High Sensitive Temperature Sensor Using a Liquid-core Optical Fiber with Small Refractive Index Difference Between Core and Cladding Materials.
An intensive temperature sensor based on a liquid-core optical fiber has been demonstrated for the measuring the temperature of the environment. The core of fiber is filled with a mixture of toluene and chloroform in order to make the refractive index of the liquid-core and the cladding of the fiber close. The experiment shows that a temperature sensitivity of about 5 dB/K and a tunable temperature range (from 20 oC to 60 oC) can be achieved. Based on the dielectric-clad liquid core fiber model, a simulation was carried out and the calculated results were in good accord with the experimental measurement.


Sudden infant death syndrome in infants of substance-abusing mothers.
A population-based study was performed to determine whether substance abuse during the perinatal period may be a risk factor for sudden infant death syndrome (SIDS). The incidence of SIDS was studied in 2143 infants of substance-abusing mothers (ISAM) born in Los Angeles County during 1986 and 1987 who were reported to the Los Angeles County Department of Health Services because of a history of drug exposure or positive urine test results in the mother, infant, or both. By comparing the ISAM birth reports with records of autopsy-proven SIDS in Los Angeles County, we found 19 SIDS cases in the population of 2143 ISAM, a SIDS rate of 8.87 cases per 1000 ISAM (95% confidence interval 5.3 to 13.8). This was significantly higher than the SIDS rate for the non-ISAM general population: 396 SIDS deaths among 325,372 live births, an incidence rate of 1.22 cases per 1000 births, p less than 0.00001. The age of ISAM at death was 99 +/- 63 (mean +/- SD) days compared with 91 +/- 52 days for the non-ISAM population (not significant). The incidence of SIDS was significantly greater in male infants, during the winter months, in black infants, and in non-Hispanic white infants in the non-ISAM population. Such differences were not observed in the ISAM group. A greater incidence of symptomatic apnea was reported before SIDS for the ISAM than for the non-ISAM population (22% vs 5.4%, p = 0.022). We conclude that ISAM have a higher incidence of SIDS than the non-ISAM general population. However, it was not possible to separate maternal substance abuse from other confounding variables that may also have had an impact on SIDS risk in the ISAM group.


A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-alpha inhibitor.
Dose-limiting diarrhea and myelosuppression compromise the success of irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycamptothecin) (CPT-11)-based chemotherapy. A recent pilot study indicates that thalidomide attenuates the toxicity of CPT-11 in cancer patients. This study aimed to investigate whether coadministered thalidomide modulated the toxicities of CPT-11 and the underlying mechanisms using several in vivo and in vitro models. Diarrhea, intestinal lesions, cytokine expression, and intestinal epithelial apoptosis were monitored. Coadministered thalidomide (100 mg/kg i.p. for 8 days) significantly attenuated body weight loss, myelosuppression, diarrhea, and intestinal histological lesions caused by CPT-11 (60 mg/kg i.v. for 4 days). This was accompanied by inhibition of tumor necrosis factor-alpha, interleukins 1 and 6 and interferon-gamma, and intestinal epithelial apoptosis. Coadministered thalidomide also significantly increased the systemic exposure of CPT-11 but decreased that of SN-38 (7-ethyl-10-hydroxycampothecin). It significantly reduced the biliary excretion and cecal exposure of CPT-11, SN-38, and SN-38 glucuronide. Thalidomide hydrolytic products inhibited hydrolysis of CPT-11 in rat liver microsomes but not in primary rat hepatocytes. In addition, thalidomide and its major hydrolytic products, such as phthaloyl glutamic acid (PGA), increased the intracellular accumulation of CPT-11 and SN-38 in primary rat hepatocytes. They also significantly decreased the transport of CPT-11 and SN-38 in Caco-2 and parental MDCKII cells. Thalidomide and PGA also significantly inhibited P-glycoprotein (PgP/MDR1), multidrug resistance-associated protein (MRP1)- and MRP2-mediated CPT-11 and SN-38 transport in MDCKII cells. These results provide insights into the pharmacodynamic and pharmacokinetic mechanisms for the protective effects of thalidomide against CPT-11-induced intestinal toxicity.


A Nomogram Based on a TRUS Five-Grade Scoring System for the Prediction of Prostate Cancer and High Grade Prostate Cancer at Initial TRUS-Guided Biopsy.
Purpose: To evaluate the efficacy of transrectal ultrasound five-grade scoring system (TRUS-5) in predicting prostate cancer (PCa) and high grade PCa (HGPCa), compared with TRUS two-grade scoring system (TRUS-2), and establish a TRUS-5 based nomogram for the prediction of PCa and HGPCa at initial biopsy (IPBx). Methods: Data were collected from 862 men who underwent initial TRUS-guided 12-core prostate biopsy. Age, prostate-specific antigen (PSA), percent free PSA, digital rectal examination (DRE), prostate volume (PV), PSA density (PSAD) and TRUS findings were included in the analysis. For TRUS-5, the probability of PCa was quantified on a scale from 1 (benign) to 5 (malignant). TRUS-2 used the grades "normal" and "suspicious". After univariate and multivariate logistic regression analyses, nomogram models were developed and internally validated based on independent predictors to predict the probability of PCa and HGPCa. Results: Overall PCa was detected in 42% (362/862) with 26.22% (226/862) showing HGPCa. TRUS-5 significantly outperformed TRUS-2 for the risk prediction of PCa and HGPCa (area under the receiver operating characteristic curve [AUC]: 0.787 vs. 0.694 for PCa, 0.841 vs. 0.713 for HGPCa, P<0.05). The TRUS-5 based nomogram showed higher AUCs (0.905 for PCa, 0.903 for HGPCa) than PSA alone, clinical base model, the TRUS-2 based model, and other predictive models (P<0.05). Conclusions: TRUS-5 represents a better imaging predictor than TRUS-2 for PCa and HGPCa. Our TRUS-5 based nomogram models performed well for the prediction of PCa and HGPCa at IPBx, which may help to make the decision to biopsy.


Children's work: the less-considered childhood occupation.
Children's work has largely been overlooked by researchers of many disciplines due to sociohistorical trends that fostered the notion that childhood should be a time free of work. Likewise, it has received little attention in occupational therapy most likely due to the influence of these historical developments on occupational therapy rhetoric and values. This paper begins by describing the influence of child labor laws and reformation on children's participation in work. Next, using a comprehensive review of the literature gathered from social sciences, a critical examination of the historical and current research on children's work is provided. This synthesis is framed in concepts of occupational science analyzing the evidence that describes the nature, form, function, and meaning of children's work. For occupational therapists working with children with disabilities, this research provides beginning guidelines for occupation-based work interventions and typical expectations for nondisabled children that may be applied using clinical reasoning to populations with disabilities.


Parp1 activation in mouse embryonic fibroblasts promotes Pol beta-dependent cellular hypersensitivity to alkylation damage.
Alkylating agents induce cell death in wild-type (WT) mouse embryonic fibroblasts (MEFs) by multiple mechanisms, including apoptosis, autophagy and necrosis. DNA polymerase beta (Pol beta) knockout (KO) MEFs are hypersensitive to the cytotoxic effect of alkylating agents, as compared to WT MEFs. To test the hypothesis that Parp1 is preferentially activated by methyl methanesulfonate (MMS) exposure of Pol beta KO MEFs, we have examined the relationship between Pol beta expression, Parp1 activation and cell survival following MMS exposure in a series of WT and Pol beta deficient MEF cell lines. Consistent with our hypothesis, we observed elevated Parp1 activation in Pol beta KO MEFs as compared to matched WT MEFs. Both the MMS-induced activation of Parp1 and the MMS-induced cytotoxicity of Pol beta KO MEFs are attenuated by pre-treatment with the Parp1/Parp2 inhibitor PJ34. Further, elevated Parp1 activation is observed following knockdown (KD) of endogenous Pol beta, as compared to WT cells. Pol beta KD MEFs are hypersensitive to MMS and both the MMS-induced hypersensitivity and Parp1 activation is prevented by pre-treatment with PJ34. In addition, the MMS-induced cellular sensitivity of Pol beta KO MEFs is reversed when Parp1 is also deleted (Pol beta/Parp1 double KO MEFs) and we observe no MMS sensitivity differential between Pol beta/Parp1 double KO MEFs and those that express recombinant mouse Pol beta. These studies suggest that Parp1 may function as a sensor of BER to initiate cell death when BER is aborted or fails. Parp1 may therefore function in BER as a tumor suppressor by initiating cell death and preventing the accumulation of cells with chromosomal damage due to a BER defect.


Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) associated with progressive cognitive and behavioral deterioration.
Autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) is an emerging syndrome caused by mutations in the C-terminus end of the TS domain of the DNMT1 gene. ADCA-DN is also associated with sensorimotor polyneuropathy, extrapyramidal, and dysautonomic signs, as well as dementia. Little has been reported about the progressive cognitive impairment associated with ADCA-DN. Our objective is to provide a detailed characterization of the cognitive profile of ADCA-DN. Three members of a kindred with ADCA-DN underwent comprehensive neuropsychological testing and neuroimaging. At baseline, 2 individuals demonstrated cognitive profiles with executive difficulties in some areas consistent with frontal-system dysfunction behaviorally and on standardized testing. The third individual was further in the disease course and exhibited more globally impaired cognition consistent with a diagnosis of dementia. This family demonstrated progressive neurodegeneration beginning with isolated areas of executive dysfunction and leading to globally impaired cognition and dementia. Cognitive decline occurred in parallel with neurological deterioration. The cognitive profile is similar to case reports of other individuals with an allelic neurological phenotype, Hereditary Sensory Autonomic Neuropathy 1E, also caused by DNMT1 mutations. (PsycINFO Database Record


[mRNA expression of voltage-dependent potassium channels in the brain of rats after middle cerebral artery occlusion].
To study the mRNA expression changes in the brain of rats after middle cerebral artery occlusion. Middle cerebral artery occlusion was used to induce ischemia in rat brain. The mRNA expression of voltage-dependent potassium channel subtypes, including Kv1.4, Kv1.5, Kv2.1 and Kv4.2, were detected in rat hippocampus and cortex by RT-PCR. Middle cerebral artery occlusion induced a significant neurological injury in rats. After ischemia 2 h, the mRNA of Kv1.4, Kv2.1 and Kv4.2 in hippocampus increased by 50%, 67% and 90% , respectively. And the mRNA of Kv1.4 and Kv4.2 maintained at a high level in hippocampus after ischemia 24 h. In cortex, the mRNA level of all the four subtypes were not changed significantly after ischemia 2 h, but the mRNA of Kv2.1 and Kv4.2 increased by 70% and 62% after ischemia 24 h, respectively. The mRNA expression levels of voltage-dependent potassium channels were up-regulated in rat hippocampus and cortex after middle cerebral artery occlusion.


