Inferring about individual drug and schizotypy effects on cognitive functioning in polydrug using mephedrone users before and after clubbing.
Mephedrone has been recently made illegal in Europe, but little empirical evidence is available on its impact on human cognitive functions. We investigated acute and chronic effects of mephedrone consumption on drug-sensitive cognitive measures, while also accounting for the influence of associated additional drug use and personality features. Twenty-six volunteers from the general population performed tasks measuring verbal learning, verbal fluency and cognitive flexibility before and after a potential drug-taking situation (pre-clubbing and post-clubbing at dance clubs, respectively). Participants also provided information on chronic and recent drug use, schizotypal (Oxford-Liverpool Inventory of Feelings and Experiences) and depressive symptoms (Beck Depression Inventory), sleep pattern and premorbid IQ. We found that (i) mephedrone users performed worse than non-users pre-clubbing and deteriorated from the pre-clubbing to the post-clubbing assessment; (ii) pre-clubbing cannabis and amphetamine (not mephedrone) use predicted relative cognitive attenuations; (iii) post-clubbing, depression scores predicted relative cognitive attenuations; and (iv) schizotypy was largely unrelated to cognitive functioning, apart from a negative relationship between cognitive disorganisation and verbal fluency. Results suggest that polydrug use and depressive symptoms in the general population negatively affect cognition. For schizotypy, only elevated cognitive disorganisation showed potential links to a pathological cognitive profile previously reported along the psychosis dimension.


Trends in cigarette demand and supply in Africa.
Since the tobacco epidemic is moving from developed to developing countries, it is important to understand trends in cigarette demand and supply. We focus on the African market since it offers the tobacco industry one of the best expansion potentials. A large variety of data from commercial (Canadean, Euromonitor International, tobacco industry reports), governmental (United Nations Comtrade, national statistics), and academic sources (Cigarette Citadels Map and journal articles) were utilized. We compile data from multiple sources to study cigarette demand in Africa from 1990 to 2012. We then focus on cigarette production and international cigarette trade to detect structural changes in cigarette supply over the past few decades. We contrast data from these different sources. Cigarette demand and supply data in Africa is limited and is sometimes inconsistent across different sources. Given this caveat, we found that the overall demand for cigarettes (measured by sales) in the 22 countries covered by Canadean, which represents 80% of Africa's population, increased by 44% (from 165.6 billion cigarettes to 238.5 billion cigarettes) from 1990 to 2012. This higher demand has been met by cigarette production increasing in these 22 countries by 106% during the same period. As a result, Africa has moved from being a net importer to a net exporter of cigarettes. At the same time, cigarette production has become more concentrated as the tobacco industry has strategically identified certain countries as production hubs. Monitoring the production, consumption and trade of cigarettes by improving the quality of surveillance is necessary to understand the demand and supply of cigarettes not only in Africa, but globally.


Subtle chromosomal rearrangements in children with unexplained mental retardation.
No explanation for moderate to severe mental retardation is apparent in about 40% of cases. Although small chromosomal rearrangements may account for some undiagnosed cases, a lack of genome-wide screening methods has made it impossible to ascertain the frequency of such abnormalities. A fluorescence in-situ hybridisation (FISH) test was used to examine the integrity of chromosome ends in 284 children with unexplained moderate to severe retardation, and in 182 children with unexplained mild retardation. 75 normal men were also tested. When a chromosomal rearrangement was found, its size was estimated, and members of the child's family were investigated. Subtle chromosomal abnormalities occurred with a frequency of 7.4% in the children with moderate to severe mental retardation, and of 0.5% in the children with mild retardation. The abnormalities had an estimated population prevalence of 2.1 per 10,000, and were familial in almost half of cases. Once recognisable syndromes have been excluded, abnormalities that include the ends of chromosomes are the commonest cause of mental retardation in children with undiagnosed moderate to severe mental retardation. Owing to the high prevalence of familial cases, screening for subtle chromosomal rearrangements is warranted in children with unexplained moderate to severe mental retardation.


Differences in autoimmune hepatitis based on inflammation localization.
Histopathology is essential for the diagnosis and evaluation of disease activity of autoimmune hepatitis (AIH). We aimed to elucidate the characteristics of AIH from the localization of inflammation. We re-evaluated a nationwide survey that was performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017. A total of 303 patients were enrolled, and the clinical and treatment characteristics were compared between the patients with predominantly portal inflammation (230 patients) or lobular inflammation (73 patients). AIH patients with lobular inflammation had a higher probability of being diagnosed with acute hepatitis than those with portal inflammation. Liver enzyme levels were higher in patients with lobular inflammation, whereas immunoglobulin G levels were higher in patients with portal inflammation. The prevalence of an alanine aminotransferase level < 30 U/L after 6 months of treatment was significantly higher in patients with lobular inflammation than in those with portal inflammation (81.7% vs. 67.3%, P = 0.046). The localization of inflammation may be useful for evaluating the onset of AIH.


The binding of adenosine(5')tetraphospho(5')adenosine to calf thymus histones measured by non-equilibrium dialysis.
Binding of adenosine(5')tetraphospho(5')adenosine (Ap4A) to histones of calf thymus was investigated by non-equilibrium dialysis. Histone H1 interacts with the dinucleotide via two strong sites and competes with Mg2+ ions. Intrinsic dissociation constants were 1.6 +/- 0.1 microM and 11 +/- 1 microM for zero and 0.4 mm-Mg2+ concentration respectively. Binding of poly(dT) and of other nucleotides to histone H1 was measured in an [3H]Ap4A-competition assay. The tendency to form complexes among nucleotides was highest for bisnucleoside tetraphosphates and decreased in the order poly(dT) greater than or equal to Ap4A approximately Gp4G greater than Ap4 much greater than Ap3A approximately Ap5A greater than or equal to ATP, GTP and dTTP. The co-ordination complex derived from Ap4A and cis-diammine-dichloroplatinum(II) was not reactive. The other histones of calf thymus also bound Ap4A with affinities decreasing in the order H4 approximately H3 greater than H1 greater than H2b greater than H2a. Ap4A stimulated the exchange of histone H1 between nucleosomes, but this effect was referred to ionic strength. It did not bind to assembled nucleosomes. Binding of Ap4A to histone H1 was decreased by salt (NaCl). At physiological saline concentration the value of the dissociation constant is commensurable with the value of the Ap4A concentration in the nucleus and thus indicative of complex-formation in vivo.


Environmental Control on Microbial Turnover of Leaf Carbon in Streams - Ecological Function of Phototrophic-Heterotrophic Interactions.
In aquatic ecosystems, light availability can significantly influence microbial turnover of terrestrial organic matter through associated metabolic interactions between phototrophic and heterotrophic communities. However, particularly in streams, microbial functions vary significantly with the structure of the streambed, that is the distribution and spatial arrangement of sediment grains in the streambed. It is therefore essential to elucidate how environmental factors synergistically define the microbial turnover of terrestrial organic matter in order to better understand the ecological role of photo-heterotrophic interactions in stream ecosystem processes. In outdoor experimental streams, we examined how the structure of streambeds modifies the influence of light availability on microbial turnover of leaf carbon (C). Furthermore, we investigated whether the studied relationships of microbial leaf C turnover to environmental conditions are affected by flow intermittency commonly occurring in streams. We applied leaves enriched with a 13C-stable isotope tracer and combined quantitative and isotope analyses. We thereby elucidated whether treatment induced changes in C turnover were associated with altered use of leaf C within the microbial food web. Moreover, isotope analyses were combined with measurements of microbial community composition to determine whether changes in community function were associated with a change in community composition. In this study, we present evidence, that environmental factors interactively determine how phototrophs and heterotrophs contribute to leaf C turnover. Light availability promoted the utilization of leaf C within the microbial food web, which was likely associated with a promoted availability of highly bioavailable metabolites of phototrophic origin. However, our results additionally confirm that the structure of the streambed modifies light-related changes in microbial C turnover. From our observations, we conclude that the streambed structure influences the strength of photo-heterotrophic interactions by defining the spatial availability of algal metabolites in the streambed and the composition of microbial communities. Collectively, our multifactorial approach provides valuable insights into environmental controls on the functioning of stream ecosystems.


Health care professionals' familiarity with non-pharmacological strategies for managing cancer pain.
Many studies have confirmed unnecessary suffering among cancer patients, due to the inadequate use of analgesic medication and other effective interventions. While pharmacological treatments are appropriately the central component of cancer pain management, the under-utilization of effective nonpharmacological strategies (NPS) may contribute to the problem of pain and suffering among cancer patients. The purpose of this study was to determine health care professionals' familiarity with, and perceptions regarding, NPS for managing cancer pain, and to assess their interest in learning more about NPS as adjuncts to pharmacological analgesics. Two-hundred and fourteen health care professionals were surveyed at two cancer treatment centres in Ontario, Canada. The self-report questionnaire included questions regarding 11 psychological strategies (e.g. imagery) and eight other NPS (e.g. acupuncture). The response rate was 67% (141/214). Subjects were found to be the least familiar with autogenic training, operant conditioning, and cognitive therapy. Other than radiation and surgery, subjects most commonly reported recommending support groups (67%), imagery (54%), music or art therapy (49%) and meditation (43%) for managing cancer pain. Participants were most interested in learning more about acupuncture, massage therapy, therapeutic touch, hypnosis, and biofeedback. Participants were somewhat familiar with most of the 19 NPS presented; however, they use or recommend few NPS for managing cancer pain. Health professionals' interest in NPS has important implications for the supportive care of cancer patients.


