Aggravation of chronic stress effects on hippocampal neurogenesis and spatial memory in LPA₁ receptor knockout mice.

BACKGROUND The lysophosphatidic acid LPA₁ receptor regulates plasticity and neurogenesis in the adult hippocampus. Here, we studied whether absence of the LPA₁ receptor modulated the detrimental effects of chronic stress on hippocampal neurogenesis and spatial memory. METHODOLOGY/PRINCIPAL FINDINGS Male LPA₁-null (NULL) and wild-type (WT) mice were assigned to control or chronic stress conditions (21 days of restraint, 3 h/day). Immunohistochemistry for bromodeoxyuridine and endogenous markers was performed to examine hippocampal cell proliferation, survival, number and maturation of young neurons, hippocampal structure and apoptosis in the hippocampus. Corticosterone levels were measured in another a separate cohort of mice. Finally, the hole-board test assessed spatial reference and working memory. Under control conditions, NULL mice showed reduced cell proliferation, a defective population of young neurons, reduced hippocampal volume and moderate spatial memory deficits. However, the primary result is that chronic stress impaired hippocampal neurogenesis in NULLs more severely than in WT mice in terms of cell proliferation; apoptosis; the number and maturation of young neurons; and both the volume and neuronal density in the granular zone. Only stressed NULLs presented hypocortisolemia. Moreover, a dramatic deficit in spatial reference memory consolidation was observed in chronically stressed NULL mice, which was in contrast to the minor effect observed in stressed WT mice. CONCLUSIONS/SIGNIFICANCE These results reveal that the absence of the LPA₁ receptor aggravates the chronic stress-induced impairment to hippocampal neurogenesis and its dependent functions. Thus, modulation of the LPA₁ receptor pathway may be of interest with respect to the treatment of stress-induced hippocampal pathology.

Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial.

BACKGROUND Granulocyte colony-stimulating factors (G-CSFs) have been shown to help prevent febrile neutropenia in certain subgroups of cancer patients undergoing chemotherapy, but their role in treating febrile neutropenia is controversial. The purpose of our study was to evaluate-in a prospective multicenter randomized clinical trial-the efficacy of adding G-CSF to broad-spectrum antibiotic treatment of patients with solid tumors and high-risk febrile neutropenia. METHODS A total of 210 patients with solid tumors treated with conventional-dose chemotherapy who presented with fever and grade IV neutropenia were considered to be eligible for the trial. They met at least one of the following high-risk criteria: profound neutropenia (absolute neutrophil count <100/mm(3)), short latency from previous chemotherapy cycle (<10 days), sepsis or clinically documented infection at presentation, severe comorbidity, performance status of 3-4 (Eastern Cooperative Oncology Group scale), or prior inpatient status. Eligible patients were randomly assigned to receive the antibiotics ceftazidime and amikacin, with or without G-CSF (5 microg/kg per day). The primary study end point was the duration of hospitalization. All P values were two-sided. RESULTS Patients randomly assigned to receive G-CSF had a significantly shorter duration of grade IV neutropenia (median, 2 days versus 3 days; P = 0.0004), antibiotic therapy (median, 5 days versus 6 days; P = 0.013), and hospital stay (median, 5 days versus 7 days; P = 0.015) than patients in the control arm. The incidence of serious medical complications not present at the initial clinical evaluation was 10% in the G-CSF group and 17% in the control group (P = 0.12), including five deaths in each study arm. The median cost of hospital stay and the median overall cost per patient admission were reduced by 17% (P = 0.01) and by 11% (P = 0.07), respectively, in the G-CSF arm compared with the control arm. CONCLUSIONS Adding G-CSF to antibiotic therapy shortens the duration of neutropenia, reduces the duration of antibiotic therapy and hospitalization, and decreases hospital costs in patients with high-risk febrile neutropenia.

Compliance with guidelines-recommended processes in pneumonia: impact of health status and initial signs