Nitric oxide interacts with salicylate to regulate biphasic ethylene production during the hypersensitive response.
C(2)H(4) is associated with plant defense, but its role during the hypersensitive response (HR) remains largely uncharacterized. C(2)H(4) production in tobacco (Nicotiana tabacum) following inoculation with HR-eliciting Pseudomonas syringae pathovars measured by laser photoacoustic detection was biphasic. A first transient rise (C(2)H(4)-I) occurred 1 to 4 h following inoculation with HR-eliciting, disease-forming, and nonpathogenic strains and also with flagellin (flg22). A second (avirulence-dependent) rise, at approximately 6 h (C(2)H(4)-II), was only seen with HR-eliciting strains. Tobacco leaves treated with the C(2)H(4) biosynthesis inhibitor, aminoethoxyvinylglycine, suggested that C(2)H(4) influenced the kinetics of a HR. Challenging salicylate hydroxylase-expressing tobacco lines and tissues exhibiting systemic acquired resistance suggested that C(2)H(4) production was influenced by salicylic acid (SA). Disrupted expression of a C(2)H(4) biosynthesis gene in salicylate hydroxylase tobacco plants implicated transcriptional control as a mechanism through which SA regulates C(2)H(4) production. Treating leaves to increase oxidative stress or injecting with SA initiated monophasic C(2)H(4) generation, but the nitric oxide (NO) donor sodium nitroprusside initiated biphasic rises. To test whether NO influenced biphasic C(2)H(4) production during the HR, the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester was coinoculated with the avirulent strain of P. syringae pv phaseolicola into tobacco leaves. The first transient C(2)H(4) rise appeared to be unaffected by N(G)-nitro-L-arginine methyl ester, but the second rise was reduced. These data suggest that NO and SA are required to generate the biphasic pattern of C(2)H(4) production during the HR and may influence the kinetics of HR formation.


Preschool hyperactivity specifically elevates long-term mental health risks more strongly in males than females: a prospective longitudinal study through to young adulthood.
Evidence of continuities between preschool hyperactivity and adult mental health problems highlights the potential value of targeting early identification and intervention strategies. However, specific risk factors are currently unclear. This large-scale prospective longitudinal study aimed to identify which hyperactive preschoolers are at the greatest long-term risk of poor mental health. One hundred and seventy children (89 females) rated as hyperactive by their parents, and 88 non-hyperactive controls (48 females) were identified from a community sample of 4215 3-year-olds. Baseline data relating to behavioral/emotional problems and background characteristics were collected. Follow-up mental health and functional impairment outcomes were collected between 14 and 25 years of age. At age 3 years, males and females in the hyperactive group had similarly raised levels of hyperactivity and other behavior problems. In adolescence/young adulthood, these individuals showed elevated symptoms of ADHD, conduct disorder, mood disorder, anxiety and autism, as well as functional impairment. Preschool hyperactivity was strongly predictive of poor adolescent/adult outcomes for males across domains with effects being specifically driven by hyperactivity. For females, the effects of preschool hyperactivity were smaller and dropped to non-significant levels when other preschool problems were taken into account. Environmental risk factors also differed between the sexes, although these may also have been mediated by genetic risk. In conclusion, these results demonstrate marked sex differences in preschool predictors of later adolescent/adult mental health problems. Future research should include a measure of preschool inattention as well as hyperactivity. The findings highlight the potential value of tailored approaches to early identification strategies.


Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study.
This longitudinal study investigated survival, risk factors and causes of death in the multicentre ItinérAIR-Sclérodermie cohort of patients with SSc without severe pulmonary fibrosis or severe left heart disease at baseline. At 3-year follow-up, vital status was obtained from investigators or French national death records. Causes of death were classified as SSc-related or otherwise. Data were censored at 37 months, time of death or loss to follow-up, whichever was earlier. Survival was estimated using the Kaplan-Meier method. Multivariate survival analyses were conducted using the Cox model. In total, 546 patients were followed for a median duration of 37 months, representing 1547 patient-years. At baseline, the majority of patients were female, with lcSSc, mean age 54.9 +/- 13.0 years and mean duration of SSc of 8.8 +/- 8.1 years. In total, 47 patients died, giving a 3-year survival of 91.1% and cumulative mortality of 3.04 deaths per 100 patient-years; 17 deaths (32.2%) resulted from pulmonary arterial hypertension (PAH) and eight (17.1%) from cancer. Of the 47 patients with PAH at baseline, 20 died during follow-up, giving a 3-year survival of 56.3%. In a multivariate analysis, PAH [hazard ratio (HR) 7.246], age at first symptom (HR 1.052), duration of SSc (HR 1.047 per year) and Rodnan skin score (per one point) (HR 1.045) were associated with increased mortality. This 3-year study observed survival and mortality estimates that were comparable with previous reports. PAH increased the HR for mortality in patients with SSc, justifying yearly echocardiographic screening.


Electric motor assisted bicycle as an aerobic exercise machine.
The goal of this study is to maintain a continuous level of exercise intensity around the aerobic threshold (AT) during riding on an electric motor assisted bicycle using a new control system of electrical motor assistance which uses the efficient pedaling rate of popular bicycles. Five male subjects participated in the experiment, and the oxygen uptake was measured during cycling exercise using this new pedaling rate control system of electrical motor assistance, which could maintain the pedaling rate within a specific range, similar to that in previous type of electrically assisted bicycles. Results showed that this new pedaling rate control system at 65 rpm ensured continuous aerobic exercise intensity around the AT in two subjects, and this intensity level was higher than that observed in previous type. However, certain subjects were unable to maintain the expected exercise intensity because of their particular cycling preferences such as the pedaling rate. It is necessary to adjust the specific pedaling rate range of the electrical motor assist control according to the preferred pedaling rate, so that this system becomes applicable to anyone who want continuous aerobic exercise.


Sympathetic regulation of blood pressure in normotension and hypertension: when sex matters.
What is the topic of this review? Hypertension is a major problem in Western society. Risk of hypertension increases with age, especially in women, who have lower risk compared with men until menopause. This review outlines the sex differences in the sympathetic control of blood pressure and how these mechanisms change with age. What advances does it highlight? It has recently been recognized that men and women regulate blood pressure by different physiological mechanisms. This is important for both the understanding and the clinical management of individual patients with hypertension. This review summarizes recent advances in understanding how the regulation of blood pressure in hypertension by the sympathetic nervous system differs between men and women. The sympathetic nervous system has a central role in the regulation of arterial blood pressure (BP) and in the development of hypertension in humans. Recent evidence points to differences between the sexes in the integrative mechanisms by which BP is controlled, suggesting that the development of hypertension may follow distinct pathways in women compared with men. An important aspect of sympathetic control of BP is its substantial interindividual variability. In healthy young men, the variability in sympathetic nerve activity (SNA) is balanced by variability in cardiac output and vascular adrenergic responses, such that BP remains similar, and normal, across a severalfold range of resting SNA values. In young women, variability in resting SNA is similar to that seen in men, but the 'balancing' mechanisms are strikingly different; women exhibit greater β-adrenergic vasodilatation compared with men, which minimizes the pressor effects of a given level of SNA. Ageing is associated with increased SNA and a loss of the balancing factors seen in younger people, leading to an increased risk of hypertension in older people. Loss of oestrogen with menopause in women appears to be linked mechanistically with the decrease in β-adrenergic vasodilatation and the increased risk of hypertension in older women. Other important factors contributing to hypertension via sympathetic mechanisms are obesity and arterial stiffening, both of which increase with ageing. We conclude with a discussion of important areas in which more work is needed to understand and manage appropriately the sex-specific mechanisms in the development and maintenance of hypertension.


Propagation of flat-topped multi-Gaussian laser beams.
The multi-Gaussian beam shape is proposed as a model for aperture functions and laser beam profiles that have a nearly flat top but whose sides decrease continuously. Beams and apertures of this type represent a simple, elegant, and intuitive alternative to super-Gaussian beams, which are important in a number of applications such as laser resonator design. Analytical formulas are developed for the propagation of these beams through free space and optical systems representable by ABCD matrices.


Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease.
Despite the recent launch of tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox (CPX) or its olamine salt (CPX-O) is contained in a number of commercially available antifungal agents. CPX is also reported to possess anticancer activity. Several mechanisms of action have been proposed, including chelation of iron and inhibition of iron-dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human PKD cyst-lining epithelial cells cultured in a 3D collagen matrix. To assess the in vivo role of CPX-O, we treated PKD mice with CPX-O. CPX-O reduced the kidney-to-body weight ratios of PKD mice. The CPX-O treatment was also associated with decreased cell proliferation, decreased cystic area, and improved renal function. Ferritin levels were markedly elevated in cystic kidneys of PKD mice, and CPX-O treatment reduced renal ferritin levels. The reduction in ferritin was associated with increased ferritinophagy marker nuclear receptor coactivator 4, which reversed upon CPX-O treatment in PKD mice. Interestingly, these effects on ferritin appeared independent of iron. These data suggest that CPX-O can induce ferritin degradation via ferritinophagy, which is associated with decreased cyst growth progression in PKD mice. Most importantly these data indicate that CPX-O has the potential to treat autosomal dominant PKD.


