Impact of soluble CD26 on treatment outcome and hepatitis C virus-specific T cells in chronic hepatitis C virus genotype 1 infection.

BACKGROUND: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50-80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells. METHODS: Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8(+) T cells. RESULTS: Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8(+) T cells (P = 0.02). CONCLUSIONS: Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8(+) T cells.

Influence of Assisted Reproductive Techniques in the occurrence of weight discordance in twin gestations

Background:There is no actual evidence that the ART are directly related to the occurrence of weight discordance. In some studies, ART-­‐conceived twin pregnancies are at greater risk than non-­‐ART-­‐conceived ones for pregnancy complications and adverse perinatal outcome: the incidences of pregnancy-­‐induced hypertension, uterine bleeding, premature contractions, IUGR, fetal death, discordance, and cesarean section were significantly higher. Discordance rate was elevated (25.3% vs.17.0%) among ART twins, which can increase perinatal risk (increased incidence of SGA and NICU admission). Other studies say that perinatal and neonatal morbidity, gestational age at delivery, and birth weight are not affected by ART. Regarding the first trimester ultrasound, some studies didn’t notice significant differences in CRL disparity or birth weight discordance between spontaneous and ART-­‐ conceived dichorionic twin pregnancies. In ART-­‐conceived dichorionic twin pregnancies, CRL disparity may be associated with birth weight discordance. In some studies, CRL discordance in twin pregnancies in the first trimester was a frequent finding. Objectives: To analyze the association of the ART in the occurrence of weight discordance in the pregnancies between 2010 and 2013 in the Hospital Universitari de Girona Doctor Josep Trueta, and to describe the proportion of diagnosis of growth discordance in the first trimester by the ultrasonography technology. Methods: A retrospective cohort study will be performed in those patients with twin pregnancies between 2010 and 2013, within the Hospital Universitari de Girona Doctor Josep Trueta (HUJT). A retrospective and descriptive study will be done in those cases with discordance weight in the moment of the birth, in which the CRL will be studied in the first trimester ultrasound, describing the percentage of discordance detected in that moment. The general characteristics of the sample are going to be analyzed by Logistic RegressionInfluenceof

Is screening for fetal anomalies reliable in HIV-infected pregnant women? A multicentre study.

OBJECTIVE: To assess the impact of HIV infection on the reliability of the first-trimester screening for Down syndrome, using free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A and fetal nuchal translucency, and of the second-trimester screening for neural tube defects, using alpha-fetoprotein. PATIENTS AND METHODS: Multicentre study comparing the multiples of the median of markers for Down syndrome and neural tube defect screening among 214 HIV-infected pregnant women and 856 HIV-negative controls undergoing a first-trimester Down syndrome screening test, and 209 HIV-positive women and 836 HIV-negative controls with a risk evaluation for neural tube defect. The influence of treatment, chronic hepatitis and HIV disease characteristics were also evaluated. RESULTS: Multiples of the median medians for pregnancy-associated plasma protein-A and beta-human chorionic gonadotrophin were lower in HIV-positive women than controls (0.88 vs. 1.05 and 0.84 vs. 1.09, respectively; P < 0.005), but these differences had no impact on risk estimation; no differences were observed for the other markers. No association was found between HIV disease characteristics, antiretroviral treatment use at the time of screening or chronic hepatitis and marker levels. CONCLUSION: Screening for Down syndrome during the first trimester and for neural tube defect during the second trimester is accurate for HIV-infected women and should be offered, similar to HIV-negative women.

Preoperative upper gastrointestinal testing can help predicting long-term outcome after gastric banding for morbid obesity.

BACKGROUND: Gastric banding (GB) is one of the most popular bariatric procedures for morbid obesity. Apart from causing weight loss by alimentary restriction, it can interfere with functions of the esophagus and upper stomach. The aim of this study was to evaluate if the results of extensive preoperative upper GI testing were correlated with long-term outcome and complications after GB. METHODS: Using a prospectively maintained computerized database including all the patients undergoing bariatric operations in both our hospitals, we performed a retrospective analysis of the patients who underwent complete upper gastrointestinal (GI) testing (endoscopy, pH monitoring, and manometry) before GB. RESULTS: One hundred thirty-four patients underwent complete testing before GB. Abnormal pH monitoring (increased total reflux time, increased diurnal reflux time, increased number of reflux episodes) predicted the development of complications and especially pouch dilatation and food intolerance. The mean De Meester score was higher among patients who developed complications than in the remaining ones (25.4 vs 17.7, P=0.03). High lower esophageal sphincter pressure also predicted progressive long-term food intolerance. Endoscopic findings were not predictive of the long-term outcome. CONCLUSIONS: There is some association between the function of the upper digestive tract and long-term complications after gastric banding. Abnormal pH monitoring predicts overall long-term complications, especially food intolerance with or without reflux, and pouch dilatation, and a high lower esophageal sphincter pressure predicts long-term food intolerance. Extended upper gastrointestinal testing with endoscopy, 24-h pH monitoring, and esophageal manometry is probably worthwhile in selecting patients for gastric banding.

