Presence of JC virus-specific CTL in the cerebrospinal fluid of PML patients: rationale for immune-based therapeutic strategies.

OBJECTIVES: There is urgent need of a treatment for progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). To evaluate the rationale for immunotherapy of PML, we explored whether JCV-specific cytotoxic T lymphocytes (CTL) can penetrate the central nervous system (CNS). In addition, we studied the breadth of their T-cell receptor (TCR) repertoire, and sought to establish a reliable method to expand these cells in vitro. DESIGN AND METHODS: We enrolled 18 patients in this study, including 16 with proven or possible PML (15 HIV-positive and one HIV-negative), and two HIV-positive patients with other neurological diseases. Detection of JCV-specific CTL in the blood and the cerebrospinal fluid was performed by Cr release and tetramer staining assays in 15 patients. RESULTS: Of 11 PML patients with analyzable cerebrospinal fluid (CSF), two had no detectable JCV-specific CTL in the blood and CSF and died 3.7 and 7.2 months later. The nine remaining patients had an inactive course of PML and detectable JCV-specific CTL in the blood. In addition, four of them (44%) also had detectable JCV-specific CTL in the CSF. Both HIV-positive patients with OND had detectable JCV-specific CTL in the blood and one in the CSF. Using tetramer technology, we obtained highly enriched JCV-specific CTL lines that were able to kill target cells presenting JCV peptides. The breadth of the TCR repertoire was CTL epitope dependent. CONCLUSIONS: These results indicate that JCV-specific CTL are present in the CNS of PML patients and pave the way for an immune-based therapeutic approach.

Escalating epidemiology of eosinophilic esophagitis: 21 years of prospective population-based documentation in Olten county

Background and Aims: Eosinophilic Esophagitis (EoE) is detected with a dramatically increasingfrequency during the last decades. However, it is still unknown whether this reflects atrue increase in incidence or just an increased awareness by gastroenterologists. We therefore,prospectively assessed incidence and prevalence of EoE in an epidemiologically well definedindicator area over the last 21 years. Methods: Olten County is an area of approximately90,000 inhabitants without pronounced demographic changes during the last two decades.Two EoE-experienced gastroenterologists and one pathology centre are responsible forcovering the gastroenterological service of the area. No public programs for increasingawareness of EoE were implemented in this region. Since 1989 all individuals with confirmeddiagnosis of EoE living in Olten County were entered prospectively into the database. Results:Forty-six patients (76% males, mean age 41±16 yrs) were diagnosed with EoE between1989 and 2009. Ninety-four percent of patients presented with dysphagia. An average annualincidence rate of 1.88/100,000 was found (range 0-8) with a marked increase in the periodfrom 2004 to 2009. The cumulative EoE prevalence rose up to 35.1/100,000 inhabitantsin 2009. No significant change was observed for the median diagnostic delay, as it was 3years from 1989 to 1998 and 2 years from 1999 to 2009 with age < 40 years representinga risk factor for retarded diagnosis. The number of upper endoscopies per year increasedby 63% in the period from 1999 to 2009 compared to the years 1989 to 1998 which ismarkedly less then the increase in the incidence rate of 150% for the same periods. Conclusions:Over the last 21 years, a significant increase in EoE incidence and prevalence wasfound in an epidemiologically stable indicator region of Switzerland. The constant diagnosticdelay, the number of newly diagnosed EoE cases that was much more pronounced thanthe modest increase of performed upper endoscopies, as well as the lack of EoE awarenessprograms in Olten County indicates a true increase in EoE incidence.

Angiostrongylus costaricensis: complete redescription of the migratory pathways based on experimental Sigmodon hispidus infection

Angiostrongylus costaricensis lives in the cecal and mesenteric arteries of its vertebrate hosts, and causes an inflammatory disease in humans. To investigate unknown aspects of the abdominal angiostrogyliasis pathogenesis, infected Sigmodon hispidus were sequentially studied in different times of infection. The study revealed that L3 goes alternatively through two migratory courses during its development into an adult worm: lymphatic/venous-arterial and venous portal pathways. The former is considered the principal one, because it is used by most of the larvae. Like other metastrongylides, A. costaricensis passes over the pulmonary circulation to migrate from the lymphatic system to the arterial circulation, where they circulate during some days before reaching their definitive habitat. The oviposition by mature females began on 15th day. Eggs and L1 were detected mainly in the intestine and stomach, surrounded by inflammatory reaction constituted by macrophages, monocytes, and eosinophils. They were also spread to the lungs, mesenteric lymph nodes, pancreas, spleen, and kidneys. The larvae (L1) exhibited the centripetal capacity to invade the lymphatic and venous vessels of the intestine and mesentery. Adult worms that developed in the venous intrahepatic pathway migrated downstream to reach the mesenteric veins and laid eggs that embolized in the portal hepatic vessels.

