6% for repaglinide and 2% for rosiglitazone. Individual weight gains for combination therapy were correlated to HbA(1c) response. The combination therapy regimen was well tolerated. In patients previously showing unsatisfactory response to oral monotherapy, glycaemic reductions were greater for the repaglinide/rosiglitazone combination regimen than for use of either repaglinide or rosiglitazone alone.


Biochemical effects of piceatannol in human HL-60 promyelocytic leukemia cells--synergism with Ara-C.
Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene; PCA) is a naturally occurring metabolite of resveratrol (3,4',5-trihydroxy-trans-stilbene; RV). In this study, we identified additional biochemical targets of PCA in human HL-60 promyelocytic leukemia cells. Incubation with PCA led to a significant proportion of apoptotic cells and caused an arrest in the G2-M phase of the cell cycle. PCA depleted intracellular dCTP and dGTP pools, and inhibited the incorporation of 14C-labeled cytidine into DNA. PCA significantly abolished all NTP pools, and sequential treatment with PCA and Ara-C yielded synergistic growth inhibitory effects because of remarkably increased Ara-CTP formation after PCA preincubation. Due to these promising results, PCA may support conventional chemotherapy of human malignancies and therefore, deserves further preclinical and in vivo testing.


Involvement of an ATP-dependent protease, PA0779/AsrA, in inducing heat shock in response to tobramycin in Pseudomonas aeruginosa.
The adaptive resistance of Pseudomonas aeruginosa to aminoglycosides is known to occur during chronic lung infections in cystic fibrosis patients in response to nonlethal concentrations of aminoglycosides. Not only is it difficult to achieve high levels of drug throughout the dehydrated mucus in the lung, but also steep oxygen gradients exist across the mucus layer, further reducing the bactericidal activity of aminoglycosides. In this study, microarray analysis was utilized to examine the gene responses of P. aeruginosa to lethal, inhibitory, and subinhibitory concentrations of tobramycin under aerobic and anaerobic conditions. While prolonged exposure to subinhibitory concentrations of tobramycin caused increased levels of expression predominantly of the efflux pump genes mexXY, the greatest increases in gene expression levels in response to lethal concentrations of tobramycin involved a number of heat shock genes and the PA0779 gene (renamed here asrA), encoding an alternate Lon protease. Microarray analysis of an asrA::luxCDABE transposon mutant revealed that the induction of heat shock genes in response to tobramycin in this mutant was significantly decreased compared to that in the parent strain. The level of expression of asrA was induced from an arabinose-inducible promoter to 35-fold greater than wild-type expression levels in the absence of tobramycin, and this overexpression alone caused an increased expression of the heat shock genes, as determined by quantitative PCR (qPCR). This overexpression of asrA conferred short-term protection against lethal levels (4 μg/ml) of tobramycin but did not affect the tobramycin MIC. The RpoH heat shock sigma factor was found to be involved in the regulation of asrA in response to both heat shock and tobramycin at the posttranscriptional level. The results of this work suggest that the tobramycin concentration has a significant impact on the gene expression of P. aeruginosa, with lethal concentrations resulting in immediate adaptations conferring short-term protection, such as the induction of the heat shock response, and with subinhibitory concentrations leading to more sustainable long-term protection mechanisms, such as increased efflux.


Radiosensitivity of T and B lymphocytes. III. Effect of radiation on immunoglobulin production by B cells.
Radiation injury in defined populations of B cells was investigated utilizing an allotype congenic transfer system. The amount of donor immunoglobulin present in the recipient's serum was found to be directly proportional to the number of viable cells injected, and on this basis approximate D37 values for the inoculated B cells were determined in several experiments and found to fall in the 70 to 145 rad range depending upon the specific experimental conditions. Since the sensitivity of T cells to radiation-induced interphase death can be modified by prior exposure to select mitogens and antigens, an attempt was made to demonstrate a similar phenomenon with respect to B cells. The results indicate that the radiosensitivity of B cells can be slightly influenced by prior incubation with mitogens and only equivocally changed by activation with antigen.


Primary progressive aphasia.
Primary progressive aphasia (PPA) is a focal dementia characterized by an isolated and gradual dissolution of language function. The disease starts with word-finding disturbances (anomia) and frequently proceeds to impair the grammatical structure (syntax) and comprehension (semantics) of language. The speech output in PPA can be fluent or nonfluent. Memory, visual processing, and personality remain relatively well-preserved until the advanced stages and help to distiguish PPA from frontal lobe dementia and the typical forms of Alzheimer's disease. The term "semantic dementia" was originally introduced to designate a different group of patients with a combination of verbal and visual processing deficits. In practice, however, this diagnosis is also being used in a variant sense to denote a subtype of PPA with fluent speech and impaired comprehension, even in the absence of visual processing deficits. Insofar as the diagnosis of semantic dementia can have these two different meanings, it is important to specify whether it is being used in the original sense or to denote a subtype of PPA. Structural and physiological neuroimaging confirms the selective predilection of PPA for the left hemisphere, especially for its language-related cortices. A few patients with PPA display the neuropathological markers of Alzheimer's disease, but in an unusual distribution. The majority of the autopsies in PPA have shown either Pick's disease or lobar atrophy without distinctive histopathology. The suggestion has been made that PPA and frontal lobe dementia constitute phenotypical variations of a unitary disease process within the "Pick-lobar atrophy" spectrum. Recent advances in chromosome 17-linked dementias justify a rigorous search for tau polymorphisms and tauopathy in sporadic PPA. An informed approach to this syndrome will increase the effectiveness with which clinicians can address the unique challenges associated with the diagnosis and care of PPA.


