Transient nerve root compression load and duration differentially mediate behavioral sensitivity and associated spinal astrocyte activation and mGLuR5 expression.
Injury to the cervical nerve roots is a common source of neck pain. Animal models of nerve root compression have previously established the role of compression magnitude and duration in nerve root-mediated pain and spinal inflammation; yet, the response of the spinal glutamatergic system to transient nerve root compression and its relationship to compression mechanics have not been studied. The glutamate receptor, mGluR5, has a central role in pain, and its expression by neurons and astrocytes in the spinal cord may be pivotal for neuronal-glial signaling. This study quantified spinal GFAP and mGluR5 expression following nerve root compressions of different magnitudes and durations in the rat. Compression to the C7 nerve root was applied for a duration that was either above (10 min) or below (3 min) the critical duration for mediating afferent discharge rates during compression. To also test for the effect of the magnitude of the compression load, either a 10 gf or a 60 gf was applied to the nerve root for each duration. Mechanical allodynia was assessed, and the C7 spinal cord was harvested on day 7 for immunofluorescent analysis. Double labeling was used to localize the expression of mGluR5 on astrocytes (GFAP) and neurons (MAP2). Seven days after injury, 10 min of compression produced significantly greater behavioral sensitivity (P<0.001) and spinal GFAP expression (P=0.002) than 3 min of compression, regardless of the compression magnitude. Nerve root compression at 60 gf produced a significant increase (P<0.001) in spinal mGluR5 for both of the durations studied. There was no difference in the distribution of mGluR5 between astrocytes and neurons following nerve root compression of any type. The glutamatergic and glial systems are differentially modulated by the mechanics of nerve root compression despite the known contribution of glia to pain through glutamatergic signaling.


Preterm children's long-term academic performance after adaptive computerized training: an efficacy and process analysis of a randomized controlled trial.
Adaptive computerized interventions may help improve preterm children's academic success, but randomized trials are rare. We tested whether a math training (XtraMath®) versus an active control condition (Cogmed®; working memory) improved school performance. Training feasibility was also evaluated. Preterm born first graders, N = 65 (28-35 + 6 weeks gestation) were recruited into a prospective randomized controlled multicenter trial and received one of two computerized trainings at home for 5 weeks. Teachers rated academic performance in math, reading/writing, and attention compared to classmates before (baseline), directly after (post), and 12 months after the intervention (follow-up). Total academic performance growth was calculated as change from baseline (hierarchically ordered-post test first, follow-up second). Bootstrapped linear regressions showed that academic growth to post test was significantly higher in the math intervention group (B = 0.25 [95% confidence interval: 0.04-0.50], p = 0.039), but this difference was not sustained at the 12-month follow-up (B = 0.00 [-0.31 to 0.34], p = 0.996). Parents in the XtraMath group reported higher acceptance compared with the Cogmed group (mean difference: -0.49, [-0.90 to -0.08], p = 0.037). Our findings do not show a sustained difference in efficacy between both trainings. Studies of math intervention effectiveness for preterm school-aged children are warranted. Adaptive computerized math training may help improve preterm children's short-term school performance. Computerized math training provides a novel avenue towards intervention after preterm birth. Well-powered randomized controlled studies of math intervention effectiveness for preterm school-aged children are warranted.


Unusual Presentation of Tubercular Liver Abscess in an Immune-Competent Adult.
Isolated hepatobiliary tuberculosis (TB) has been uncommonly described with or without biliary involvement and accounts for less than 1% of all tubercular infections. Isolated hepatic TB is even rare and poses a great diagnostic challenge. We report a case of isolated tubercular liver abscess with extension into the chest wall in an immune-competent adult, which was diagnosed and managed successfully with antitubercular treatment.


The impact of powdered keramsite on activated sludge and wastewater treatment in a sequencing batch reactor.
As the efficiency of biological wastewater treatment in activated sludge systems can be increased if powdered mineral materials are added, the work described here investigated the effect of powdered keramsite on activated sludge and wastewater treatment in a sequencing batch reactor on the laboratory scale. Specifically, experiments were carried out on two sequencing batch reactors, with the reference system being the classical SBR with conventional activated sludge, while the second system involved a K-SBR (Keramsite - Sequencing Batch Reactor) with powdered keramsite added with a view to enhancing the effectiveness of the activated sludge. The concentration of powdered keramsite in the latter reactor was maintained at 0.75 g/L. The results confirmed the greater efficiency of biological wastewater treatment processes where activated sludge was supported by the keramsite.


[Analysis of reproductive parameters of urban and rural population of Chuvashia].
Genetic and demographic characteristics for urban and rural population of the Chuvash Republic (Chuvashes and Russians) were calculated based on 1122 questionnaires. The sibship sizes for Chuvashes were 2.05 (urban) and 2.78 (rural). For Russians these indices were 1.75 (urban) and 2.00 (rural), respectively. Crow's index and its components were I(m) = 0.04; I(f) = 0.18; and I(tot) = 0.22 for urban, and I(m) = 0.07; I(f) = 0.27; and I(tot) = 0.36 for rural Chuvashes, respectively; and I(m) = 0.04; I(f) = 0.30; and I(tot) = 0.36 for urban, and I(m) = 0.03; I(f) = 0.29; and I(tot) = 0.33 for rural Russians, respectively.


Substrate regulation of calcium binding in Ca2+-ATPase molecules of the sarcoplasmic reticulum. I. Effect of ATP.
The effect of ATP on calcium binding of the Ca2+-ATPase of the sarcoplasmic reticulum has not been clarified. By comparing the calcium dependence of the ATPase activity and of phosphorylation of the ATPase molecules with that of calcium binding in the absence of ATP, we show the existence of two types of regulatory site of the enzyme molecules at which ATP binding variously improves the calcium binding performance of the molecules depending on the aggregation state of the molecules and pH; the two regulatory sites bind ATP at submillimolar (0.25 mm) and millimolar (5 mm) ATP, respectively. The results are discussed based on a model of two conformational variants (A and B forms) of the chemically equivalent ATPase molecules (Nakamura, J., and Furukohri, T. (1994) J. Biol. Chem. 269, 30818-30821). For example, in the sarcoplasmic reticulum membrane at pH 7.40, submillimolar ATP converted the calcium binding manner of the A form from noncooperative (Hill number (n(H)) of approximately 1) to cooperative (n(H) approximately 2), concurrent with a decrease in the apparent calcium affinity (K(0.5)) from 2-6 to 0.1-0.3 microm. The binding of the A form became almost the same as that of the B form (n(H) approximately 2, K(0.5) approximately 0.2 microm), which was not affected by ATP. Millimolar ATP further decreased the K(0.5) of the cooperative binding of the two forms to approximately 0.05 microm. Regulation of the calcium binding performance by ATP is discussed in terms of monomeric and oligomeric pathway models.


Feeding enhances extracellular lactate of local origin in the rostromedial hypothalamus but not in the cerebellum.
The use of brain microdialysis together with chronic vascular catheterization allowed us to assay extracellular fluid lactate (ECFL) in both the ventromedial-paraventricular (VMH-PVN) area of the hypothalamus and the cerebellum, in parallel with measures of plasma levels, and in relation to food intake. A 45 min scheduled meal increased VMH-PVN ECFL by 28%. This increase was not observed in the cerebellum. The prandial increase in plasma glucose (43%, from 4.74 to 6.77 mM) and lactate (84%, from 0.83 to 1.53 mM) showed a different temporal pattern and lasted longer than that of the ECFL. Glucose delivery by reverse dialysis for 45 min into the VMH-PVN area increased ECFL by 49%. When local glucose utilization was prevented by reverse dialysis-delivered 2-deoxy-d-glucose (2-DG), not only did VMH-PVN ECFL drop, but the feed-related increase in ECFL was blocked without affecting the normal rise in plasma glucose and in lactate. These results indicate that meal-related ECFL production and variations are independent of circulating lactate, but may depend on substrate availability in these hypothalamic structures.


Clinical response to antibiotics in indigenous versus non-indigenous children under 5 years old with community-acquired pneumonia in Otavalo, Ecuador.
Community-acquired pneumonia (CAP) is an important cause of morbidity and mortality worldwide. This study compares the clinical response to antimicrobials between indigenous and non-indigenous Kichwa children under 5 years old with CAP in Otavalo, Ecuador. All children with CAP who met the inclusion criteria and were admitted at the San Luis de Otavalo Hospital between March 2017 and June 2018 were evaluated. No significant differences were observed in clinical responses between indigenous and non-indigenous children. The improved healthcare access of the Otavalo's Kichwa population may have contributed to the observed clinical response to CAP treatment.


How do carers of people with multiple sclerosis engage with websites containing the personal experiences of other carers and patients?
The Internet supports the peer-to-peer healthcare and the promotion of shared patient narratives. Websites incorporating these narratives or personal accounts are known to offer support to carers of people with multiple sclerosis, but little is known about how carers make choices about what websites to visit and why. In total, 20 carers viewed a range of websites and online personal accounts about multiple sclerosis and subsequently took part in either a group discussion or an individual interview, followed by 2 weeks and 12 months and later by a telephone interview. Data were subjected to thematic analysis with the aim of understanding more about what drives engagement with the stories of others. We found that carers' interpersonal and coping needs shaped their selection of online narratives, and that they were most likely to engage with online personal accounts that provided a good match in terms of experience and perspective.


Individual variation and effect of priming dose level on establishment, growth and fecundity of Cooperia oncophora in re-infected calves.
We investigated the effect of bovine anamnestic immunity on a range of parasitological variables. To this end, calves were primed with a single oral dose of 30000 or 100000 infective larvae (L3) of Cooperia oncophora, drenched with anthelmintic, maintained worm free in the following 2.5 months and subsequently re-infected with 100000 L3. Parasitological profiles of low, intermediate, and high responders were compared. The reduction in establishment of the worms was shown by a lower worm burden and increased percentage of fourth-stage (L4) larvae. Worm length and fecundity were similarly reduced by both priming doses but, the speed by which the effect occurred differed between animals primed with 30000 or 100000 L3. The difference in establishment between the responder types demonstrates that the ability of intermediate responders to mount a more effective and faster immune response compared to low responders is sustained after secondary infection.