Seroepidemiology of Herpes Simplex virus type 1 and 2 in Western and Southern Switzerland in adults aged 25-74 in 1992-93: a population-based study.

BACKGROUND: Genital herpes is one of the most prevalent sexually-transmitted diseases, and accounts for a substantial morbidity. Genital herpes puts newborns at risk for very severe disease and also increases the risk of horizontal HIV transmission. It thus stands as an important public health problem. The recent availability of type-specific gG-based assays detecting IgG against HSV-1 and HSV-2 allows to establish the prevalence of each subtype. Worldwide, few data have been published regarding the seroprevalence in general populations of HSV-2, the major causative agent for genital herpes, while no data exist regarding the Swiss population. METHODS: To evaluate the prevalence of IgG antibodies against HSV-1 and HSV-2 in Switzerland, we used a population-based serum repository from a health examination survey conducted in the Western and Southern area of Switzerland in 1992-93. A total of 3,120 sera were analysed by type-specific gG-based ELISA and seroprevalence was correlated with available volunteers characteristics by logistic regression. RESULTS: Overall, seroprevalence rates were 80.0 +/- 0.9% (SE, 95% CI: 78.1-81.8) for HSV-1 and 19.3 +/- 0.9% (SE, 95% CI: 17.6-21.1) for HSV-2 in adults 35-64 year old. HSV-1 and HSV-2 seroprevalence increased with age, with a peak HSV-2 seroprevalence in elderly gentlemen, possibly a seroarcheological evidence of sexually transmitted disease epidemics during World War II. Risk factors for HSV-2 infection included female sex, marital status other than married, and size of town of residence larger than 1500 inhabitants. Unexpectedly and conversely to HSV-1, HSV-2 seroprevalence increased with educational level. HSV-2 infection was less prevalent among HSV-1 infected individuals when compared to HSV-1 uninfected individuals. This effect was most apparent among women at high risk for HSV-2 infection. CONCLUSIONS: Our data demonstrate that by the early nineties, HSV-2 had spread quite largely in the Swiss population. However, the epidemiology of HSV-2 in Switzerland presents paradoxical characteristics, e.g. positive correlation with education level, that have not been observed elsewhere.

Molecular characterization of Leptospira sp. strains isolated from human subjects in São Paulo, Brazil using a polymerase chain reaction-based assay: a public health tool

A polymerase chain reaction (PCR)-based assay which amplifies repetitive DNA elements present within bacterial genomes was used to characterize and differentiate Leptospira sp. Thirty-five strains from a reference culture collection and 18 clinical isolates which had been previously analyzed by cross agglutinin absorption test (CAAT) were evaluated by this technique. PCR results from analysis of the reference culture collection showed no bands corresponding to serogroups Australis, Autumnalis, Bataviae, Celledoni, Cynopteri, Djasiman, Panama, Pomona, Pyrogenes, and Tarassovi. However, the PCR method was able to clearly discriminate the serogroups Andamana, Ballum, Canicola, Grippotyphosa, Hebdomadis, Icterohaemorrhagiae, Javanica, Sejroe, Semaranga, and Shermani. Clinical isolates previously characterized by CAAT as serovar Copenhageni, serovar Castellonis, and as serovar Canicola were in agreement with PCR results. The clinical isolate previously characterized as serovar Pomona was not differentiated by PCR. Forty additional clinical isolates from patients with leptospirosis obtained in São Paulo, Brazil were also evaluated by this PCR method. Thirty-nine of these were determined to belong to serogroup Icterohaemorrhagiae (97.5%) and one to serogroup Sejroe (2.5%). These results demonstrate that the PCR method described in this study has utility for rapid typing of Leptospira sp. at the serogroup level and can be used in epidemiological survey.

Quality of Web-based information on obsessive compulsive disorder.

BACKGROUND: The Internet is increasingly used as a source of information for mental health issues. The burden of obsessive compulsive disorder (OCD) may lead persons with diagnosed or undiagnosed OCD, and their relatives, to search for good quality information on the Web. This study aimed to evaluate the quality of Web-based information on English-language sites dealing with OCD and to compare the quality of websites found through a general and a medically specialized search engine. METHODS: Keywords related to OCD were entered into Google and OmniMedicalSearch. Websites were assessed on the basis of accountability, interactivity, readability, and content quality. The "Health on the Net" (HON) quality label and the Brief DISCERN scale score were used as possible content quality indicators. Of the 235 links identified, 53 websites were analyzed. RESULTS: The content quality of the OCD websites examined was relatively good. The use of a specialized search engine did not offer an advantage in finding websites with better content quality. A score ≥16 on the Brief DISCERN scale is associated with better content quality. CONCLUSION: This study shows the acceptability of the content quality of OCD websites. There is no advantage in searching for information with a specialized search engine rather than a general one. Practical implications: The Internet offers a number of high quality OCD websites. It remains critical, however, to have a provider-patient talk about the information found on the Web.