Abnormal fatty acid metabolism is a core component of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/- mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.


Early withdrawal of calcineurin inhibitors and everolimus monotherapy in de novo liver transplant recipients preserves renal function.
We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA-based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy-eight patients were randomized (Evr n = 52; CsA n = 26). The 1-year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ≥ 3 (estimated glomerular filtration rate < 60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications.


Effects of aldose reductase inhibitors and galactose withdrawal on fluorescein angiographic lesions in galactose-fed dogs.
To assess the effect of aldose reductase inhibitor (ARI) M79175 (2-methyl-6-fluoro-spiro-chroman-4-5'-imidazolidine-2',4'-dione) administration and galactose withdrawal on the progression of retinal changes using fluorescein angiography in galactose-fed dogs. Thirty male beagles were randomized into 4 groups. Three dogs were fed a normal control diet containing 30% nonnutritive fiber for 74 months (control group), 11 dogs a 30% galactose diet for 74 months (continuous galactose group), 8 dogs a 30% galactose diet for 36 months followed by replacement with a normal diet for 36 months (galactose withdrawal group), and 8 dogs a 30% galactose diet supplemented with M79175 for 34 months followed by replacement with a normal diet and removal of M79175 treatment for 38 months (ARI-treated galactose withdrawal group). Stereoscopic color fundus photography and fluorescein angiography, performed at baseline and follow-up, were assessed for the clinical development of retinopathy, including the first appearance of hyperfluorescence, varying severity of retinal nonperfusion, and retinal neovascularization. Histopathologic features were examined in selected dogs. All dogs in the 3 groups fed the 30% galactose diet developed areas of hyperfluorescence and nonperfusion. Of these dogs, only those supplemented with the ARI did not develop areas of nonperfusion greater than or equal to half the field and retinal neovascularization. Parametric survival analysis showed significant differences (galactose withdrawal group vs ARI-treated galactose withdrawal group) in the median times to the development of nonperfusion greater than or equal to half the field (P =.003) and retinal neovascularization (P =.03). Normalization of glycemic control with galactose withdrawal and ARI treatment may delay the onset and progression of retinal lesions in galactose-fed dogs. Clinical Relevance Perfect glycemic control after a period of poor control does not completely prevent the progression of retinal lesions. Therapy with ARIs may potentially be important in the prevention of retinal lesions associated with diabetic eye disease.


[Anticoagulation in cardiac pathologies (except atrial fibrillation)].
Anticoagulants, including heparins and antivitamins K are medicines which are largely prescribed in cardiology. Even though the outlines of the treatment have been clearly established for a few decades, new cardiological indications have recently appeared. The long-term treatment of cardiac valvular prosthesis by oral anticoagulants significantly reduces the risk of thrombo-embolic incident among people carrying a cardiac valvular prosthesis. In case of non-operated valvulopathy, treatment indication must be evaluated for each patient; in so doing, the connection benefit/risk must always be taken into account. In case of dilated cardiomyopathy, the treatment prescription must be limited to the patients with a high embolic risk. Other cardiological indications (apart from atrial fibrillation) must be carefully weighed up.


Comparison of chemical and thermal protein denaturation by combination of computational and experimental approaches. II.
Chemical and thermal denaturation methods have been widely used to investigate folding processes of proteins in vitro. However, a molecular understanding of the relationship between these two perturbation methods is lacking. Here, we combined computational and experimental approaches to investigate denaturing effects on three structurally different proteins. We derived a linear relationship between thermal denaturation at temperature T(b) and chemical denaturation at another temperature T(u) using the stability change of a protein (ΔG). For this, we related the dependence of ΔG on temperature, in the Gibbs-Helmholtz equation, to that of ΔG on urea concentration in the linear extrapolation method, assuming that there is a temperature pair from the urea (T(u)) and the aqueous (T(b)) ensembles that produces the same protein structures. We tested this relationship on apoazurin, cytochrome c, and apoflavodoxin using coarse-grained molecular simulations. We found a linear correlation between the temperature for a particular structural ensemble in the absence of urea, T(b), and the temperature of the same structural ensemble at a specific urea concentration, T(u). The in silico results agreed with in vitro far-UV circular dichroism data on apoazurin and cytochrome c. We conclude that chemical and thermal unfolding processes correlate in terms of thermodynamics and structural ensembles at most conditions; however, deviations were found at high concentrations of denaturant.


