Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials.

BACKGROUND: Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial. METHODS: A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia. RESULTS: A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39). CONCLUSION: There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.

Informal consultation at a teaching hospital infectious diseases department.

INTRODUCTION: Informal consultations for advice in the infectious diseases department (IDD) induce a significant workload for physicians. Our aim was to retrospectively quantify and describe this activity in our institution. METHOD: The data was obtained from files documented and faxed by physicians from October 2009 to May 2012. One thousand nine hundred and seventy-two files were included. The file was faxed to the IDD specialist, analyzed, then a telephone conversation allowed making precisions, and the documented form was faxed back. RESULTS: The requests for advice concerned 39% of female and 61% of male patients with a mean age of 64±21 years. Twenty-nine percent of requests came from surgical departments and 71% from medical departments (P<0.01). The departments most frequently concerned were cardiology (10%), gastro-enterology (10%) and cardiovascular surgery (9.7%). The most frequent infections were urogenital (19%), osteoarticular (14%), and cardiovascular (11%). Forty-nine percent were considered as nosocomial and 25.3% were bacteremic. The requests concerned diagnostic aid in 16.2% of cases and therapeutic issues in 95.6%. The IDD specialist made therapeutic recommendation in 96.5% of cases and gave diagnostic advice in 43.7%. Treatment modification was suggested in 38.5% of cases. Twenty-two percent of consultations required a second one. CONCLUSION: This study documented the importance of antibiotic changes among medical and surgical units, the increasing need of these units to be helped, and also the complexity of the medical cases, all requiring the advice of an ID specialist. Our fax-phone-fax procedure seems to prevent the bias associated with informal consultations by phone, which is the most commonly used in other institutions.

Performance of two commercially available automated immunoassays for the determination of Epstein-Barr virus serological status.

This study evaluated the performance of two automated Vidas (V) and Liaison (L) immunoassays for Epstein-Barr virus (EBV) serology. The detection of the viral capsid antigen (VCA) IgM, the VCA/early antigen (VCA/EA) IgG, and the Epstein-Barr nuclear antigen (EBNA) IgG was assessed on 526 sera collected for routine EBV testing in immunocompetent subjects. The determination of expected EBV status (186 EBV primary infections, 183 past EBV infections, and 157 EBV-seronegative individuals) was based on results of routine laboratory enzyme immunoassays (EIAs) together with clinical data. The sensitivity and specificity of each individual marker were determined in comparison to the expected EBV status. The agreement between the V and L profiles and the expected EBV status was established through the interpretation of combinations of the different EBV markers. Statistically significant differences between the two tests were found for the specificity of the VCA IgM marker (96.2% for V versus 93.2% for L), the sensitivity of the VCA/EA IgG marker (89% for V versus 94% for L), and the specificity of the EBNA IgG marker (96.5% for V versus 74.2% for L). The results determined for the two assays with respect to overall agreement with the established expected EBV status were not significantly different (89.7% for V versus 88.2% for L), with discrepancies mainly observed in sera referenced as primary infections. These findings demonstrated the similar performances of the Vidas and the Liaison assays for the establishment of an EBV serological status using the VCA, EA, and EBNA markers.

[Incidence, prevalence and risk factors for a first infectious complication on a totally implantable venous-access port]. / Incidence, prévalence et facteurs de risque de survenue d'une première complication infectieuse sur chambres à cathéter implantables.

BACKGROUND: Totally implantable venous-access ports (TIVAP) should present less risk of complications than central venous catheters over a long time period. AIMS: Firstly, the study's objective was to assess the prevalence and incidence of a first infectious complication on a TIVAP and secondly, to assess the risk factors associated with this first infection. METHODS: The authors made a longitudinal historical cohort study of patients with a TIVAP in 2003, in the Dijon University Hospital. RESULTS: Two hundred and nineteen patients (sex-ratio 1.9) were included, with a total follow-up of 92,773 patients-days. Ninety percent of the TIVAP were used for chemotherapy, 5% for antibiotic drug administration, 2% for parenteral nutrition and 3% for other reasons (recurrent blood transfusions, etc.). Overall, 34 (16.3%) out of 209patients presented with at least one infectious complication, with an incidence rate of 0.37infection/1,000patients-days. The 5-year cumulative probability to be free of infectious complication was only 62.8%. In multivariate analysis, only underlying hematological neoplasia (by contrast with solid tumors) was significantly associated to a higher risk of infectious complication. CONCLUSIONS: The infectious risk linked to the use of TIVAP is significant, higher in case of underlying hematological neoplasia and during the first months of use.