Initial care has been associated with improved survival of community-acquired pneumonia (CAP). We aimed to investigate patient comorbidities and health status measured by the Charlson index and clinical signs at diagnosis associated with adherence to recommended processes of care in CAP. We studied 3844 patients hospitalized with CAP. The evaluated recommendations were antibiotic adherence to Spanish guidelines, first antibiotic dose <6 hours and oxygen assessment. Antibiotic adherence was 72.6%, first dose <6 h was 73.4% and oxygen assessment was 90.2%. Antibiotic adherence was negatively associated with a high Charlson score (Odds ratio [OR], 0.91), confusion (OR, 0.66) and tachycardia ≥100 bpm (OR, 0.77). Delayed first dose was significantly lower in those with tachycardia (OR, 0.75). Initial oxygen assessment was negatively associated with fever (OR, 0.61), whereas tachypnea ≥30 (OR, 1.58), tachycardia (OR, 1.39), age >65 (OR, 1.51) and COPD (OR, 1.80) were protective factors. The combination of antibiotic adherence and timing <6 hours was negatively associated with confusion (OR, 0.69) and a high Charlson score (OR, 0.92) adjusting for severity and hospital effect, whereas age was not an independent factor. Deficient health status and confusion, rather than age, are associated with lower compliance with antibiotic therapy recommendations and timing, thus identifying a subpopulation more prone to receiving lower quality care.

Lung cancer in HIV-infected patients

Purpose: Several studies have shown that HIV patients are at higher risk of lung cancer. Our aim is to analyse the prevalence and features of lung cancer in HIV-infected patients. Methods: The clinical charts of 4,721 HIV-infected patients seen in three hospitals of southeast Spain (study period 1992-2012) were reviewed, and all patients with a lung cancer were analysed. Results: There were 61 lung cancers, giving a prevalence of 1.2%. There was a predominance of men (82.0%), and smokers (96.6%; mean pack-years 35.2), with a median age of 48.0 (41.7-52.9) years, and their distribution according to risk group for HIV was: intravenous drug use 58.3%, homosexual 20.0%, and heterosexual 16.7%. Thirty-four (56.7%) patients were Aids cases, and 29 (47.5%) had prior pulmonar events: tuberculosis 16, bacterial pneumonia 9, and P. jiroveci pneumonia 4. The median nadir CD4 count was 149/mm3 (42-232), the median CD4 count at the time of diagnosis of the lung cancer was 237/mm3 (85-397), and 66.1% <350/mm3. 66.7% were on ART, and 70% of them had undetectable HIV viral load. The most common histological types of lung cancer were adenocarcinoma and epidermoid, with 24 (40.0%) and 23 (38.3%) cases, respectively. There were 49 (80.3%) cases with advanced stages (III and IV) at diagnosis. The distribution of treatments was: only palliative 23 (39.7%), chemotherapy 14 (24.1%), surgery and chemotherapy 8 (13.8%), radiotherapy 7 (12.1%), surgery 4 (6.9%), and other combined treatments 2 (3.4%). Forty-six (76.7%) patients died, with a median survival time of 3 months. The Kaplan-Meier survival rate at 6 months was 42.7% (at 12 months 28.5%). Conclusions: The prevalence of lung cancer in this cohort of HIV-patients is high. People affected are mainly men, smokers, with transmission of HIV by intravenous drug use, and around half of them with prior opportunistic pulmonary events. Most patients had low nadir CD4 count, and were immunosuppressed at the time of diagnosis. Adenocarcinoma is the most frequent histological type. The diagnosis is usually made at advanced stages of the neoplasm, and mortality is high.

Intelligent PCA contribution analysis for quality estimation in batch processes. Application in a sequencing batch reactor for wastewater treatment

En aquest treball, es proposa un nou mètode per estimar en temps real la qualitat del producte final en processos per lot. Aquest mètode permet reduir el temps necessari per obtenir els resultats de qualitat de les anàlisi de laboratori. S'utiliza un model de anàlisi de componentes principals (PCA) construït amb dades històriques en condicions normals de funcionament per discernir si un lot finalizat és normal o no. Es calcula una signatura de falla pels lots anormals i es passa a través d'un model de classificació per la seva estimació. L'estudi proposa un mètode per utilitzar la informació de les gràfiques de contribució basat en les signatures de falla, on els indicadors representen el comportament de les variables al llarg del procés en les diferentes etapes. Un conjunt de dades compost per la signatura de falla dels lots anormals històrics es construeix per cercar els patrons i entrenar els models de classifcació per estimar els resultas dels lots futurs. La metodologia proposada s'ha aplicat a un reactor seqüencial per lots (SBR). Diversos algoritmes de classificació es proven per demostrar les possibilitats de la metodologia proposada.

A three-year aeropalynological study in Estepona (southern Spain).