Prevalence of drug resistance associated mutations in Plasmodium vivax against sulphadoxine-pyrimethamine in southern Pakistan.
In Pakistan, Plasmodium vivax and Plasmodium falciparum co-exist and usage of sulphadoxine-pyrimethamine (SP) against P. falciparum exposes P. vivax to the drug leading to generation of resistant alleles. The main aim of this study was to investigate frequency distribution of drug resistance associated mutations in pvdhfr, pvdhps genes and provide baseline molecular epidemiological data on SP-associated resistance in P. vivax from southern Pakistan. From January 2008 to May 2009, a total of 150 samples were collected from patients tested slide-positive for P. vivax, at the Aga Khan University Hospital, Karachi, or its collection units located in Baluchistan and Sindh Province. Nested PCR using pvdhfr and pvdhps specific primers was performed for all samples.91.3% (137/150) of the samples were tested PCR positive of which 87.3% (131/137) were successfully sequenced. Sample sequencing data was analysed and compared against wild type reference sequences. In dhfr, mutations were observed at codons F57L, S58R and S117N/T. Novel non-synonymous mutations were observed at codon positions N50I, G114R and E119K while a synonymous mutation was observed at codon position 69Y. In dhps, mutations were observed at codon position A383G and A553G while novel non-synonymous mutations were observed at codon positions S373T, E380K, P384L, N389T, V392D, T393P, D459A, M601I, A651D and A661V. This is the first report from southern Pakistan on SP resistance in clinical isolates of P. vivax. Results from this study confirm that diverse drug resistant alleles are circulating within this region.


Probing formation of cargo/importin-α transport complexes in plant cells using a pathogen effector.
Importin-αs are essential adapter proteins that recruit cytoplasmic proteins destined for active nuclear import to the nuclear transport machinery. Cargo proteins interact with the importin-α armadillo repeat domain via nuclear localization sequences (NLSs), short amino acids motifs enriched in Lys and Arg residues. Plant genomes typically encode several importin-α paralogs that can have both specific and partially redundant functions. Although some cargos are preferentially imported by a distinct importin-α it remains unknown how this specificity is generated and to what extent cargos compete for binding to nuclear transport receptors. Here we report that the effector protein HaRxL106 from the oomycete pathogen Hyaloperonospora arabidopsidis co-opts the host cell's nuclear import machinery. We use HaRxL106 as a probe to determine redundant and specific functions of importin-α paralogs from Arabidopsis thaliana. A crystal structure of the importin-α3/MOS6 armadillo repeat domain suggests that five of the six Arabidopsis importin-αs expressed in rosette leaves have an almost identical NLS-binding site. Comparison of the importin-α binding affinities of HaRxL106 and other cargos in vitro and in plant cells suggests that relatively small affinity differences in vitro affect the rate of transport complex formation in vivo. Our results suggest that cargo affinity for importin-α, sequence variation at the importin-α NLS-binding sites and tissue-specific expression levels of importin-αs determine formation of cargo/importin-α transport complexes in plant cells.


Unique chemistry of non-heme iron enzymes in fungal biosynthetic pathways.
Covering: up to 2018 Non-heme iron enzymes are a versatile family of oxygenases that catalyze remarkable types of chemistry. This review highlights the intriguing chemistry of non-heme iron enzymes, especially those utilizing α-ketoglutarate (α-KG) as a co-substrate, in fungal secondary metabolism and aims to summarize how nature diversifies and complexifies natural products.


[Extensive joint problems in a child].
A twelve-year-old girl was admitted to the paediatric department with progressive joint problems following a mild trauma. Diagnostic follow-up showed a Staphylococcus aureus infection. Generally, S. aureus infection mainly involves the skin and the nasal mucosa. In some cases it can cause a fulminant invasive infection in previously healthy young patients. If this is the case, it is important to consider PVL (Panton-Valentine-leukocidin)-positive S. aureus and underlying immune deficiencies when performing a differential diagnosis. In addition, it is important to remember that previous trauma can cause increased susceptibility to septic arthritis or osteomyelitis in children, as is seen in this case. Aggressive treatment of an invasive S. aureus infection is important even in apparently healthy young patients, to prevent morbidity or mortality.


[Ascorbic acid in the plasma and blood cells of women with breast cancer. The effect of the consumption of food with an elevated content of this vitamin].
The levels of ascorbic acid in plasma and in blood cells (erythrocytes, neutrophils, and platelets) was studied in a group of 30 women with recent onset of breast cancer, and they were compared with a group of 30 healthy women, thus establishing the possible correlations between them. At the same time, these levels were related to the frequency of consumption of foods with a high content of this vitamin (fruits, potatoes, and vegetables). The women with breast cancer present plasma levels of ascorbic acid which are significantly lower (p < 0.01), and platelet levels which are significantly higher (p < 0.05). There are no differences with respect to the levels in erythrocytes or neutrophils. The frequency of consumption of vegetables, which is higher in the controls (p < 0.001), is significantly related to higher levels of ascorbic acid in plasma (r = 0.458), and erythrocytes (r = 0.444) in this group, but we did not find any correlation in the group of the patients. The frequency of fruit or potatoes consumption, which is very similar in both groups, does not appear to lead to significant differences in the ascorbic acid contents.