An analysis of radiation necrosis of the central nervous system treated with bevacizumab.
Radiation necrosis is a devastating complication following radiation to the central nervous system. The purpose of this study was to perform a comprehensive analysis of cases in the literature using bevacizumab, a monoclonal antibody against vascular endothelial growth factor, as treatment for radiation necrosis. A MEDLINE/PubMed search of articles about the use of bevacizumab for radionecrosis treatment yielded 16 studies published between 2007 and 2012. Data was summarized according to patient characteristics, treatment received and outcomes measured. A total of 71 unique cases were identified that met the inclusion criteria. The median age at the time of treatment with bevacizumab was 47 years. The most common tumors treated were glioblastoma (31 %), anaplastic glioma (14 %), and metastatic brain tumors (15 %). The median time from ending radiotherapy to starting treatment with bevacizumab was 11 months and the median follow up time after bevacizumab treatment was 8 months. The median number of cycles of bevacizumab was administered was 4, and the median dosage of bevacizumab was 7.5 mg/kg. The median time elapsed between cycles of bevacizumab was 2 weeks. Overall, pre and post treatment imaging revealed a median decrease in T1 contrast enhancement of 63 %, and a 59 % median decrease in T2/FLAIR signal abnormality. Treatment with bevacizumab resulted in a significant radiographic response for patients with radionecrosis. The median dosage of bevacizumab of 7.5 mg/kg for four cycles every 2 weeks should be considered as a treatment option in this patient population.


QT Interval Length in Elderly Prostatic Cancer Patients on Anti-Testosterone Treatment.
Background: QT segment prolongation is a high risk factor for fatal arrhythmias. Several studies have indicated a possible relation between low testosterone levels and QT interval prolongation. To compare the QT interval length in elderly patients with prostate carcinoma who were on anti-testosterone treatment and those who were not. We screened the electrocardiograms (ECGs) of 100 prostate cancer patients divided into two groups: 50 patients on anti-testosterone drug treatment and 50 patients not. QT interval length was measured according to the accepted methods. The mean QTc 12 leads in the entire group was 0.45 ± 0.04 sec, which is close to the upper limit. Mean QTc was actually longer in the control group and there was no QTc difference between the groups after adjustment for possible confounders. Prolonged QTc 12-lead ECG (48% in treated and 54% in non-treated) and lead L2 QT interval (50% in treated and 56% in non-treated) did not differ significantly between the groups. The analysis of QTc 12-lead ECG indicated no significant effects of anti-testosterone drug treatment. Only the use of furosemide was associated with QT prolongation. The results of this preliminary study do not support our initial concern of an alarmingly prolonged QT interval in the anti-testosterone treated group. However, further prospectively designed studies are needed. In the meanwhile we call for a close follow-up of the QT interval length in patients receiving anti-testosterone treatment.


A gene-by-gene population genomics platform: de novo assembly, annotation and genealogical analysis of 108 representative Neisseria meningitidis genomes.
Highly parallel, 'second generation' sequencing technologies have rapidly expanded the number of bacterial whole genome sequences available for study, permitting the emergence of the discipline of population genomics. Most of these data are publically available as unassembled short-read sequence files that require extensive processing before they can be used for analysis. The provision of data in a uniform format, which can be easily assessed for quality, linked to provenance and phenotype and used for analysis, is therefore necessary. The performance of de novo short-read assembly followed by automatic annotation using the pubMLST.org Neisseria database was assessed and evaluated for 108 diverse, representative, and well-characterised Neisseria meningitidis isolates. High-quality sequences were obtained for >99% of known meningococcal genes among the de novo assembled genomes and four resequenced genomes and less than 1% of reassembled genes had sequence discrepancies or misassembled sequences. A core genome of 1600 loci, present in at least 95% of the population, was determined using the Genome Comparator tool. Genealogical relationships compatible with, but at a higher resolution than, those identified by multilocus sequence typing were obtained with core genome comparisons and ribosomal protein gene analysis which revealed a genomic structure for a number of previously described phenotypes. This unified system for cataloguing Neisseria genetic variation in the genome was implemented and used for multiple analyses and the data are publically available in the PubMLST Neisseria database. The de novo assembly, combined with automated gene-by-gene annotation, generates high quality draft genomes in which the majority of protein-encoding genes are present with high accuracy. The approach catalogues diversity efficiently, permits analyses of a single genome or multiple genome comparisons, and is a practical approach to interpreting WGS data for large bacterial population samples. The method generates novel insights into the biology of the meningococcus and improves our understanding of the whole population structure, not just disease causing lineages.


Korean Red Ginseng water extract arrests growth of xenografted lymphoma cells.
Although numerous studies of the anticancer activities of Korean Red Ginseng (KRG) have been performed, the therapeutic effect of KRG on leukemia has not been fully elucidated. In this study, we investigated the antileukemia activities of KRG and its cellular and molecular mechanisms. An established leukemia tumor model induced by xenografted T cell lymphoma (RMA cells) was used to test the therapeutic activity of KRG water extract (KRG-WE). Direct cytotoxic activity of KRG-WE was confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The immunomodulatory activities of KRG-WE were verified by immunohistochemistry, nitric oxide production assay. The inhibitory effect of KRG-WE on cell survival signaling was also examined. Orally administered KRG-WE reduced the sizes of tumor masses. Levels of apoptosis regulatory enzymes and cleaved forms of caspases-3 and -8 were increased by this extract. In addition, expression of matrix metalloproteinase-9, a metastasis regulatory enzyme, was decreased by KRG-WE treatment. The proportion of CD11c+ cells was remarkably increased in the KRG-treated group compared to the control group. However, KRG-WE did not show significant direct cytotoxicity against RMA cells. Our results strongly suggest that the KRG might have antileukemia activity through CD11c+ cell-mediated antitumor immunity.


The effect of induced forelimb lameness on thoracolumbar kinematics during treadmill locomotion.
Lameness has often been suggested to result in altered movement of the back, but there are no detailed studies describing such a relationship in quantitative terms. To quantify the effect of induced subtle forelimb lameness on thoracolumbar kinematics in the horse. Kinematics of 6 riding horses was measured at walk and at trot on a treadmill before and after the induction of reversible forelimb lameness grade 2 (AAEP scale 1-5). Ground reaction forces (GRF) for individual limbs were calculated from kinematics. The horses significantly unloaded the painful limb by 11.5% at trot, while unloading at walk was not significant. The overall flexion-extension range of back motion decreased on average by 0.2 degrees at walk and increased by 3.3 degrees at trot (P<0.05). Changes in angular motion patterns of vertebral joints were noted only at trot, with an increase in flexion of 0.9 degrees at T10 (i.e. angle between T6, T10 and T13) during the stance phase of the sound diagonal and an increase in extension of the thoracolumbar area during stance of the lame diagonal (0.7degrees at T13, 0.8 degres at T17, 0.5 degres at L1, 0.4 degrees at L3 and 0.3 degrees at L5) (P<0.05). Lameness further caused a lateral bending of the cranial thoracic vertebral column towards the lame side (1.3 degrees at T10 and 0.9 degrees at T13) (P<0.05) during stance of the lame diagonal. Both range of motion and vertebral angular motion patterns are affected by subtle forelimb lameness. At walk, the effect is minimal, at trot the horses increased the vertebral range of motion and changed the pattern of thoracolumbar motion in the sagittal and horizontal planes, presumably in an attempt to move the centre of gravity away from the lame side and reduce the force on the affected limb. Subtle forelimb lameness affects thoracolumbar kinematics. Future studies should aim at elucidating whether the altered movement patterns lead to back and/or neck dysfunction in the case of chronic lameness.


High Frequency Spinal Cord Stimulation for Complex Regional Pain Syndrome: A Case Report.
Complex regional pain syndrome (CRPS) is a chronic, debilitating, neuropathic pain condition which is often misdiagnosed, difficult to manage, and lacks proven methods for remission. Most available methods provide some relief to a small percentage of patients. Recent FDA approval and superiority of the Nevro Senza 10-kHz high frequency (HF10) spinal cord stimulation (SCS) therapy over traditional low-frequency spinal cord stimulation for treatment of chronic back and leg pain may provide a new interventional therapeutic option for patients suffering from CRPS. We provide a case report of a 53-year-old Caucasian woman who suffered with CRPS in the right knee and thigh for over 7 years. Implantation of the HF10 device provided over 75% relief of pain, erythema, heat, swelling, and tissue necrosis to the entire region within 1 month of treatment. Because the HP10 therapy provides pain relief without paresthesia typical of traditional low-frequency, this system may provide relief for patients suffering from chronic pain.Key words: Complex regional pain syndrome, spinal cord stimulation, Nevro Senza HF10, erythema, knee, thigh.


[National health index].
Recently, a booklet presenting a national health index was published by the Israel Medical Association (IMA]. The publication of an objective tool for the measurement and evaluation of the health of the population in Israel and the assessment of the healthcare system is an important and valued action. A tool of this sort, which analyzes the situation of the healthcare system relative to that of other countries in the world and allows for international comparisons-- is necessary for the promotion of a public debate on health and medical issues in Israel and serves as a useful tool for decision-makers. In this work, certain difficulties are delineated regarding the choice of factors and variables that comprise the national health index published--specifically in the significance accorded to the selected parameters and methodology upon which the Index was determined. The creation of a suitable national health index requires additional work necessitating, first and foremost, the integration of a methodology that correctly reflects the state of health and healthcare in Israel. An international comparison is also required--one which will be evaluated based on the determined methodology and the chosen parameters. The detailing of these issues serves to ensure a reliable and quality database, so that among other uses, it may serve its important purpose as a national health index that determines short and long-term goals, for the setting of priorities and for the tracking of trends and directions of development. Thereby, it would contribute to the improvement and promotion of the health of the residents of the State of Israel.