Biochemical efficacy, molecular docking and inhibitory effect of 2, 3-dimethylmaleic anhydride on insect acetylcholinesterase.
Evolution of resistance among insects to action of pesticides has led to the discovery of several insecticides (neonicotinoids and organophosphates) with new targets in insect nervous system. Present study evaluates the mode of inhibition of acetylchlonesterase (AChE), biochemical efficacy, and molecular docking of 2,3-dimethylmaleic anhydride, against Periplaneta americana and Sitophilus oryzae. The knockdown activity of 2,3-dimethylmaleic anhydride was associated with in vivo inhibition of AChE. At KD99 dosage, the 2,3-dimethylmaleic anhydride showed more than 90% inhibition of AChE activity in test insects. A significant impairment in antioxidant system was observed, characterized by alteration in superoxide dismutase and catalase activities along with increase in reduced glutathione levels. Computational docking programs provided insights in to the possible interaction between 2,3-dimethylmaleic anhydride and AChE of P. americana. Our study reveals that 2,3-dimethylmaeic anhydride elicits toxicity in S. oryzae and P. americana primarily by AChE inhibition along with oxidative stress.


Novel C-H···C contacts involving 3,5-dimethylpyrazole ligands in a tetracoordinate Co(II) complex.
A violet-blue cobalt(II) complex [Co(4-nbz)(2)(DMP)(2)] (1), where 4-nbz = 4-nitrobenzoate and DMP = 3,5-dimethylpyrazole, has been prepared at room temperature. Crystallographic studies on 1·0.5H(2)O reveal that the molecules of 1 are linked by a variety of non-covalent bonds including a novel type of C-H···C contact forming, with assistance from N-H···O, C-H···O and C-H···π interactions, an intricate 3-D supramolecular network. Theoretical calculations suggest that the observed C-H···C interactions are energetically quite significant.


The kinase Isr1 negatively regulates hexosamine biosynthesis in S. cerevisiae.
The S. cerevisiae ISR1 gene encodes a putative kinase with no ascribed function. Here, we show that Isr1 acts as a negative regulator of the highly-conserved hexosamine biosynthesis pathway (HBP), which converts glucose into uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the carbohydrate precursor to protein glycosylation, GPI-anchor formation, and chitin biosynthesis. Overexpression of ISR1 is lethal and, at lower levels, causes sensitivity to tunicamycin and resistance to calcofluor white, implying impaired protein glycosylation and reduced chitin deposition. Gfa1 is the first enzyme in the HBP and is conserved from bacteria and yeast to humans. The lethality caused by ISR1 overexpression is rescued by co-overexpression of GFA1 or exogenous glucosamine, which bypasses GFA1's essential function. Gfa1 is phosphorylated in an Isr1-dependent fashion and mutation of Isr1-dependent sites ameliorates the lethality associated with ISR1 overexpression. Isr1 contains a phosphodegron that is phosphorylated by Pho85 and subsequently ubiquitinated by the SCF-Cdc4 complex, largely confining Isr1 protein levels to the time of bud emergence. Mutation of this phosphodegron stabilizes Isr1 and recapitulates the overexpression phenotypes. As Pho85 is a cell cycle and nutrient responsive kinase, this tight regulation of Isr1 may serve to dynamically regulate flux through the HBP and modulate how the cell's energy resources are converted into structural carbohydrates in response to changing cellular needs.


Simultaneous presence of two hematological malignancies: chronic lymphocytic leukemia and myelofibrosis in a patient.
Coexistence of chronic lymphocytic leukemia (CLL) with myelofibrosis is a rare association with only isolated case reports in the literature. We report an unusual case of CLL in which the cause of anemia was coexistent myelofibrosis. In a case of CLL presenting with refractory anemia, besides common causes like autoimmune hemolytic anemia and marrow infiltration, other causes like myelofibrosis should be searched for.


Common Gray Matter Reductions in Alcohol Use and Obsessive-Compulsive Disorders: A Meta-analysis.
Though compulsive drinking is a hallmark of alcohol use disorder (AUD), little is known of the neural mechanisms driving this behavior. To further the understanding of the neural underpinnings of this compulsivity, a meta-analytic approach was used to examine gray matter (GM) volume differences related to AUD, and contrast these differences with GM volume differences in obsessive-compulsive disorder (OCD), to find common underlying regional brain differences. We systematically meta-analyzed case-control studies investigating GM volume that used whole-brain voxel-based morphometry separately for AUD and OCD and then directly compared the results of both. Seed-based d Mapping software was used to perform the meta-analyses. The AUD meta-analysis used 19 citations, with 736 individuals with AUD and 827 control individuals. The OCD meta-analysis had 25 citations, with 995 individuals with OCD and 1177 control individuals. The AUD group showed decreased GM in areas including frontal, limbic, temporal, and cerebellar regions. The OCD group had decreased GM in frontal and insular regions but increases in the hypothalamus and brainstem. Importantly, the main outcome showed that both groups had decreased GM overlapping in the anterior cingulate cortex and insula. Brain regions were p < .05 corrected. Common brain regional differences in the anterior cingulate cortex and insula that overlap between AUD and OCD suggest that interventions targeting these regions could prove to be beneficial in treating compulsive drinking related to AUD. Further research into the functional role of these brain regions in the etiology of compulsive drinking in AUD is warranted.


Association of N-terminal pro-brain natriuretic peptide and cardiac troponin T with in-hospital cardiac events in elderly patients undergoing coronary artery surgery.
Despite evidence of their prognostic power for non-surgical patients, the value of perioperative natriuretic peptides and cardiac troponins as markers of cardiac events is incompletely defined. This study sought to examine whether perioperative N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) levels could be used for the prediction of in-hospital cardiac events in elderly patients undergoing elective coronary artery bypass grafting. Ninety-eight elderly patients (>75 yr) undergoing elective coronary artery bypass grafting with cardiopulmonary bypass were enrolled and followed up for 121 and 0.66 1 for NT-proBNP and cTnT (sensitivity, specificity, positive predictive value and negative predictive value of 84.3%, 89.4%, 78.9% and 92.4%, and 93.7%, 74.2%, 63.8% and 96.1%, respectively) at 24 h after surgery to be associated with in-hospital cardiac events. An elevation of both biomarkers above these threshold values was independently associated with individual postoperative complications (odds ratio, 18.9; 95%, CI, 2.3-106.1). In elderly patients undergoing elective coronary artery bypass grafting surgery, high values of NT-proBNP and cTnT measured 24 h after the end of surgery were independently associated with in-hospital cardiac events.


Serial echocardiographic appearance of healing bacterial vegetations.
Serial M mode and cross-sectional echocardiograms were obtained from six patients who had been treated with antibiotic drugs for infectious endocarditis. Three to six M mode echocardiograms and one to six cross-sectional echocardiograms were obtained from each patient over a follow-up period averaging 50 weeks (range 10 to 108 weeks). On echocardiography, vegetations were observed to have become smaller and more echo-reflective with healing. A dramatic change was seen in two patients after peripheral embolization. M mode echocardiography was particularly helpful in determining the quality of echo reflection by vegetations; cross-sectional echocardiography was more helpful in judging the size and shape of a vegetation. Echocardiography is ideally suited for the serial visualization of healing vegetations in patients who do not require early valve replacement. It may prove helpful to examine serially valve vegetations with both M mode and cross-sectional echocardiography when following up patients with infectious endocarditis treated with antibiotic agents.


Tree breeding, a necessary complement to genetic engineering.
The fields of tree breeding and genetic engineering can be perceived as being antagonistic towards each other-genetic engineers suggesting that tree breeding is too slow and expensive and tree breeders suggesting that genetic engineering is not practical and too expensive. We argue here that both fields have much to offer forestry and the success of each is intimately tied to the other. The major purposes of genetic engineering in forestry are described as well as the importance of evaluating tree engineering initiatives in the context of tree improvement and silviculture and integrating genetic engineering with tree breeding from start to finish. A generalized approach is developed that meets these requirements and demonstrates the interrelationships between the activities and phases of each program. In addition, a case study of the American chestnut (Castanea dentata) is provided to underscore the value of integrating genetic engineering and tree breeding programs to achieve a long-term conservation goal.


Functional versus dysfunctional coping with physical pain: An experimental comparison of acceptance vs. avoidance coping.
This study compared acceptance vs. avoidance coping with acute physical pain, in a pain-induction experiment and examined both between and within-group differences, multi-methodically and multi-dimensionally using behavioral, physiological and self-report measures. The sample consisted of 88 University students (76.1% females; Mage = 21.33 years). Participants were randomly assigned to four instructed groups and participated twice in the Cold Pressor Task: (a) Acceptance followed by avoidance; (b) Avoidance followed by acceptance; (c) No instructions (control) followed by acceptance, and (d) No instructions (control) followed by avoidance. All analyses were conducted using repeated-measures ANOVAs. Randomized techniques analyses showed that participants receiving no instructions followed by acceptance reported significantly greater changes in physiological and behavioral measures across time. Low adherence to acceptance instructions was found, especially during the first phase. Exploratory analyses on actual techniques used (as opposed to taught technique) showed that participants using avoidance followed by acceptance exhibited significantly greater changes in physiological and behavioral measures across time. No significant differences were found for the self-report of negative affect outcome. Overall, our findings provide support to ACT theory, as participants might have to use firstly ineffective coping to understand what works best to cope with pain. This is the first study examining acceptance vs. avoidance coping both between and within individuals in physical pain, multi-methodically and multi-dimensionally.


Associations of depression and anxiety symptoms with sexual behaviour in women and heterosexual men attending sexual health clinics: a cross-sectional study.
To assess the association of symptoms of depression and anxiety with sexual risk behaviour and history, among women and heterosexual men attending genitourinary medicine (GUM) clinics. Attitudes to and Understanding of Risk of Acquisition of HIV (AURAH) was a cross-sectional, self-administered questionnaire study recruited from 20 GUM clinics in England, 2013-2014. This analysis included women and heterosexual men. The prevalence of depression and anxiety symptoms was assessed. Modified Poisson regression was used to produce adjusted prevalence ratios (aPR) for the association of t demographic, socioeconomic and lifestyle factors with depression and anxiety, adjusted for gender, age, ethnicity, education level and study region. Among individuals reporting sex in the past 3 months, associations of depression and anxiety with sexual risk behaviour and history were assessed separately by gender, adjusted for age, ethnicity, study region, education and relationship status. Questionnaires were completed by 676 women and 470 heterosexual men. Depression symptoms were reported by 100 (14.8%) women and 33 men (7.0%). Anxiety symptoms were reported by 79 women (11.7%) and 21 men (4.5%). Among women reporting recent sex, those with depression symptoms were more likely to report condomless sex with a non-regular partner, aPR 1.38 (1.07-1.77) and recent condomless sex with two or more partners, 1.80 (1.25-2.59). Women with anxiety symptoms more likely to report recent condomless sex with two or more partners, 1.68 (1.13-2.50), low self-efficacy for condom use, 1.54 (1.02-2.31) and STI diagnosis in the last year 1.51 (1.04-2.20). Among heterosexual men reporting recent sex, depression and anxiety symptoms were associated with low self-efficacy with condom use, 2.32 (1.29-4.19) for depression and 2.23 (1.26-3.94) for anxiety, but not with measures of condomless sex. The associations between psychological symptoms and sexual risk behaviours highlight the importance of holistic assessment of need by both general and sexual health clinicians. We highlight the challenge in delivering holistic care associated with fragmentation of sexual health services.