Evaluation of the pituitary-adrenal axis in hyperandrogenic women with polycystic ovary syndrome.
Impaired adrenal function is common in patients with polycystic ovary syndrome (PCOS). Abnormal regulation of cytochrome P450 17 alpha is believed to cause the exaggerated 17-hydroxyprogesterone (17OHP) response to ACTH stimulation. The aim of the study was to evaluate cortisol and 17OHP response to low dose (1 microg) ACTH test and to compare it with the standard ACTH (250 microg) test in hyperandrogenic women with PCOS. We studied 27 PCOS and 22 control women. All participants were examined for mutations of the CYP21 gene, Cortisol and 17OHP levels before, 30 and 60 minutes after the IV injection of 250 microg ACTH (SDT) and after 1 microg ACTH (LDT). Fasting serum levels of LH, FSH, testosterone, DHEAS were determined in all participants. Basal and ACTH stimulated Cortisol during the SDT (470+/-138 nmol/L and 761+/-143, respectively) were significantly higher in PCOS vs. controls (232+/-124 and 670+/-130, respectively) (p<0.03, p<0.02, respectively). Basal 17OHP (6.1+/-2.1 nmol/L) and the peak response to SDT (14.2+/-3.6 nmol/L) were significantly higher in PCOS vs. controls (4.2+/-2.1, 10.9+/-3.0, respectively) (p<0.003, p<0.004, respectively). Abnormally elevated 17OHP response to SDT was detected in 6/27 PCOS women (22%). No statistically significant difference between the PCOS and control groups were noted during the LDT in both cortisol and 17OHP levels. These data suggest that the exaggerated 17-hydroxyprogesterone (17OHP) response to ACTH stimulation in PCOS is revealed by stimulation at a pharmacological dose (250 microg) but not by a physiological dose (1 microg).


Drug-induced interstitial lung diseases.
Any discussion of drug-induced interstitial lung disease is fraught with the problem of having a syndrome in which information is composed predominantly of case reports. When the information is taken as a whole, however, the picture becomes clearer: (1) Some drugs can produce significant pulmonary toxicity; (2) the clinical history, physical examination, and chest roentgenogram are not unique or specific for drug-induced interstitial lung disease; and (3) the lung reacts in limited ways to various insults, producing pathologic changes that are not unique for drug-induced interstitial lung disease. The work of Crystal et al. has shed new light on interstitial lung disease. Their concept that the alveolitis is the key initiating step in interstitial lung disease fits with the pathologic findings in many situations of drug-induced interstitial lung disease. Furthermore, as they proposed, if the primary alveolitis has not progressed to derangement of alveolar structures, then the process can be reversed. This may explain the variable response seen with drug withdrawal and the use of corticosteroids. These concepts have not been extensively studied in drug-induced interstitial lung disease and this needs to be done to fully evaluate their ideas. A keen awareness of the potential for any drug to cause drug-induced interstitial lung disease can be of immense benefit to the patient, for early discontinuation of the agent is likely to increase the chance of reversing the pulmonary toxicity.


A Variant in the Precursor of MicroRNA-146a is Responsible for Development of Erectile Dysfunction in Patients with Chronic Prostatitis via Targeting NOS1.
BACKGROUND The morbidity of erectile dysfunction (ED) has been found to be substantially increased in patients with chronic prostatitis (CP). Accumulating evidence shows that single-nucleotide polymorphism (SNP) located in pre-miRNA or mature microRNA may affect the processing of microRNA (miRNA) and alter the expression of the miRNA, as well as its target gene. In this study we investigated the association between rs2910164 G/C polymorphism and risk of ED in patients with CP, as well as the underlying molecular mechanism. MATERIAL AND METHODS Computational analysis was used to search for the target of miR-146a, and the luciferase reporter assay system was used to validate NOS1 to be the target gene of miR-146a. We also treated PC-3 cells with miR-146a mimics/inhibitors to verify the negative regulatory relationship between miR-146a and NOS1, and real-time PCR and Western blot analysis were used to estimate the expression of the NOS1 mRNA and miR-146a. RESULTS The binding site of miR-146a was found to be located within the 3'-UTR of the NOS1 by searching an online miRNA database (www.mirdb.org), and luciferase reporter assay was done to confirm that NOS1 is a direct target gene of miR-146a. We also found that mRNA and protein expression level of NOS1 in PC-3 cells treated with miR-146a mimics and NOS1 siRNA was substantially down-regulated compared with scramble control, while cells treated with miR-146a inhibitors showed increased expression of NOS1. In addition, 705 people were recruited for our research - 342 CP patients with ED and 363 CP patients without ED - and we found that the presence of minor allele of rs2910164 polymorphism is significantly associated with reduced risk of ED in patients with CP. CONCLUSIONS The findings indicate a decreased risk of ED in patients with CP who are carriers of miR-146a rs2910164 C allele, and this association might be due to its ability to compromise the expression of miR-146a, and thereby increase the expression of its target gene, NOS1.


Construction of yellow fever/St. Louis encephalitis chimeric virus and the use of chimeras as a diagnostic tool.
St. Louis encephalitis (SLE) and West Nile (WN) flaviviruses are genetically closely related and cocirculate in the United States. Virus neutralization tests provide the most specific means for serodiagnosis of infections with these viruses. However, use of wild-type SLE and WN viral strains for laboratory testing is constrained by the biocontainment requirements. We constructed two highly attenuated yellow fever (YF) virus chimeras that contain the premembrane-envelope (prM-E) protein genes from the virulent MSI-7 (isolated in the United States) or the naturally attenuated CorAn9124 (Argentina) SLE strains. The YF/SLE (CorAn version) virus and the previously constructed YF/WN chimera were shown to specifically distinguish between confirmed human SLE and WN cases in a virus neutralization test using patient sera. These chimeras have the potential for use as diagnostic reagents and vaccines against SLE and WN.


First Report of Pratylenchus neglectus on Winter Wheat in China.
Root-lesion nematodes are major pathogens of wheat and have been reported in the United States, Mexico, India, Australia, Egypt, Canary Islands, South Africa, Iran, Japan, the Netherlands, Belgium, Italy, Germany, and Yugoslavia (1). They can also cause injury in a large number of crops, including grasses, cereal grains, and vegetables. In 2009 and 2010, a survey was conducted for nematodes in winter wheat fields near Taian city, Shandong, northern China. Root tissues were stained via the acid fuchsin tissue stain technique, and nematode numbers were recorded under a stereo microscope. Sixty-eight root samples were collected during the winter wheat growing season, and root lesion nematode was found in all samples. The highest average lesion nematode populations in fresh roots were 154.3 nematodes/g in 2009 and 236.7 nematodes/g in 2010. Nematodes were collected from infested wheat roots by a modified Baermann funnel method. Dimensions of the nematodes were: length, 0.42 to 0.54 mm; a, 18.8 to 24.2; b, 4.4 to 5.7; c, 19.8 to 25.4; V, 80.4 to 84.8; and spear, 17.1 to 18.9 μm. DNA was extracted from individual nematodes using liquid nitrogen. Amplification of rDNA-internal transcribed spacer region using the forward primers 5'-CGTAACAAGGTAGCTGTAG-3' and the reverse primer 5'-TTTCACTCGCCGTTACTAAGG-3' yielded a PCR fragment of approximately 900 bp. PCR products were purified using Universal Plant DNA Purification Kit (Tiangen, China) and ligated to the pMD18-T vector system (TaKaRa Bio, Japan) and transformed to E. coli strain DH5α. Plasmid DNA carrying the insert was extracted and used as the template for DNA sequencing. DNA sequencing was carried out in an ABI 3730, compared and aligned using MEGA 5.0. Sequences showed 96% sequence identity with those of Pratylenchus neglectus (GenBank Accession No. FR692291.1). The sequence was submitted to the GenBank database (JX228136). To our knowledge, this is the first report of P. neglectus infesting winter wheat in China. P. neglectus has been reported as causing economically significant damage to wheat production of up to 70% yield loss in the Pacific Northwest. Damage from lesion nematode may therefore be potentially significant to wheat production in Shandong Province, and further information should be obtained on its prevalence. References: (1) P. A. A. Loof. The family Pratylenchidae Thorne, 1949. W. R. Nickle, ed., Manual of Agricultural Nematol. Marcel Dekker, Inc. New York, 1991. (2) R. W. Smiley et al. J. Nematol. 37:45, 2005.


Do improvements in client-provider interaction increase contraceptive continuation? Unraveling the puzzle.
Evidence on the association between client-provider interaction (CPI) and contraceptive continuation has been mixed. This paper attempts to unravel the puzzle by examining various factors that may have contributed to the mixed results. This paper critically reviews key studies that examined the association between CPI and contraceptive continuation. A scan of peer reviewed publications and project reports was undertaken with a focus on CPI and contraceptive continuation. In addition, a review of key studies that examined the impact of interventions to improve CPI in compliance with medical regimens was carried out. The inconsistency of results may be attributed to methodological factors, characteristics of interventions to improve CPI, or conceptual factors related to the complexity of the issue of contraceptive continuation. More rigorous research is needed to understand the role played by CPI in contraceptive continuation as well as socio-demographic, behavioral and contextual factors that moderate the relationship between CPI and contraceptive continuation. Counseling services should be expanded to address physical, social and emotional needs of continuing clients. Moreover, interventions to improve CPI should also address contextual and health system factors that prevent clients from using family planning consistently and effectively.


The bile response repressor BreR regulates expression of the Vibrio cholerae breAB efflux system operon.
Enteric pathogens have developed several resistance mechanisms to survive the antimicrobial action of bile. We investigated the transcriptional profile of Vibrio cholerae O1 El Tor strain C6706 under virulence gene-inducing conditions in the presence and absence of bile. Microarray analysis revealed that the expression of 119 genes was affected by bile. The mRNA levels of genes encoding proteins involved in transport were increased in the presence of bile, whereas the mRNA levels of genes encoding proteins involved in pathogenesis and chemotaxis were decreased. This study identified genes encoding transcriptional regulators from the TetR family (vexR and breR) and multidrug efflux pumps from the resistance-nodulation-cell division superfamily (vexB and vexD [herein renamed breB]) that were induced in response to bile. Further analysis regarding vexAB and breAB expression in the presence of various antimicrobial compounds established that vexAB was induced in the presence of bile, sodium dodecyl sulfate, or novobiocin and that the induction of breAB was specific to bile. BreR is a direct repressor of the breAB promoter and is able to regulate its own expression, as demonstrated by transcriptional and electrophoretic mobility shift assays (EMSA). The expression of breR and breAB is induced in the presence of the bile salts cholate, deoxycholate, and chenodeoxycholate, and EMSA showed that deoxycholate is able to abolish the formation of BreR-P(breR) complexes. We propose that deoxycholate is able to interact with BreR and induce a conformational change that interferes with the DNA binding ability of BreR, resulting in breAB and breR expression. These results provide new insight into a transcriptional regulator and a transport system that likely play essential roles in the ability of V. cholerae to resist the action of bile in the host.