Proliferative and Osteogenic Differentiation Potentials of Human Fetal Bone Cells

BACKGROUND. Human primary fetal bone cells (hFBC) are being characterized for use in bone tissue regeneration. Unlike human mesenchymal stem cells (hMSC), hFBC are partially differentiated with high expansion and regeneration potential. To date, proliferative and osteoblastic differentiation capacities of fetal bone cells remain poorly examined. The goal of this study was to define an environmental culture conditions for optimal proliferation and production of extracellular bone matrix leading to efficient bone repair. METHODS. Human primary FBC derived from our dedicated, consistent banks of bone cells comprising several fetal donors. For proliferation study, monolayer cultures of both cell types were expanded in DMEM or α- MEM media. Osteoblastic differentiation potentials of both hFBC and hMSC were evaluated through RT-PCR. Regulation of osteogenic differentiation by protein ligands Wnt3a and Wnt5a was studied by ALP enzymatic activity measurement. RESULTS. Evaluation of the proliferation rate demonstrated that hFBC proliferated more rapidly in α-MEM medium. Regarding growth factors that could stimulate cell proliferation rate, we observed that PDGF, FGF2 and Wnt3a had positive effects on proliferation of hFBC. Gene expression analysis demonstrated a higher expression of runx2 in hFBC cultured in basal conditions, which was was similar than that was observed in hMSC in osteoinductive culture conditions. Expression of sox9 was very low in hBFC and hMSC, compared to expression observed in fetal cartilage cells. Looking at osteogenic differentiation capacity, ALP activity was positively regulated byWnt5awhen hFBCwere cultured inα-MEM, but not in DMEM. Conversely, Wnt3a was shown to block the effect of osteogenic inductors on differentiation of both cell types. CONCLUSION. Data presented in this study indicate that the proliferation and differentiation of fetal and mesenchymal stem cells is optimal in α- MEM. Evidence for a pre-differentiated state of hBFC was given by extracellular matrix spontaneous mineralization as well as by higher ALP activity levels observed for these cells in baseline culture conditions, in comparison with hMSC. As we showed that, in vitro, hFBC express a higher capacity to differentiate in osteoblasts, they represent an attractive and promising prospect for fundamental research, and specifically for a new generation of skeletal tissue engineering.

Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study.

BACKGROUND: We investigated the incidence and outcome of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected individuals before and after the introduction of combination antiretroviral therapy (cART) in 1996. METHODS: From 1988 through 2007, 226 cases of PML were reported to the Swiss HIV Cohort Study. By chart review, we confirmed 186 cases and recorded all-cause and PML-attributable mortality. For the survival analysis, 25 patients with postmortem diagnosis and 2 without CD4+ T cell counts were excluded, leaving a total of 159 patients (89 before 1996 and 70 during 1996-2007). RESULTS: The incidence rate of PML decreased from 0.24 cases per 100 patient-years (PY; 95% confidence interval [CI], 0.20-0.29 cases per 100 PY) before 1996 to 0.06 cases per 100 PY (95% CI, 0.04-0.10 cases per 100 PY) from 1996 onward. Patients who received a diagnosis before 1996 had a higher frequency of prior acquired immunodeficiency syndrome-defining conditions (P = .007) but similar CD4+ T cell counts (60 vs. 71 cells/microL; P = .25), compared with patients who received a diagnosis during 1996 or thereafter. The median time to PML-attributable death was 71 days (interquartile range, 44-140 days), compared with 90 days (interquartile range, 54-313 days) for all-cause mortality. The PML-attributable 1-year mortality rate decreased from 82.3 cases per 100 PY (95% CI, 58.8-115.1 cases per 100 PY) during the pre-cART era to 37.6 cases per 100 PY (95% CI, 23.4.-60.5 cases per 100 PY) during the cART era. In multivariate models, cART was the only factor associated with lower PML-attributable mortality (hazard ratio, 0.18; 95% CI, 0.07-0.50; P < .001), whereas all-cause mortality was associated with baseline CD4+ T cell count (hazard ratio per increase of 100 cells/microL, 0.52; 95% CI, 0.32-0.85; P = .010) and cART use (hazard ratio, 0.37; 95% CI, 0.19-0.75; P = .006). CONCLUSIONS: cART reduced the incidence and PML-attributable 1-year mortality, regardless of baseline CD4+ T cell count, whereas overall mortality was dependent on cART use and baseline CD4+ T cell count.

Success of thrombolysis as a predictor of outcome in acute thrombosis of popliteal aneurysms.