Reye syndrome.
Reye syndrome has emerged as the quintessential example of an acute metabolic encephalopathy. The clinical presentation is quite stereotyped in most instances permitting rapid, accurate diagnosis and early therapeutic intervention. Intoxications and certain inborn metabolic errors may mimic Reye syndrome. All patients with a recurrent episode should be investigated thoroughly for evidence of a metabolic disorder associated with an enzyme deficiency. Notable in this regard are inborn errors affecting organic acid, ammonia, and carbohydrate metabolism. The mitochondrial disturbance in Reye syndrome is well documented but the pathophysiologic sequence linking the antecedent viral illness to the mitochondrial injury remains obscure. Recent identification of a spontaneous Reye-like illness in mice that is associated with a coronavirus infection may provide an opportunity to investigate this initial phase of the pathophysiologic sequence. The primary cerebral insult presumably derives from insufficient substrate availability and results in massive cytotoxic cerebral edema. Treatment revolves around the continuous infusion of hypertonic glucose and intermittent infusion of hypertonic mannitol. Management is designed to attenuate or avoid the various compounding metabolic insults during this critical period when the child is metabolically crippled. In 1963, the disorder was considered to be rare and almost irreversibly fatal. Today, the disorder is recognized to be more common, and the outcome is very satisfactory in 85 to 90 per cent of the cases. The role of aspirin remains very controversial. A number of studies suggest an association between this potential mitochondrial toxin and Reye syndrome, but a causal relationship has not been established. Until better understood, it seems advisable to avoid use of aspirin in children exhibiting symptoms suggestive of Reye syndrome.


An improved Diagnostic PCR Assay for identification of Cryptic Heterozygosity for CGG Triplet Repeat Alleles in the Fragile X Gene (FMR1).
Fragile X syndrome (OMIM #300624) is the most common, recognised, heritable cause of mental retardation. Widespread testing is warranted by the relatively high frequency of the disorder, the benefits of early detection and the identification of related carriers whose offspring are at a 1 in 2 risk of inheriting the expanded pathogenic mutation. However, cost-effective screening of mentally retarded individuals has been impeded by the lack of a single, simple laboratory test. Currently, Fragile X syndrome can be excluded in males and a majority of females using a simple high-throughput PCR test. Due to the limited sensitivity of the PCR test, we find in our diagnostic service that approximately 40% of females appear homozygous and a labour intensive and expensive Southern blot test is required to distinguish these from females carrying one normal allele and an expanded allele. We describe an improved PCR test which displays a high level of precision allowing alleles differing by a single triplet to be resolved. Using the new assay, we detected 46/83 (53%) cryptic heterozygotes previously labelled as homozygotes. The assay also extended the range of repeats amplifiable, up to 170 CGG repeats in males and 130 CGG repeats in females. Combined with the high precision, the assay also improves discrimination of normal (CGG repeats < 45) from grey zone (45 < CGG repeats < 54) alleles and grey zone alleles from small premutations (55 < CGG repeats < 100). Use of this PCR test provides significantly improved precision and amplification of longer alleles. The number of follow-up Southern blot tests required is reduced (up to 50%) with consequent improvement in turnaround time and cost.


[Hypertension].
Hypertension is the largest risk factor for cardiovascular disease (CVD), and the most common life-style related disease in Japan. Hypertension is, overall, a male-dominant disease, however its impact on CVD in female grows markedly after menopause. The alteration in estrogen/androgen balance causes endothelial dysfunction, obesity, sympathetic activation, renin-angiotensin-aldosterone system activation, salt sensitivity and oxidative stress. These mechanisms enhance the elevation of systemic blood pressure and get caught in a vicious circle in female hypertension.


Modulation of the immune response to transplanted tumors in rats by selective depletion of neutrophils in vivo using a monoclonal antibody: abrogation of specific transplantation resistance to chemical carcinogen-induced syngeneic tumors by selective depletion of neutrophils in vivo.
The role of neutrophils in transplantation immunity to syngeneic rat tumors was examined using a monoclonal antibody (RP-3) that depletes rat neutrophils selectively in vivo. We used 2 chemical carcinogen-induced transplanted tumors of different antigenic specificity (KMT-17 and KDH-8 of WKA rat origin). When neutrophils were selectively depleted by i.p. injection of RP-3 at the time of in vivo priming with X-irradiated tumor cells, the growth of subsequently s.c. transplanted identical tumors was not inhibited, in contrast to the group of rats immunized without RP-3 treatment. Tumor growth was also not inhibited when the immune rats were treated with RP-3 at the time of identical viable tumor cell challenge. These results suggest that neutrophils play a role in both the priming and effector phases of specific transplantation resistance to syngeneic tumors.


Differential tramadol and O-desmethyl metabolite levels in brain vs. plasma of mice and rats administered tramadol hydrochloride orally.
To investigate a possible differential brain uptake of tramadol vs. its major metabolite (O-desmethyl tramadol; M1) in mice and rats. An extraction and measurement technique (gas chromatograph equipped with a nitrogen phosphorus detector) was used to measure plasma and brain levels of tramadol and M1 at intervals 10-300 min after oral dosing of tramadol hydrochloride to mice and rats. For all doses of tramadol administered (5, 10, 20, or 40 mg/kg), tramadol and M1 plasma levels were greatest 10 min after dosing: in mice, peak tramadol plasma levels were 47.75-736.72 ng/mL and peak M1 levels were 75.30-1084.92 ng/mL; in rats, peak tramadol plasma levels were 185.03-455.81 ng/mL and peak M1 levels were 106.74-455.70 ng/mL. Tramadol brain levels were also greatest 10 min after dosing. In mice, peak tramadol brain levels were 226.42-1847.46 ng/g. Peak M1 levels (72.17-572.97 ng/g) occurred 20-60 min after dosing. In rats, peak tramadol brain levels were 258.50-1777.37 ng/g and peak M1 levels were 80.35-289.60 ng/g. In mice, the ratio of tramadol/M1 in plasma was 0.5-1.0 throughout the measurements, whereas the ratio in brain was about 10 at 10 min and about 2 from 20 to 50 min. In rats, the ratio of tramadol/M1 in plasma was 0.5-1.5, whereas the ratio in brain was about 15 at 10 min and about 4-7 thereafter. In mice and rats, there appears to be preferential brain vs. plasma distribution of tramadol over M1.


Cellobiose as a model system to reveal cellulose dissolution mechanism in acetate-based ionic liquids: Density functional theory study substantiated by NMR spectra.
Cellulose dissolution mechanism in acetate-based ionic liquids was systematically studied in Nuclear Magnetic Resonance (NMR) spectra and Density Functional Theory (DFT) methods by using cellobiose and 1-butyl-3-methylimidazolium acetate (BmimAc) as a model system. The solubility of cellulose in ionic liquid increased with temperature increase in the range of 90-140°C. NMR spectra suggested OAc(-) preferred to form stronger hydrogen bonds with hydrogen of hydroxyl in cellulose. Electrostatic potential method was employed to predict the most possible reaction sites and locate the most stable configuration. Atoms in molecules (AIM) theory was used to study the features of bonds at bond critical points and the variations of bond types. Simultaneously, noncovalent interactions were characterized and visualized by employing reduced density gradient analysis combined with Visual Molecular Dynamics (VMD) program. Natural bond orbital (NBO) theory was applied to study the noncovalent nature and characterize the orbital interactions between cellobiose and Bmim[OAc].


Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect.
Loop diuretic resistance characterized by inefficient sodium excretion complicates many patients with acutely decompensated heart failure (ADHF). Mineralocorticoid receptor antagonists (MRAs) in natriuretic doses may improve spot urine sodium excretion and outcomes. Our primary aim was to assess the association of high-dose spironolactone with short-term spot urine sodium excretion, and our secondary aim was to determine if this higher short-term spot urine sodium excretion is associated with reduction in the composite clinical outcome (of cardiovascular mortality and/or ADHF hospitalization) event rate at 180 days. Single-centre, non-randomized, open-label study enrolling 100 patients with ADHF. Patients were treated with standard ADHF therapy alone (n = 50) or oral spironolactone 100 mg/day plus standard ADHF therapy (n = 50). Spot urine samples were collected at day 1 and day 3 of hospitalization. Spironolactone group had significantly higher spot urine sodium levels compared to standard care group at day 3 (84.13 ± 28.71 mmol/L vs 70.74 ± 34.43 mmol/L, p = 0.04). The proportion of patients with spot urinary sodium <60 mmol/L was lower in spironolactone group at day 3 (18.8 vs 45.7, p = 0.01). In multivariate analysis, spironolactone was independently associated with increased spot urinary sodium and urinary sodium/potassium ratio of >2 at day 3 (both, p < 0.05). Higher spot urine sodium levels were associated with a lower event rate [HR for urinary sodium >100 mmol/L = 0.16 (0.06-0.42), p < 0.01, compared to <60], and provided a significant prognostic gain measured by net reclassification indexes. Spot urinary sodium levels >60 mmol/L and urinary sodium/potassium ratio >2 measured at day 3 of hospitalization for ADHF are associated with improved mid-term outcomes. Spironolactone is associated with increased spot urinary sodium and sodium/potassium ratio >2.