Severe traumatic brain injury and controlled hemorrhage in rats: quest for the optimal mean arterial blood pressure after whole fresh donor blood resuscitation.
Treatment of combined traumatic brain injury and hypovolemic shock poses a particular challenge due to the possible conflicting consequences. While restoring diminished volume is the treatment goal for hypovolemia, maintaining and adequate cerebral perfusion pressure and avoidance of secondary damage remain a treatment goal for the injured brain. Various treatment modalities have been proposed, but the optimal resuscitation fluid and goals have not yet been clearly defined. In this study, we investigate the physiological and neurological outcomes in a rat model of combined traumatic brain injury and hypovolemic shock, submitted to treatment with varying amounts of fresh blood. Forty-eight male Lewis rats were divided into control and treatment groups. Traumatic brain injury was inflicted by a free-falling rod on the exposed cranium. Hypovolemia was induced by controlled hemorrhage of 30% blood volume. Treatment groups were treated by fresh whole blood with varying volumes, reaching resuscitation goals of a mean arterial blood pressure (MAP) of 80, 100, and 120 mmHg at 15 min. Mean arterial blood pressure was assessed at 60 min and neurological outcomes and mortality in the subsequent 48 h. At 60 min, MAP was highest for the group resuscitated most aggressively. Neurological outcomes and mortality inversely correlated with the aggressiveness of resuscitation. In this study, we find that mild resuscitation with goals of restoring MAP to 80 mmHg (which is lower than baseline) provided best results when considering hemodynamic stability, survival, and neurological outcomes. An aggressive resuscitation may be detrimental, inducing processes that eventually cause a significant decrease in survival.


Premature mortality in active convulsive epilepsy in rural Kenya: causes and associated factors.
We estimated premature mortality and identified causes of death and associated factors in people with active convulsive epilepsy (ACE) in rural Kenya. In this prospective population-based study, people with ACE were identified in a cross-sectional survey and followed up regularly for 3 years, during which information on deaths and associated factors was collected. We used a validated verbal autopsy tool to establish putative causes of death. Age-specific rate ratios and standardized mortality ratios were estimated. Poisson regression was used to identify mortality risk factors. There were 61 deaths among 754 people with ACE, yielding a rate of 33.3/1,000 persons/year. Overall standardized mortality ratio was 6.5. Mortality was higher across all ACE age groups. Nonadherence to antiepileptic drugs (adjusted rate ratio [aRR] 3.37), cognitive impairment (aRR 4.55), and age (50+ years) (rate ratio 4.56) were risk factors for premature mortality. Most deaths (56%) were directly related to epilepsy, with prolonged seizures/possible status epilepticus (38%) most frequently associated with death; some of these may have been due to sudden unexpected death in epilepsy (SUDEP). Possible SUDEP was the likely cause in another 7%. Mortality in people with ACE was more than 6-fold greater than expected. This may be reduced by improving treatment adherence and prompt management of prolonged seizures and supporting those with cognitive impairment.


Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial.
Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed. Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28·4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18·5% of patients in the control group (adjusted odds ratio [aOR] 1·71 [95% CI 0·80-3·63]; p=0·17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30·7% of patients) compared with the control group (5·0% of patients; aOR 11·48 [95% CI 1·35-97·83]; p=0·026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose. Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low. This study was funded, in part, by the Medical Research Council UK.


Testosterone replacement in 49,XXXXY syndrome: andrological, metabolic and neurological aspects.
We report the case of a 19-year-old boy, presenting several congenital malformations (facial dysmorphisms, cardiac and musculoskeletal abnormalities), mental retardation, recurrent respiratory infections during growth and delayed puberty. Although previously hospitalised in other medical centres, only psychological support had been recommended for this patient. In our department, genetic, biochemical/hormonal and ultrasound examinations were undertaken. The karyotype was 49,XXXXY, a rare aneuploidy with an incidence of 1/85 000-100 000, characterised by the presence of three extra X chromosomes in phenotypically male subjects. The hormonal/biochemical profile showed hypergonadotropic hypogonadism, insulin resistance and vitamin D deficiency. The patient was then treated with testosterone replacement therapy. After 12 months of treatment, we observed the normalisation of testosterone levels. There was also an increase in pubic hair growth, testicular volume and penis size, weight loss, homeostatic model assessment index reduction and the normalisation of vitamin D values. Moreover, the patient showed greater interaction with the social environment and context. In cases of plurimalformative syndrome, cognitive impairment, recurrent infections during growth and, primarily, delayed puberty, it is necessary to ascertain as soon as possible whether the patient is suffering from hypogonadism or metabolic disorders due to genetic causes. In our case, the diagnosis of hypogonadism, and then of 49,XXXXY syndrome, was unfortunately made only at the age of 19 years.The testosterone replacement treatment, even though delayed, induced positive effects on: i) development of the reproductive system, ii) regulation of the metabolic profile and iii) interaction with the social environment and context.However, earlier and timely hormonal replacement treatment could probably have improved the quality of life of this subject and his family.


Immigrants' outcome after a first-episode psychosis.
Immigration is a risk factor for psychosis emergence, and previous studies show that immigrants are less likely to engage in treatment for psychosis. However, the literature on outcome is scant and heterogeneous. This study was designed to compare first-generation (FGI) and second-generation immigrants (SGI) to non-immigrants' symptomatic and functional outcomes 2 years after a first-episode psychosis (FEP). A 2-year prospective longitudinal study of 223 FEP patients between 18 and 30 years took place in two early intervention services (EIS) in Montreal, Canada. Forty-two per cent of the sample were immigrants (FGI (n = 56), SGI (n = 38)). Compared with non-immigrants, immigrants had similar symptomatic and functioning profiles at baseline, 1 and 2 years, except that fewer SGI had a history of homelessness and more were living with their families. FGI were less likely to have a substance use disorder but more likely to pursue their studies and to present depressive symptoms. Even if immigrants are known to be at greater risk of developing psychosis, probably secondary to stress related to immigration, their symptomatic and functional outcomes, once engaged in EIS treatment, are similar to or sometimes better than non-immigrants' outcomes. Because immigrants tend to be less engaged in their follow-up, understanding why they disengage from treatment is crucial to develop better therapeutic approaches to better engage them as EIS treatment can improve their outcomes effectively.


A randomised controlled trial of an exercise plus behaviour change intervention in people with multiple sclerosis: the step it up study protocol.
Exercise has consistently yielded short-term, positive effects on health outcomes in people with multiple sclerosis (MS). However, these effects have not been maintained in the long-term. Behaviour change interventions aim to promote long-term positive lifestyle change. This study, namely, "Step it Up" will compare the effect of an exercise plus Social Cognitive Theory (SCT)-based behaviour change intervention with an exercise plus control education intervention on walking mobility among people with MS. People with a diagnosis of MS who walk independently, score of 0-3 on the Patient Determined Disease Steps, who have not experienced an MS relapse or change in their MS medication in the last 12 weeks and who are physically inactive will be randomised to one of two study conditions. The experimental group will undergo a 10-week exercise plus SCT-based behavioural change intervention. The control group will undergo a 10-week exercise plus education intervention to control for contact. Participants will be assessed at weeks 1, 12, 24 and 36. The primary outcome will be walking mobility. Secondary outcomes will include: aerobic capacity, lower extremity muscle strength, participant adherence to the exercise programme, self-report exercise intensity, self-report enjoyment of exercise, exercise self-efficacy, outcome expectations for exercise, goal-setting for exercise, perceived benefits and barriers to exercise, perceptions of social support, physical and psychological impact of MS and fatigue. A qualitative evaluation of Step it Up will be completed among participants post-intervention. This randomised controlled trial will examine the effectiveness of an exercise plus SCT-based behaviour change intervention on walking mobility among people with MS. To this end, Step it Up will serve to inform future directions of research and clinical practice with regard to sustainable exercise interventions for people with MS. ClinicalTrials.gov, NCT02301442.


Cyclohexane-based low molecular weight hydrogelators: a chirality investigation.
Seven new 1,3,5-cyclohexyltricarboxamide-phenylalanine derivatives were synthesized in order to investigate the effect of the amino acid chirality on the gelating properties of these small molecules in water. Gelation tests have shown that enantiomerically pure homochiral 1,3,5-cyclohexyltricarboxamide-L-phenylalanine is a non-hydrogelator as it crystallizes from water, whereas the heterochiral derivatives with either two L-phenylalanine moieties and one D-phenylalanine (LLD), or vice versa (DDL), are very good hydrogelators. Concentration-dependent gel-to-sol transition-temperature (T(gs)) curves for LLD or DDL gels show a sigmoidal behaviour, which is in contrast to the logarithmic curves generally observed for gels derived from low molecular weight gelators (LMWGs). Such sigmoidal behaviour can be related to interactions between fibre bundles, which give rise to intertwined bundles of fibres. Transmission electron microscopy (TEM) images of LLD and DDL gels show a network of thin, unbranched, fibre bundles with diameters of 20 nm. Right-handed twisted fibre bundles are present in the LLD gel, whereas left-handed structures can be found in the DDL gel. Each bundle of fibres consists of a finite number of primary fibres. Gels consisting of mixtures of gelators, LLD and DDL, and nongelators (LLL or DDD) were investigated by means of T(gs) measurements, CD spectroscopy and TEM. Results show that the incorporation of nongelator molecules into gel fibres occurs; this leads to higher T(gs) values and to changes in the helicity of the fibre bundles. Furthermore, it was found that peripheral functionalization of the homochiral derivatives LLL or DDD by means of a second amino acid or a hydrophilic moiety can overcome the effect of chirality; this process in turn leads to good hydrogelators.