Alcohol MOT part one

The Alcohol MOT is designed to support those working in primary care to carry out alcohol brief interventions. There is extensive evidence to show that primary care-based brief interventions are very effective at reducing drinking at both hazardous and harmful levels. MOT Part 1 enables patients to work out if they are drinking at hazardous or harmful levels. MOT Part 2 helps motivate and support patients to reduce their drinking. Both tools are designed so that a practitioner can work through them with a patient, or a patient can work through them alone.

Cladistic analysis of the subgenus Anopheles (Anopheles) Meigen (Diptera: Culicidae) based on morphological characters

In the present study, we used morphological characters to estimate phylogenetic relationships among members of the subgenus Anopheles Meigen. Phylogenetic analyses were carried out for 36 species of Anopheles (Anopheles). An. (Stethomyia) kompi Edwards, An. (Lophopodomyia) gilesi (Peryassú), Bironella hollandi Taylor, An. (Nyssorhynchus) oswaldoi (Peryassú) and An. (Cellia) maculatus Theobald were employed as outgroups. One hundred one characters of the external morphology of the adult male, adult female, fourth-instar larva, and pupa were scored and analyzed under the parsimony criterion in PAUP. Phylogenetic relationships among the series and several species informal groups of Anopheles (Anopheles) were hypothesized. The results suggest that Anopheles (Anopheles) is monophyletic. Additionally, most species groups included in the analysis were demonstrated to be monophyletic.

'Bio-nano interactions: new tools, insights and impacts': summary of the Royal Society discussion meeting

Bio-nano interactions can be defined as the study of interactions between nanoscale entities and biological systems such as, but not limited to, peptides, proteins, lipids, DNA and other biomolecules, cells and cellular receptors and organisms including humans. Studying bio-nano interactions is particularly useful for understanding engineered materials that have at least one dimension in the nanoscale. Such materials may consist of discrete particles or nanostructured surfaces. Much of biology functions at the nanoscale; therefore, our ability to manipulate materials such that they are taken up at the nanoscale, and engage biological machinery in a designed and purposeful manner, opens new vistas for more efficient diagnostics, therapeutics (treatments) and tissue regeneration, so-called nanomedicine. Additionally, this ability of nanomaterials to interact with and be taken up by cells allows nanomaterials to be used as probes and tools to advance our understanding of cellular functioning. Yet, as a new technology, assessment of the safety of nanomaterials, and the applicability of existing regulatory frameworks for nanomaterials must be investigated in parallel with development of novel applications. The Royal Society meeting 'Bio-nano interactions: new tools, insights and impacts' provided an important platform for open dialogue on the current state of knowledge on these issues, bringing together scientists, industry, regulatory and legal experts to concretize existing discourse in science law and policy. This paper summarizes these discussions and the insights that emerged.

Patterns of pain freedom response in 497 cases with classical trigeminal neuralgia and at least one year of follow-up treated by gamma knife radiosurgery

Purpose: To identify patterns of initially pain freedom response in patients with classical trigeminal neuralgia (CTN) with Gamma Knife surgery (GKS) and to compare their associated hypoesthesia and recurrence rates. Methods: In this study we analysed only 497 patients treated between July 1992 and November 2010, with a follow-up longer than 1 year, after excluding megadolichobasilar artery and multiple sclerosis related trigeminal neuralgia, as well as the second GKS treatments so as to have only cases with CTN and single radiosurgical treatment. GKS using a Gamma Knife (model B or C or Perfexion) was performed, based on both MRI and computer tomography (CT) targeting. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.8 mm (range 4.5-14) anteriorly to the emergence of the nerve. A median maximum dose of 85 Gy (range 70-90) was delivered. After empiric methods but also by using a chart with clear cut-off periods of pain free distribution, we were able to divide the initially pain free patients into 3 separate groups: within the first 48 hours, after 48 hours till 30 days and after 30 days, respectively. Results: The median follow- up period was 43.75 months (range 12-174.41). Four hundred and fifty-four patients (91.75%) were initially pain free in a median time of 10 days (range 1-459): 169 (37.2%) became pain free within the first 48 hours (pf<=48 h), compared to 194 (42.8%) between the 3-rd day and the day 30 (pf (>48 h, <=30 d)), inclusively and 91 (20%) patients after 30 days (pf>30d). Differences in terms of postoperative hypoesthesia were found with a p value of 0.014 as follows: the group pf<=48 h had 18 (13.7%) compared to pf (>48 h, <=30 d) with 30 (19%) and pf>30d with 22 (30.5%) patients developing a postoperative GKS hypoesthesia. One hundred and fifty seven (34.4%) patients initially pain free experienced a recurrence with a median delay of 24 months (range 0.62-150.06). There were no statistically significant differences between the three groups concerning recurrence (p value of 0.515). Conclusions: An important number of patients (169 cases, 37.2%) became pain free in the first 48 hours. Hypoesthesia rate was higher within the group becoming pain free after 30 days with a statistically significant difference between the three populations (p= 0.014). Further analysis will eventually help to elucidate the differences observed among groups.