Induction of long-term potentiation is associated with major ultrastructural changes of activated synapses.
Long-term potentiation (LTP), an increase in synaptic efficacy believed to underlie learning and memory mechanisms, has been proposed to involve structural modifications of synapses. Precise identification of the morphological changes associated with LTP has however been hindered by the difficulty in distinguishing potentiated or activated from nonstimulated synapses. Here we used a cytochemical method that allowed detection in CA1 hippocampus at the electron microscopy level of a stimulation-specific, D-AP5-sensitive accumulation of calcium in postsynaptic spines and presynaptic terminals following application of high-frequency trains. Morphometric analyses carried out 30-40 min after LTP induction revealed dramatic ultrastructural differences between labeled and nonlabeled synapses. The majority of labeled synapses (60%) exhibited perforated postsynaptic densities, whereas this proportion was only 20% in nonlabeled synaptic contacts. Labeled synaptic profiles were also characterized by a larger apposition zone between pre- and postsynaptic structures, longer postsynaptic densities, and enlarged spine profiles. These results add strong support to the idea that ultrastructural modifications and specifically an increase in perforated synapses are associated with LTP induction in field CA1 of hippocampus and they suggest that a majority of activated contacts may exhibit such changes.


Sensitive and Direct Detection of Heterodera filipjevi in Soil and Wheat Roots by Species-Specific SCAR-PCR Assays.
Cereal cyst nematodes are the most important plant-parasitic nematodes on cereal crops in wheat producing areas of the world. Heterodera filipjevi was first reported in China in 2010. In this study, species-specific sequence characterized amplified region-polymerase chain reaction (SCAR-PCR) assays for detection and identification of H. filipjevi from infected wheat roots and soil were developed. The species-specific primers were designed according to the randomly amplified polymorphic DNA (RAPD) markers amplified with random primer OPK16. A 646-bp specific fragment of sequence was generated, which characterized amplified regions in H. filipjevi. The detection limitation of the PCR assay was as low as 0.125 μl second-stage juvenile (J2) lysate, 3.9 × 10-3 μl adult female lysate, and 10-3 μl cyst lysate. The method was able to detect the various stages (J2, J3, J4, and female) of H. filipjevi, and a single of nematode in 0.5 g of soil. H. filipjevi was detected by the method in two of six field samples, and one of those samples contained a mixed population of H. filipjevi and H. avenae. This study is the first to provide a definitive diagnostic assay for H. filipjevi in wheat roots and soil.


Implementation of a complex intervention to improve participation in older people with joint contractures living in nursing homes: a process evaluation of a cluster-randomised pilot trial.
Joint contractures in frail older people are associated with serious restrictions in participation. We developed the Participation Enabling CAre in Nursing (PECAN) intervention, a complex intervention to enable nurses to promote participation in nursing home residents with joint contractures. The aim of this study was to examine the feasibility of the implementation strategy and to identify enablers and barriers for a successful implementation. The implementation of PECAN was investigated in a 6-month pilot cluster-randomised controlled trial (c-RCT). As a key component of the implementation strategy, nominated nurses were trained as facilitators in a one-day workshop and supported by peer-mentoring (visit, telephone counselling). A mixed-methods approach was conducted in conjunction with the pilot trial and guided by a framework for process evaluations of c-RCTs. Data were collected using standardised questionnaires (nursing staff), documentation forms, problem-centred qualitative interviews (facilitators, therapists, social workers, relatives, peer-mentors), and a group discussion (facilitators). A set of predefined criteria on the nursing home level was examined. Quantitative data were analysed using descriptive statistics. Qualitative data were analysed using directed content analysis. Seven nursing homes (n = 4 intervention groups, n = 3 control groups) in two regions of Germany took part in the study. Facilitators responded well to the qualification measures (workshop participation: 14/14; workshop rating: "good"; peer-mentor visit participation: 10/14). The usage of peer-mentoring via telephone varied (one to seven contacts per nursing home). Our implementation strategy was not successful in connection with supplying the intervention to all the nurses. The clear commitment of the entire nursing home and the respect for the expertise of different healthcare professionals were emphasised as enablers, whereas a lack of impact on organisational conditions and routines and a lack of time and staff competence were mentioned as barriers. The PECAN intervention was delivered as planned to the facilitators but was unable to produce comprehensive changes in the nursing homes and subsequently for the residents. Strategies to systematically include the management and the nursing team from the beginning are needed to support the facilitators during implementation in the main trial. German clinical trials register, DRKS00010037 . Registered 12 February 2016.


SOCIAL SUPPORT DISPARITIES FOR CAREGIVERS OF AIDS-ORPHANED CHILDREN IN SOUTH AFRICA.
Drawing upon a sample of 1,599 adults caring for children in HIV-endemic Umlazi Township in South Africa, this cross-sectional survey investigated whether perceived social support varied among caregivers of AIDS-orphaned children (n=359) as compared to caregivers of children orphaned by other causes (n=171) and caregivers of non-orphaned children (n=1,069). Results of multivariate linear regressions indicate that caregivers of AIDS-orphaned children reported significantly lower levels of social support compared to caregivers of other-orphaned children and non-orphaned children independent of socio-demographic covariates. Caregivers of other-orphaned and non-orphaned children reported similar levels of social support. In terms of sources of support, all caregivers were more likely to draw support from family and significant others rather than friends. These findings indicate a need to develop interventions that can increase levels of social support for caregivers of AIDS-orphaned children, particularly networks that include friends and significant others.


Functional characterization of a novel PBX1 de novo missense variant identified in a patient with syndromic congenital heart disease.
Pre-B cell leukemia factor 1 (PBX1) is an essential developmental transcription factor, mutations in which have recently been associated with CAKUTHED syndrome, characterized by multiple congenital defects including congenital heart disease (CHD). During analysis of a whole-exome-sequenced cohort of heterogeneous CHD patients, we identified a de novo missense variant, PBX1:c.551G>C p.R184P, in a patient with tetralogy of Fallot with absent pulmonary valve and extra-cardiac phenotypes. Functional analysis of this variant by creating a CRISPR-Cas9 gene-edited mouse model revealed multiple congenital anomalies. Congenital heart defects (persistent truncus arteriosus and ventricular septal defect), hypoplastic lungs, hypoplastic/ectopic kidneys, aplastic adrenal glands and spleen, as well as atretic trachea and palate defects were observed in the homozygous mutant embryos at multiple stages of development. We also observed developmental anomalies in a proportion of heterozygous embryos, suggestive of a dominant mode of inheritance. Analysis of gene expression and protein levels revealed that although Pbx1 transcripts are higher in homozygotes, amounts of PBX1 protein are significantly decreased. Here, we have presented the first functional model of a missense PBX1 variant and provided strong evidence that p.R184P is disease-causal. Our findings also expand the phenotypic spectrum associated with pathogenic PBX1 variants in both humans and mice.


Establishment of primary stroke centers: a survey of physician attitudes and hospital resources.
To survey US physicians involved in acute stroke care to determine the proportion of hospitals that currently meet the recommended Brain Attack Coalition (BAC) criteria for Primary Stroke Centers (PSC) and obtain opinions regarding the value of stroke centers. A survey regarding the BAC guidelines for the establishment of stroke centers was mailed to 3,245 US neurologists, neurosurgeons, and emergency physicians. A total of 1,032 responses were received. Seventy-nine percent (range by specialty 58 to 98%) of respondents believed there was a need for stroke centers. If formal stroke center designation were established, 81% (range 72 to 90%) would like their hospital to become a PSC. Although 77% of respondents believed that their hospital currently met recommended criteria for a PSC, only 7% actually meet all recommended elements. However, 44% of hospitals already provide most acute stroke services. The BAC criteria most frequently lacking were continuing medical education for professional stroke center staff, stroke training for emergency department staff, formal establishment of a stroke unit, and designation of a stroke center director. The majority of emergency medicine and neuroscience physician respondents involved in acute stroke care support the designation of primary stroke centers. Although respondents globally overestimated the extent to which their facilities currently meet BAC recommended criteria for PSC, detailed responses suggested that over 40% of hospitals possess substantial existing acute stroke care resources and are poised to function as PSC with modest additional administrative and financial commitment.


Effectiveness of the NAMI Homefront Program for Military and Veteran Families: In-Person and Online Benefits.
This study aimed to evaluate the effectiveness of Homefront, a six-session, peer-taught family education program by the National Alliance on Mental Illness (NAMI), delivered in person or online, for families or support persons of military service members or of veterans with mental illness. Program participants completed online surveys at baseline, at the end of the program (postprogram), and at 3-month follow-up, which measured subjective empowerment, burden, coping, psychological distress, family functioning, experience of caregiving, and knowledge of mental illness. A mixed-effects model examined change over time. A total of 119 individuals (in person, N=63 [53%]; online, N=56 [47%]) enrolled. Participants showed statistically significant improvement on all dimensions between baseline, postprogram, and follow-up, except for subjective burden, which improved between baseline and follow-up. Results for in-person and online formats did not differ. The six-session NAMI Homefront program was associated with benefits for military and veteran family members and support persons.


Temporal sequence of the bidirectional relationship between hyperglycemia and periodontal disease: a community-based study of 5,885 Taiwanese aged 35-44 years (KCIS No. 32).
The relationship between hyperglycemia (including diabetes) and periodontal disease (PD) has been noted previously, but its temporal sequence in the same study based on a population-based study has been barely addressed. Our study sought to clarify temporal bidirectional relationships between both diseases among Taiwanese aged 35-44 years. A prospective follow-up cohort study was designed by following over time the two normal cohorts (PD-free or hyperglycemia-free) derived from 5,885 subjects aged 35-44 years who were periodically attending a screening program. We ascertained both incident cases of PD (defined by Community Periodontal Index score ≧ 3) and hyperglycemia [fasting plasma glucose (FPG) ≧100 mg/dL] or type 2 diabetes (FPG ≧ 126 mg/dL) with 5-year follow-up. Cox proportional hazards regression model was used to assess the effect of PD on hyperglycemia and vice versa with adjustment for other confounding factors. Participants with PD presented a 33 % increase in their risk of incident hyperglycemia (including diabetes) [adjusted hazard ratio (aHR) = 1.33 (95 % CI 1.09-1.63)] after controlling for potential confounding factors. Conversely, prediabetes and type 2 diabetes mellitus led to a significant elevated risk for PD [aHR = 1.25 (95 % CI 1.00-1.57) and aHR = 1.95 (95 % CI 1.22-3.13)] after adjustment for other confounding factors. In conclusion, a significant bidirectional relationships was found between hyperglycemia and PD, suggesting that both diseases may share common latent traits and pathways that are worthy of being further elucidated by continuing a long-term follow-up of this cohort.