A structurally available encephalitogenic epitope of myelin oligodendrocyte glycoprotein specifically induces a diversified pathogenic autoimmune response.
Multiple sclerosis is an inflammatory disease of the CNS that involves immune reactivity against myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the outer surface of CNS myelin. The epitope MOG92-106 is a DR4-restricted Th cell epitope and a target for demyelinating autoantibodies. In this study, we show that the immune response elicited by immunization with this epitope is qualitatively different from immune responses induced by the well-defined epitopes myelin basic protein (MBP) 84-96 and proteolipid protein (PLP) 139-151. Mice with MOG92-106-, but not with MBP84-96- or PLP139-151-induced experimental autoimmune encephalomyelitis developed extensive B cell reactivity against secondary myelin Ags. These secondary Abs were directed against a set of encephalitogenic peptide Ags derived from MBP and PLP as well as a broad range of epitopes spanning the complete MBP sequence. The observed diversification of the B cell reactivity represents a simultaneous spread toward a broad range of antigenic epitopes and differs markedly from T cell epitope spreading that follows a sequential cascade. The Abs were of the isotypes IgG1 and IgG2b, indicating that endogenously recruited B cells receive help from activated T cells. In sharp contrast, B cell reactivity in MBP84-96- and PLP139-151-induced experimental autoimmune encephalomyelitis was directed against the disease-inducing Ag only. These data provide direct evidence that the nature of the endogenously acquired immune reactivity during organ-specific autoimmunity critically depends on the disease-inducing Ag. They further demonstrate that the epitope MOG92-106 has the specific capacity to induce a widespread autoimmune response.


The aryl hydrocarbon (Ah) receptor transcriptional regulator hepatitis B virus X-associated protein 2 antagonizes p23 binding to Ah receptor-Hsp90 complexes and is dispensable for receptor function.
To further understand the role that the hepatitis B virus X-associated protein 2 (XAP2) plays in regulating aryl hydrocarbon receptor (AhR) function, a point mutation was introduced at tyrosine 408 of the AhR, changing the residue to an alanine or lysine. These mutations resulted in the loss of AhR binding to endogenous XAP2 in COS-1 cells and reduced binding of exogenously expressed XAP2. Cellular localization of the mutant AhR-yellow fluorescent protein fusion proteins remained nuclear when XAP2 was co-expressed, while the non-mutant receptor was redistributed to the cytoplasm. XAP2 expression caused an overall repression of constitutive and ligand-induced AhR transcriptional activity. However, increased expression of XAP2 had no effect on the AhRY408A mutant transcriptional activity. Additionally the XAP2 binding-deficient AhR mutants showed overall higher transcriptional activity when compared with the non-mutant receptor. Interestingly reduced incorporation of the Hsp90 associated co-chaperone p23 in the unliganded AhR complex was observed with increasing XAP2 expression. The displacement of p23 from Hsp90 did not occur when increasing levels of XAP2 were introduced in COS-1 cells in the absence of the AhR; thus this displacement event occurs specifically within an AhR complex. Finally XAP2 itself was capable of existing in multimeric complexes, and these complexes did not require Hsp90 or AhR to form. However, it is not yet clear whether XAP2 can exist within the AhR complex in more than one copy.


Vitamin A deficiency decreases natural killer cell activity and interferon production in rats.
We examined the effect of vitamin A deficiency on natural killer (NK) cell activity and interferon (IFN) production. Rats were weaned at 16 or 21 d of age onto semisynthetic diets containing either 0 or 4 micrograms retinol/g diet. At the time of study, retinol-depleted rats had serum vitamin A concentrations less than 7% of those of pair-fed controls. In two studies, rats exhibited no external signs of retinol deficiency, but with further depletion some symptoms were observed. Splenic NK cell activity against chromium-51-labeled YAC-1 cells was significantly decreased in vitamin A-depleted rats (22-80% of values for control rats, depending on the degree of retinol deficiency), regardless of the ratio of effector to target cells used. When vitamin A-depleted rats were repleted orally with retinol, NK cell activity was consistently normalized. To understand the possible mechanisms involved in decreasing NK cell activity, we investigated IFN production by concanavalin A-stimulated spleen cells from vitamin A-depleted, from repleted and from control animals. IFN titers were significantly decreased (22-33% of values for control rats) in supernatants of spleen cell cultures of the vitamin A-depleted rats. Repletion with vitamin A resulted in IFN activities ranging from 80 to 130% of controls. Adding alpha/beta IFN in vitro to the spleen cells of vitamin A-depleted animals increased their NK cell activity. The number of spleen cells reacting with a monoclonal antibody specific for rat NK cells was slightly lower in retinol-depleted rats, but not enough to account for the differences in NK cell and IFN activities. These data suggest that vitamin A deficiency affect the nonspecific arm of the immune system, possibly by altering the functional capacity of cells to produce lymphokines needed for the generation of an appropriate cytolytic response.