A sylvatic lifecycle of Echinococcus equinus in the Etosha National Park, Namibia.
Various species of Echinococcus have been described in the past from wild mammals of sub-Saharan Africa. However, it is only recently, that a few isolates have become available for molecular identification; therefore, the involvement of wildlife in the lifecycles of the various cryptic species within Echinococcus granulosus sensu lato is still only partially known. A preliminary survey was undertaken in Etosha National Park, Namibia, from August to October 2012. Faecal samples were obtained from 34 individual wild carnivores, and metacestodes were collected from carcasses of 18 culled herbivores. Single eggs and metacestode tissue were lysed and identified from sequences of the mitochondrial nad1 gene. In case of metacestodes, the cox1 gene was additionally sequenced and haplotype networks were constructed. Echinococcus equinus was found in lions (4 of 6), black-backed jackals (2 of 7) and Burchell's zebras (11 of 12). The frequency of this parasite in the absence of domestic dogs, horses and donkeys strongly indicates its transmission in a wildlife cycle. Further, a variety of sequences were obtained from eggs and cysticerci from lions, cheetahs, caracals, spotted hyenas and oryx, which most closely clustered with species of Taenia. Only 3 of them, 2 of lion and 1 of hyena origin, could be allocated to Hydatigera (=Taenia) taeniaeformis (lion), Taenia regis (lions and oryx) and Taenia cf. crocutae (spotted hyena and oryx).


Rare vascular perforation complicating radial approach to percutaneous coronary angioplasty.
A transradial arterial approach to coronary angiography and percutaneous coronary intervention has become increasingly embraced by cardiologists as it is associated with decreased vascular complications and allows early mobilisation of patients when compared with transfemoral arterial access. Major vascular complication post-transradial access is uncommon. We describe a very rare case of perforation of the costocervical trunk (a branch of the right subclavian artery at the site of the thoracic inlet) presenting shortly after percutaneous transradial coronary intervention. The resulting rapidly expanding cervical haematoma caused airway compromise necessitating emergent intubation in the catheter laboratory recovery area. Transfemoral catheter coil embolisation of the feeder artery was successful in obliterating blood flow to the perforated vessel with eventual resolution of the neck haematoma.


Cannabinoids and psychotic symptoms: A potential role for a genetic variant in the P2X purinoceptor 7 (P2RX7) gene.
To investigate the biological mechanisms underlying the higher risk for psychosis in those that use cannabis, we conducted a genome-wide environment-interaction study (GWEIS). In a sample of individuals without a psychiatric disorder (N = 1262), we analyzed the interactions between regular cannabis use and genotype with psychotic-like experiences (PLE) as outcome. PLE were measured using the Community Assessment of Psychic Experiences (CAPE). The sample was enriched for those at the extremes of both cannabis use and PLE to increase power. A single nucleotide polymorphism in the P2RX7 gene (rs7958311) was associated with risk for a high level of psychotic experiences in regular cannabis users (p = 1.10 x10-7) and in those with high levels of lifetime cannabis use (p = 4.5 × 10-6). This interaction was replicated in individuals with high levels of lifetime cannabis use in the IMAGEN cohort (N = 1217, p = 0.020). Functional relevance of P2RX7 in cannabis users was suggested by in vitro experiments on activated monocytes. Exposure of these cells to tetrahydrocannabinol (THC) or cannabidiol (CBD) reduced the immunological response of the P2X7 receptor, which was dependent on the identified genetic variant. P2RX7 variants have been implicated in psychiatric disorders before and the P2X7 receptor is involved in pathways relevant to psychosis, such as neurotransmission, synaptic plasticity and immune regulation. We conclude that P2RX7 plays a role in vulnerability to develop psychotic symptoms when using cannabis and point to a new pathway that can potentially be targeted by newly developed P2X7 antagonists.


Haem and nitric oxide: synergism in the modulation of the endothelial haem oxygenase-1 pathway.
NO potently up-regulates vascular haem oxygenase-1 (HO-1), an inducible defensive protein that degrades haem to CO, iron and the antioxidant bilirubin. Since several pathological states are characterized by increased NO production and liberation of haem from haem-containing proteins, we examined how NO influences HO-1 induction mediated by haemin. Aortic endothelial cells treated with S-nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside (SNP) or diethylenetriamine-NONOate (DETA/NO) and haemin exhibited higher levels of haem oxygenase activity compared with cells exposed to NO donors or haemin alone. This was accompanied by a marked increase in bilirubin production and, notably, by a strong magnification of cellular haem uptake. A role for haem metabolites in modulating HO-1 expression by NO was assessed by exposing cells to SNAP, SNP or DETA/NO in medium derived from cells treated with haemin, which contained increased bilirubin levels. This treatment considerably potentiated HO-1 expression and haem oxygenase activity mediated by NO and the use of a haem oxygenase inhibitor abolished this effect. Both iron liberated during haem breakdown and the formation of nitroxyl anion from NO appeared to partially contribute to the amplifying phenomenon; in addition, medium from haemin-treated cells significantly augmented the release of NO by NO donors. Thus we have identified novel mechanisms related to the induction of HO-1 by NO indicating that the signalling actions of NO vary significantly in the presence of haem and haem metabolites, ultimately increasing the defensive abilities of the endothelium to counteract oxidative and nitrosative stress.


Shear-Wave Elastography: Basic Physics and Musculoskeletal Applications.
In the past 2 decades, sonoelastography has been progressively used as a tool to help evaluate soft-tissue elasticity and add to information obtained with conventional gray-scale and Doppler ultrasonographic techniques. Recently introduced on clinical scanners, shear-wave elastography (SWE) is considered to be more objective, quantitative, and reproducible than compression sonoelastography with increasing applications to the musculoskeletal system. SWE uses an acoustic radiation force pulse sequence to generate shear waves, which propagate perpendicular to the ultrasound beam, causing transient displacements. The distribution of shear-wave velocities at each pixel is directly related to the shear modulus, an absolute measure of the tissue's elastic properties. Shear-wave images are automatically coregistered with standard B-mode images to provide quantitative color elastograms with anatomic specificity. Shear waves propagate faster through stiffer contracted tissue, as well as along the long axis of tendon and muscle. SWE has a promising role in determining the severity of disease and treatment follow-up of various musculoskeletal tissues including tendons, muscles, nerves, and ligaments. This article describes the basic ultrasound physics of SWE and its applications in the evaluation of various traumatic and pathologic conditions of the musculoskeletal system. ©RSNA, 2017.


Pd-Supported on N-doped carbon: improved heterogeneous catalyst for base-free alkoxycarbonylation of aryl iodides.
Novel Pd-based heterogeneous catalysts were prepared through immobilization of Pd(OAc)2/phenanthroline on carbon and subsequent pyrolysis. The most active catalyst was characterized by TEM, XPS and XRD techniques and was successfully used for the base-free methoxycarbonylation of aryl iodides. Notably, no metal contamination (detection limit < 0.5 ppm) in the final products was observed.


Evaluation of serum thymidine kinase 1 activity as a biomarker for treatment effectiveness and prediction of relapse in dogs with non-Hodgkin lymphoma.
Serum thymidine kinase 1 (sTK1) activity is closely correlated with DNA synthesis. Evaluate sTK1 activity as a biomarker for treatment response and early detection of relapse in dogs with lymphoma. Ninety-seven client-owned dogs with naive or relapsed lymphoma and 23 healthy dogs. Prospective study. Serum TK1 activity measured by refined ELISA-based method (DiviTum assay, Biovica International) before treatment, at clinical response, and every 4 weeks until relapse or last follow-up. Serum TK1 activity was ≤20 Du/L in 96% (22/23) of healthy dogs. Pretreatment sTK1 activity was >20 Du/L in 88% (85/97) dogs with lymphoma. At clinical response, sTK1 activity was significantly lower in dogs with complete (CR, n = 36) versus partial (PR, n = 29) response (P < .0001). Sensitivity (Se) and specificity (Sp) of sTK1 activity for detecting nonfully responders were 76% and 100%, respectively, with cutoff of 119.5 Du/L (AUC, 0.90; 95%-CI, 0.81-0.98; P < .0001). In dogs with CR, a 5-fold increase in sTK1 activity at a 4-week interval predicted relapse at the subsequent 4-week assessment with a Se 50% and Sp 94% (AUC, 0.72; 95%-CI, 0.55-0.90; P = .02). An increase of sTK1 activity (>2.7-fold value measured at clinical response) predicted relapse at subsequent 4-week assessment with a Se 61% and Sp 88% (AUC, 0.79; 95%-CI, 0.64-0.95; P = .004). Monitoring sTK1 activity could help to detect complete responders and early disease progression in dogs with lymphoma.