An aeropalynological study was carried out in the atmosphere of Estepona, a very popular tourist resort situated in the "Costa del Sol", (southern Spain) based on the data obtained during a three year air-monitoring programme (March 1995 to March 1998) using a volumetric pollen trap. The 34 taxa that reached a 10-day mean air pollen concentration equal to or greater than 1 grain of pollen/m(3) of air are reflected in the calendar. The first 10 taxa, in order of abundance, were: Cupressaceae, Olea europaea, Quercus, Poaceae, Urticaceae, Plantago, Pinus, Chenopodiaceae-Amaranthaceae, Ericaceae and Castanea, the first 3 of which accounted for approximately 56 % of the annual total pollen count. The greatest diversity of pollen type occurred during spring, while the highest pollen concentrations were reached from February-June, when approximately more than 80 % of the annual total pollen was registered. The lowest concentrations were obtaining during January, August and September. The annual quantity of pollen collected, the intensity and the dates on which the maximum peaks were recorded differed for the 3 years studied, which can be explained by reference to various meteorological parameters, especially rainfall and temperature. The pollen calendar spectrum is typically Mediterranean and similar to those of nearby localities, in which many pollen types are represented and the long tails indicating long flowering periods.

Candidiasis cutánea generalizada en recién nacido a término.

INTRODUCTION Cutaneous candidiasis is a disease that affects children as well as adults. The presentation may be localized or systemic, and with multiple etiological agents. The most prevalent infecting species in children differs from that of the adult. OBJECTIVE A case is presented where a congenital cutaneous candidiasis was transmitted to the child during birth. MATERIALS AND METHODS A full term newborn was exposed to a subclinical vaginal candidiasis infection, and 24 hr after birth, developed congenital cutaneous candidiasis. The etiological agent was Candida albicans, and was associated with sepsis and respiratory distress. Blood cultures, cutaneous biopsy of vesicular lesions, blood tests and lumbar puncture were performed. RESULTS Biochemistry and blood count showed a CRP of 5.7 mg/dl, leukocytosis with left shift and mild anemia. After 24 hr, the blood analyses showed an increase in a CRP (7.8 mg/dl) and increased progressively for three days; consequently, a lumbar puncture was performed. Blood culture was positive for Staphylococcus aureus. Cutaneous biopsy confirmed the cutaneous candidiasis. CONCLUSIONS The early diagnosis is essential to prevent complications derived by the Candida albicans in newborns.

Inference about the number of contributors to a DNA mixture: Comparative analyses of a Bayesian network approach and the maximum allele count method.

In the forensic examination of DNA mixtures, the question of how to set the total number of contributors (N) presents a topic of ongoing interest. Part of the discussion gravitates around issues of bias, in particular when assessments of the number of contributors are not made prior to considering the genotypic configuration of potential donors. Further complication may stem from the observation that, in some cases, there may be numbers of contributors that are incompatible with the set of alleles seen in the profile of a mixed crime stain, given the genotype of a potential contributor. In such situations, procedures that take a single and fixed number contributors as their output can lead to inferential impasses. Assessing the number of contributors within a probabilistic framework can help avoiding such complication. Using elements of decision theory, this paper analyses two strategies for inference on the number of contributors. One procedure is deterministic and focuses on the minimum number of contributors required to 'explain' an observed set of alleles. The other procedure is probabilistic using Bayes' theorem and provides a probability distribution for a set of numbers of contributors, based on the set of observed alleles as well as their respective rates of occurrence. The discussion concentrates on mixed stains of varying quality (i.e., different numbers of loci for which genotyping information is available). A so-called qualitative interpretation is pursued since quantitative information such as peak area and height data are not taken into account. The competing procedures are compared using a standard scoring rule that penalizes the degree of divergence between a given agreed value for N, that is the number of contributors, and the actual value taken by N. Using only modest assumptions and a discussion with reference to a casework example, this paper reports on analyses using simulation techniques and graphical models (i.e., Bayesian networks) to point out that setting the number of contributors to a mixed crime stain in probabilistic terms is, for the conditions assumed in this study, preferable to a decision policy that uses categoric assumptions about N.

Syphilis in HIV-infected patients: Predictors for serological failure and serofast state.