Role of curcumin and the inhibition of NF-kappaB in the onset of chemotherapy-induced mucosal barrier injury.
The inhibition of nuclear factor kappa B (NF-kappaB) by, for instance, curcumin is becoming an important new approach in combination with chemotherapy or irradiation for the treatment of a variety of cancers including haematological malignancies. A dose-limiting side effect of anticancer therapy in the gastrointestinal tract is mucosal barrier injury. It is hypothesised that mucosal barrier injury is initiated and amplified by proinflammatory-and NF-kappaB-regulated mediators. Therefore, the effect of NF-kappaB inhibition was studied in the onset of mucosal barrier injury. In response to cytostatic drug treatment (arabinoside cytosine (Ara-C) and methotrexate (MTX)), NF-kappaB was activated in intestinal epithelial cells (IEC-6) resulting in an NF-kappaB-related induction of tumour necrosis factor alpha and monocyte chemoattractant protein-1. NF-kappaB inhibition increased the susceptibility of IEC-6 cells to Ara-C as well as MTX-induced cell death when obtained by the addition of caffeic acid phenethyl ester (CAPE), but not using curcumin. In an animal model for MTX-induced mucosal barrier injury, the induction of NF-kappaB-related cytokines and chemokines was detected upon treatment with MTX. Despite increased susceptibility shown in vitro, the inhibition of NF-kappaB resulted in a partial amelioration of villous atrophy normally seen in the small intestine upon MTX treatment. These results show that the inhibition of NF-kappaB does not increase intestinal side effects of the anticancer treatment, suggesting a safe use of curcumin and CAPE in combination with anticancer treatment.


Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis.
TGF-β is a pleiotropic cytokine that accumulates during kidney injuries, resulting in various renal diseases. We have reported previously that TGF-β1 induces the selective up-regulation of mitochondrial Nox4, playing critical roles in podocyte apoptosis. Here we investigated the regulatory mechanism of Nox4 up-regulation by mTORC1 activation on TGF-β1-induced apoptosis in immortalized podocytes. TGF-β1 treatment markedly increased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4EBP1. Blocking TGF-β receptor I with SB431542 completely blunted the phosphorylation of mTOR, p70S6K, and 4EBP1. Transient adenoviral overexpression of mTOR-WT and constitutively active mTORΔ augmented TGF-β1-treated Nox4 expression, reactive oxygen species (ROS) generation, and apoptosis, whereas mTOR kinase-dead suppressed the above changes. In addition, knockdown of mTOR mimicked the effect of mTOR-KD. Inhibition of mTORC1 by low-dose rapamycin or knockdown of p70S6K protected podocytes through attenuation of Nox4 expression and subsequent oxidative stress-induced apoptosis by TGF-β1. Pharmacological inhibition of the MEK-ERK cascade, but not the PI3K-Akt-TSC2 pathway, abolished TGF-β1-induced mTOR activation. Inhibition of either ERK1/2 or mTORC1 did not reduce the TGF-β1-stimulated increase in Nox4 mRNA level but significantly inhibited total Nox4 expression, ROS generation, and apoptosis induced by TGF-β1. Moreover, double knockdown of Smad2 and 3 or only Smad4 completely suppressed TGF-β1-induced ERK1/2-mTORactivation. Our data suggest that TGF-β1 increases translation of Nox4 through the Smad-ERK1/2-mTORC1 axis, which is independent of transcriptional regulation. Activation of this pathway plays a crucial role in ROS generation and mitochondrial dysfunction, leading to podocyte apoptosis. Therefore, inhibition of the ERK1/2-mTORC1 pathway could be a potential therapeutic and preventive target in proteinuric and chronic kidney diseases.


Fixational eye movements in the earliest stage of metazoan evolution.
All known photoreceptor cells adapt to constant light stimuli, fading the retinal image when exposed to an immobile visual scene. Counter strategies are therefore necessary to prevent blindness, and in mammals this is accomplished by fixational eye movements. Cubomedusae occupy a key position for understanding the evolution of complex visual systems and their eyes are assumedly subject to the same adaptive problems as the vertebrate eye, but lack motor control of their visual system. The morphology of the visual system of cubomedusae ensures a constant orientation of the eyes and a clear division of the visual field, but thereby also a constant retinal image when exposed to stationary visual scenes. Here we show that bell contractions used for swimming in the medusae refresh the retinal image in the upper lens eye of Tripedalia cystophora. This strongly suggests that strategies comparable to fixational eye movements have evolved at the earliest metazoan stage to compensate for the intrinsic property of the photoreceptors. Since the timing and amplitude of the rhopalial movements concur with the spatial and temporal resolution of the eye it circumvents the need for post processing in the central nervous system to remove image blur.


Restorative effects of platelet derived growth factor-BB in rodent models of Parkinson's disease.
Parkinson's disease is characterized by motor deficits caused by loss of midbrain dopaminergic neurons. Neurotrophic factors and cell transplantation have partially restored function in models of Parkinson's disease, but have had limited effects in humans. Here we show that intracerebroventricular administration of platelet-derived growth factor-BB can offer an alternative strategy to restore function in Parkinson's disease; In animal models of nigrostriatal injury, a two weeks treatment with platelet-derived growth factor-BB resulted in long-lasting restoration of striatal dopamine transporter binding sites and expression of nigral tyrosine hydroxylase. It also normalized amphetamine-induced rotational behavior in 6-hydroxydopamine lesioned rats. Platelet-derived growth factor-BB promoted proliferation of neural progenitor cells in the subventricular zone. The effects on dopaminergic neurons and functional recovery could be blocked by co-infusion with a proliferation inhibitor, indicating a link between the proliferative and anti-parkinsonian effects. Based on the current data, we consider platelet-derived growth factor-BB a clinical candidate drug for treatment of Parkinson's disease.


Morphological descriptions on the larvae of Hypopygiopsis fumipennis (Walker, 1856) (Diptera: Calliphoridae).
The study on biodiversity of forensically important Diptera in the tropical rain forest in Malaysia is scarce. Thus, a preliminary survey was conducted at a jungle fringe near Kampung Bahagia Bukit Lagong, Sungai Buloh, Selangor. A rat carcass was offered to attract carrion flies and we collected an adult female calliphorid, Hypopygiopsis fumipennis (Walker, 1856) during the fresh stage of carcass decomposition. The female fly was allowed to oviposit on chicken liver in a container and the resulting larvae were reared to the adult stage. Along the developmental process, several individuals from each instar were collected and preserved in 70% ethanol and then processed on the slides. We recorded the duration of development for each instar and described its larval features for the first time. The third instar larvae of H. fumipennis showed accessory oral sclerite present, anterior spiracle with 13-15 papillae, intersegmental spines mostly unicuspid with pointed end, and posterior spiracles heavily sclerotized with inter-slit projections. Some larval differences between H. fumipennis and Hypopygiopsis violacea were noted.


Opportunistic screening for alcohol use disorders in primary care: comparative study.
To evaluate the efficacy and relative costs of different screening methods for the identification of alcohol use disorders in an opportunistic screening programme in primary care in the United Kingdom. Comparative study. Six general practices in south Wales. 194 male primary care attendees aged 18 or over who completed an alcohol use disorders identification test (AUDIT) questionnaire. Scores on alcohol use disorders identification test and measures of gamma-glutamyltransferase, aspartate aminotransferase, per cent carbohydrate deficient transferrin, and erythrocyte mean cell volume. Hazardous alcohol consumption, weekly binge consumption, and monthly binge consumption were ascertained using the time line follow back method over the previous 180 days. Alcohol dependence was determined using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Unit costs were established from published resource references and from actual costs of analysing the biochemical tests. A significant correlation was observed be alcohol consumption and score on the alcohol use disorders identification test (Pearson's correlation coefficient r = 0.74) and measures of gamma-glutamyltransferase (r = 0.20) and per cent carbohydrate deficient transferrin (r = 0.36) but not aspartate aminotransferase (r = 0.08) or erythrocyte mean cell volume (r = 0.02). The alcohol use disorders identification test exhibited significantly higher sensitivity, specificity, and positive predictive value than all of the biochemical markers for hazardous consumption (69%, 98%, and 95%), weekly binge consumption (75%, 90%, and 71%), monthly binge consumption (66%, 97%, and 91%), and alcohol dependence (84%, 83%, and 41%). The questionnaire was also more cost efficient, with a lower cost per true positive for all consumption outcomes. The alcohol use disorders identification test questionnaire is an efficient and cost efficient diagnostic tool for routine screening for alcohol use disorders in primary care.