Association of an Electronic Health Record-Linked Glaucoma Medical Reminder With Patient Satisfaction.
While dosing reminders for glaucoma medications have been shown to increase drug adherence, an outstanding limitation preventing broad adoption is difficulty linking reminders to medication in each patient's electronic health record (EHR). To examine the feasibility of implementing an EHR-linked, automated reminder system for glaucoma medications and assess patient satisfaction with it. In this prospective, cross-sectional study, patients receiving glaucoma medications were recruited from a university-based glaucoma clinic from April 2017 to January 2018. Analysis began in February 2018. A web-based application was added to the EHR patient portal, allowing patients to configure telecommunication-based reminders for their glaucoma medications. For all potential participants, basic information was collected to determine risk of nonadherence with glaucoma medications. Those consenting to participate then answered questions on medication adherence, reminders, and their likelihood of using EHR-linked reminders. They then configured reminders using the EHR patient portal. After 3 months, they answered questions about their satisfaction with the system. Proportions of patients and high-risk patients willing to use the reminders, and patient satisfaction with the system. Of 147 patients approached, 100 (68%) agreed to participate, of whom the majority were men (54 [54%]) and white (51 [51%]), with a mean (SD) age of 65 (12.4) years. There were no differences between those willing and unwilling to participate, except for a slightly lower self-reported medication adherence rate among those who participated (mean [SD], 91% [13.6%] vs 97% [6.0%]). Based on a previously validated risk assessment score, 9% (9 of 100) of participants were categorized as being at high risk for poor adherence (≥50% probability of nonadherence) compared with 11% (5 of 47) of nonparticipants. Of 100 participants, 94 ultimately configured reminders, of whom 89 (95%) completed follow-up. On follow-up, 74% (n = 66; 95% CI, 65-83) of participants found the reminders to be useful, 15% (n = 13) were neutral, and 11% (n = 10) found them not useful. Most participants (72 [81%]; 95% CI, 77-85) had help configuring reminders. Electronic health records-linked reminders had good uptake and were well received among patients at a tertiary glaucoma clinic. These portals may represent a new and convenient method of allowing patients to link their glaucoma medications to automated reminders, although the generalizability of these results and the effect on glaucoma outcomes remains unknown.


The acoustics and acoustic behavior of the California spiny lobster (Panulirus interruptus).
Numerous animals produce sounds during interactions with potential predators, yet little is known about the acoustics of these sounds, especially in marine environments. California spiny lobsters (Panulirus interruptus) produce pulsatile rasps when interacting with potential predators. They generate sound using frictional structures located at the base of each antenna. This study probes three issues--the effect of body size on signal features, behavioral modification of sound features, and the influence of the ambient environment on the signal. Body size and file length were positively correlated, and larger animals produced lower pulse rate rasps. Ambient noise levels (149.3 dB re 1 microPa) acoustically obscured many rasps (150.4+/-2.0 dB re 1 microPa) at distances from 0.9-1.4 m. Significantly higher numbers of pulses, pulse rate, and rasp duration were produced in rasps generated with two antennae compared to rasps produced with only one antenna. Strong periodic resonances were measured in tank-recorded rasps, whereas field-recorded rasps had little frequency structure. Spiny lobster rasps exhibit flexibility in acoustic signal features, but their propagation is constrained, perhaps beneficially, by the noisy marine environment. Examining the connections between behavior, environment, and acoustics is critical for understanding this fundamental type of animal communication.


Effective subthalamic nucleus deep brain stimulation sites may differ for tremor, bradykinesia and gait disturbances in Parkinson's disease.
Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective therapy for Parkinson's disease (PD). This study investigates whether improvement for particular PD symptoms varies differentially with respect to stimulation location in the STN. Ten PD patients treated with bilateral STN DBS were enrolled in the study. Each electrode contact was stimulated independently to assess for changes in tremor, bradykinesia, and gait. Electrode contacts were localized via MRI. A novel iterative volumetric analysis was used to search the contact space for stimulation regions corresponding to alleviation of specific symptoms. Tremor was best controlled with DBS applied to the more dorsal, anterior, and medial areas of the contact space. Improvement in bradykinesia was seen largely within the middle of the contact space. Gait improvement was observed with ventral contacts, likely bordering the ventral boundaries of the STN. The iterative volumetric analysis is a valuable tool in identifying anatomic regions responsive to DBS across a subject population treated for PD. In the subjects tested, overlapping efficacy for all symptoms was observed in the region of the STN, but anatomic variances in the responsiveness for tremor, bradykinesia, and gait were found.


Trends in management, hospital and long-term outcomes of elderly patients with acute myocardial infarction.
The number of elderly patients with acute myocardial infarction (AMI) is growing rapidly, and their early and postdischarge mortality is high. Several studies have reported a decline in mortality after myocardial infarction; however, the magnitude of the decline among the elderly has not been fully investigated. We assessed trends in management, in-hospital, and long-term outcomes of 1475 elderly patients (aged > or =75 years, 42% women) hospitalized with AMI in all 25 operating coronary care units in Israel between 1992 and 2002, from our prospective nationwide biennial surveys. Between 1992 and 2002, a significant increase was observed in the use of acute reperfusion therapy (27%-48%), coronary angiography (6%-47%), percutaneous coronary intervention (3%-33%), coronary bypass (2%-8%), aspirin (53%-88%), beta-blockers (18%-65%), angiotensin-converting enzyme inhibitors (26%-63%), and lipid-lowering drugs (0%-43%). These changes were associated with a 42% reduction in 30-day mortality (27.6%-16.1%; adjusted odds ratio 0.57; 95% confidence interval [CI], 0.36-0.93). One-year cumulative mortality declined by 20% (37%-29%; adjusted odds ratio 0.74; 95% CI, 0.49-1.13). The management of elderly patients with AMI changed substantially during the last decade. This change was associated with a significant reduction in early mortality, whereas cumulative 1-year mortality improved only slightly. Better adherence to in-hospital management guidelines and better implementation of postdischarge health policy may further decrease mortality and morbidity in the elderly after AMI.


Thrombophilia and new anticoagulant drugs.
Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is the result of an imbalance among procoagulant, anticoagulant and profibrinolytic processes. This imbalance reflects a complex interplay between genetic and environmental or acquired risk factors. Genetic thrombophilic defects influence the risk of a first episode of thrombosis. How these defects influence the risk of recurrence in patients whose first episode of venous thromboembolism was unprovoked is less certain. Thus, when anticoagulants are stopped, patients with unprovoked venous thromboembolism have a risk of recurrence of at least 7% to 10% per year, even in the absence of an underlying thrombophilic defect. Consequently, there is a trend toward longer durations of anticoagulation therapy for these patients, which is problematic given the limitation of existing anticoagulants. This chapter provides an overview of the thrombophilic defects and how they influence the risk of venous thromboembolism. The chapter also details advances in anticoagulant therapy, focusing on new inhibitors of factor Xa and thrombin. In Section I, Dr. Saskia Middeldorp describes the various thrombophilic defects and reviews their relative importance in the pathogenesis of a first episode of venous thromboembolism. She then discusses the influence of these defects on the risk of recurrent thrombotic events in patients with unprovoked venous thromboembolism and in those whose thrombosis occurred in association with a known risk factor, such as surgery. In Section II, Dr. William Geerts reviews the pharmacology of new parenteral and oral factor Xa inhibitors and describes the results of the Phase II and III clinical trials with these agents. He then provides perspective on the potential advantages and drawbacks of these drugs for the prevention and treatment of venous thromboembolism. In Section III, Dr. John Heit focuses on direct thrombin inhibitors. He discusses their mechanism of action and compares and contrasts their pharmacological profiles prior to describing the results of Phase II and III clinical trials. Dr. Heit then provides perspective on the potential advantages and limitations of these drugs relative to existing anticoagulants.


Effects of regular Tai Chi practice and jogging on neuromuscular reaction during lateral postural control in older people.
This study examined the effects of regular Tai Chi practice and jogging on the neuromuscular activity of the trunk, hip, and ankle joint muscles of older people during lateral postural perturbation. A total of 42 older people participated in the study and formed the Tai Chi, jogging, and sedentary control groups. Electromyography signals were collected from the peroneus longus, anterior tibialis, gluteus medius, and erector spinae during unpredictable mediolateral perturbation. The Tai Chi group exhibited significantly faster latencies of the tibialis anterior and erector spinae than the control group. The jogging group showed a significantly shorter neuromuscular reaction time of the erector spinae than the control group. No significant difference was observed between the Tai Chi and jogging groups. Long-term regular Tai Chi practice enhanced the neuromuscular reaction of the erector spinae and tibialis anterior to lateral perturbation and will help timely posture correction when lateral postural distributions occur.


Oxidative stress and male infertility: a cross sectional study.
To compare stress markers and antioxidants in fertile and infertile males, and to explore their effects on reproductive hormones and fertility. The cross-sectional case-control study was conducted from July 2017 to July 2018 at the Islamabad Clinic Serving Infertile Couples, Islamabad, Pakistan, and comprised male subjects aged 25-55 years. Infertile subjects were the cases, while healthy fertile males acted as the controls. Stress hormones cortisol and adrenaline and antioxidants glutathione peroxidase and superoxide dismutase were measured using enzyme-linked immunosorbent assay. Data was analysed using SPSS 22. Of the 376 subjects, 241(64%) were cases and 135(36%) were controls. Median cortisol, adrenaline, superoxide dismutase and glutathione levels were significantly higher among the cases compared to te controls (p<0.05). Follicle stimulating hormone and luteinizing hormone levels were higher in cases compared to the controls (p=0.05). Mean testosterone level was higher among the controls than the cases (p<0.001). After adjusting for other covariates, every increase of 7 units in cortisol increased the prevalence of infertility by 3% (p=0.001). There was significant interaction between luteinizing hormone and testosterone in the final model (p<0.05). Stress together with decrease in antioxidants was found to play a significant role in reducing the fertilising potential of male infertile subjects.


Local electronic structure and density of edge and facet atoms at Rh nanoclusters self-assembled on a graphene template.
The chemical and physical properties of nanoclusters largely depend on their sizes and shapes. This is partly due to finite size effects influencing the local electronic structure of the nanocluster atoms which are located on the nanofacets and on their edges. Here we present a thorough study on graphene-supported Rh nanocluster assemblies and their geometry-dependent electronic structure obtained by combining high-energy resolution core level photoelectron spectroscopy, scanning tunneling microscopy, and density functional theory. We demonstrate the possibility to finely control the morphology and the degree of structural order of Rh clusters grown in register with the template surface of graphene/Ir(111). By comparing measured and calculated core electron binding energies, we identify edge, facet, and bulk atoms of the nanoclusters. We describe how small interatomic distance changes occur while varying the nanocluster size, substantially modifying the properties of surface atoms. The properties of under-coordinated Rh atoms are discussed in view of their importance in heterogeneous catalysis and magnetism.