PURPOSE: Acute limb ischemia after thrombosis of a popliteal aneurysm is a distinct and limb-threatening entity. Preoperative intra-arterial thrombolysis may improve the outcome in this challenging situation. This study retrospectively analyzed a consecutive series of patients treated with preoperative thrombolysis and subsequent revascularization. METHODS: Thirteen patients with acute limb ischemia caused by thrombosis of a popliteal aneurysm underwent catheter-directed intra-arterial thrombolysis with urokinase and subsequent vascular reconstruction. The angiographic and clinical outcome was analyzed and compared with that in the literature. RESULTS: Complete aneurysm thrombosis with absence of runoff was documented in 12 cases. Thrombolysis restored perfusion with patency of the popliteal artery and a one- or two-vessel runoff in 77% of cases (10/13). Early cumulative graft patency and limb salvage rates were 68% and 83%, respectively, with an ankle/brachial index of 0.8 +/- 0.2. Lytic failure followed by attempts at bypass grafting was present in three patients (23%) and resulted in above-knee amputation. Severe rhabdomyolysis and fatal pulmonary embolism were responsible for a 15% early mortality rate. CONCLUSION: Preoperative thrombolysis followed by bypass grafting is a valid treatment option for patients who can withstand an additional period of ischemia that does not require immediate revascularization and intraoperative lysis. Lytic failure identifies patients with a highly compromised runoff who are probably best treated by means of subsequent amputation, without any attempts at bypass grafting.

Influence of misoprostol or prostaglandin E(2) for induction of labor on the incidence of pathological CTG tracing: a randomized trial.

OBJECTIVE: To compare the efficacy and safety of misoprostol (prostaglandin E(1) (PGE(1))) with dinoprostone (prostaglandin E(2) (PGE(2))) for third trimester cervical ripening and labor induction. STUDY DESIGN: Patients requiring induction of labor were randomly assigned to receive either 50 microg of intravaginal misoprostol every 4 h or 0.5 mg of intracervical dinoprostone gel every 6 h. Eligibility criteria included gestation = 36 weeks. Primary outcome was the time interval from induction to delivery; secondary outcomes were mode of delivery, perinatal outcome, and interpretation of cardiotocogram (CTG) records. RESULTS: Two hundred women were randomly enrolled to receive either misoprostol (n = 100) or dinoprostone (n = 100). Time induction-to-delivery at 12, 24 and 48 h and the need for oxytocin were reduced with misoprostol (P < 0.05). Pathological CTG tracing according to FIGO and Melchior scores were more frequent in the misoprostol-treated group (P < 0.001). CONCLUSION: Misoprostol shortened the induction-to-delivery interval, but is associated with a higher incidence of abnormal CTG than prostaglandin E(2).

Pretreatment and outcome correlates of sexual and physical trauma in an epidemiological cohort of first-episode psychosis patients.

OBJECTIVES: High prevalence of trauma has been reported in psychosis. While role of trauma as a risk factor for developing psychosis is still debated, its negative impact on outcome has been described. Few studies have explored this issue in first-episode psychosis (FEP) patients. We assessed rate of stressful events, as well as premorbid and outcome correlates of past sexual and/or physical abuse (SPA) in an epidemiological FEP patients cohort. METHODS: The Early Psychosis Prevention and Intervention Centre admitted 786 FEP patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. A total of 704 files were available, 43 excluded because of a nonpsychotic diagnosis at end point and 3 due to missing data regarding past stressful events; 658 patients were analyzed. RESULTS: A total of 83% patients had been exposed to at least one stressful event and 34% to SPA. SPA patients were more likely to have presented other psychiatric disorders before psychosis onset (posttraumatic stress disorder, substance use disorder), to have made suicide attempts in the past, and to have had poorer premorbid functional levels. Additionally, SPA patients had higher rate of comorbid diagnosis at program entry and were more likely to attempt suicide during treatment. CONCLUSIONS: SPA prevalence is high in FEP patients and must be explored by clinicians considering its durable impact on psychological balance and link with long-lasting suicidal risk. More research is warranted to better understand mechanisms involved between trauma and its potential consequences, as well as to develop psychological interventions adapted to this very sensitive and complex issue.