Purpose: HIV-infected patients treated for syphilis may be at increased risk for serological failure and serofast state. Our aim was to analyse serological response to treatment in HIV-infected patients diagnosed with syphilis, and factors associated with serological cure and serofast state. Methods: Open-label, no controlled study of a series of HIV- patients diagnosed with syphilis during 2004-2011. Patients were categorized by rapid plasma reagin titer (RPR) into success (4-fold decrease in RPR by 12 or 24 months after treatment of early or late syphilis), serofast (success with persistently stable reactive RPR), and failure/ re-infection ( failure to decrease 4-fold in RPR by 12 or 24 months after treatment or sustained 4-fold increase in RPR after treatment response). Results: 141 HIV- patients were diagnosed with syphilis during the study period (104 early syphilis, 36 late or indeterminate latent syphilis). The mean age was 36.3 years, 98.5% were male, and 87.2% homosexual men. In 46 (32.6%) cases, HIV and syphilis infection diagnosis were coincident (mean CD4 457/mm3 and HIV-VL 4.72 log10). Among patients with prior known HIV infection, 65 were on antiretroviral therapy (ART) at syphilis diagnosis (mean CD4 469/ mm3, 76.9% undetectable HIV-VL). 116 patients satisfied criteria for serological response analysis (89 early, 24 late/indeterminate). At 12 months of early syphilis treatment (89.2% penicillin) there were 16 (18%) failures, and at 24 months of late/indeterminate syphilis (91.7% penicillin) there were 5 (18.5%) failures. Overall, 36 (31.0%) patients presented serofast state. Treatment failure was related with lower CD4 count (295 vs 510/μL; p=0.045) only in patients with coincident diagnosis. Serofast state was related with older age (41 vs 36 years; p=0.024), and lower CD4 count (391 vs 513/mm3; p=0.026). Conclusions: In this series of HIV-infected patients, with many patients on ART and with good immunological and virological parameters, serological failure and serofast state were frequent. Immunological status, and age could influence on serological response to syphilis treatment in HIV-infected patients.

Bone turnover markers in HIV-infected patients before starting antiretroviral therapy.

Purpose: Bone turnover markers (BTM) - aminoterminal propeptide of type 1 collagen (P1NP) and C-terminal telopeptide of type 1 collagen (b-CTX) - are related to bone density and fracture risk. A high prevalence of osteopenia/osteoporosis and hypovitaminosis D has been reported in HIV patients, however there are few data about BTM in this population. Our aim was to analyse the prevalence of elevated serum levels of BTM in HIV patients before starting antiretroviral therapy (ART), and related factors. Methods: Cross-sectional study of a series of HIV-patients who started ART during June/11-June/12 in our hospital. Patients with presence of diseases or treatments known to affect bone metabolism were excluded. Epidemiological, clinical, and immunovirological data in addition to serum fasting levels of glucose, lipid profile, calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D3 (25OHD), parathyroid hormone (PTH), P1NP, and β-CTX were collected. Definitions: hypovitaminosis D if 25OHD<30 ng/ml, vitamin D deficiency if 25OHD<20 ng/ml; elevated levels of BTM if β-CTX (ng/ml) >0.64 (men<70 years),>0.85 (men>70 years),>0.58 (pre-menopause women), >0.99 (post-menopause women), or P1NP (ng/mL)>69.4 (men<60 years), >71.1 (men>60 years), >55.7 (pre-menopause women), >61.2 (post-menopause women). Results: 47 patients were included, 91.5% men, median age 37.1 years (30.0-44.3), and 93.6% sexual transmission of HIV (34 HMX, 10 HTX). Median time since the diagnosis of HIV was 3.4 months (1.4- 31.7); there were 7 (14.9%) Aids cases, median CD4 count was 277/ mm3 (155-433), and HIV-VL 4.8 log10 (4.1-5.2). Median serum 25OHD was 29 mg/L (21.9-41.1), with a prevalence of hypovitaminosis of 52.2%, and deficiency of 17.4%. PTH was in range in all cases. Median serum P1NP was 33.3 ng/mL (24.5-52.5) and β-CTX 0.25 ng/mL (0.20-0.45); five (11.4%) patients presented high levels of BTM: 4 men, median age 37.1 years, median CD4 count 247/mm3, median HIV-VL 5.18 log10, and one with hypovitaminosis D. Elevated BTM were related with no clinical, analytical, immunovirological parameters nor with serum levels of 25OHD nor PTH. Conclusions: The prevalence of elevated BTM was high in this series of HIV-patients, mostly young men, with short time of HIV infection and with no immunovirologic control. BTM were related with no clinical nor analytical data.

Long-term efficacy and safety of atazanavir/ritonavir treatment in a cohort of treatment-naïve HIV patients: An interim analysis of the REMAIN study.