Past Decline Versus Current eGFR and Subsequent ESRD Risk.
eGFR is a robust predictor of ESRD risk. However, the prognostic information gained from the past trajectory (slope) beyond that of the current eGFR is unclear. We examined 22 cohorts to determine the association of past slopes and current eGFR level with subsequent ESRD. We modeled hazard ratios as a spline function of slopes, adjusting for demographic variables, eGFR, and comorbidities. We used random effects meta-analyses to combine results across studies stratified by cohort type. We calculated the absolute risk of ESRD at 5 years after the last eGFR using the weighted average baseline risk. Overall, 1,080,223 participants experienced 5163 ESRD events during a mean follow-up of 2.0 years. In CKD cohorts, a slope of -6 versus 0 ml/min per 1.73 m(2) per year over the previous 3 years (a decline of 18 ml/min per 1.73 m(2) versus no decline) associated with an adjusted hazard ratio of ESRD of 2.28 (95% confidence interval, 1.88 to 2.76). In contrast, a current eGFR of 30 versus 50 ml/min per 1.73 m(2) (a difference of 20 ml/min per 1.73 m(2)) associated with an adjusted hazard ratio of 19.9 (95% confidence interval, 13.6 to 29.1). Past decline contributed more to the absolute risk of ESRD at lower than higher levels of current eGFR. In conclusion, during a follow-up of 2 years, current eGFR associates more strongly with future ESRD risk than the magnitude of past eGFR decline, but both contribute substantially to the risk of ESRD, especially at eGFR<30 ml/min per 1.73 m(2).


Self-assembly of penta-selenopeptides into amyloid fibrils.
Here, we report the synthesis of a penta-selenopeptide consisting of five benzyl protected selenocysteine residues. This selenopeptide was well characterized by both one- and two-dimensional (D) NMR spectroscopies. We find that the solution conformation is enriched with β-sheet structures, which have a propensity to self-assemble and form amyloid fibrils.


Abortion: at the still point of the turning conscientious objection debate.
Abortion is the central issue in the conscientious objection debate. In this article I demonstrate why this is so for two philosophical viewpoints prominent in American culture. One, represented by Patrick Lee and Robert P. George, holds that the fundamental moral value of being human can be found in bare life and the other, represented by Tom Beauchamp and James Childress, holds that this fundamental value is found in the life that can choose and determine itself. First, I articulate Lee and George's philosophical theory and demonstrate how the fundamental moral value of their theory, personhood, is represented in the issue of abortion. Second, I examine Beauchamp and Childress' theoretical vision and demonstrate how their fundamental moral value, the right to autonomous self-determination, is represented in abortion. Third, I sketch the theoretical and practical dynamics of the conscientious objection debate as well as each author's understanding of conscience. Fourth, I demonstrate how abortion, which represents their respective fundamental value, shapes each perspectives' approach to the conscientious objection debate. I conclude that because each theory finds its fundamental value represented in the issue of abortion, each perspective is bound to engage the conscientious objection debate in a way that centers on the issue of abortion.


Associations between Early Markers of Parkinson's Disease and Sarcopenia.
Introduction: Sarcopenia and Parkinson's disease (PD) are both common age-related syndromes, and there is preliminary evidence that the probability of the co-occurrence of these syndromes within one individual is higher than expected. However, it is unclear to date whether one of the syndromes induces the other, or whether there may be common underlying causes. This pilot study thus aimed at investigating the association of the features of increased risk for PD with early stage sarcopenia (ESS). Method: Two hundred and fifty-five community-dwelling individuals were recruited from the Tübinger evaluation of Risk factors for Early detection of NeuroDegeneration (TREND) study. The following features that are associated with an increased risk for future PD were evaluated: the motor part of the Unified PD Rating Scale (UPDRS-III), hyperechogenicity of the substantia nigra, prevalence of lifetime depression, hyposmia, REM sleep behavior disorder and the recently introduced probability score for prodromal PD. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People, which was adapted to this cohort of healthy adults. Multiple linear regression analysis was used to identify associations of PD-related features with ESS. Results: The UPDRS-III score was significantly associated with ESS. The result remained significant after the adjustment for age, gender and physical activity. No association was found between the other PD-related features and ESS. Conclusion: The significant association of the UPDRS-III score with ESS in this cohort might indicate a common and early pathway in both diseases and supports the existence of an "extended neurodegenerative overlap syndrome." Moreover, the potential of EES to serve as a prodromal marker of PD should be evaluated in future studies.


One-year outcome following biological or mechanical valve replacement for infective endocarditis.
Nearly half of patients require cardiac surgery during the acute phase of infective endocarditis (IE). We describe the characteristics of patients according to the type of valve replacement (mechanical or biological), and examine whether the type of prosthesis was associated with in-hospital and 1-year mortality. Among 5591 patients included in the International Collaboration on Endocarditis Prospective Cohort Study, 1467 patients with definite IE were operated on during the active phase and had a biological (37%) or mechanical (63%) valve replacement. Patients who received bioprostheses were older (62 vs 54years), more often had a history of cancer (9% vs 6%), and had moderate or severe renal disease (9% vs 4%); proportion of health care-associated IE was higher (26% vs 17%); intracardiac abscesses were more frequent (30% vs 23%). In-hospital and 1-year death rates were higher in the bioprosthesis group, 20.5% vs 14.0% (p=0.0009) and 25.3% vs 16.6% (p<.0001), respectively. In multivariable analysis, mechanical prostheses were less commonly implanted in older patients (odds ratio: 0.64 for every 10years), and in patients with a history of cancer (0.72), but were more commonly implanted in mitral position (1.60). Bioprosthesis was independently associated with 1-year mortality (hazard ratio: 1.298). Patients with IE who receive a biological valve replacement have significant differences in clinical characteristics compared to patients who receive a mechanical prosthesis. Biological valve replacement is independently associated with a higher in-hospital and 1-year mortality, a result which is possibly related to patient characteristics rather than valve dysfunction.


Essential surgery: Integral to the right to health.
In a rights-based approach to health, the provision of essential surgical services is not a luxury, but a critical component of the "highest attainable standard of health." Yet while access to select basic health care interventions has increasingly been discussed as part of the human right to health, essential surgical services have generally not been part of this discussion. This is despite the substantial global burden of surgical conditions in low- and middle-income countries, extreme global disparities in access to surgical care, and the fact that relatively simple, cost-effective, and curative surgical procedures can avert disability and premature death from many life-threatening emergencies and other conditions. Many barriers, both supply and demand-related, such as constraints in human resources, infrastructure, and access to care, have limited the ability of health systems to deliver surgical services. In this paper, the authors share their experience - as a group of surgeons, anesthesiologists, emergency physicians, and public health experts working with colleagues in varied resource-constrained settings to provide basic surgical care - in addressing the challenge of realizing the right to surgery in resource-poor settings. We argue that essential surgical care should be included in the basic human right to health, and that the current emphasis on "vertical" disease-specific models of health service delivery should be broadened to include systems needed to provide surgical services. We outline the global burden of surgical conditions, discuss the public health importance of surgery, identify the most significant global disparities in access to surgical care, and provide economic arguments for surgical delivery.


Temporal analysis of blister evolution during anion intercalation in graphite.
In the currently accepted picture, when graphite is immersed and polarized in a diluted sulfuric acid electrolyte, the surface undergoes an invasive process due to the intercalation of solvated sulphate anions inside the crystal. The following evolution of CO, CO2 and O2 promotes the surface swelling and the growth of blisters. Here, we give evidence that the appearance of blisters affects the graphite surface as soon as the oxygen potential is reached, i.e. before the traditionally accepted anion intercalation stage, which instead is demonstrated slowing the blister development. These results suggest a new picture of the solvated anion intercalation in graphite with respect to the current interpretative model.


Second harmonic generation in thin optical fibers via cladding modes.
Since silica goes under the category of amorphous materials, it is difficult to investigate important processes such as second harmonic generation (SHG) in silica-based fibers. In this paper, we proposed a method for SHG relaying on cladding modes as pump modes. Cladding modes are introduced in optical fibers through tilted long period grating (T-LPG), where power of core mode is transferred into cladding modes. By functionalizing T-LPG with nonlinear coating, the interaction occurs between cladding modes and the coating material, consequently second harmonic signal (SHS) is generated with efficiency up to 0.14%.


Meredys, a multi-compartment reaction-diffusion simulator using multistate realistic molecular complexes.
Most cellular signal transduction mechanisms depend on a few molecular partners whose roles depend on their position and movement in relation to the input signal. This movement can follow various rules and take place in different compartments. Additionally, the molecules can form transient complexes. Complexation and signal transduction depend on the specific states partners and complexes adopt. Several spatial simulator have been developed to date, but none are able to model reaction-diffusion of realistic multi-state transient complexes. Meredys allows for the simulation of multi-component, multi-feature state molecular species in two and three dimensions. Several compartments can be defined with different diffusion and boundary properties. The software employs a Brownian dynamics engine to simulate reaction-diffusion systems at the reactive particle level, based on compartment properties, complex structure, and hydro-dynamic radii. Zeroth-, first-, and second order reactions are supported. The molecular complexes have realistic geometries. Reactive species can contain user-defined feature states which can modify reaction rates and outcome. Models are defined in a versatile NeuroML input file. The simulation volume can be split in subvolumes to speed up run-time. Meredys provides a powerful and versatile way to run accurate simulations of molecular and sub-cellular systems, that complement existing multi-agent simulation systems. Meredys is a Free Software and the source code is available at http://meredys.sourceforge.net/.