The significance of pre-existing minority Y181C mutations on virological failure of NNRTI-based, first-line antiretroviral therapy

Background: Reduced re'nal function has been reported with tenofovir disoproxil fumarate (TDF). It is not clear whether TDF co-administered with a boosted protease inhibitor (PI) leads to a greater decline in renal function than TDF co-administered with a non-nucleoside reverse transcriptase inhibitor (NNRTI).Methods: We selected ail antiretroviral therapy-naive patients in the Swiss HIV Cohort Study (SHCS) with calibrated or corrected serum creatinine measurements starting antiretroviral therapy with TDF and either efavirenz (EFV) or the ritonavir-boosted PIs, lopinavir (LPV/r) or atazanavir (ATV/r). As a measure of renal function, we used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate the glomerular filtration rate (eGFR). We calculated the difference in eGFR over time between two therapies using a marginal model for repeated measures. In weighted analyses, observations were weighted by the product of their point of treatment and censoring weights to adjust for differences both in the sort of patients starting each therapy and in the sort of patients remaining on each therapy over time.Results: By March 2011, 940 patients with at least one creatinine measurement on a first therapy with either TDF and EFV (n=484), TDF and LPVlr (n=269) or TDF and ATV/r (n=187) had been followed for a median of 1. 7, 1.2 and 1.3 years, respectively. Table 1 shows the difference in average estimated GFR (eGFR) over time since starting cART for two marginal models. The first model was not adjusted for potential confounders; the second mode! used weights to adjust for confounders. The results suggest a greater decline in renal function during the first 6 months if TDF is used with a PI rather than with an NNRTI, but no further difference between these therapies after the first 6 months. TDF and ATV/r may lead to a greater decline in the first 6 months than TDF and LPVlr.Conclusions: TDF co-administered with a boosted PI leads to a greater de cline in renal function over the first 6 months of therapy than TDF co-administered with an NNRTI; this decline may be worse with ATV/r than with LPV/r.

Association between social relationships and survival of Swiss octogenarians. A five-year prospective, population-based study.

BACKGROUND AND AIMS: Data from the literature reveal the contrasting influences of family members and friends on the survival of old adults. On one hand, numerous studies have reported a positive association between social relationships and survival. On the other, ties with children may be associated with an increased risk of disability, whereas ties with friends or other relatives tend to improve survival. A five-year prospective, population-based study of 295 Swiss octogenarians tested the hypothesis that having a spouse, siblings or close friends, and regular contacts with relatives or friends are associated with longer survival, even at a very old age. METHODS: Data were collected through individual interviews, and a Cox regression model was applied to assess the effects of kinship and friendship networks on survival, after adjusting for socio-demographic and health-related variables. RESULTS: Our analyses indicate that the presence of a spouse in the household is not significantly related to survival, whereas the presence of siblings at baseline improves the oldest old's chances of surviving five years later. Moreover, the existence of close friends is a central component in the patterns of social relationships of oldest adults, and one which is significantly associated with survival. Overall, the protective effect of social relationships on survival is more related to the quality of those relationships (close friends) than to the frequency of relationships (regular contacts). CONCLUSIONS: We hypothesize that the existence of siblings or close friends may beneficially affect survival, due to the potential influence on the attitudes of octogenarians regarding health practices and adaptive strategies.