670nm photobiomodulation as a novel protection against retinopathy of prematurity: evidence from oxygen induced retinopathy models.
To investigate the validity of using 670nm red light as a preventative treatment for Retinopathy of Prematurity in two animal models of oxygen-induced retinopathy (OIR). During and post exposure to hyperoxia, C57BL/6J mice or Sprague-Dawley rats were exposed to 670 nm light for 3 minutes a day (9J/cm²). Whole mounted retinas were investigated for evidence of vascular abnormalities, while sections of neural retina were used to quantify levels of cell death using the TUNEL technique. Organs were removed, weighed and independent histopathology examination performed. 670 nm light reduced neovascularisation, vaso-obliteration and abnormal peripheral branching patterns of retinal vessels in OIR. The neural retina was also protected against OIR by 670 nm light exposure. OIR-exposed animals had severe lung pathology, including haemorrhage and oedema, that was significantly reduced in 670 nm+OIR light-exposed animals. There were no significance differences in the organ weights of animals in the 670 nm light-exposed animals, and no adverse effects of exposure to 670 nm light were detected. Low levels of exposure to 670 nm light protects against OIR and lung damage associated with exposure to high levels of oxygen, and may prove to be a non-invasive and inexpensive preventative treatment for ROP and chronic lung disease associated with prematurity.


Mechanisms of iron-sulfur protein maturation in mitochondria, cytosol and nucleus of eukaryotes.
Iron-sulfur (Fe/S) clusters are important cofactors of numerous proteins involved in electron transfer, metabolic and regulatory processes. In eukaryotic cells, known Fe/S proteins are located within mitochondria, the nucleus and the cytosol. Over the past years the molecular basis of Fe/S cluster synthesis and incorporation into apoproteins in a living cell has started to become elucidated. Biogenesis of these simple inorganic cofactors is surprisingly complex and, in eukaryotes such as Saccharomyces cerevisiae, is accomplished by three distinct proteinaceous machineries. The "iron-sulfur cluster (ISC) assembly machinery" of mitochondria was inherited from the bacterial ancestor of mitochondria. ISC components are conserved in eukaryotes from yeast to man. The key principle of biosynthesis is the assembly of the Fe/S cluster on a scaffold protein before it is transferred to target apoproteins. Cytosolic and nuclear Fe/S protein maturation also requires the function of the mitochondrial ISC assembly system. It is believed that mitochondria contribute a still unknown compound to biogenesis outside the organelle. This compound is exported by the mitochondrial "ISC export machinery" and utilised by the "cytosolic iron-sulfur protein assembly (CIA) machinery". Components of these two latter systems are also highly conserved in eukaryotes. Defects in the mitochondrial ISC assembly and export systems, but not in the CIA machinery have a strong impact on cellular iron uptake and intracellular iron distribution showing that mitochondria are crucial for both cellular Fe/S protein assembly and iron homeostasis.


A facile approach to fabricate functional 3D macroscopic silica microtube networks using N,N'-methylenediacrylamide organogel as template.
Using N,N'-methylenediacrylamide organogel as a template and gamma-aminopropyltriethoxysilane as the precursor, functional silica microtube networks (MTNs) with adequate mechanical strength and different surface groups were prepared by an easy and effective approach.


Abnormalities of tumor suppressor gene p16 in pancreatic carcinoma: immunohistochemical and genetic findings compared with clinicopathological parameters.
Abnormalities of the tumor suppressor gene p16 have been reported in a variety of human tumors but are rare in pancreatic carcinoma except for cancer cell lines and xenografts. Their clinicopathological significance remains unknown. The purpose of this study was to examine immunohistochemical and genetic alterations of p16 in primary pancreatic carcinoma tissues and to investigate the relation between abnormalities of p16 and clinicopathological parameters to elucidate their clinicopathological significance. We investigated p16 expression in 60 pancreatic carcinoma cases by immunohistochemistry using a monoclonal antibody clone G175-405. In addition, we analyzed genetic alterations of the p16 gene using DNA extracted from microdissected tissue of pancreatic carcinoma, by polymerase chain reaction, nonradioisotopic single-strand conformation polymorphism (non-RI-SSCP), DNA sequencing, and hypermethylation analyses using restriction enzymes. We compared the abnormalities of p16 alterations with clinicopathological parameters to elucidate their significance. On immunohistochemical study, staining for p16 protein was strongly positive in 22 (37%) of 60 pancreatic carcinoma cases, weakly positive in 24 (40%), and negative in 14 (23%). In contrast, p16 mutations were recognized in 9 (15%) of the 60 pancreatic carcinoma cases. The incidence of p16 mutations was 2 (9%) in 22 cases of pancreatic carcinoma with strongly positive staining, 4 (17%) in 24 with weakly positive staining, and 3 (21%) in 14 with negative staining. Hypermethylation of p16 was detected in the two pancreatic carcinoma cases with weakly positive staining, although homozygous deletions were not found in any case. There was no significant correlation between the expression of p16 protein and any of the clinicopathological parameters. However, there was a tendency for the tumor to be larger in patients with decreased expression of p16 protein than in those with normal expression levels. In contrast, the tumor was significantly larger and the survival period significantly shorter for patients with pancreatic carcinoma with p16 mutation or hypermethylation than for those with pancreatic carcinoma with an intact p16 gene (P < 0.05). These findings suggest that p16 alterations may participate in the aggressiveness of pancreatic carcinoma.


Determination of xylometazoline in plasma and urine by gas chromatography using a fused-silica capillary column and an electron-capture detector.
A sensitive method is described for the determination of unchanged xylometazoline in plasma and urine at concentrations down to 35 nmol/l. After addition of naphazoline as an internal standard, both compounds are extracted with dichloromethane-diethyl ether (20:80) at pH 10, back-extracted with an acidic solution and re-extracted from a sodium hydroxide solution with dichloromethane-diethyl ether (20:80). The compounds are then derivatized with heptafluorobutyric anhydride in the presence of pyridine. The derivatives are determined by capillary gas chromatography using electron-capture detection.


The Hungerford shooting incident.
Thirty people sustained gunshot injuries on one afternoon in Hungerford, a small rural town in Berkshire. Fourteen people died at the scene of the shootings and three of the 16 patients who were admitted to hospital subsequently died. We describe the management of the 14 patients admitted to Princess Margaret Hospital, Swindon.


Xanthoma disseminatum and Waldenström's macroglobulinemia.
A 71-year-old woman had a 7-month history of multiple asymptomatic papules on the upper part of the body. The clinical picture and histopathologic findings confirmed the diagnosis of xanthoma disseminatum. Further studies revealed Waldenström's macroglobulinemia. Treatment with chlorambucil and prednisone led to a dramatic reduction in her paraprotein level. In addition, cutaneous lesions improved and new lesions stopped appearing. Treatment of selected papules by cryotherapy or intralesional corticosteroid injection provided further improvement. This case is notable because (1) it is the first report of xanthoma disseminatum in a patient with Waldenström's macroglobulinemia and (2) there was an unusually good response to therapy.


Polysaccharide hydrogels: Functionalization, construction and served as scaffold for tissue engineering.
Polysaccharide hydrogels have been widely utilized in tissue engineering. They interact with the organismal environments, modulating the cargos release and realizing of long-term survival and activations of living cells. In this review, the potential strategies for modification of polysaccharides were introduced firstly. It is not only used to functionalize the polysaccharides for the consequent formation of hydrogels, but also used to introduce versatile side groups for the regulation of cell behavior. Then, techniques and underlying mechanisms in inducing the formation of hydrogels by polysaccharides or their derivatives are briefly summarized. Finally, the applications of polysaccharide hydrogels in vivo, mainly focus on the performance for alleviation of foreign-body response (FBR) and as cell scaffolds for tissue regeneration, are exemplified. In addition, the perspectives and challenges for further research are addressed. It aims to provide a comprehensive framework about the potentials and challenges that the polysaccharide hydrogels confronting in tissue engineering.


Ambulatory heart rate and ST-segment depression during painful and silent myocardial ischemia in chronic stable angina pectoris.
The relation between heart rate and ischemic ST-segment depression was studied in 70 patients with documented obstructive coronary artery disease (CAD) and reproducible effort angina. Symptom-limited treadmill exercise testing was performed before and after a 2-week placebo period and 24-hour FM ambulatory electrocardiographic monitoring at the end of the placebo period. The means (+/- standard deviation) of the basal and placebo values for exercise time, heart rate and maximal ST-segment depression were: 6.4 +/- 2.6 minutes vs 6.9 +/- 2.8 minutes (difference not significant [NS]), 125 +/- 17 beats/min vs 125 +/- 19 beats/min (NS) and 2.3 +/- 0.8 mm vs 2.1 +/- 0.8 (NS), respectively. Ambulatory monitoring revealed 205 episodes of significant ST-segment depression (J + 80 ms; 49 episodes with more than 1 mm, 83 with more than 2 mm, 39 with more than 3 mm and 34 with more than 4 mm). Of all episodes of ST-segment depression, 130 (64%) were asymptomatic. The episodes lasted for 3 to 110 minutes. The maximal 24-hour ambulatory heart rate and ST-segment depression during ischemic episodes were expressed as a percentage of those seen during exercise-induced ischemia. When all ambulatory ischemic episodes (both symptomatic and asymptomatic) were compared with exercise-induced ischemic changes in the individual patient, there was little difference in heart rate (91 +/- 15% vs 90 +/- 18%, NS) but there was a greater magnitude of ST-segment depression (122 +/- 57% vs 104 +/- 52%, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Genomic and transcriptomic insights into Raffaelea lauricola pathogenesis.
Laurel wilt caused by Raffaelea lauricola is a lethal vascular disease of North American members of the Lauraceae plant family. This fungus and its primary ambrosia beetle vector Xyleborus glabratus originated from Asia; however, there is no report of laurel wilt causing widespread mortality on native Lauraceae trees in Asia. To gain insight into why R. lauricola is a tree-killing plant pathogen in North America, we generated and compared high quality draft genome assemblies of R. lauricola and its closely related non-pathogenic species R. aguacate. Relative to R. aguacate, the R. lauricola genome uniquely encodes several small-secreted proteins that are associated with virulence in other pathogens and is enriched in secondary metabolite biosynthetic clusters, particularly polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS) and PKS-NRPS anchored gene clusters. The two species also exhibit significant differences in secreted proteins including CAZymes that are associated with polysaccharide binding including the chitin binding CBM50 (LysM) domain. Transcriptomic comparisons of inoculated redbay trees and in vitro-grown fungal cultures further revealed a number of secreted protein genes, secondary metabolite clusters and alternative sulfur uptake and assimilation pathways that are coordinately up-regulated during infection. Through these comparative analyses we have identified potential adaptations of R. lauricola that may enable it to colonize and cause disease on susceptible hosts. How these adaptations have interacted with co-evolved hosts in Asia, where little to no disease occurs, and non-co-evolved hosts in North America, where lethal wilt occurs, requires additional functional analysis of genes and pathways.