[Pyogenic psoas abscess: six cases and review of the literature]. / Les abcès pyogènes secondaires du psoas: à propos de six cas et revue de la littérature.

PURPOSE: Psoas abscess is a rare disease in developed countries. Its diagnosis is difficult and any delay could lead to a worsen prognosis. The aim of this study is to determine the best diagnostic and therapeutic practices. METHODS: A retrospective study of psoas abscess that occurred during six months was performed. RESULTS: Six cases of secondary psoas abscess are reported. They were associated with spondylodiscitis in three cases, arthritis and gynaecologic infection in the three remaining cases. Anatomic diagnosis was performed by tomodensitometry. Microbiologic diagnosis was obtained by blood culture or direct puncture of the abscess. Antibiotics were associated with percutaneous drainage in two cases, with simple puncture in one case, and with surgery in one case. A local improvement w observed in all cases. The oldest patients presented the worst complications which were not directly caused by the abscess. CONCLUSION: Physicians must be aware of psoas abscess because of their increasing incidence. Despite the fact that digestive pathologies are the main cause of secondary psoas abscess, bone infections, particularly spine infections, should be taken into consideration. Tomodensitometry guided puncture or percutaneous drainage are of diagnostic and therapeutic interest. Infectious samples must be taken before starting antibiotics, which have to be efficient against Gram negative bacillus, anaerobes and Staphylococcus aureus. Surgery must be quickly performed when the primary infection localisation need it, in case of voluminous abscess or when antibiotics and drainage are inefficient.

A prospective study of Epstein-Barr virus load in 85 hematopoietic stem cell transplants.

EBV viral load (EBV-VL) in PBMC was prospectively determined by semi-quantitative PCR in 85 stem cell transplants (40 genoidentical, 45 non-genoidentical) in order to characterize the kinetics of EBV-VL and to assess the ability of this measure to predict the development of EBV-induced lymphoproliferative disease (EBV-LPD). PCR was performed prior to and after transplantation. An EBV-VL >300 copies/microg DNA was chosen as the threshold for risk of developing an EBV-LPD. Two hundred and fifty-eight EBV-VL measures were evaluable. Five patients (5.9%) developed an EBV-LPD. All had an elevated EBV DNA peak level before EBV-LPD. Fifteen out of 80 recipients (18.7%) without EBV-LPD had EBV levels over 300 copies/microg DNA at least once during the follow-up. Overall, the manifestation of at least one EBV-VL over 300 copies/microg DNA during the entire follow-up demonstrated a sensitivity, specificity, positive and negative predictive value for the diagnosis of EBV-LPD of 100%, 81%, 25% and 100%, respectively. In patients without EBV-LPD, HLA incompatibility, grade > or = II acute GVHD and use of an unmanipulated graft were significantly associated with an EBV-VL >300 copies/microg DNA. This strategy appears sensitive for the diagnosis of EBV-LPD but its positive predictive value has to be improved in order to guide pre-emptive therapy.

Coronary heart disease associated with the use of human immunodeficiency virus (HIV)-1 protease inhibitors: report of four cases and review.

Four cases of human immunodeficiency virus (HIV)-infected patients who developed coronary heart disease (CHD) while under treatment with a protease inhibitor (PI) are described, and the epidemiologic and clinical features of 18 cases reported in the literature are analyzed. Cardiac manifestations mostly included myocardial infarctions. Smoking and hyperlipidemia were the most common risk factors for CHD, reported in 72 and 81% of the patients, respectively. Hypercholesterolemia was observed in 75% of the cases at the time of the cardiovascular event. Ninety percent of the patients with pretreatment normal lipid values experienced a rise in the plasma lipid levels during PI therapy. Although a definite relationship between the development of CHD and HIV PIs can not be made, this analysis suggests that PI-induced hyperlipidemia may play a role in accelerating coronary atherosclerosis in patients with concomitant risk factors. Evaluation and control of risk factors for CHD should be performed in each patient for whom treatment with a PI is indicated.

Incidence of gynecomastia in men infected with HIV and treated with highly active antiretroviral therapy.