Music as a mnemonic to learn gesture sequences in normal aging and Alzheimer's disease.
Strong links between music and motor functions suggest that music could represent an interesting aid for motor learning. The present study aims for the first time to test the potential of music to assist in the learning of sequences of gestures in normal and pathological aging. Participants with mild Alzheimer's disease (AD) and healthy older adults (controls) learned sequences of meaningless gestures that were either accompanied by music or a metronome. We also manipulated the learning procedure such that participants had to imitate the gestures to-be-memorized in synchrony with the experimenter or after the experimenter during encoding. Results show different patterns of performance for the two groups. Overall, musical accompaniment had no impact on the controls' performance but improved those of AD participants. Conversely, synchronization of gestures during learning helped controls but seemed to interfere with retention in AD. We discuss these findings regarding their relevance for a better understanding of auditory-motor memory, and we propose recommendations to maximize the mnemonic effect of music for motor sequence learning for dementia care.


Combined use of clinical assessment and d-dimer to improve the management of patients presenting to the emergency department with suspected deep vein thrombosis (the EDITED Study).
Suspected deep vein thrombosis (DVT) is a common problem facing emergency physicians. Timely diagnostic testing must be performed to accurately identify patients with DVT. The purpose of this study was to evaluate the safety and effectiveness of a management strategy that combined consideration of clinical pretest probability and a d-dimer test to evaluate patients presenting to the emergency department with suspected deep vein thrombosis (DVT). A prospective cohort study was performed in the emergency departments of four tertiary care institutions involving 1075 patients with suspected DVT. An emergency physician determined the pretest probability for DVT to be low, moderate, or high using an explicit clinical model. A blood sample was taken for d-dimer testing. Subsequent investigations (compression ultrasound, venography) were performed based upon the pretest probability and the d-dimer result. Patients considered at low pretest probability with negative d-dimer had no further diagnostic testing performed. All patients in whom the diagnosis of DVT was excluded by the algorithm did not receive anticoagulant therapy and were followed up for 90 days for the development of proximal DVT or pulmonary embolism. Overall, 195 (18.1%; 95% CI 15.9% to 20.6%) of 1075 patients were confirmed to have proximal DVT. Of the 882 patients who had proximal DVT excluded during the initial evaluation period using the algorithms, four (0.5%; 95% CI 0.1% to 1.2%) were subsequently diagnosed with proximal DVT in the follow-up period, including three patients in the low pretest probability group (1.0%; 95% CI 0.2% to 2.1%) who had normal d-dimer and no additional diagnostic testing performed. None of the 882 patients (0%: 95% CI 0% to 0.5%) developed pulmonary embolism in the follow-up period. A diagnostic strategy for the evaluation of patients with suspected DVT based on pretest probability and d-dimer is safe and feasible in the emergency department setting.


Non-thrombotic Pulmonary Embolism Due to Liver Hydatic Cyst: A Case Report.
A non-thrombotic pulmonary embolism is defined as embolization to the pulmonary circulation. It may be caused by microorganisms, foreign bodies, different cell types or gas in the pulmonary circulation. Pulmonary hydatid cyst-induced embolization is a rare complication of heart or liver hydatid cysts. We describe the fatal case of a 15-year-old boy without any known prior illness who was admitted to the hospital after feeling unwell and dropping to the ground while playing ball. During the autopsy, a lesional mass, with dimensions of 13x6 cm, was observed in the left lobe of the liver. The histomorphological examination of pulmonary sections showed scolices observed in pulmonary vessel lumina, thus a non-thrombosis hydatid embolism was diagnosed. Based on the findings, the cause of death was recorded as a non-thrombotic hydatid embolism. The present case is interesting because a non-thrombotic pulmonary embolism rarely results in sudden death, and a definitive diagnosis was possible only by a histopathological examination.


Acute and chronic effects of free radicals on alpha1-adrenergic-induced vasoconstriction in mesenteric beds of spontaneously hypertensive rats.
To determine whether free radicals participate in the increased sensitivity of the alpha-adrenergic pathway in mesenteric arteries from spontaneously hypertensive rats (SHRs). SHRs are characterized by a greater vasoconstriction (P < 0.001) in response to phenylephrine in isolated and perfused mesenteric arteries. Deferoxamine (DFX) produced a significant increase in the phenylephrine-induced vasoconstriction in isolated mesenteric beds from both SHRs (P < 0.001) and Wistar-Kyoto (WKY) rats (P < 0.05), but with a greater magnitude in SHRs (P < 0.01). Acutely, activation of the hypoxanthine-xanthine oxidase (HX-XO) system produced an endothelium- and NO-dependent vasoconstriction at low concentration (P < 0.01), followed by an endothelium-independent vasorelaxation at greater concentrations in phenylephrine-preconstricted mesenteric beds (P < 0.01). Catalase and SOD (P < 0.01) prevented this endothelium-dependent response, whereas the endothelium-independent vasorelaxation induced by HX-XO was blocked by catalase, SOD and DFX (P < 0.01). Chronic administration of a diet deficient in selenium and vitamin E decreased the glutathione peroxidase activity in erythrocytes and plasma from SHRs and WKY rats (P < 0.001). Moreover, the deficient diet significantly increased the sensitivity of mesenteric arteries to phenylephrine in SHRs (P < 0.001) and WKY rats (P < 0.05), whereas it decreased acetylcholine-induced vasodilatation in SHRs only (P < 0.05). The KCl-induced vasoconstriction in response to oxygen radicals was enhanced only in mesenteric bed from SHRs. Free radicals seem to potentiate the alpha-adrenergic pathway acutely in low concentrations and to sensitize this pathway chronically in SHRs. These observations may explain the potentiated response to alpha-adrenergic agonists observed in SHRs.


Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila.
Progressive cystic kidney degeneration underlies diverse renal diseases, including the most common cause of kidney failure, autosomal dominant Polycystic Kidney Disease (PKD). Genetic analyses of patients and animal models have identified several key drivers of this disease. The precise molecular and cellular changes underlying cystogenesis remain, however, elusive. Drosophila mutants lacking the translational regulator Bicaudal C (BicC, the fly ortholog of vertebrate BICC1 implicated in renal cystogenesis) exhibited progressive cystic degeneration of the renal tubules (so called "Malpighian" tubules) and reduced renal function. The BicC protein was shown to bind to Drosophila (d-) myc mRNA in tubules. Elevation of d-Myc protein levels was a cause of tubular degeneration in BicC mutants. Activation of the Target of Rapamycin (TOR) kinase pathway, another common feature of PKD, was found in BicC mutant flies. Rapamycin administration substantially reduced the cystic phenotype in flies. We present new mechanistic insight on BicC function and propose that Drosophila may serve as a genetically tractable model for dissecting the evolutionarily-conserved molecular mechanisms of renal cystogenesis.


Health-related quality of life in Romanian postmenopausal women with osteoporosis and fragility fractures.
Osteoporosis is a common skeletal disorder characterized by decreased bone mass and increased susceptibility to fractures, which are associated with pain and decrease in physical function, social function, and well-being, which are all aspects of quality of life (QoL). The purpose of this study was to evaluate the burden of osteoporosis and fragility fractures in Romanian postmenopausal women from Cluj County using the 36-Item Short Form Health Survey (SF-36) and Quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO-41) questionnaires. An analytical cross-sectional study on 364 postmenopausal women was carried out between June 2016 and August 2017 in the Clinical Rehabilitation Hospital in Cluj-Napoca, Cluj County, Romania. Data were collected by interview and from the medical documents: clinical and demographic data, personal medical history, risk factors for osteoporosis, and bone mineral density at the lumbar spine and femur. The patients included in the study were asked to complete the Romanian versions of the SF-36 and QUALEFFO-41 questionnaires. Women with osteoporosis had significantly lower scores in the SF-36 domains (P<0.001) than healthy controls. In the osteoporosis group, a significant association was found in the SF-36 pain domain, where women with a history of fracture had higher scores (P=0.035). As for QUALEFFO-41, a statistical significance was found in the total score (P<0.05), revealing a significantly lower QoL in osteoporotic women with a history of fracture. The SF-36 scores registered a loss of QoL in women with osteoporosis. The QUALEFFO-41 total score was significantly lower in the osteoporosis associated with fracture, revealing a lower health-related QoL in these patients.


Leadership for health commissioning in the new NHS.
The purpose of this paper is to explore the early experiences of those involved with the development of Clinical Commissioning Groups (CCGs), examining how the aspiration towards a "clinically-led" system is being realised. The authors investigate emerging leadership approaches within CCGs in light of the criterion for authorisation that calls for "great leaders". Qualitative research was carried out in eight case studies (CCGs) across England over a nine-month period (September 2011 to May 2012) when CCGs were in their early development. The authors conducted a mix of interviews (with GPs and managers), observations (at CCG meetings) and examined associated documentation. Data were thematically analysed. The authors found evidence of two identified approaches to leadership - positive deviancy and responsible guardianship - being undertaken by GPs and managers in the developing CCGs. Historical experiences and past ways of working appeared to be influencing current developments and a commonly emerging theme was a desire for the CCG to "do things differently" to the previous commissioning bodies. The authors discuss how the current reorganisation threatens the guardianship approach to leadership and question if the new systems being implemented to monitor CCGs' performance may make it difficult for CCGs to retain creativity and innovation, and thus the ability to foster the positive deviant approach to leadership. This is a large scale piece of qualitative research carried out as CCGs were beginning to develop. It provides insight into how leadership is developing in CCGs highlighting the complexity involved in these roles.