Cerebellar morphology as a predictor of symptom and psychosocial outcome in schizophrenia.
In this study, we examined whether brain morphology assessed early in the course of schizophrenia predicted psychosocial or symptomatic outcome. We acquired magnetic resonance images on 63 subjects with schizophrenia spectrum disorders and manually traced regions of interest, including the cerebrum, temporal lobes, ventricles, and cerebellum. Subjects were then prospectively assessed every 6 months for an average of 7 years. Outcome symptom measures were longitudinal rather than cross-sectional, and included average number of weeks per year spent in a psychotic negative, or disorganized symptom syndrome, and average number of weeks of inpatient treatment per year. A psychosocial outcome measure summed ratings of impairment in employment, recreation, sexual activity, and interpersonal relationships. Negative associations were found between cerebellar volume and three outcome measures: negative and psychotic symptom duration, and psychosocial impairment. These results underscore the potential role of cerebellar abnormalities in the etiology and pathophysiology of schizophrenia.


Female-female aggression and male responses to the two colour morphs of female common cuckoos.
Female-only colour polymorphism is rare in birds, but occurs in brood parasitic cuckoos (Cuculidae). Obligate brood parasites leave incubation and parental care to other species (hosts), so female-female interactions can play a role in how parasites guard critical resources (host nests) within their laying areas. The plumage of adult female common cuckoos (Cuculus canorus) is either rufous (typically rare) or grey (common), whereas adult male conspecifics are monochromatic (grey). In previous studies, hosts and conspecific males responded with less intensity toward the rare female morph in support of a negative frequency-dependent benefit of female plumage polychromatism. Here, we assessed responses of both conspecific females and males to vocal playbacks of female calls, coupled with one of two 3D models of the different morphs of female cuckoos. At our study population, the rufous female morph was as common as the grey morph; therefore, we predicted similarly high rates of conspecific responses in both treatments. Both female and male cuckoos responded to playbacks acoustically, which demonstrated the primary role of acoustic communication in social interactions amongst cuckoos. Following this, some cuckoos flew closer to the models to inspect them visually. As predicted, no significant differences were detected between the live cuckoos' responses toward the two colour morphs in this population. We conclude that dichromatism in female cuckoos evolved to serve one or more functions other than conspecific signalling.


Analysis of night-time and weekend otolaryngology service.
The night-time and weekend otolaryngology service provided to an urban population slightly in excess of half a million people in analysed over a six month period. During this time, 147 calls were received, of which 116 (79%) required a hospital visit by the Registrar-on-call. Children accounted for 39% of patients seen and adults 61%. The problems encountered were in keeping with traditional perceptions of otolaryngology. The most common diagnosis necessitating a hospital visit was a suspected foreign body in the upper aerodigestive tract (39 cases), followed by epistaxis (28 cases) and some form of ear sepsis (12 cases). There was a noticeable lack of primary involvement in such areas as facial and neck trauma.


Rate coding versus temporal order coding: a theoretical approach.
The belief that neurones transmit information in the form of a firing rate code is almost universal. However, we argue that at least in some situations, the efficiency of a coding strategy based on rate coding is surprisingly poor. A simple mathematical analysis reveals that, due to the stochastic nature of spike generation, even transmitting the simplest signals reliably would require either: (1) excessively long observation periods incompatible with the speed of sensory processing or (2) excessively large numbers of redundant neurones, incompatible with the anatomical constraints imposed by sensory pathways. We argue that such problems may be avoided by using alternative temporal codes which rely on the asynchrony of firing across a population of afferent neurones.


Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping.
A genetic description of the human genome requires maps of three types. The first shows the frequency of chromosomal interchange during meiosis, relying on many equally spaced markers, and is limited to interchanges that do not unmask defects lethal to the conceptus, whose every cell will contain such abnormalities. The second is the physical description of genomic regions defined by karyotypic rearrangements, DNA segments, genes, or their products. A third description of somatic chromosomal interchanges at mitosis is also required. Because mitotic exchanges occur in a single postembryonic somatic progenitor cell, lethal effects on the organism are reduced. These events have been important in genetic mapping in Drosophila melanogaster and fungi, but they have rarely been detected in mammals. Here we report a significant frequency of mitotic recombination in human tumours and the first application of this information in localizing their predisposing locus.


Viruses and neurodegeneration.
Neurodegenerative diseases (NDs) are chronic degenerative diseases of the central nervous system (CNS), which affect 37 million people worldwide. As the lifespan increases, the NDs are the fourth leading cause of death in the developed countries and becoming increasingly prevalent in developing countries. Despite considerable research, the underlying mechanisms remain poorly understood. Although the large majority of studies do not show support for the involvement of pathogenic aetiology in classical NDs, a number of emerging studies show support for possible association of viruses with classical neurodegenerative diseases in humans. Space does not permit for extensive details to be discussed here on non-viral-induced neurodegenerative diseases in humans, as they are well described in literature.Viruses induce alterations and degenerations of neurons both directly and indirectly. Their ability to attack the host immune system, regions of nervous tissue implies that they can interfere with the same pathways involved in classical NDs in humans. Supporting this, many similarities between classical NDs and virus-mediated neurodegeneration (non-classical) have been shown at the anatomic, sub-cellular, genomic and proteomic levels suggesting that viruses can explain neurodegenerative disorders mechanistically. The main objective of this review is to provide readers a detailed snapshot of similarities viral and non-viral neurodegenerative diseases share, so that mechanistic pathways of neurodegeneration in human NDs can be clearly understood. Viruses can guide us to unveil these pathways in human NDs. This will further stimulate the birth of new concepts in the biological research, which is needed for gaining deeper insights into the treatment of human NDs and delineate mechanisms underlying neurodegeneration.


Interaction between the urea cycle and the orotate pathway: studies with isolated hepatocytes.
Two enzymes catalyze the synthesis of carbamylphosphate (CP) in the liver. One is intramitochondrial and utilizes ammonia to make CP for ureagenesis; the second is cytoplasmic and utilizes glutamine to produce CP for pyrimidine biosynthesis. The extent to which the metabolic independence of the two pathways is abridged by the use of a common precursor was examined with measurements of the incorporation of [14C]NaHCO3 into orotic acid, uridine nucleotides, and urea in isolated hepatocytes. Pyrimidine synthesis was markedly stimulated by physiological concentrations of ammonia, and the stimulation was antagonized by ornithine. At intracellular concentrations of ornithine and levels of ammonia found in the portal circulation, some 90% of pyrimidine synthesis was ammonia-dependent. When the glutamine-dependent activity was released from feedback inhibition with galactosamine, the ammonia-dependent incorporation still accounted for 2/3 of pyrimidine synthesis. These results do not support the widely held view that the cytoplasmic enzyme is the sole source of CP for pyrimidine biosynthesis in the liver. They suggest instead that the bulk of the CP incorporated into hepatic pyrimidines is of mitochondrial origin. However, an experiment with intact animals failed to provide decisive evidence on this interpretation. Pyrimidine biosynthesis was sharply inhibited by the addition of uridine, but ureagenesis was unaffected. When physiological levels of ammonia were provided, the sensitivity of pyrimidine biosynthesis to uridine was lost. Although inhibition of the ammonia-dependent enzyme by pyrimidines has been observed with cell-free preparations, it was not evident in the intact cell. Thus, to the extent that the CP consumed in pyrimidine biosynthesis is of mitochondrial origin, feedback control of the orotate pathway appears to be thwarted.


A Frizzled4-LRP5 agonist promotes blood-retina barrier function by inducing a Norrin-like transcriptional response.
Norrin (NDP) and WNT7A/B induce and maintain the blood-brain and blood-retina barrier (BBB, BRB) by stimulating the Frizzled4-LDL receptor related protein 5/6 (FZD4-LRP5/6) complex to induce beta-catenin-dependent signaling in endothelial cells (ECs). Recently developed agonists for the FZD4-LRP5 complex have therapeutic potential in retinal and neurological diseases. Here, we use the tetravalent antibody modality F4L5.13 to identify agonist activities in Tspan12-/- mice, which display a complex retinal pathology due to impaired NDP-signaling. F4L5.13 administration during development alleviates BRB defects, retinal hypovascularization, and restores neural function. In mature Tspan12-/- mice F4L5.13 partially induces a BRB de novo without inducing angiogenesis. In a genetic model of impaired BRB maintenance, administration of F4L5.13 rapidly and substantially restores the BRB. scRNA-seq reveals perturbations of key mediators of barrier functions in juvenile Tspan12-/- mice, which are in large parts restored after F4L5.13 administration. This study identifies transcriptional and functional activities of FZD4-LRP5 agonists.


Managing the supply-demand mismatches and potential flows of ecosystem services from the perspective of regional integration: A case study of Hangzhou, China.
Regional integration is a development strategy that synergizes various components as a whole to maximize overall benefits. The natural heterogeneity and fluidity of ecosystem service (ES) make it a promising target for regional integration. However, the current focus on regional integration was more on the socio-economic factors rather than ecological resources, and the understanding of the supply-demand relationship and potential flow of ecosystem services was still limited. Therefore, we attempted to interpret ecological integration management by linking ES budgets, bundles, and flows in this study. The results showed that the spatial mismatches of ESs supply-demand were observed in all six selected ES types. Most of the ESs deficit regions were concentrated in urban centers, while ES surplus regions were scattered in surrounding rural areas. Multiple heterogeneous ES resources could ideally benefit an additional 0.13-4.84 million people in 9-70 townships through potential ES flows under ecological integration management. Therefore, we connected the service provisioning areas (SPAs) and service beneficiary areas (SBAs) with three types of ES flows and drew the potential provider-beneficiary relationship networks at the townships/bundles scale, demonstrating the interactive relationship of ecological integration within the region. On this basis, we also proposed the applicability matrix of governance tools for the first time according to the type of ES flows, and then put forward the corresponding governance opinions around the two aspects of "improving ES budges within clusters" and "strengthening ES flow among clusters". This study provided an ecological perspective for understanding regional integration, and relevant conclusions can inform environmental policy priorities for sustainable decision-making in urbanized areas.