Effects of arginine supplementation on mucosal immunity in rats with septic peritonitis.
Supplemental Arginine (Arg) has been demonstrated to improve the immunologic response and reduce mortality in rodents with sepsis. However, the effects of Arg on gut-associated lymphoid tissue function after infection and sepsis are not clear. The aim of this study was to study the effect of Arg-supplemented diets before and Arg-enriched total parenteral nutrition (TPN) after sepsis or both on the intestinal immunity of rats with septic peritonitis. Rats were assigned to four groups. Groups 1 and 2 were fed a semipurified diet, while in the diets of groups 3 and 4, part of the casein was replaced with Arg. After feeding the experimental diets for 10 days, sepsis was induced by cecal ligation and puncture (CLP); at the same time, the internal jugular vein was cannulated. All rats were maintained on TPN for 3 days. Groups 1 and 3 were infused with conventional TPN, while groups 2 and 4 were given a TPN solution supplemented with Arg, which replaced 10% of the total amino acids. All rats were sacrificed 3 days after CLP. Intestinal immunoglobin (Ig) A levels, total lymphocyte yields, and lymphocyte subpopulations in Peyer's patches were analyzed. In vitro cytokine secretion by splenocytes and Peyer's patch lymphocytes were also measured. Total lymphocyte yields in Peyer's patches, and small intestinal immunoglobulin A (IgA) secretion in group 4 were significantly higher than the groups 1 and 2. No differences were observed between groups 3 and 4. There were no differences in the interleukin (IL)-2 and interferon- gamma levels among all groups when splenocytes were stimulated with mitogen. However, in vitro splenocyte IL-10 production in group 4 was significantly higher than those of groups 1 and 2, and had no difference from group 3. There were no differences in the ratios of B and T lymphocyte subpopulations in Peyer's patches among all groups. Enteral Arg supplementation before sepsis tended to enhance total lymphocyte yields in Peyer's patches and intestinal IgA secretion. Arg administered both before and after CLP had a synergistic effect on improving intestinal immunity, possibly by enhancing systemic IL-10 secretion. However, intravenous Arg administration after CLP had no favorable effects on mucosal immunity in rats with septic peritonitis.


Outcome of patients who have therapy withheld or withdrawn in ICU.
Many deaths among patients treated in intensive care units (ICUs) occur following the withdrawal or withholding of life support. Following limitation of life support, most of these patients die in the ICU or ward after the decision to limit life support is made, although some may survive to hospital discharge. This study described the characteristics of patients who had life support limitations in ICU and their subsequent in-hospital and out-of-hospital survival using linked data from the state's death registry. Among 26,019 ICU admissions between 1987 and 2002 there were 396 patients (1.5%) who had life support limitations. The hospital mortality of the patients who had life support limitations was 97.7% and this accounted for 16.2% of the hospital mortality of all ICU admissions. Of the 396 patients who had life support limitations, 315 patients (79.5%) died in the ICU, 72 patients (18.2%) died in the wards and nine patients (2.3%) were discharged from hospital. Of these nine patients who survived to hospital discharge, four died within 10 days of hospital discharge and a further two died within six months. There were two patients, both with significant neurological disabilities at hospital discharge, who survived for longer than three years after hospital discharge. Long-term survival in critically ill patients who had life support limitations was very rare in this ICU.


Drug doping in senior Australian rules football: a survey for frequency.
To determine by survey whether the frequency of use of performance enhancing drugs (drug doping) is significant in elite players of Australian Rules football, and to compare this frequency with that in other competitions. Randomised unannounced prospective urine testing during the period 1990-95 of players from the Australian Football League out of competition, in competition matches, and in finals matches; testing was performed according to Olympic International Committee protocols and standards. The players' identities and clubs were unknown during testing. Of 900 random urine tests, no positive results were obtained for anabolic steroids, diuretics, caffeine, or peptide hormones. Five positive results (0.6%) were obtained-for pseudoephedrine in two instances, and for probenecid, methoxyphenamine, and dextropropoxyphene in one instance each. Each were inadvertent medical doping and declared before testing. Drug doping is not a problem in the Australian Football League. This is probably because no doping method is considered to be of value to Australian Rules football, because an educational programme is run by football authorities, and because random during season and out of season testing for drugs occurs.


Correlates of physical activity: why are some people physically active and others not?
Physical inactivity is an important contributor to non-communicable diseases in countries of high income, and increasingly so in those of low and middle income. Understanding why people are physically active or inactive contributes to evidence-based planning of public health interventions, because effective programmes will target factors known to cause inactivity. Research into correlates (factors associated with activity) or determinants (those with a causal relationship) has burgeoned in the past two decades, but has mostly focused on individual-level factors in high-income countries. It has shown that age, sex, health status, self-efficacy, and motivation are associated with physical activity. Ecological models take a broad view of health behaviour causation, with the social and physical environment included as contributors to physical inactivity, particularly those outside the health sector, such as urban planning, transportation systems, and parks and trails. New areas of determinants research have identified genetic factors contributing to the propensity to be physically active, and evolutionary factors and obesity that might predispose to inactivity, and have explored the longitudinal tracking of physical activity throughout life. An understanding of correlates and determinants, especially in countries of low and middle income, could reduce the eff ect of future epidemics of inactivity and contribute to effective global prevention of non-communicable diseases.


Fufang Kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via TRPV1 signaling pathways.
Cancer pain is a deleterious consequence of tumor growth and related inflammation. Opioids and anti-inflammatory drugs provide first line treatment for cancer pain, but both are limited by side effects. Fufang Kushen injection (FKI) is GMP produced, traditional Chinese medicine used alone or with chemotherapy to reduce cancer-associated pain. FKI limited mouse sarcoma growth both in vivo and in vitro, in part, by reducing the phosphorylation of ERK and AKT kinases and BAD. FKI inhibited TRPV1 mediated capsaicin-induced ERK phosphorylation and reduced tumor-induced proinflammatory cytokine production. Thus, FKI limited cancer pain both directly by blocking TRPV1 signaling and indirectly by reducing tumor growth.


Low-loss hybrid plasmonic modes guided by metal-coated dielectric wedges for subwavelength light confinement.
The optical characteristics of a metal-coated dielectric wedge structure are investigated at a wavelength of 1550 nm. The effects of the metal/gap layers' thicknesses, as well as the dimension of the dielectric wedge on the guided modes' properties, are systematically analyzed. It is revealed that the characteristics of the fundamental quasi-TE and quasi-TM plasmonic modes supported by the configuration demonstrate similar trends against the variation of the metal layer thickness while exhibiting quite different behaviors with the change of the wedge size. By choosing appropriate physical dimensions, both modes could simultaneously achieve low modal loss and subwavelength field confinement, along with reasonable mode power inside the low-index gap region. Investigations on the directional coupling between adjacent identical waveguides indicate that ultralow crosstalk can be enabled by the quasi-TE mode, with the coupling length more than two orders of magnitude larger than that achieved by the plasmonic mode in conventional hybrid counterparts. The presented metal-coated dielectric wedge structures can be employed as important building blocks for a number of integrated nanophotonic components, and could also enable numerous applications at the subwavelength scale.


Bedtime and evening light exposure influence circadian timing in preschool-age children: A field study.
Light exposure and sleep timing are two factors that influence inter-individual variability in the timing of the human circadian clock. The aim of this study was to quantify the degree to which evening light exposure predicts variance in circadian timing over and above bedtime alone in preschool children. Participants were 21 children ages 4.5-5.0 years (4.7 ± 0.2 years; 9 females). Children followed their typical sleep schedules for 4 days during which time they wore a wrist actigraph to assess sleep timing and a pendant light meter to measure minute-by-minute illuminance levels in lux. On the 5th day, children participated in an in-home dim-light melatonin onset (DLMO) assessment. Light exposure in the 2 h before bedtime was averaged and aggregated across the 4 nights preceding the DLMO assessment. Mean DLMO and bedtime were 19:22 ± 01:04 and 20:07 ± 00:46, respectively. Average evening light exposure was 710.1 ± 1418.2 lux. Children with later bedtimes (lights-off time) had more delayed melatonin onset times (r=0.61, p=0.002). Evening light exposure was not independently associated with DLMO (r=0.32, p=0.08); however, a partial correlation between evening light exposure and DLMO when controlling for bedtime yielded a positive correlation (r=0.46, p=0.02). Bedtime explained 37.3% of the variance in the timing of DLMO, and evening light exposure accounted for an additional 13.3% of the variance. These findings represent an important step in understanding factors that influence circadian phase in preschool-age children and have implications for understanding a modifiable pathway that may underlie late sleep timing and the development of evening settling problems in early childhood.


Tried and true: a survey of successfully promoted academic hospitalists.
Academic hospital medicine is a new and rapidly growing field. Hospitalist faculty members often fill roles not typically held by other academic faculty, maintain heavy clinical workloads, and participate in nontraditional activities. Because of these differences, there is concern about how academic hospitalists may fare in the promotions process. To determine factors critical to the promotion of successfully promoted hospitalists who have achieved the rank of either associate professor or professor. A cross-sectional survey. Thirty-three hospitalist faculty members at 22 academic medical centers promoted to associate professor rank or higher between 1995 and 2008. Respondents were asked to describe their institution, its promotions process, and the activities contributing to their promotion. We identified trends across respondents. Twenty-six hospitalists responded, representing 20 institutions (79% response rate). Most achieved promotion in a nontenure track (70%); an equal number identified themselves as clinician-administrators and clinician educators (40%). While hospitalists were engaged in a wide range of activities in the traditional domains of service, education, and research, respondents considered peer-reviewed publication to be the most important activity in achieving promotion. Qualitative responses demonstrated little evidence that being a hospitalist was viewed as a hindrance to promotion. Successful promotion in academic hospital medicine depends on accomplishment in traditional academic domains, raising potential concerns for academic hospitalists with less traditional roles. This study may provide guidance for early-career academic hospitalists and program leaders.