Social and economic burden of walking and mobility problems in multiple sclerosis.
Multiple sclerosis (MS) is a chronic progressive neurological disease and the majority of patients will experience some degree of impaired mobility. We evaluated the prevalence, severity and burden of walking and mobility problems (WMPs) in 5 European countries. This was a cross-sectional, patient record-based study involving 340 neurologists who completed detailed patient record forms (PRF) for patients (>18 years) attending their clinic with MS. Patients were also invited to complete a questionnaire (PSC). Information collected included demographics, disease characteristics, work productivity, quality of life (QoL; EuroQol-5D and Hamburg Quality of Life Questionnaire Multiple Sclerosis [HAQUAMS]) and mobility (subjective patient-reported and objectively measured using the timed 25 foot walk test [T25FW]). Relationships between WMPs and disease and other characteristics were examined using Chi square tests. Analysis of variance was used to examine relationships between mobility measures and work productivity. Records were available for 3572 patients of whom 2171 also completed a PSC. WMPs were regarded as the most bothersome symptom by almost half of patients who responded (43%; 291/683). There was a clear, independent and strong directional relationship between severity of WMPs (subjective and objective) and healthcare resource utilisation. Patients with longer T25FW times (indicating greater walking impairment) were significantly more likely to require additional caregiver support (p < 0.0001), visit a variety of healthcare professionals including their primary care physicians (p = 0.0044) and require more long-term non-disease modifying drugs (p = 0.0001). A similar pattern was observed when subjective reporting of the severity of WMPs was considered. Work productivity was also markedly impacted by the presence of WMPs with fewer patients working full time and a reduction in weekly working hours as T25FW times and the subjective severity of WMPs increased. In Europe, WMPs in MS represent a considerable personal and social burden both financially and in terms of quality of life. Interventions to improve mobility could have significant benefits for patients and society as a whole.


Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma.
To evaluate long-term progression-free survival and overall survival, quality of life, and cognitive function in primary central nervous system lymphoma after systemic and intraventricular chemotherapy without radiotherapy. A long-term follow-up was conducted on surviving primary central nervous system lymphoma patients having been enrolled in a pilot/phase II trial between September 1995 and December 2001. Initially, 65 patients (median age, 62 years) had been treated with systemic and intraventricular chemotherapy without radiotherapy. All living patients were contacted, and a neurological examination, comprehensive neuropsychological testing, quality-of-life assessment, and imaging were performed. Twenty-one of all 65 patients (32 %) and 17 of 30 patients 60 years or younger (57%), respectively, were still alive at median follow-up of 100 months (range, 77-149 months). Nineteen of 21 patients completed all investigations; 1 was lost to follow-up. In three patients, an exclusively extraneural relapse of a high-grade non-Hodgkin's lymphoma was diagnosed after 9, 31, and 40 months, respectively. All of them experienced complete remission to high dose. Neither late neurotoxicity nor compromise of quality of life was found in any of the patients examined. Primary polychemotherapy based on high-dose methotrexate (MTX) and cytarabine (Ara-C) is highly efficient in treatment of primary central nervous system lymphoma. About half of patients 60 years or younger can obviously be cured with this regimen without long-term neurotoxic sequelae or quality-of-life compromise.


Pesticide Health and Safety Challenges Facing Informal Sector Workers: A Case of Small-scale Agricultural Workers in Tanzania.
The Tanzania informal sector is growing fast, with precarious working conditions and particular hazards for women and children in agriculture. Hazardous agricultural chemicals including pesticides are mostly imported and have been used for many years. Despite the role played by pesticides in food security and vector control, these chemicals are responsible for acute and chronic illnesses among communities. The availability of obsolete persistent organic pesticides on the open market indicates existence of an inadequate regulatory system. People who get injured or ill in the agriculture sector in Tanzania receive health services in primary health care facilities where professionals have little or no knowledge of pesticides. We are presenting the pesticide health and safety challenges faced by small-scale farmers who fall in the informal sector. Achievements that have been made by the government and other players to reduce and prevent pesticide exposures and poisoning are also outlined.


Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer.
The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P < 0.001). Using specific thresholds, patients with > or = 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P < 0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.


Social influence and the collective dynamics of opinion formation.
Social influence is the process by which individuals adapt their opinion, revise their beliefs, or change their behavior as a result of social interactions with other people. In our strongly interconnected society, social influence plays a prominent role in many self-organized phenomena such as herding in cultural markets, the spread of ideas and innovations, and the amplification of fears during epidemics. Yet, the mechanisms of opinion formation remain poorly understood, and existing physics-based models lack systematic empirical validation. Here, we report two controlled experiments showing how participants answering factual questions revise their initial judgments after being exposed to the opinion and confidence level of others. Based on the observation of 59 experimental subjects exposed to peer-opinion for 15 different items, we draw an influence map that describes the strength of peer influence during interactions. A simple process model derived from our observations demonstrates how opinions in a group of interacting people can converge or split over repeated interactions. In particular, we identify two major attractors of opinion: (i) the expert effect, induced by the presence of a highly confident individual in the group, and (ii) the majority effect, caused by the presence of a critical mass of laypeople sharing similar opinions. Additional simulations reveal the existence of a tipping point at which one attractor will dominate over the other, driving collective opinion in a given direction. These findings have implications for understanding the mechanisms of public opinion formation and managing conflicting situations in which self-confident and better informed minorities challenge the views of a large uninformed majority.


Adenosine A(1) receptors regulate bone resorption in mice: adenosine A(1) receptor blockade or deletion increases bone density and prevents ovariectomy-induced bone loss in adenosine A(1) receptor-knockout mice.
Accelerated osteoclastic bone resorption plays a central role in the pathogenesis of osteoporosis and other bone diseases. Because identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and developing new treatments, we studied the effect of adenosine A(1) receptor blockade or deletion on bone density. The bone mineral density (BMD) in adenosine A(1) receptor-knockout (A(1)R-knockout) mice was analyzed by dual x-ray absorptiometry (DXA) scanning, and the trabecular and cortical bone volume was determined by microfocal computed tomography (micro-CT). The mice were ovariectomized or sham-operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analyzed by DXA scanning and micro-CT. A histologic examination of bones obtained from A(1)R-knockout and wild-type mice was carried out. Visualization of osteoblast function (bone formation) after tetracycline double-labeling was performed by fluorescence microscopy. Micro-CT analysis of bones from A(1)R-knockout mice showed significantly increased bone volume. Electron microscopy of bones from A(1)R-knockout mice showed the absence of ruffled borders of osteoclasts and osteoclast bone resorption. Immunohistologic analysis demonstrated that although osteoclasts were present in the A(1)R-knockout mice, they were smaller and often not associated with bone. No morphologic changes in osteoblasts were observed, and bone-labeling studies revealed no change in the bone formation rates in A(1)R-knockout mice. These results suggest that the adenosine A(1) receptor may be a useful target in treating diseases characterized by excessive bone turnover, such as osteoporosis and prosthetic joint loosening.


Variation in vector competence for dengue viruses does not depend on mosquito midgut binding affinity.
Dengue virus genotypes of Southeast Asian origin have been associated with higher virulence and transmission compared to other genotypes of serotype 2 (DEN-2). We tested the hypothesis that genetic differences in dengue viruses may result in differential binding to the midgut of the primary vector, Aedes aegypti, resulting in increased transmission or vectorial capacity. Two strains of each of the four DEN-2 genotypes (Southeast Asian, American, Indian, and West African) were tested to determine their binding affinity for mosquito midguts from two distinct populations (Tapachula, Chiapas, Mexico and McAllen, Texas, USA). Our previous studies demonstrated that Southeast Asian viruses disseminated up to 65-fold more rapidly in Ae. aegypti from Texas and were therefore more likely to be transmitted to humans. Results shown here demonstrate that viruses from all four genotypes bind to midguts at the same rate, in a titer-dependent manner. In addition, we show population differences when comparing binding affinity for DEN-2 between the Tapachula and McAllen mosquito colonies. If midgut binding potential is the same for all DEN-2 viruses, then viral replication differences in these tissues and throughout the mosquito can thus probably explain the significant differences in dissemination and vector competence. These conclusions differ from the established paradigms to explain mosquito barriers to infection, dissemination, and transmission.


Synthesis of novel and stable g-C3N4/N-doped SrTiO3 hybrid nanocomposites with improved photocurrent and photocatalytic activity under visible light irradiation.
Hybrid nanocomposites based on N-doped SrTiO3 nanoparticles wrapped in g-C3N4 nanosheets were successfully prepared by a facile and reproducible polymeric citrate and thermal exfoliation method. The results clearly indicated that the N-doped SrTiO3 nanoparticles are successfully wrapped in layers of the g-C3N4 nanosheets. The g-C3N4/N-doped SrTiO3 nanocomposites showed absorption edges at longer wavelengths compared with the pure g-C3N4 as well as N-doped SrTiO3. The hybrid nanocomposites exhibit an improved photocurrent response and photocatalytic activity under visible light irradiation. Interestingly, the hybrid nanocomposite possesses high photostability and reusability. Based on experimental results, the possible mechanism for prolonged lifetime of the photoinduced charge carrier was also discussed. The high performance of the g-C3N4/N-doped SrTiO3 photocatalysts is due to the synergic effect at the interface of g-C3N4 and N-doped SrTiO3 hetero/nanojunction including the high separation efficiency of the charge carrier, band energy matching and the suppressed recombination rate. Therefore, the hybrid photocatalyst could be of potential interest for water splitting and environmental remediation under natural sunlight.


Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer.
The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF-alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor-infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF-alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.


Management and attitudes toward patients with epilepsy in general practice: How far have we come in three decades?
Previous surveys of Australian primary care physicians' attitudes regarding epilepsy and persons with epilepsy (PWE), conducted 20-30 years ago, identified the need for further education in epilepsy care for frontline clinicians. This follow-up study of general practitioners (GPs) in Sydney was conducted to determine the degree of changes in knowledge, attitudes, and management of PWE, with the purpose of evaluating if there had been significant improvement during this period. A questionnaire, evaluating various aspects of epilepsy care, including investigations, preferred healthcare provider (HCP), and attitudes toward epilepsy was developed, largely based on the previous work, piloted, and completed by a representative sample of Sydney GPs. A total of 52 completed responses were received. Thirty-six out of 47 GPs (77%) chose neurologists as the most important HCP followed by the GP (9/47; 18.7%). Almost half of the GPs (25/51; 49%) mentioned that they never initiated antiepileptic medication (AEM) therapy by themselves yet half of these GPs would alter the neurologist's regimen, without necessitating referral back to that neurologist. Another 27% (14/51 GPs) rarely commenced AEM therapy. Six out of 50 GPs did not mention an electroencephalogram (EEG) as a routine investigation, and 21/50 did not mention magnetic resonance imaging (MRI) as routine for PWE. The five most commonly used AEMs, identified by at least 10% of respondents, were sodium valproate (42), carbamazepine (37), levetiracetam (31), lamotrigine (16), and phenytoin (15). Emotional, behavioral, and psychosocial issues were perceived to be more common among PWE; however, they could contribute equally well to society as people without epilepsy. The results of the study indicate a perceptual shift regarding GP's attitudes to epilepsy; however, there remain deficiencies in knowledge, particularly with regard to investigations and management. The study highlights the need for more formal training of GPs in caring for PWE.