Enzyme-linked immunosorbent assay for C1q in human serum by use of monoclonal antibodies.
A sandwich ELISA system has been developed for the detection of C1q in human serum. It is specific, uses monoclonal antibodies, is sensitive into the nanogram range and is rapidly performed. Therefore, it may be a helpful tool for clinical routine diagnosis, e.g., detecting abnormal C1q levels in patients with rheumatic disorders. Various combinations of poly- and monoclonal antibodies were tested in a sandwich assay. One of these combinations, in particular, resulted in a highly reproducible standard curve: C1q bound to solid-phase polyclonal anti-C1q was detected by the monoclonal antibody 242 G3. In this assay, the C1q concentration in sera of normal individuals was found to be 160 micrograms/ml (mean value of 70 normal human sera). This ELISA detected nanogram levels of C1q and gave results comparable to those obtained by haemolytic C1q titration. One nanogram of C1q corresponded to ca. 2.6 X 10(10) effective C1q molecules. With this technique, selective C1q deficient sera as well as sera from patients with rheumatoid diseases were analysed.


Dependence of small-scale atomic clock performance on frequency modulation parameters used in the frequency control loop.
We demonstrate a direct correspondence between FM parameters used in a frequency-locked loop that is based on multifield FM spectroscopy and the stability of a small-scale coherent population trapping atomic clock. Optimized FM parameters lead to an Allan deviation of 2.8 x 10(-11)/square root tau, while the clock stability deteriorates in a predictable manner for the other FM parameters.


Factors Affecting Neurocognitive Function in Children with Chronic Kidney Disease: A Systematic Review.
In children, chronic kidney disease (CKD) has been known to affect neurocognitive function which can impair the quality of life. This study aims to determine the factors and treatment modalities which might affect neurocognitive function in pediatric population with CKD. A systematic review was done using 3 electronic databases: PubMed, ScienceDirect, SpringerLink, and carried out based on PRISMA guidelines. Our review included articles published in the last 10 years (2011-2021) in English, on children aged 0-18 years with CKD. Factors affecting the children's neurocognitive function were assessed. Eight articles were included in this study. Three articles reported that parent's education, especially maternal education affect the neurocognitive function of children with CKD. In relation with modalities, in general, children with CKD who had kidney transplant had a better neurocognitive outcome. A longer duration of hemodialysis (HD) was associated with poorer neurocognitive outcomes. Other factors that can affect the neurocognitive function included depression, a history of abnormal births, seizures, and hypertension. In children, CKD might cause neurocognitive function disorders through various complex and interconnected mechanisms. Further studies are needed to determine the mechanism and prevention of neurocognitive disorders, as well as the best choice of therapeutic modality to improve both kidney function and neurocognitive function in children with CKD.


Cancer genetics and their application to individualised medicine.
One of the great challenges of basic research is to translate scientific discoveries into the improved treatment of patients. For colorectal cancer, our increased understanding of the molecular aetiology of the disease has not yet been paralleled by an improvement in patient care. However, several new approaches are on the verge of clinical implementation. Technical advances such as real-time polymerase chain reaction (PCR) and microarray techniques coupled to insight in the molecular pathways in colorectal cancer makes it possible to develop new clinical tools for the diagnosis, classification and treatment of patients. The ultimate goal of the incorporation of cancer genetics into the clinical treatment of patients is individualised medicine; therapeutic strategies based on the molecular taxonomy of tumours and individually constructed for each patient.


Multi-Institutional Variation in Performance of Low-Dose Computed Tomography for the Evaluation of Suspected Nephrolithiasis.
Introduction and Objective: Guidelines from the American Urological Association (AUA) and American College of Radiology (ACR) recommend that patients with suspected nephrolithiasis undergo low-dose CT of the kidney, ureter, and bladder (LD CT KUB) as opposed to higher dose conventional imaging. We hypothesized that even at institutions with established LD protocols, higher dose imaging is common. Materials and Methods: We identified four academic medical centers where LD CT KUB protocols were implemented to yield an effective dose (EDose) consistent with national guidelines. Fifty consecutive adult patients who underwent CT KUB specifically for the evaluation of nephrolithiasis were retrospectively reviewed at each site. Patient age, sex, body mass index (BMI), imaging location, and EDose (millisieverts [mSv]) were recorded. Results: Two hundred patients with a mean age of 54 years were identified. Forty-six patients (23%) underwent CT KUB with an EDose ≤4 mSv, accounting for 10% to 48% of each institution's cohort. One hundred sixteen patients had a BMI <30, and would have been expected to receive LD CTs by the AUA criteria for LD CT KUB. Within this subset, only 37 patients (32%) actually underwent LD CT KUB. The highest dose CT KUB at each institution resulted in an EDose of 33.8 to 44.6 mSv, exceeding the recommended exposure of LD CT KUB by 10-fold. Conclusions: At academic institutions where LD CT KUB was implemented for the evaluation of nephrolithiasis, a minority of patients with BMI <30 received guideline-concordant imaging. Differences in patient BMI did not account for the variation in radiation exposure. Further research is necessary to elucidate barriers to LD CT implementation.


Proteins in whey: chemical, physical, and functional properties.
There is abundant information concerning the functional behavior of whey proteins in model systems. The data on functional properties reported by different researchers, however, reveal wide discrepancies in values. For example, in the case of comparable whey preparations, apparent solubilities may range from 10 to 100%; strength of gels from 0.3 to greater than 10 N, foam overruns from 250 to 1500%, and foam stabilities from 0.5 to 30 min. Many of the data are of limited value in assessing the true functional characteristics of different preparations, treatments, or processing effects. Reports to date are useful in indicating the relative behavior of different proteins; however, the data do not always predict the performance of such proteins in actual food systems. This reflects the fact that in foods, extensive interactions with other components may occur, resulting in modified behavior of the proteins. Harper, (1984) has advocated the testing of these various preparations in simulated food systems which should validly relate the behavior to performance in commercial systems. Emphasis on standardization of specific protocols, with regard to order of addition in ingredients, temperature, pH control, and amount of energy input during mixing, homogenization, emulsification, etc. deserves serious consideration. While this approach is justifiable in terms of providing valuable data to commercial users, it does not minimize the importance of examining these proteins in model systems where the physicochemical basis of each functional attribute can be described in molecular terms (Kinsella, 1987). Such information is necessary to expedite appropriate methods of processing in order to control compositional variability, extent of denatauration, and possible protein modification. In addition, rapid, reliable tests for routine quality assurance that can provide practical information concerning functional applications would be of great value. Whey protein preparations vary immensely in functional behavior and are presently relegated to limited use as functional ingredients in the food industry. This need not be the case since conventional and new technologies permit rigorous control of production protocols, e.g., careful control of heat treatments can result in the production of whey protein preparations with consistent, reliable functional properties (deWit, 1981, 1984; Harper, 1984; Morr, 1985). As the market for functional proteins continues to expand, the whey industry must seek the means to refine whey protein products; determine useful functional properties; develop standardized manufacturing protocols; demonstrate the effectiveness of whey as a functional ingredient; promote, and then market, whey on the basis of performance at competitive cost.


Association of Age, Sex, Body Size and Ethnicity with Electrocardiographic Values in Community-based Older Asian Adults.
Existing electrocardiographic (ECG) reference values were derived in middle-aged Caucasian adults. We aimed to assess the association of age, sex, body size and ethnicity on ECG parameters in a multi-ethnic Asian population. Resting 12-lead ECG and anthropometric measurements were performed in a community-based cohort of 3777 older Asians (age 64.7±9.1 years, 1467 men, 88.8% Chinese, 7.7% Malay, 3.5% Indian, body mass index [BMI] 24.0±3.9kg/m(2)). Men had longer PR interval, wider QRS, shorter QTc interval and taller SV3. In both sexes, older age was associated with longer PR interval, wider QRS, larger R aVL and more leftward QRS axis, while higher BMI was associated with longer PR interval, wider QRS, larger RaVL and more negative QRS axis. There were significant inter-ethnic differences in QRS duration among men, as well as in PR and QTc intervals among women (all adjusted p<0.05). Findings were similar in a healthy subset of 1158 adults (age 61.2±9.1 years, 365 men) without cardiovascular risk factors. These first community-based ECG data in multi-ethnic older Asians highlight the independent effects of age, sex, body size and ethnicity on ECG parameters.


In vivo and in vitro models to test the hypothesis of particle-induced effects on cardiac function and arrhythmias.
Exposure to ultrafine particles (UFPs) by inhalation increases the number and severity of cardiac events. The specific mechanism(s) of action are unknown. This study was designed to examine whether UFPs could exert a direct effect on the cardiovascular system without dependence upon lung-mediated responses. The direct effects of UFPs were determined in normal rats (infused intravenously with UFPs), and in the isolated Langendorff perfused rat heart. UFPs from either ambient air (UFAAs) or diesel engine exhaust (UFDGs) were studied. Infusion of UFDGs prepared in our laboratory caused ventricular premature beats (VPBs) in 2 of 3 rats in vivo. Ejection fraction increased slightly (approximately 4.5%) in rats receiving UFPAA and was unchanged in the UFDG and saline groups in vivo. In the isolated rat heart, perfused according to Langendorff, UFDGs caused a marked increase in left-ventricular end-diastolic pressure (LVEDP; from 12.0 +/- 4.6 mmHg to 24.8 +/- 11.2 mmHg, p < 0.05) after 30 min of exposure. UFPs isolated from industrial diesel particulate matter (UFIDs), obtained from the National Institute of Standards and Technology, caused a significant decrease in left-ventricular systolic pressure (LVSP; from 85.7 +/- 4.0 mmHg to 37.9 +/- 20.3 mmHg, p < 0.05) and +/- dP/dt (from 2,365 +/- 158 mmHg/s to 1,188 +/- 858 mmHg/s, p < 0.05) at 30 min after the start of infusion. This effect was absent when the soluble fraction (containing no particles) isolated from the UFIDs was studied. These findings indicate that UFPs can have direct effects on the cardiovascular system that are independent of effects of particles on the lungs.