A longitudinal study found that the incidence of gynecomastia in HIV-infected male patients treated with highly active antiretroviral therapy was 0.8/100 patient-years, with a prevalence of 2.8% in those treated for > or = 2 y. Even though the physiopathology remains unclear, this study suggests that gynecomastia should be monitored in these patients.

Functional determinants of the Epstein-Barr virus protease.

Herpesvirus proteases are essential for the production of progeny virus. They cleave the assembly protein that fills the immature capsid in order to make place for the viral DNA. The recombinant protease of the human gamma-herpesvirus Epstein-Barr virus (EBV) was expressed in Escherichia coli and purified. Circular dichroism indicated that the protein was properly folded with a secondary structure content similar to that of other herpesvirus proteases. Gel filtration and sedimentation analysis indicated a fast monomer-dimer equilibrium of the protease with a K(d) of about 60 microM. This value was not influenced by glycerol but was lowered to 1.7 microM in the presence of 0.5 M sodium citrate. We also developed an HPLC-based enzymatic assay using a 20 amino acid residue synthetic peptide substrate derived from one of the viral target sequences for the protease. We found that conditions that stabilised the dimer also led to a higher enzymatic activity. Through sequential deletion of amino acid residues from either side of the cleavage site, the minimal peptide substrate for the protease was determined as P5-P2'. This minimal sequence is shorter than that for other herpesvirus proteases. The implications of our findings are discussed with reference to the viral life-cycle. These results are the first ever published on the EBV protease and represent a first step towards the development of protease inhibitors.

Frequency and genome load of Epstein-Barr virus in 509 breast cancers from different geographical areas.

Since the few data exploring a possible association between Epstein-Barr virus (EBV) and breast cancer are conflicting, we investigated this association together with the influences of geographical areas. 509 breast cancers were sampled from areas with varying risks of nasopharynx carcinoma (NPC) such as North Africa (Algeria and Tunisia, high-risk area); southern France (Marseille, intermediate-risk area); and northern Europe (northern France, the Netherlands and Denmark; low-risk areas). Polymerase chain reaction (PCR) of a subregion of EBV BamHIC encoding the EBERs demonstrated that 31.8% of the tumours contained the viral genome. No significant differences were observed among the geographical areas. However, positive samples showed higher loads of the EBV genome in the NPC high- and intermediate-risk areas than in the low-risk areas. EBV type 1 was the dominant strain. In situ hybridization studies using a(35)S-labelled riboprobe for EBER1 and a laser capture microdissection, combined with quantitative PCR, showed that EBV localization was restricted to some tumour epithelial cell clusters. EBV could not be detected in the stroma. Considering the whole population covered, the presence of the EBV genome was not correlated with age, menopausal status, tumour, size, nodal status or histological grade.

Epstein-Barr virus EB2 protein exports unspliced RNA via a Crm-1-independent pathway.

Human herpesviruses encode posttranscriptional activators that are believed to up-regulate viral replication by facilitating early and late gene expression. We have reported previously that the Epstein-Barr virus protein EB2 (also called M or SM) promotes nuclear export of RNAs that are poor substrates for spliceosome assembly, an effect that closely resembles the human immunodeficiency virus type 1 Rev-dependent nuclear export of unspliced viral RNA. Here we present experimental data showing that EB2 efficiently promotes the nuclear export of unspliced RNA expressed from a Rev reporter construct. Site-directed mutagenesis as well as domain swapping experiments indicate that a leucine-rich region found in the EB2 protein, which matches the consensus sequence for the leucine-rich nuclear export signal, is not a nuclear export signal per se. Accordingly, leptomycin B (LMB), a specific Crm-1 inhibitor, impairs Rev- but not EB2-dependent nuclear export of unspliced RNA. Moreover, EB2 nucleocytoplasmic shuttling visualized by a heterokaryon assay is, unlike Rev shuttling, not affected by LMB. We also show that overexpression of an N-terminal deletion mutant of Nup214/can, a major nucleoporin of the nuclear pore complex involved in several aspects of nuclear transport, blocks both Rev- and EB2-dependent nuclear export of RNA. These results strongly suggest that EB2 nuclear export of unspliced RNA is mediated by a Crm-1-independent pathway.

Ubinuclein, a novel nuclear protein interacting with cellular and viral transcription factors.