Method for assessing the effect of the screen in an integrating sphere, with an application to the photometry of a tubular lamp.
By distinguishing six areas (four on the sphere plus both sides of the screen) according to possible mutual exchanges and direct illumination, the approach leads for any given source to sets of six equations between the unknown illumination levels of these areas. From one of them defining the measurement, correction factors, restricted to the effect of the screen, are deduced for the comparison between a standard and an unknown lamp. Applied to the controversial case of the photometry of a fluorescent lamp, the method shows that its direction is irrelevant provided that both lamps are centered at the same place. The screen should be small. The paper demonstrates serious errors in the photometric method in which the luminance of the back of the screen is measured.


Attenuation coefficients for water quality trading.
Water quality trading has been proposed as a cost-effective approach for reducing nutrient loads through credit generation from agricultural or point source reductions sold to buyers facing costly options. We present a systematic approach to determine attenuation coefficients and their uncertainty. Using a process-based model, we determine attenuation with safety margins at many watersheds for total nitrogen (TN) and total phosphorus (TP) loads as they transport from point of load reduction to the credit buyer. TN and TP in-stream attenuation generally increases with decreasing mean river flow; smaller rivers in the modeled region of the Ohio River Basin had TN attenuation factors per km, including safety margins, of 0.19-1.6%, medium rivers of 0.14-1.2%, large rivers of 0.13-1.1%, and very large rivers of 0.04-0.42%. Attenuation in ditches transporting nutrients from farms to receiving rivers is 0.4%/km for TN, while for TP attenuation in ditches can be up to 2%/km. A 95 percentile safety margin of 30-40% for TN and 6-10% for TP, applied to the attenuation per km factors, was determined from the in-stream sensitivity of load reductions to watershed model parameters. For perspective, over 50 km a 1% per km factor would result in 50% attenuation = 2:1 trading ratio.


Genetic mapping of two loci affecting DDT resistance in the malaria vector Anopheles gambiae.
Resistance to the insecticide DDT in the mosquito vectors of malaria has severely hampered efforts to control this disease and has contributed to the increase in prevalence of malaria cases seen in recent years. Over 90% of the 300-500 million annual cases of malaria occur in Africa, where the major vector is Anopheles gambiae. DDT resistance in the ZAN/U strain of An. gambiae is associated with an increased metabolism of the insecticide, catalysed by members of the glutathione S-transferase (GST) enzyme family, but the molecular mechanism underlying this metabolic resistance is not known. Genetic crosses show that resistance is autosomal and semidominant. We have used microsatellite markers to identify two quantitative trait loci (QTL), which together explain over 50% of the variance in susceptibility to DDT in the ZAN/U strain of An. gambiae. The first locus, rtd1, is on chromosome 3 between markers H341 and H88 and has a recessive effect with respect to susceptibility. The second locus, rtd2 is on chromosome 2L, close to marker H325 and has an additive genetic effect. The markers flanking these two QTL have been physically mapped to An. gambiae polytene chromosomes. They do not coincide with any of the GST genes that have been cloned and mapped in this species. Characterization of these QTL will lead to a clearer understanding of the mechanisms of metabolic resistance to DDT.


Nicotinamide adenine dinucleotide tetrazolium reductase identifies microvasculature activation in muscle from adult patients with dermatomyositis.
Previous work has suggested involvement of the muscle microvasculature in the pathogenesis of dermatomyositis (DM). Our study evaluates whether standard histochemical reactions can identify microvascular changes in muscle biopsies from patients with DM compared to myopathic and nonmyopathic controls. Muscle biopsies were obtained from 111 patients, including 45 patients with DM. Microvascular quantitation was performed on transversely oriented 1-μm toluidine blue-stained plastic sections. Histoenzymatic procedures included alkaline phosphatase (AP), nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR), succinate dehydrogenase (SDH), cytochrome C oxidase (COX), and myosin ATPase reactions. Capillary density was significantly lower in DM muscle biopsies compared to biopsies from patients with noninflammatory myopathies (NIM; n = 26) and healthy control muscle (n = 27; mean ± SD: 252 ± 114 vs 402 ± 56 and 325 ± 109 capillaries/mm(2), respectively; p values < 0.05). In contrast, a marked increase in the number of capillaries staining with NADH-TR was noted in DM compared to other idiopathic inflammatory myopathies (IIM; n = 13), NIM, and controls (49.8 ± 50.7 vs 8.0 ± 7.1, 6.7 ± 7.2, and 3.6 ± 2.8 capillaries/mm(2); p < 0.05 compared to DM). DM capillaries also demonstrated mildly increased staining with AP compared to controls; however, no increased SDH or COX reactivity was observed. DM muscle capillaries are highly reactive with NADH-TR compared to myopathic and nonmyopathic controls. The lack of staining of DM capillaries with mitochondrial SDH and COX reactions suggests that NADH-TR reactivity may be secondary to activation of the microvascular endoplasmic reticulum, rather than mitochondrial hyperplasia.