Production of recombinant lytic polysaccharide monooxygenases and evaluation effect of its addition into Aspergillus fumigatus var. niveus cocktail for sugarcane bagasse saccharification.
Lignocellulosic biomass is a promising alternative for producing biofuels, despite its recalcitrant nature. There are microorganisms in nature capable of efficiently degrade biomass, such as the filamentous fungi. Among them, Aspergillus fumigatus var. niveus (AFUMN) has a wide variety of carbohydrate-active enzymes (CAZymes), especially hydrolases, but a low number of oxidative enzymes in its genome. To confirm the enzymatic profile of this fungus, this study analyzed the secretome of AFUMN cultured in sugarcane bagasse as the sole carbon source. As expected, the secretome showed a predominance of hydrolytic enzymes compared to oxidative activity. However, it is known that hydrolytic enzymes act in synergy with oxidative proteins to efficiently degrade cellulose polymer, such as the Lytic Polysaccharide Monooxygenases (LPMOs). Thus, three LPMOs from the fungus Thermothelomyces thermophilus (TtLPMO9D, TtLPMO9H, and TtLPMO9O) were selected, heterologous expressed in Aspergillus nidulans, purified, and used to supplement the AFUMN secretome to evaluate their effect on the saccharification of sugarcane bagasse. The saccharification assay was carried out using different concentrations of AFUMN secretome supplemented with recombinant T. thermophilus LPMOs, as well as ascorbic acid as reducing agent for oxidative enzymes. Through a statistic design created by Design-Expert software, we were able to analyze a possible cooperative effect between these components. The results indicated that, in general, the addition of TtLPMO9D and ascorbic acid did not favor the conversion process in this study, while TtLPMO9O had a highly significant cooperative effect in bagasse saccharification compared to the control using only AFUMN secretome.


Network screening for large urban road networks: Using GPS data and surrogate measures to model crash frequency and severity.
Crash frequency and injury severity are independent dimensions defining crash risk in road safety management and network screening. Traditional screening techniques model crashes using regression and historical crash data, making them intrinsically reactive. In response, surrogate measures of safety have become a popular proactive alternative. The purpose of this paper is to develop models for crash frequency and severity incorporating GPS-derived surrogate safety measures (SSMs) as predictive variables. SSMs based on vehicle manoeuvres and traffic flow were extracted from data collected in Quebec City. The mixed multivariate outcome is estimated using two models; a Full Bayes Spatial Negative Binomial model for crash frequency estimated using the Integrated Nested Laplace Approximation approach and a fractional Multinomial Logit model for crash severity. Model outcomes are combined to generate posterior expected crash frequency at each severity level and rank sites based on crash cost. The crash frequency model was accurate at the network scale, with the majority of proposed SSMs statistically significant at 95% confidence and the direction of their effect generally consistent with previous research. In the crash severity model, fewer variables were significant, yet the direction of the effect of all significant variables was again consistent with previous research. Correlations between rankings predicted by the mixed multivariate model and by the crash data were adequate for intersections (0.46) but were poorer for links (0.25). The ability to prioritize sites based on GPS data and SSMs rather than historical crash data represents a substantial contribution to the field of road safety.


Severe fever with thrombocytopenia syndrome virus induces platelet activation and apoptosis via a reactive oxygen species-dependent pathway.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate. Thrombocytopenia is a major clinical manifestation observed in SFTS patients, but the underlying mechanism remains largely unclear. Here, we explored the effects of SFTSV infection on platelet function in vivo in severely infected SFTSV IFNar-/- mice and on mouse and human platelet function in vitro. Results showed that SFTSV-induced platelet clearance acceleration may be the main reason for thrombocytopenia. SFTSV-potentiated platelet activation and apoptosis were also observed in infected mice. Further investigation showed that SFTSV infection induced platelet reactive oxygen species (ROS) production and mitochondrial dysfunction. In vitro experiments revealed that administration of SFTSV or SFTSV glycoprotein (Gn) increased activation, apoptosis, ROS production, and mitochondrial dysfunction in separated mouse platelets, which could be effectively ameliorated by the application of antioxidants (NAC (N-acetyl-l-cysteine), SKQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) and resveratrol). In vivo experiments showed that the antioxidants partially rescued SFTSV infection-induced thrombocytopenia by improving excessive ROS production and mitochondrial dysfunction and down-regulating platelet apoptosis and activation. Furthermore, while SFTSV and Gn directly potentiated human platelet activation, it was completely abolished by antioxidants. This study revealed that SFTSV and Gn can directly trigger platelet activation and apoptosis in an ROS-MAPK-dependent manner, which may contribute to thrombocytopenia and hemorrhage during infection, but can be abolished by antioxidants.


Optimization of nonribosomal peptides production by a psychrotrophic fungus: Trichoderma velutinum ACR-P1.
Trichoderma is an anamorphic filamentous fungal genus with immense potential for production of small valuable secondary metabolites with indispensable biological activities. Microbial dynamics of a psychrotrophic strain Trichoderma velutinum ACR-P1, isolated from unexplored niches of the Shiwalik region, bestowed with rich biodiversity of microflora, was investigated for production of nonribosomal peptides (NRPs) by metabolite profiling by intact-cell mass spectrometry (ICMS) employing matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometer. Being the first report on NRPs production by T. velutinum, studies on optimization of growth conditions by Response Surface Methodology (RSM) for production of NRPs by ACR-P1 was carried out strategically. Multifold enhancement in the yield of NRPs belonging to subfamily SF4 with medium chain of amino acid residues having m/z 1437.9, 1453.9, and 1452.0 at pH 5.9 at 20 °C and of subfamily SF1 with long-chain amino acid residues having m/z 1770.2, 1784.2, 1800.1, 1802.1, and 1815.1 was achieved at pH 7.0 at 25 °C. Complexities of natural mixtures were thus considerably reduced under respective optimized culture conditions accelerating the production of novel microbial natural products by saving time and resources.


Sequence of two phosphorylated sites in the catalytic subunit of bovine cardiac muscle adenosine 3':5'-monophosphate-dependent protein kinase.
The sequences of two phosphopeptides isolated from the catalytic subunit of bovine cardiac muscle cAMP-dependent protein kinase (type II) and from two of its cyanogen bromide fragments, have been determined. One phosphorylation site is a threonyl residue located approximately 180 residues from the blocked NH2 terminus. Its sequence is: -Gly-Arg-Thr-Trp-Thr(P)-Leu-Cys- and includes one of the three sulfhydryl groups present in the molecule. The second phosphorylated site within the sequence: -Val-Ser(P)-Ile-Asn- is located towards the carboxyl end of the protein where the other 2 cysteinyl residues also reside. The finding that phosphorylation of the catalytic subunit occurs on two discrete sites rather than at random suggests that it might be of physiological importance, e.g. in the regulation of enzyme activity.


A case of Coxsackie A9 virus infection with orchitis.
A thirteen-year-old boy with bilateral orchitis was diagnosed as being infected by Coxsackie A9 virus by isolation of the virus from a throat swab and a fecal specimen. Serologic investigations revealed the development of transitory specific neutralizing IgM antibodies against the isotate and of persistent antibodies belonging to the other immunoglobulin classes. An etiology of the orchitis by any of the infectious agents usually found with this condition could be excluded.


A systematic review of anatomical and visual function outcomes in preterm infants after scleral buckle and vitrectomy for retinal detachment.
This article is a systematic review of the literature examining the anatomical and visual function outcomes after scleral buckle and/or vitrectomy for Stage 4 or 5 retinopathy of prematurity. The literature published between 1994 through May 2003 was reviewed via a computer search accessing MEDLINE via OVID. Eight applicable studies were retrieved and analyzed. The study designs were descriptive, retrospective, non-comparative, consecutive case series. The postoperative anatomical outcomes varied dramatically between studies with retinal reattachment rates of 0.8% to 90%. Surgeries that achieved a 50% or higher rate of reattachment occurred primarily between 2 and 9 months of age. Surgeries that occurred between 7 and 11 months of age achieved a lower percentage of retinal reattachment. Further, the longer the duration of follow-up, the lower the percentage of retinas that remained attached. Most importantly, at least in these reports, the degree of retinal reattachment did not correlate well with the level of visual function. One report demonstrated no statistical correlation between visual and anatomical success. Poor visual outcomes were noted in both timely and delayed cases of surgical reattachment of the retina. Many of the reports described challenges in accurately measuring low levels of vision.


Penicillin G-resistant viridans group streptococcal endocarditis and interpretation of the American Heart Association's Guidelines for the Treatment of Infective Endocarditis.
We report a case of endocarditis due to a penicillin-"resistant" Streptococcus parasanguinis, discuss interpretations of the American Heart Association's guidelines for the treatment of viridans group streptococcal infection, and comment on therapy for infective endocarditis due to penicillin-resistant viridans group streptococci.


Tumor encapsulation in hepatocellular carcinoma. A pathologic study of 189 cases.
One hundred eighty-nine surgically resected hepatocellular carcinomas (HCC) were analyzed to study tumor encapsulation and the pathologic features that might account for the better prognosis in relation to it, and to examine the prognostic and pathobiologic significance of capsular thickness. Tumor encapsulation was found in 72 (46.8%) of the 154 cases with adequate histologic sections of the tumor-nontumor junctions. Encapsulated tumors showed a much lower incidence of direct liver invasion (P less than 0.0001), tumor microsatellites (P less than 0.0001), and venous permeation (P = 0.02) when compared with nonencapsulated ones. Significantly better disease-free and actuarial survival times were observed in patients with encapsulated tumors (medians, 9.9 and 18.3 months, respectively), compared with those with nonencapsulated ones (medians, 4.0 and 5.9 months, respectively; P = 0.0001 and 0.001, respectively). The incidence of tumor encapsulation did not increase or decrease with tumor size. Tumor encapsulation did not correlate with the presence of cirrhosis or the abundance of tumor stroma, suggesting that formation of the tumor capsule was independent of the degree of fibrosis within and outside the tumor. Among the 72 cases of encapsulated HCC, the capsular thickness ranged from 0.13 to 3.09 mm (mean +/- standard deviation = 0.87 +/- 0.59 mm), and it was unrelated to tumor size or presence of cirrhosis. Although it was apparent that a lower extensive tumor invasiveness contributed significantly to the better prognosis in encapsulated HCC, there was no correlation between capsular thickness and liver invasion, microsatellites, venous permeation, or survivals. Therefore, the thickness of tumor capsules was not helpful in prognostication.


Home hemodialysis needs you!
This special supplement of Hemodialysis International focuses on home hemodialysis (HD). It has been compiled by a group of international experts in home HD who were brought together throughout 2013-2014 to construct a home HD "manual." Drawing upon both the literature and their own extensive expertise, these experts have helped develop this supplement that now stands as an A-to-Z guide for any who may be unfamiliar or uncertain about how to establish and maintain a successful home HD program.