Oxidative responses of resistant and susceptible cereal leaves to symptomatic and nonsymptomatic cereal aphid (Hemiptera: Aphididae) feeding.
The impact of the leaf-chlorosis-eliciting Russian wheat aphid, Diuraphis noxia (Mordvilko), and the nonchlorosis-eliciting bird cherry-oat aphid, Rhopalosiphum padi (L.), feeding on D. noxia-susceptible and -resistant cereals was examined during the period (i.e., 3, 6, and 9 d after aphid infestation) that leaf chlorosis developed. After aphid number, leaf rolling and chlorosis ratings, and fresh leaf weight were recorded on each sampling date, total protein content, peroxidase, catalase, and polyphenol oxidase activities of each plant sample were determined spectrophotometrically. Although R. padi and D. noxia feeding caused significant increase of total protein content in comparison with the control cereal leaves, the difference in total protein content between R. padi and D. noxia-infested leaves was not significant. Although R. padi-feeding did not elicit any changes of peroxidase specific activity in any of the four cereals in comparison with the control leaves, D. noxia feeding elicited greater increases of peroxidase specific activity only on resistant 'Halt' wheat (Triticum aestivum L.) and susceptible 'Morex' barley (Hordeum vulgare L.), but not on susceptible 'Arapahoe' and resistant 'Border' oat (Avena sativa L.). D. noxia-feeding elicited a ninefold increase in peroxidase specific activity on Morex barley and a threefold on Halt wheat 9 d after the initial infestation in comparison with control leaves. Furthermore, D. noxia feeding did not elicit any differential changes of catalase and polyphenol oxidase activities in comparison with either R. padi feeding or control leaves. The findings suggest that D. noxia feeding probably results in oxidative stress in plants. Moderate increase of peroxidase activity (approximately threefold) in resistant Halt compared with susceptible Arapahoe wheat might have contributed to its resistance to D. noxia, whereas the ninefold peroxidase activity increase may have possibly contributed to barley's susceptibility. Different enzymatic responses in wheat, barley, and oat to D. noxia and R. padi feeding indicate the cereals have different mechanisms of aphid resistance.


Sarcomas in patients over 90: Natural history and treatment-A nationwide study over 6 years.
Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of human cancers. While the highest incidence of sarcomas is observed in elderly, this population is often excluded or poorly represented in clinical trials. The present study reports on clinicopathological presentation, and outcome of sarcoma patients over 90 recorded in the Netsarc.org French national database. NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor board (MDTB), funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB, second pathological review, and collection of sarcoma patient characteristics and follow-up are collected in a database Information of patients registered from January 1, 2010, to December 31, 2016, in NETSARC were collected, analyzed and compared to the younger population. Patients with sarcomas aged >90 have almost exclusively sarcomas with complex genomics (92.0% vs. 66.3%), are less frequently metastatic (5.3% vs. 14·7%) at diagnosis, have more often superficial tumors (39.8% vs. 14.7%), as well as limbs and head and neck sites (75.2% vs. 38.7%) (all p < 0.001). Optimal diagnostic procedures and surgery were less frequently performed in patients over 90 (p < 0.001). These patients were less frequently operated in NETSARC centers, as compared to those of younger age groups including aged 80-90. However, local relapse-free survival, metastatic relapse-free survival and relapse-free survival were not significantly different from those of younger patients, in the whole cohort, as well as in the subgroup of operated patients. As expected overall survival was worse in patients over 90 (p < 0.001). Patients over 90 who were not operated had worse overall survival than younger patients (9.9 vs. 27.3 months, p < 0.001). Patients with STS diagnosed after 90 have distinct clinicopathological features, but comparable relapse-free survival, unless clinical practice guidelines recommendations are not applied. Standard management should be proposed to these patients if oncogeriatric status allows.


Comparison of BMI and percentage of body fat of Indian and German children and adolescents.
Today, serious health problems as overweight and obesity are not just constricted to the developed world, but also increase in the developing countries (Prentice 2006, Ramachandram et al. 2002). Focusing on this issue, BMI and percentage of body fat were compared in 2094 schoolchildren from two cross-sectional studies from India and Germany investigated in 2008 and 2009. The German children are in all age groups significantly taller, whereas the Indian children show higher values in BMI (e.g. 12 years: Indian: around 22 kg/m2; German: around 19 kg/m2) and in the percentage of body fat (e.g. 12 years: Indian: around 27%; German: around 18-20%) in most of the investigated age groups. The Indian children have significantly higher BMI between 10 and 13 (boys) respectively 14 years (girls). Indian children showed significant higher percentage of body fat between 10 and 15 years (boys) and between 8 and 16 years (girls). The difference in overweight between Indian and German children was strongest at 11 (boys) and 12 (girls) years: 70% of the Indian but 20% of the German children were classified as overweight. In countries such as India that undergo nutritional transition, a rapid increase in obesity and overweight is observed. In contrast to the industrialized countries, the risk of overweight in developing countries is associated with high socioeconomic status. Other reasons of the rapid increase of overweight in the developing countries caused by different environmental or genetic factors are discussed.


Neuraminidase inhibitors during pregnancy and risk of adverse neonatal outcomes and congenital malformations: population based European register study.
Objective To evaluate the possible effects of exposure to neuraminidase inhibitors during embryo-fetal life with respect to adverse neonatal outcomes and congenital malformations.Design Population based multinational observational cohort study and meta-analysis.Setting National registers covering information on maternal healthcare, births, and prescriptions in Denmark, Norway, and Sweden and the EFEMERIS database from the Haute-Garonne district in France.Participants All women together with their singleton infants born between 1 January 2008 and 31 December 2010. Only infants born at 154 days of gestation or later were included. Infants were defined as exposed if the women filled a prescription during pregnancy for either of the two neuraminidase inhibitors oseltamivir or zanamivir.Main outcomes Low birth weight, low Apgar score, preterm birth, small for gestational age birth, stillbirth, neonatal mortality, neonatal morbidity, and congenital malformations. Crude and adjusted hazard ratios of preterm birth were estimated using Cox regression models. Crude and adjusted odds ratios for other outcomes were estimated by logistic regression models.Results The study included 5824 (0.8%) exposed women and their infants and 692 232 who were not exposed. Exposure to neuraminidase inhibitors in utero was not associated with increased risks of any of the investigated neonatal outcomes, including low birth weight (adjusted odds ratio 0.77, 95% confidence interval 0.65 to 0.91), low Apgar score (adjusted odds ratio 0.87, 0.67 to 1.14), preterm birth (adjusted hazard ratio 0.97, 0.86 to 1.10), small for gestational age birth (adjusted odds ratio 0.72, 0.59 to 0.87), stillbirth (adjusted odds ratio 0.81, 0.51 to 1.30), neonatal mortality (adjusted odds ratio 1.13, 0.56 to 2.28), and neonatal morbidity (adjusted odds ratio 0.92, 0.86 to 1.00). No increased risk of congenital malformations overall associated with maternal exposure was observed during the first trimester (adjusted odds ratio 1.06, 0.77 to 1.48). Similarly, no significantly increased risks of any of the outcomes were observed in an analysis restricted to oseltamivir alone.Conclusions This large multinational register study found no increased risks of adverse neonatal outcomes or congenital malformations associated with exposure to neuraminidase inhibitors during embryo-fetal life. The results support previously reported findings that the use of neuraminidase inhibitors is not associated with increased risks of adverse fetal or neonatal outcomes.


REG3β modifies cell tumor function by impairing extracellular vesicle uptake.
Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-sized membrane vesicles containing proteins and nucleic acids, which act as intercellular messengers. They play an important role in a variety of physiological processes, as well as in pathological situations such as inflammation or cancer. Here, we show that in the case of pancreatic ductal adenocarcinoma (PDAC), the healthy pancreatic tissue surrounding the tumor releases REG3β, a lectin that binds to the glycoproteins present in the surface of EVs, thus interfering with their uptake and internalization by target cells. In vitro, the disruption of the signaling mediated by EVs due to the presence of REG3β, prevents the EV-induced phenotypic switch in macrophages, inhibits the increased cell migration of cancer cells and reverses a number of metabolomic changes promoted by EVs. In vivo, the uptake of REG3β+ EVs by tumor cells is significantly impaired. Furthermore, it results in an increase of circulating REG3β+ EVs in blood of pancreatic cancer patients. Our findings highlight the effect of a lectin released by the healthy pancreatic tissue surrounding the tumor in modulating the EV-mediated interactions between different cell types in PDAC.


Impaired endothelium-dependent vascular reactivity in patients with familial combined hyperlipidaemia.
Familial combined hyperlipidaemia (FCHL) is associated with a markedly increased risk of premature coronary artery disease. This study was designed to evaluate whether preclinical atherosclerotic functional abnormalities are detectable in the arteries of patients with FCHL. 60 subjects were recruited for the study: 30 probands of families with FCHL (mean (standard deviation (SD)) age 48 (10) years, 77% men), defined by fasting total plasma cholesterol or triglyceride concentration >250 mg/dl (>6.5 mmol/l cholesterol, >2.8 mmol/l triglyceride) and by the occurrence of multiple lipoprotein phenotypes within a family, and 30 age-matched and sex-matched healthy controls. All subjects underwent high-resolution B-mode ultrasound examination and the brachial arterial reactivity, a marker of endothelial function, was measured by a semiautomated computerised program. Lipid profile, resting blood pressure, body mass index (BMI), smoking status, insulin and homocysteine levels were also determined. Compared with controls, patients with FCHL had significantly higher BMI, diastolic blood pressure and insulin levels. No difference was observed in baseline brachial diameter between the two groups (mean (SD) 3.45 (0.51) mm for FCHL v 3.60 (0.63) mm for controls; p = 0.17). In response to flow increase, the arteries of the controls dilated (mean (SD) 8.9% (4.9%), range 2.3-20.8%), whereas in the patients with FCHL, brachial arterial reactivity was significantly impaired (5.5% (2.5%), range 0-10.1%; p = 0.002). In multivariate linear regression analysis, apolipoprotein B and BMI were independent determinants of brachial artery response to reactive hyperaemia. The findings of our study suggest that vascular reactivity is impaired in the arteries of patients with FCHL.