Purpose: Combined antiretroviral therapy has dramatically improved HIV-infected individuals survival. Long-term strategies are currently needed to achieve the goal of durable virologic suppression. However, long-term available data for specific antiretrovirals (ARV) are limited. In clinical trials, boosted atazanavir (ATV/r) regimens has shown good efficacy and tolerability in ARV-naïve patients for up to 4 years. The REMAIN study aimed to evaluate the long-term outcomes of ATV/r regimens in ARV-naïve patients in a real life setting. Methods: Non-comparative, observational study conducted in Germany, Portugal and Spain. Historical and longitudinal follow-up data was extracted six monthly from the medical record of HIV-infected, treatment-naïve patients, who initiated an ATV/r-regimen between 2008 and 2010. The primary endpoint was the proportion of patients remaining on ATV treatment over time. Secondary endpoints included virologic response (HIV-1 RNA <50 c/mL and <500 c/mL), reasons for discontinuation and long-term safety. The duration of treatment and time to virologic failure (VF) were analyzed using the Kaplan- Meier method. Data from an interim analysis including patients with at least one year of follow-up are reported here. Results: A total of 411 patients were included in this interim analysis [median (Q1, Q3) follow-up: 23.42 (16.25, 32.24) months≥: 77% male; median age 40 years [min, max: 19, 78≥; 16% IDUs; 18% CDC C; 18% hepatitis C. TDF/FTC was the most common backbone (85%). At baseline, median (Q1, Q3) HIV-RNA and CD4 cell count were 4.91 (4.34, 5.34) log10 c/mL and 256 (139, 353) cells/mm3, respectively. The probability of remaining on treatment was 0.84 (95% CI: 0.80, 0.87) and 0.72 (95% CI: 0.67, 0.76) for the first and second year, respectively. After 2 years of follow-up, 84% (95% CI: 0.79, 0.88) of patients were virologically suppressed (<50 c/mL). No major protease inhibitors mutations were observed at VF. Overall, 125 patients (30%) discontinued ATV therapy [median (Q1, Q3) time to discontinuation: 11.14 (6.24, 19.35) months]. Adverse events (AEs) were the main reason for discontinuation (n =47, 11%). Hyperbilirubinaemia was the most common AE leading to discontinuation (14 patients). No unexpected AEs were reported. Conclusions: In a real life clinical setting, ATV/r regimens showed durable virologic efficacy with good tolerability in an ARV-naïve population. Data from longer follow-up will provide additional valuable information.

Gender differences in cardiovascular risk factors in HIV infected patients on antiretroviral therapy: Data from the Spanish Coronator study.

Purpose: HIV-infected patients present an increased cardiovascular risk (CVR) of multifactorial origin, usually lower in women than in men. Information by gender about prevalence of modifiable risk factors is scarce. Methods: Coronator is a cross-sectional survey of a representative sample of HIV-infected patients on ART within 10 hospitals across Spain in 2011. Variables include sociodemographics, CVR factors and 10-year CV disease risk estimation (Regicor: Framingham score adapted to the Spanish population). Results: We included 860 patients (76.3% male) with no history of CVD. Median age 45.6 years; 84.1% were Spaniards; 29.9% women were IDUs. Median time since HIV diagnosis for men and women was 10 and 13 years (p=0.001), 28% had an AIDS diagnosis. Median CD4 cell count was 596 cells/mm3, 88% had undetectable viral load. Median time on ART was 91 and 108 months (p=0.017). There was a family history of early CVD in 113 men (17.9%) and 41 women (20.6%). Classical CVR factors are described in the table. Median (IQR) Regicor Score was 3% (2-5) for men and 2% (1-3) for women (p=0.000), and the proportion of subjects with mid-high risk (>5%) was 26.1% for men and 9.4% for women (p=0.000). Conclusions: In this population of HIV-infected patients, women have lower cardiovascular risk than men, partly due to higher levels of HDL cholesterol. Of note is the high frequency of smoking, abdominal obesity and sedentary lifestyle in our population. (Table Presented).

Theory of mind and cognitive processes in aging and Alzheimer type dementia: a systematic review.

OBJECTIVES: Theory of mind (ToM) performance in aging and dementia of the Alzheimer type (DAT) has been a growing interest of researchers and recently, theoretical trends in ToM development have led to a focus on determining the cognitive skills involved in ToM performance. The aim of the present review is to answer three main questions: How is ToM assessed in aging and DAT? How does ToM performance evolve in aging and DAT? Do cognitive processes influence ToM performance in aging and DAT? METHOD: A systematic review was conducted to provide a targeted overview of recent studies relating ToM performance with cognitive processes in aging and DAT. RESULTS: RESULTS suggest a decrease in ToM performance, more pronounced in complex ToM tasks. Moreover, the review points up the strong involvement of executive functions, especially inhibition, and reasoning skills in ToM task achievement. CONCLUSION: Current data suggest that the structure of ToM tasks itself could lead to poor performance, especially in populations with reduced cognitive abilities.