Mejora diagnóstica de hepatopatías de afectación difusa mediante técnicas de inteligencia artificial

The automatic diagnostic discrimination is an application of artificial intelligence techniques that can solve clinical cases based on imaging. Diffuse liver diseases are diseases of wide prominence in the population and insidious course, yet early in its progression. Early and effective diagnosis is necessary because many of these diseases progress to cirrhosis and liver cancer. The usual technique of choice for accurate diagnosis is liver biopsy, an invasive and not without incompatibilities one. It is proposed in this project an alternative non-invasive and free of contraindications method based on liver ultrasonography. The images are digitized and then analyzed using statistical techniques and analysis of texture. The results are validated from the pathology report. Finally, we apply artificial intelligence techniques as Fuzzy k-Means or Support Vector Machines and compare its significance to the analysis Statistics and the report of the clinician. The results show that this technique is significantly valid and a promising alternative as a noninvasive diagnostic chronic liver disease from diffuse involvement. Artificial Intelligence classifying techniques significantly improve the diagnosing discrimination compared to other statistics.

Personality and melanin-based colouration traits in barn owls, tawny owl and kestrels

Individuals need to adapt to their local environment in order to survive. When selection pressures differ in local populations, polymorphism can evolve. Colour polymorphism is one of the most obvious polymorphisms since it is readily observable. Different sources of colouration exist, but melanin-based colouration is one of the most common in birds. The melanocortin system produces this colouration and because the melanocortin system has pleiotropic effects on behavioural and physiological traits, it is a good candidate to be an underlying mechanism to explain the maintenance of colour polymorphism. In this thesis I studied three different raptors which all display melanin-based colouration; barn owls (Tyto alba), tawny owls (Strix aluco) and Eurasian kestrels (Falco tinnunculus). The main question was if there was a relationship between melanin-based colouration and individual behavioural differences. The underlying hypothesis is that colour could be a signal of certain adaptive traits. Our goal was to find evolutionary explanations for the persistence of colour polymorphism. I found that nestling kestrels and barn owls differ in anti-predatory behaviour, with respect to their melanic colouration (chapters 1 and 2). Darker individuals show less reaction to human handling, but in kestrels aggression and colouration are related in opposite ways than in barn owls. More reddish barn owls travel greater distances in natal dispersal and this behaviour is repeatable between parents and same sex offspring (chapter 3). Dark reddish tawny owls defend their nests more intensely against intruders and appear to suffer less from nest predation (chapter 4). Finally I show that polymorphism in the Melanocortin 1 receptor gene (MC1R), which is strongly correlated with reddish colouration in the barn owl, is related to natal dispersal distance, providing a first indication for a genetic basis of the relation between this behaviour and colouration (chapter 5). My results demonstrate a clear link between melanin-based colouration and animal personality traits. I demonstrated this relation in three different species, which shows there is most likely a general underlying mechanism responsible. Different predation pressures might have shaped the reactions to predation, but also differences in sex-related colouration. Male-like and female-like colouration might signal more or less aggressive behaviour. Fluctuating environmental conditions might cause different individual strategies to produce equal reproductive success. The melanocortin system with its pleiotropic effects might be an underlying mechanism, as suggested by the results from the genetic polymorphism, the similar results found in these three species and by the similar relations reported in other species. This thesis demonstrates that colouration and individual differences are correlated and it provides the first glimpse of an underlying system. We can now conduct a more directed search for underlying mechanisms and evolutionary explanations with the use of quantitative genetic methods.

Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study.

Objective To compute the burden of cancer attributable to current and former alcohol consumption in eight European countries based on direct relative risk estimates from a cohort study. Design Combination of prospective cohort study with representative population based data on alcohol exposure. Setting Eight countries (France, Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Participants 109 118 men and 254 870 women, mainly aged 37-70. Main outcome measures Hazard rate ratios expressing the relative risk of cancer incidence for former and current alcohol consumption among EPIC participants. Hazard rate ratios combined with representative information on alcohol consumption to calculate alcohol attributable fractions of causally related cancers by country and sex. Partial alcohol attributable fractions for consumption higher than the recommended upper limit (two drinks a day for men with about 24 g alcohol, one for women with about 12 g alcohol) and the estimated total annual number of cases of alcohol attributable cancer. Results If we assume causality, among men and women, 10% (95% confidence interval 7 to 13%) and 3% (1 to 5%) of the incidence of total cancer was attributable to former and current alcohol consumption in the selected European countries. For selected cancers the figures were 44% (31 to 56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%) and 18% (−3 to 38%) for liver, 17% (10 to 25%) and 4% (−1 to 10%) for colorectal cancer for men and women, respectively, and 5.0% (2 to 8%) for female breast cancer. A substantial part of the alcohol attributable fraction in 2008 was associated with alcohol consumption higher than the recommended upper limit: 33 037 of 178 578 alcohol related cancer cases in men and 17 470 of 397 043 alcohol related cases in women. Conclusions In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits. These data support current political efforts to reduce or to abstain from alcohol consumption to reduce the incidence of cancer.