Artemisinin-naphthoquine for treating uncomplicated Plasmodium falciparum malaria.
The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for treating people with Plasmodium falciparum malaria. Five combinations are currently recommended, all administered over three days. Artemisinin-naphthoquine is a new combination developed in China, which is being marketed as a one-day treatment. Although shorter treatment courses may improve adherence, the WHO recommends at least three days of the short-acting artemisinin component to eliminate 90% P. falciparum parasites in the bloodstream, before leaving the longer-acting partner drug to clear the remaining parasites. To evaluate the efficacy and safety of the artemisinin-naphthoquine combination for treating adults and children with uncomplicated P. falciparum malaria. We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; and LILACS up to January 2015. We also searched the metaRegister of Controlled Trials (mRCT) using 'malaria' and 'arte* OR dihydroarte*' as search terms. Randomized controlled trials comparing artemisinin-naphthoquine combinations with established WHO-recommended ACTs for the treatment of adults and children with uncomplicated malaria due to P. falciparum. Two review authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach. Four trials, enrolling 740 adults and children, met the inclusion criteria. Artemisinin-naphthoquine was administered as a single dose (two trials), as two doses given eight hours apart (one trial), and once daily for three days (one trial), and compared to three-day regimens of established ACTs. Three additional small pharmaceutical company trials have been carried out. We have requested the data but have not received a response from the company. Artemisinin-naphthoquine versus artemether-lumefantrineIn three small trials from Benin, Côte d'Ivoire, and Papua New Guinea, both combinations had a very low incidence of treatment failure at Day 28, and there were no differences demonstrated in PCR-unadjusted, or PCR-adjusted treatment failure (three trials, 487 participants, low quality evidence). Only the single study from Papua New Guinea followed participants up to Day 42, and the number of treatment failures remained very low with both combinations (one trial, 186 participants, very low quality evidence). Artemisinin-naphthoquine versus dihydroartemisinin-piperaquineIn a single small trial from Indonesia, treatment failure at Day 28 and Day 42 was very low in both groups with no differences demonstrated (one trial, 144 participants, very low quality evidence). The results of these few trials of artemisinin-naphthoquine are promising, but further trials from multiple settings are required to reliably demonstrate the relative efficacy and safety compared to established ACTs. Future trials should be adequately powered to demonstrate non-inferiority, and regimens incorporating three days of the artemisinin component are probably preferable to the one-day regimens.


Can surveying practitioners about their practices help identify priority clinical practice guideline topics?
Clinical practice guidelines are systematically developed statements designed to assist in patient and physician clinical decision making for specific clinical circumstances. In order to establish which guideline topics are priorities, practitioners were surveyed regarding their current practice. One hundred ninety-seven practitioners in Ontario, Canada were mailed a survey exploring their current practice or opinion regarding the prophylactic use of anticonvulsant drugs in patients with malignant glioma who had never had a seizure. The survey consisted of seven questions regarding the relevance of a guideline on the subject to the practitioner's practice, the proportion of clinical cases involving anticonvulsant use, knowledge of existing guidelines on this topic, interest in reviewing a completed practice guideline and three clinical scenarios. There were 122 respondents who returned the survey (62% rate of return). Eighty percent of the practitioners who responded indicated that less than 25% of their clinical cases involved the use of anticonvulsants; however, only 16% of respondents indicated that a practice guideline would be irrelevant to their practice. Eighty percent of respondents volunteered to review a draft version of a practice guideline on the use of anticonvulsants. The survey presented the practitioners with three scenarios where anticonvulsants in patients with brain tumours may be appropriate: peri-operatively in patients without seizures, postoperatively in patients currently using anticonvulsants, and thirdly in patients not currently using anticonvulsants or undergoing surgery. In contrast to the third situation, the first two situations yielded considerable variation in practitioner response. The survey established that there is some variation present in the current practice of anticonvulsant use in the patients with brain tumours. Whether there is an optimal treatment practice has yet to be determined. Practitioners do seem to feel that a guideline on anticonvulsant use in warranted, and most practitioners would be interested in being part of the guideline development process.


Task- and stimulus-related cortical networks in language production: Exploring similarity of MEG- and fMRI-derived functional connectivity.
Large-scale networks support the dynamic integration of information across multiple functionally specialized brain regions. Network analyses of haemodynamic modulations have revealed such functional brain networks that show high consistency across subjects and different cognitive states. However, the relationship between the slowly fluctuating haemodynamic responses and the underlying neural mechanisms is not well understood. Resting state studies have revealed spatial similarities in the estimated network hub locations derived using haemodynamic and electrophysiological recordings, suggesting a direct neural basis for the widely described functional magnetic resonance imaging (fMRI) resting state networks. To truly understand the nature of the relationship between electrophysiology and haemodynamics it is important to move away from a task absent state and to establish if such networks are differentially modulated by cognitive processing. The present parallel fMRI and magnetoencephalography (MEG) experiment investigated the structural similarities between haemodynamic networks and their electrophysiological counterparts when either the stimulus or the task was varied. Connectivity patterns underlying action vs. object naming (task-driven modulations), and action vs. object images (stimulus-driven modulations) were identified in a data driven all-to-all connectivity analysis, with cross spectral coherence adopted as a metric of functional connectivity in both MEG and fMRI. We observed a striking difference in functional connectivity between conditions. The spectral profiles of the frequency-specific network similarity differed significantly for the task-driven vs. stimulus-driven connectivity modulations. While the greatest similarity between MEG and fMRI derived networks was observed at neural frequencies below 30 Hz, haemodynamic network interactions could not be attributed to a single frequency band. Instead, the entire spectral profile should be taken into account when assessing the correspondence between MEG and fMRI networks. Task-driven network hubs, evident in both MEG and fMRI, were found in cortical regions previously associated with language processing, including the posterior temporal cortex and the inferior frontal cortex. Network hubs related to stimulus-driven modulations, however, were found in regions related to object recognition and visual processing, including the lateral occipital cortex. Overall, the results depict a shift in network structure when moving from a task dependent modulation to a stimulus dependent modulation, revealing a reorganization of large-scale functional connectivity during task performance.


Oncogenic Properties of Candidate Oncogenes in Chromosome Region 17p11.2p12 in Human Osteosarcoma.
Osteosarcomas are primary tumors of bone that most often develop in adolescents. They are characterized by complex genomic changes including amplifications, deletions, and translocations. The chromosome region 17p11.2p12 is frequently amplified in human high grade osteosarcomas (25% of cases), suggesting the presence of one or more oncogenes. In previous studies, we identified 9 candidate oncogenes in this region (GID4, ARGHAP44, LRRC75A-AS1, TOP3A, COPS3, SHMT1, PRPSAP2, PMP22, and RASD1). The aim of the present study was to determine their oncogenic properties. Therefore, we generated osteosarcoma cell lines overexpressing these genes, except for LRRC75A-AS1 and PRPSAP2, and subjected these to functional oncogenic assays. We found that TOP3A, SHMT1, and RASD1 overexpression provided increased proliferation and that ARGHAP44, COPS3, and PMP22 overexpression had a stimulatory effect on migration and invasion of the cells. COPS3 and PMP22 overexpression additionally improved the ability of the cells to form new colonies. No oncogenic effect could be demonstrated for GID4 overexpression. We conclude that the concerted amplification-mediated overexpression of these genes in 17p11.2p12 may contribute to the oncogenic process in malignant osteosarcoma.


Difficulties in Differentiating Hypertensive Disorders of Pregnancy With Polyarteritis Nodosa.
Polyarteritis nodosa (PAN) is characterized by medium- or small-sized artery vasculitis with vessel wall inflammation and necrosis of muscular arteries, commonly presenting with fatigue, fever, weight loss, and joint pain. PAN in pregnancy is rare and is associated with worsening of vasculitis after delivery, resulting in myocardial infarction and heart failure which frequently lead to maternal death. We report a case of hypertensive disorders of pregnancy (HDP), which is difficult to differentiate from PAN. A 27-year-old multigravida was diagnosed with PAN 4 years prior after experiencing fever and lower extremity skin rash. During her PAN remission, she conceived her second pregnancy and opted to discontinue PAN medication and declined antihypertensive medications. At 22 weeks of gestation, her blood pressure was elevated to 200/100 mm Hg without proteinuria, for which she was admitted to our hospital. She was diagnosed with HDP-chronic hypertension without PAN recurrence due to the absence of PAN-specific skin or joint symptoms according to the PAN diagnostic criteria. Antihypertensive medication was administered. At 30 weeks of gestation, her blood pressure was poorly controlled and she developed proteinuria, which led to a diagnosis of superimposed preeclampsia that necessitated emergency cesarean section delivery. After delivery, her blood pressure was immediately controlled using antihypertensive medication. Our case report highlights the importance of carefully managing HPD as a serious complication of PAN.


Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors.
The direction of plasticity at CA3-CA1 hippocampal synapses is determined by the strength of afferent stimulation. Weak stimuli lead to long-term depression (LTD) and strong stimuli to long-term potentiation (LTP), but both require activation of synaptic N-methyl-D-aspartate receptors (NMDARs). These receptors are therefore necessary and required for the induction of plasticity at CA3-CA1 synapses even though they carry little of the current responsible for the basal excitatory post-synaptic potential (EPSP). The influx of Ca(2+) via NMDARs triggers the subsequent and persistent changes in the expression of alpha-amino-3-hydroxy-5 methylisoxazole-4-proprionic acid receptors (AMPARs) and these receptors are responsible for the major part of the basal EPSP. The degree of activity of NMDARs is determined in part by extracellular Mg(2+) and by the co-agonists for this receptor, glycine and D-serine. During strong stimulation, a relief of the voltage-dependent block of NMDARs by Mg(2+) provides a positive feedback for NMDAR Ca(2+) influx into postsynaptic CA1 spines. In this review, we discuss how the induction of LTP at CA3-CA1 synapses requires further signal amplification of NMDAR activity. We discuss how the regulation of NMDARs by protein kinases and phosphatases is brought into play. Evidence is presented that Src family kinases (SFKs) play a "core" role in the induction of LTP by enhancing the function and expression of NMDARs. At CA3-CA1 synapses, NMDARs are largely composed of NR1 (NMDA receptor subunit 1)-NR2A or NR1-NR2B containing subunits. Recent, but controversial, evidence has correlated NR1-NR2A receptors with the induction of LTP and NR1-NR2B receptors with LTD. However, LTP can be induced by activation of either subtype of NMDAR and the ratio of NR2A:NR2B receptors has been proposed as an alternative determinant of the direction of synaptic plasticity. Many transmitters and signal pathways can modify NMDAR function and expression and, for a given stimulus strength, they can potentially lead to a change in the balance between LTP and LTD. As opposed to the "core" mechanisms of LTP and LTD, the resulting alterations in this balance underlie "meta-plasticity." Thus, in addition to their contribution to core mechanisms, we will also discuss how Src-family kinases could preferentially target NR1-NR2A or NR1-NR2B receptors to alter the relative contribution of these receptor subtypes to synaptic plasticity.


Requirement of TLR2-mediated signaling for the induction of IL-15 gene expression in human monocytic cells by HSV-1.
Exposure of human monocytic cells to herpes simplex virus type 1 (HSV-1) results in immediate up-regulation of interleukin (IL)-15 gene expression. However, the receptor involved in this induction is not known. Here, we provide evidence that this induction depends on TLR2-mediated signaling pathway. Through the use of small interfering RNAs (siRNAs), we demonstrate that HSV-1-induced up-regulation of IL-15 gene expression in monocytic THP1 cells requires the presence of the adaptors MyD88, IRAK1, and TRAF6. Interestingly, TIRAP/Mal, an adaptor molecule specifically recruited to TLR2 and TLR4, was also required for maximal up-regulation of IL-15. This response was completely abrogated by anti-TLR2, but not anti-TLR4, blocking mAbs in both primary monocytes and THP1 cells. Furthermore, THP1 cells rendered defective in TLR2 expression by disrupting the expression of Sp1, a major transcription factor involved in TLR2 promoter activity, were unable to up-regulate IL-15 gene expression in response to HSV-1. In addition, HSV-1-induced NF-kappaB activation was significantly reduced after neutralization of TLR2 and the adaptor proteins. Altogether, these results unequivocally show that HSV-1 induces TLR2-dependent activation of IL-15 gene expression, which requires the recruitment of both MyD88 and TIRAP/Mal and the activation of IRAK1 and TRAF6 leading to NF-kappaB translocation to the nucleus.


Hippocampal deletion of BDNF gene attenuates gamma oscillations in area CA1 by up-regulating 5-HT3 receptor.
Pyramidal neurons in the hippocampal area CA3 express high levels of BDNF, but how this BDNF contributes to oscillatory properties of hippocampus is unknown. Here we examined carbachol-induced gamma oscillations in hippocampal slices lacking BDNF gene in the area CA3. The power of oscillations was reduced in the hippocampal area CA1, which coincided with increases in the expression and activity of 5-HT3 receptor. Pharmacological block of this receptor partially restored power of gamma oscillations in slices from KO mice, but had no effect in slices from WT mice. These data suggest that BDNF facilitates gamma oscillations in the hippocampus by attenuating signaling through 5-HT3 receptor. Thus, BDNF modulates hippocampal oscillations through serotonergic system.


[Legal contentions in thyroid surgery. Kind of preoperative information to the patients].
The question of patients information and the achievement of an informed consent to medical and/or surgical treatment by the patient still represents one of the main issue of the medical profession, having greater importance nowadays in respect to the past regarding the relationship doctor-patient and to the diagnostic-therapeutic approach to the patient. Written informed consent is a pre requisite for surgical intervention as it provides the forum for the patient to appreciate implications of the procedure and the doctor to explain details and effects of the surgery. Patients refusal is, nowadays, according to the latest orientation of the Italian Supreme Court, the major limitation to medical or surgical intervention. For these reason we have thought better to propose a written form of informed consent regarding the thyroid surgery, which implies, more than other surgery's act, the exposition of the patient to adverse iatrogenic risks and as a consequence it can expose the surgeon to criminal or civil liabilities.


Hospitals' Patterns of Use of Noninvasive Ventilation in Patients With Asthma Exacerbation.
Limited data are available on the use of noninvasive ventilation in patients with asthma exacerbations. The objective of this study was to characterize hospital patterns of noninvasive ventilation use in patients with asthma and to evaluate the association with the use of invasive mechanical ventilation and case fatality rate. This cross-sectional study used an electronic medical record dataset, which includes comprehensive pharmacy and laboratory results from 58 hospitals. Data on 13,558 patients admitted from 2009 to 2012 were analyzed. Initial noninvasive ventilation (NIV) or invasive mechanical ventilation (IMV) was defined as the first ventilation method during hospitalization. Hospital-level risk-standardized rates of NIV among all admissions with asthma were calculated by using a hierarchical regression model. Hospitals were grouped into quartiles of NIV to compare the outcomes. Overall, 90.3% of patients with asthma were not ventilated, 4.0% were ventilated with NIV, and 5.7% were ventilated with IMV. Twenty-two (38%) hospitals did not use NIV for any included admissions. Hospital-level adjusted NIV rates varied considerably (range, 0.4-33.1; median, 5.2%). Hospitals in the highest quartile of NIV did not have lower IMV use (5.4% vs 5.7%), but they did have a small but significantly shorter length of stay. Higher NIV rates were not associated with lower risk-adjusted case fatality rates. Large variation exists in hospital use of NIV for patients with an acute exacerbation of asthma. Higher hospital rates of NIV use does not seem to be associated with lower IMV rates. These results indicate a need to understand contextual and organizational factors contributing to this variability.


Global expression profile of telomerase-associated genes in HeLa cells.
Telomerase is a specialized nucleoprotein enzyme complex that maintains the telomere length. The telomerase reverse transcriptase (TERT) is the catalytically active component of the telomerase complex. In humans, the protein component (hTERT) and RNA component (hTR) are found to differentially express in cancer cells. In contrast to differentiated cells, most of the cancer cells overexpress hTERT, which is needed to maintain the proliferative potential of cells. The overexpression of telomerase is not proportionate to telomere length in cancer cells, suggesting that the immortalizing phenotype can be mediated through other factors in addition to telomere length. To investigate the role of hTERT in immortalizing process, loss of gene function studies were carried out. Short interfering RNA (siRNA) and short hairpin RNA (shRNA) against hTERT showed the reduction of hTERT transcript, reduction of telomerase activity and alteration of gene expression in HeLa cells. The molecular basis of proliferative capacity of hTERT was investigated by gene expression microarray. Analysis of microarray data for HeLa cells following siRNA and shRNA mediated knockdown of hTERT showed that 80 genes were upregulated and 73 genes downregulated. Out of these, 37 genes are known to be involved in cancer. Further analyses of previously known genes involved in cancer like KLF4, FGF2, IRF-9 and PLAU by Real Time PCR showed their upregulation. We are documenting for the first time the effect of knocking down hTERT on expression of KLF4 and FGF2. Interestingly, it has been earlier reported that KLF4 and FGF2 up-regulate the expression of hTERT in cancer cells. This suggests that hTERT may be subject to its own auto-regulatory effects.


Traumatic neuropathies of the optic nerve, optic chiasm, and ocular motor nerves.
This review focuses on traumatic chiasmal syndrome and traumatic neuropathies of cranial nerves II, III, IV, and VI. The review highlights common anatomical sites of injury to the above structures. Special emphasis is placed on review of recent literature. Other review of related material include.


Preventive measures reduce exposure to polycyclic aromatic hydrocarbons at a graphite electrode plant.
This study assessed the efficacy of preventive measures in a graphite electrode plant aimed at reducing occupational exposure to polycyclic aromatic hydrocarbons (PAHs). Electrode workers (n = 146) answered a questionnaire and provided an end of shift urine sample. Urinary 1-hydroxypyrene (1-hpur), a biological marker of exposure to PAHs, was measured by high performance liquid chromatography coupled with: (a) fluorescence detection. 1-Hydroxypyrene concentrations were compared with the concentrations measured before implementing the preventive measures; and (b) those of a control group of 54 men not occupationally exposed to PAHs. After implementation of preventive measures, median concentrations 1-hpur were significantly reduced in some groups of workers: by -24%, -37% and -30% in workers at the green electrode unit, one baking impregnation unit, and the laboratory, respectively. In workers at a second baking impregnation unit, in end product finishing and in the power station 1-hpur concentrations were unchanged. Urinary 1-hp concentrations were still significantly higher in each group of workers than in the control group (p < 0.001 for any comparison). Concentrations in the workers varied with the type of job, the highest values being found in workers engaged in the power station, in the two baking impregnation units and in the green electrode unit. Implementing preventive measures significantly reduced exposure to PAHs at a graphite electrode plant. The reduction in median and peak concentrations of 1-hpur, which reflects total exposure to, and internal dose of PAHs, was most evident in workers employed in the units where preventive measures had been taken. Despite an overall reduction, further preventive measures are needed to minimise exposure to PAHs and consequently the risk of adverse health effects.