Differences in intraoperative prep solutions: a retrospective chart review.
Surgical site infections (SSIs) are the most common type of health care-associated infection in surgical patients. We wanted to identify which intraoperative prep solution used in our health network for adult open abdominal surgical procedures resulted in the lowest incidence of SSI 30 days after surgery. In addition, we wanted to know specifically how parachoroxylenol compared with chlorhexidine gluconate, povidone-iodine, and 0.7% iodine and 74% isopropyl alcohol as an intraoperative prep solution. We conducted a retrospective medical record review of 162 consecutive patients ages 18 years and older who had undergone elective open abdominal procedures from December 2008 to December 2010 at four acute care community hospitals within an integrated, tertiary health network in the southeastern United States. No SSIs occurred after procedures in which parachoroxylenol intraoperative prep solution was used (n = 71), whereas five SSIs occurred after procedures in which other prep solutions (ie, chlorhexidine gluconate [no SSIs], povidone-iodine [two SSIs], and 0.7% iodine and 74% isopropyl alcohol [three SSIs]) were used (n = 91). A chi-square test indicated a significant difference in the incidence of SSIs among patients prepped with parachoroxylenol intraoperative prep solution compared to patients prepped with the other solutions.


Time trends of cause-specific mortality among resettlers in Germany, 1990 through 2009.
Resettlers (in German: (Spät-)Aussiedler) form one of the biggest migrant groups in Germany. It is known that migrants have different mortality patterns compared to the autochthon population. In this paper, we combined data from three resettler cohorts and examined differences in mortality from non-communicable diseases among resettlers in Germany and the German population. Furthermore, we investigated time trends of cause-specific mortality for 20 years of follow-up and compared it with the German mortality rates. To assess differences in cause-specific mortality between resettlers and the general German population, we calculated standardized mortality ratios (SMRs). To ascertain mortality trends, cause-specific age-standardized mortality rates were calculated and modeled with Poisson regression and fractional polynomials. During the observation period, the study population accumulated almost 800,000 person-years and 5572 deaths were observed. All-cause mortality among resettlers was lower (SMR = 0.91, 95% CI = 0.89-0.94) compared to the general German population, as well as cardiovascular diseases (CVD) mortality (SMR = 0.82, 95% CI = 0.79-0.86). Results for cancer mortality varied considerably by cancer site. Analyses of time trends showed that all-cause and CVD mortality were decreasing over time in resettlers, as well as in the general German population. Lower all-cause mortality among resettlers is mainly explained by lower CVD mortality. Cancer-site specific mortality showed different results. Converging mortality rates may indicate an adaption of lifestyle behavior. However, there are no data on individual risk factors in this study.


Work stress and health in a sample of U.S. police.
This study assessed responses to the Occupational Stress Indicator in the Naperville Police Department. This 40% sample of 49 police officers were compared against population norms for employed workers in a range of occupations. Although the police officers perceived less stress from "factors intrinsic to the job", they expressed greater job-related pressure from "organizational structure and climate". They also rated greater the competitiveness and assertiveness in their work behavior.


A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.
Tremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation and proliferation. The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection; and to study the safety of its administration to cirrhotic patients. Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity. Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response. Most patients were in the advanced stage and 43% had an altered liver function (Child-Pugh class B). A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events. Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles. Partial response rate was 17.6% and disease control rate was 76.4%. Time to progression was 6.48 months (95% CI 3.95-9.14). A significant drop in viral load was observed while new emerging variants of the hypervariable region 1 of HCV replaced the predominant variants present before therapy, particularly in those patients with a more prominent drop in viral load. This antiviral effect was associated with an enhanced specific anti-HCV immune response. Tremelimumab safety profile and antitumor and antiviral activity, in patients with advanced HCC developed on HCV-induced liver cirrhosis, support further investigation.


Glucocorticoids and immune function: physiological relevance and pathogenic potential of hormonal dysfunction.
The more knowledge accumulates on the molecular action of glucocorticoids, the less appears to be known about the physiological relevance of these data. Mechanisms that determine bioactivity of glucocorticoids are largely neglected in studies on their molecular actions in immunoregulation. However, alterations of these mechanisms may contribute to the pathogenesis of acute of chronic inflammation, ranging from septic shock to autoimmune disease, or even acquired immuno deficiency syndrome. In this article, Thomas Wilckens attempts to challenge the long-standing dogma of glucocorticoids being only immunosuppressive in their action, and suggests a physiological role in which they are a prerequisite for a coordinated immune response.


Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy.
We investigated the role of cardiac troponin I (cTnI) in patients with aggressive malignancies treated with high-dose chemotherapy (HDC). High dose chemotherapy is potentially limited by cardiac toxicity. Considering the fact that cardiac dysfunction may become clinically evident weeks or months after HDC, the availability of an early marker of myocardial injury, able to predict late ventricular impairment, is a current need. We measured, in 204 patients (45+/-10 years) affected by cancer resistant to conventional treatment, the cTnI plasma concentration after every single cycle of HDC. According to the cTnI value (< or = or >0.4 ng/ml), patients were divided into a troponin positive (cTnI+, n = 65) and a troponin negative (cTnI-, n = 139) group. All patients underwent echocardiographic examination during the following seven months. In the cTnI- group, left ventricular ejection fraction (LVEF) progressively decreased after HDC, reaching a maximal reduction after three months; however, myocardial depression was transient and no longer detectable at later follow-up. By contrast, in the cTnI+ group LVEF reduction was more marked and still evident at the end of the follow-up. In cTnI+ patients, a close relationship between the short-term cTnI increment and the greatest LVEF reduction was found (r = -0.87, p<0.0001). The elevation of cTnI in patients undergoing HDC for aggressive malignancies accurately predicts the development of future LVEF depression. In this setting, cTnI can be considered a sensitive and reliable marker of acute minor myocardial damage with relevant clinical and prognostic implications.


Effects of temperatures and organic loading rates on biomethanation of acidic petrochemical wastewater using an anaerobic upflow fixed-film reactor.
The effect of temperature and organic loading rate on the rate of methane production from acidic petrochemical wastewater without neutralization was investigated by continuously feeding an anaerobic upflow fixed-film reactor. The temperatures selected for the studies were 25, 37, 45 and 55 degrees C. Organic loading rate (OLR) for each temperature was varied from 3.6 to 21.7 kg COD m(-3) d(-1). Best performance with respect to COD and BOD reduction, total gas production and methane yield was obtained with the reactor operating at 37 degrees C. OLR could be increased to a maximum of 21.7 kg COD m(-3) d(-1) with 90-95% COD and BOD reduction and methane yield of 0.450 m3 kg(-1) COD d(-1) added. The reactor operating at 55 degrees C gave the highest methane yield of 0.666 m3 kg(-1) COD d(-1) at an OLR of 6 kg COD m(-3) d(-1). This decreased to 0.110 m3 kg(-1) COD d(-1) when the OLR was increased to 18.1 kg COD m(-3) d(-1). The reactor operating at 45 degrees C gave a maximum methane yield of 0.416 m3 kg(-1) COD d(-1) added at an OLR of 6 kg COD m(-3) d(-1). On further increasing the OLR to 9 kg COD m(-3) d(-1), COD reduction was 89%, however, methane yield decreased to 0.333 m3 kg(-1) COD d(-1) added. The highest methane yield of 0.333 m3 kg(-1) COD d(-1) added at an OLR of 6 kg COD m(-3) d(-1) was obtained with reactors operating at 25 degrees C. These studies indicate potential rates of methane production from acidic petrochemical wastewater under different temperatures. This provides a guideline for various kinetic analyses and economic evaluation of the potential feasibility of fermenting acidic wastewater to methane.


Assessment of Brain Tumor Response: RANO and Its Offspring.
Treatment options for most nervous system tumors remain limited and patients are often confronted with significant morbidity and reduced life expectancy. However, significant efforts are underway to find more effective therapies for patients with primary and secondary brain tumors. As more and more clinical trials for nervous system tumors are being conducted, it is increasingly important to optimize the conduct of clinical trials in neuro-oncology. One of the key aspects in this regard is the development of objective and standardized criteria that allow for accurate response assessment in clinical trials and prevent the misclassification of responders and non-responders. Such misclassification may lead to premature discontinuation of an actually effective agent, thereby withholding a potentially active treatment from the patient. Conversely, patients may be inappropriately continued on an inactive treatment. Moreover, such misclassification may confound the data obtained in such studies and may lead to false conclusions with regards to the efficacy of the investigated drug. Therefore, reliable response assessment criteria are necessary that not only accurately capture radiographic changes but also account for treatment-related changes and incorporate the assessment of clinical status and quality of life (QoL). The Response Assessment in Neuro-Oncology (RANO) working group is an international collaboration of neuro-oncologists, medical oncologists, radiation oncologists, neurosurgeons, neuroradiologists, and regulatory groups (among others) commissioned to develop objective and tumor-specific response criteria for various tumor subtypes. This article reviews the currently available response criteria for high-grade glioma, low-grade glioma, and brain metastases and discusses some of the barriers to accurate assessment of treatment response in neuro-oncology.


Detection of vancomycin nonsusceptible strains in clinical isolates of Staphylococcus aureus in northern Iran.
Glycopeptides, particularly the cell wall-acting antibiotic vancomycin, are the safest cure for methicillin-resistant Staphylococcus aureus. The aim of this study was to evaluate nonsusceptibility of clinical isolates of S. aureus to vancomycin and investigate mutations in vraSR, a cell wall synthesis regulator gene, in vancomycin-resistant strains. Susceptibility of 110 clinical strains of S. aureus to methicillin and vancomycin were determined using disc diffusion method and determination of minimum inhibitory concentration, respectively. Presence of mecA and vanA genes was determined by PCR. Determination of spa types and mutations of the vraSR gene in vancomycin nonsusceptible isolates were assessed by PCR-sequencing analyses. In total, 47 isolates (42.73%) were recognized as MRSA, three (2.73%) strains were resistant to vancomycin, and eight (7.27%) strains were vancomycin intermediates. The MIC of vancomycin was 4-64 μg/ml in these isolates. All vancomycin nonsusceptible S. aureus strains were mecA positive and one isolate was positive for the vanA gene. Spa type t030 was found as the most common type. In vraSR sequence analysis, all 11 vancomycin nonsusceptible isolates had the D59E mutation in the vraR and E45G in vraS genes. R117H, R121S, and R121I are the other identified missense mutations in the vraR gene. The identification of a high percentage of MRSA and presence of VRSA and VISA isolates is a serious warning about the treatment of future MRSA infections and reveals the need for new and effective therapeutic agents.