Surgical interventions with fatal outcome: Utility of multi-phase postmortem CT angiography

Cases of fatal outcome after surgical intervention are autopsied to determine the cause of death and to investigate whether medical error caused or contributed to the death. For medico-legal purposes, it is imperative that autopsy findings are documented clearly. Modern imaging techniques such as multi-detector computed tomography (MDCT) and postmortem CT angiography, which is used for vascular system imaging, are useful tools for determining cause of death. The aim of this study was to determine the utility of postmortem CT angiography for the medico-legal death investigation. This study investigated 10 medico-legal cases with a fatal outcome after surgical intervention using multi-phase postmortem whole body CT angiography. A native CT scan was performed as well as three angiographic phases (arterial, venous, and dynamic) using a Virtangio((R)) perfusion device and the oily contrast agent, Angiofil((R)). The results of conventional autopsy were compared to those from the radiological investigations. We also investigated whether the radiological findings affected the final interpretation of cause-of-death. Causes of death were hemorrhagic shock, intracerebral hemorrhage, septic shock, and a combination of hemorrhage and blood aspiration. The diagnoses were made by conventional autopsy as well as by postmortem CT angiography. Hemorrhage played an important role in eight of ten cases. The radiological exam revealed the exact source of bleeding in seven of the eight cases, whereas conventional autopsy localized the source of bleeding only generally in five of the seven cases. In one case, neither conventional autopsy nor CT angiography identified the source of hemorrhage. We conclude that postmortem CT angiography is extremely useful for investigating deaths following surgical interventions. This technique helps document autopsy findings and allows a second examination if it is needed; specifically, it detects and visualizes the sources of hemorrhages in detail, which is often of particular interest in such cases.

Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance.

Down syndrome (DS) is characterized by extensive phenotypic variability, with most traits occurring in only a fraction of affected individuals. Substantial gene-expression variation is present among unaffected individuals, and this variation has a strong genetic component. Since DS is caused by genomic-dosage imbalance, we hypothesize that gene-expression variation of human chromosome 21 (HSA21) genes in individuals with DS has an impact on the phenotypic variability among affected individuals. We studied gene-expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with DS and an equal number of controls. Gene expression was assayed using quantitative real-time polymerase chain reaction on 100 and 106 HSA21 genes and 23 and 26 non-HSA21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of HSA21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between DS and normal samples, although the average up-regulation of HSA21 genes was close to the expected 1.5-fold in both cell types. Gene-expression variation in DS and normal samples was evaluated using the Kolmogorov-Smirnov test. According to the degree of overlap in expression levels, we classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and DS samples. We hypothesize that, in each cell type, group A genes are the most dosage sensitive and are most likely involved in the constant DS traits, group B genes might be involved in variable DS traits, and group C genes are not dosage sensitive and are least likely to participate in DS pathological phenotypes. This study provides the first extensive data set on HSA21 gene-expression variation in DS and underscores its role in modulating the outcome of gene-dosage imbalance.

Longer term clinical and virological outcome of sub-Saharan African participants on antiretroviral treatment in the Swiss HIV Cohort Study.

OBJECTIVES: Persons from sub-Saharan Africa (SSA) are increasingly enrolled in the Swiss HIV Cohort Study (SHCS). Cohorts from other European countries showed higher rates of viral failure among their SSA participants. We analyzed long-term outcomes of SSA versus North Western European participants. DESIGN: We analyzed data of the SHCS, a nation-wide prospective cohort study of HIV-infected adults at 7 sites in Switzerland. METHODS: SSA and North Western European participants were included if their first treatment combination consisted of at least 3 antiretroviral drugs (cART), if they had at least 1 follow-up visit, did not report active injecting drug use, and did not start cART with CD4 counts >200 cells per microliter during pregnancy. Early viral response, CD4 cell recovery, viral failure, adherence, discontinuation from SHCS, new AIDS-defining events, and survival were analyzed using linear regression and Cox proportional hazard models. RESULTS: The proportion of participants from SSA within the SHCS increased from 2.6% (<1995) to 20.8% (2005-2009). Of 4656 included participants, 808 (17.4%) were from SSA. Early viral response (6 months) and rate of viral failure in an intent-to-stay-on-cART approach were similar. However, SSA participants had a higher risk of viral failure on cART (adjusted hazard ratio: 2.03, 95% confidence interval: 1.50 to 2.75). Self-reported adherence was inferior for SSA. There was no increase of AIDS-defining events or mortality in SSA participants. CONCLUSIONS: Increased attention must be given to factors negatively influencing adherence to cART in participants from SSA to guarantee equal longer-term results on cART.

Predictors for the emergence of the 2 multi-nucleoside/nucleotide resistance mutations 69 insertion and Q151M and their impact on clinical outcome in the Swiss HIV cohort study.

The 69 insertion and Q151M mutations are multi-nucleoside/nucleotide resistance mutations (MNR). The prevalence among 4078 antiretroviral therapy (ART)-experienced individuals was <1.3%. Combined ART fully prevented MNR in subtype B infections. Case-control studies were performed to identify risk factors. Control subjects were patients with ≥ 3 thymidine-analogue mutations. The 69 insertion study (27 control subjects, 14 case patients) identified didanosine exposure as a risk (odds ratio, 5.0 per year; P = .019), whereas the Q151M study (which included 44 control subjects and 25 case patients) detected no associations. Following detection, individuals with Q151M tended to have lower suppression rates and higher mortality rates, relative to control subjects. Additional studies are needed to verify these findings in non-subtype B infections.