Structural consequences of genetically engineered saturation of the fatty acids of phosphatidylglycerol in tobacco thylakoid membranes. An FTIR study.
The role of phosphatidylglycerol (PG) in protein-lipid interactions and membrane dynamics has been studied in the thylakoids of wild type and manipulated tobacco plants transformed with complementary DNAs for glycerol-3-phosphate acyltransferases (GPATs) from squash and Arabidopsis. The expression of the foreign enzymes resulted in the level of saturation of the PG molecules being higher in the squash and lower in the Arabidopsis transformants, as compared with the level in wild-type tobacco. For the analysis of fatty acyl chain dynamics in the thylakoid membranes, the nu(sym)CH(2) vibration bands of the infrared specta were decomposed into two components, corresponding to ordered and disordered fatty acyl chain segments. With this approach, it was shown that in squash GPAT-transformed tobacco thylakoids a rigid lipid domain exists below 25 degrees C. Above 25 degrees C, the dynamics of all thylakoid membranes were very similar, regardless of the manipulations. PG seems to tune the dynamics at the protein-lipid interface rather than to affect the structure of the proteins directly. Above 50 degrees C, the frequencies of the disordered nu(sym)CH(2) component bands were decreased. This lipid-related phenomenon correlated with protein denaturing. It is demonstrated that the protein aggregation appearing upon heat denaturing changes the conformational distribution of the disordered lipid population. The data also reveal that the protein stability does not depend on the fatty acid composition of the PG molecules; other lipids should provide the environment governing the protein stability in the thylakoid membrane. This is the first such detailed analysis of the infrared spectra of biological membranes that permits a differentiation between structurally different lipid populations within a membrane.


Molecular epidemiology of erythropoietic protoporphyria in the U.K.
Erythropoietic protoporphyria (EPP) is a cutaneous porphyria caused by mutations in the ferrochelatase (FECH) or, less frequently, the delta-aminolaevulinate synthase 2 (ALAS2) gene. Predictive genetic counselling requires accurate molecular diagnosis and knowledge of patterns of inheritance. To investigate the molecular epidemiology of EPP in the U.K. DNA samples from 191 unrelated patients resident in the U.K. were analysed for mutations in the FECH and ALAS2 genes and for the FECH IVS3-48 dimorphism. Mutations were identified in 179 (94%) patients. Most (169; 94%) had a FECH mutation on one allele and were classified as having pseudodominant EPP (psdEPP); seven (4%) patients had FECH mutations on both alleles (autosomal recessive EPP) and three (2%) patients had ALAS2 mutations (X-linked dominant protoporphyria). The FECH IVS3-48C allele was strongly associated with psdEPP and with the absence of mutations at the FECH or ALAS2 loci. Fifty-six FECH mutations were identified, 19 being previously unreported. Missense mutations were predominant in autosomal recessive EPP (82%) but not in psdEPP (32%). One mutation (c.314 + 2T>G) was present in 41 (24%) of EPP families, most of whom appeared to be descended from a common ancestor resident in the north of England. These data define the prevalence and molecular epidemiology of each type of EPP in the U.K.


Intravitreal erythromycin in the treatment of induced staphylococcal endophthalmitis.
Intravitreal injection of 500 mcg of erythromycin as the gluceptate caused no toxicity to ocular structures. This dose maintained bacterial inhibitory concentrations in the vitreous for up to 24 hours. Consistent aqueous levels were not obtained with intravitreal injection. Intravitreal treatment of Staphylococcus aureus endophthalmitis was successful in 11 of 13 rabbit eyes compared to 2 of 13 treated with subconjunctival erythromycin.


Automated segmentation of villi in histopathology images of placenta.
Manual analysis of clinical placenta pathology samples under the microscope is a costly and time-consuming task. Computer-aided diagnosis might offer a means to obtain fast and reliable results and also substantially reduce inter- and intra-rater variability. Here, we present a fully automated segmentation method that is capable of distinguishing the complex histological features of the human placenta (i.e., the chorionic villous structures). The proposed pipeline consists of multiple steps to segment individual placental villi structures in hematoxylin and eosin (H&E) stained placental images. Artifacts and undesired objects in the histological field of view are detected and excluded from further analysis. One of the challenges in our new algorithm is the detection and segmentation of touching villi in our dataset. The proposed algorithm uses the top-hat transformation to detect candidate concavities in each structure, which might represent two distinct villous structures in close proximity. The detected concavities are classified by extracting multiple features from each candidate concavity. Our proposed pipeline is evaluated against manual segmentations, confirmed by an expert pathologist, on 12 scans from three healthy control patients and nine patients diagnosed with preeclampsia, containing nearly 5000 individual villi. The results of our method are compared to a previously published method for villi segmentation. Our algorithm detected placental villous structures with an F1 score of 80.76% and sensitivity of 82.18%. These values are substantially better than the previously published method, whose F1 score and sensitivity are 65.30% and 55.12%, respectively. Our method is capable of distinguishing the complex histological features of the human placenta (i.e., the chorionic villous structures), removing artifacts over a large histopathology sample of human placenta, and (importantly) account for touching adjacent villi structures. Compared to existing methods, our developed method yielded high accuracy in detecting villi in placental images.