The major target tissues for Epstein-Barr virus (EBV) infection are B lymphocytes and epithelial cells of the oropharyngeal zone. The product of the EBV BZLF1 early gene, EB1, a member of the basic leucine-zipper family of transcription factors, interacts with both viral and cellular promoters and transcription factors, modulating the reactivation of latent EBV infection. Here, we characterize a novel cellular protein interacting with the basic domains of EB1 and c-Jun, and competing of their binding to the AP1 consensus site. The transcript is present in a wide variety of human adult, fetal, and tumor tissues, and the protein is detected in the nuclei throughout the human epidermis and as either grainy or punctuate nuclear staining in the cultured keratinocytes. The overexpression of tagged cDNA constructs in keratinocytes revealed that the NH(2) terminus is essential for the nuclear localization, while the central domain is responsible for the interaction with EB1 and for the phenotype of transfected keratinocytes similar to terminal differentiation. The gene was identified in tail-to-tail orientation with the periplakin gene (PPL) in human chromosome 16p13.3 and in a syntenic region in mouse chromosome 16. We designated this novel ubiquitously expressed nuclear protein as ubinuclein and the corresponding gene as UBN1.

Novel immunoblot assay using four recombinant antigens for diagnosis of Epstein-Barr virus primary infection and reactivation.

A new immunoblot assay, composed of four Epstein-Barr virus (EBV)-encoded recombinant proteins (virus capsid antigen [VCA] p23, early antigen [EA] p138, EA p54, and EBNA-1 p72), was compared with an immunofluorescence assay on a total of 291 sera. The test was accurate in 94.5% of cases of primary EBV infection, while an immunoglobulin G anti-VCA p23 band with strong intensity correlated with reactivation.

The C-terminal region but not the Arg-X-Pro repeat of Epstein-Barr virus protein EB2 is required for its effect on RNA splicing and transport.

The Epstein-Barr virus BMLF1 gene product EB2 has been shown to efficiently transform immortalized Rat1 and NIH 3T3 cells, to bind RNA, and to shuttle from the nucleus to the cytoplasm. In transient-expression assays EB2 seems to affect mRNA nuclear export of intronless RNAs and pre-mRNA 3' processing, but no direct proof of EB2 being involved in RNA processing and transport has been provided, and no specific functional domain of EB2 has been mapped. Here we significantly extend these findings and directly demonstrate that (i) EB2 inhibits the cytoplasmic accumulation of mRNAs, but only if they are generated from precursors containing weak (cryptic) 5' splice sites, (ii) EB2 has no effect on the cytoplasmic accumulation of mRNA generated from precursors containing constitutive splice sites, and (iii) EB2 has no effect on the 3' processing of precursor RNAs containing canonical and noncanonical cleavage-polyadenylation signals. We also show that in the presence of EB2, intron-containing and intronless RNAs accumulate in the cytoplasm. EB2 contains an Arg-X-Pro tripeptide repeated eight times, similar to that described as an RNA-binding domain in the herpes simplex virus type 1 protein US11. As glutathione S-transferase fusion proteins, both EB2 and the Arg-X-Pro repeat bound RNA in vitro. However, by using EB2 deletion mutants, we demonstrated that the effect of EB2 on splicing and RNA transport requires the C-terminal half of the protein but not the Arg-X-Pro repeat.

Development of an Epstein-Barr virus type 2 (EBV-2)-associated hepatic B cell non-Hodgkin's lymphoma in an HIV-1-infected patient following a change in the EBV dominant type.

From the longitudinal study of a cohort of HIV-positive patients, we report the case of a patient who initially harbored the Epstein-Barr virus (EBV) type 1 and subsequently developed an EBV-2-associated non-Hodgkin's B lymphoma a few years after an EBV-2 reactivation, or an exogenous reactivation, in the blood. At the time of diagnosis of hepatic lymphoma, the blood and the throat harbored high levels of the EBV-1 dominant strain. Sequence analysis of EBNA-2 gene revealed that: (1) type 2 EBV detected during reactivation and then in hepatic tumor was very likely to be the same strain and was mostly identical to the EBV prototype AG876; (2) type 1 virus conserved the same mutations during all the follow-up. These results suggest that EBV-2 might be associated with lymphomatogenesis and that a transient reactivation could lead to the development of an EBV-associated disease.

Human herpesvirus 8 and Epstein Barr-virus in a cutaneous B-cell lymphoma and a malignant cell line established from the blood of an AIDS patient.

Human Herpesvirus 8 (HHV-8) has been consistently associated with Primary Effusion Lymphoma (PEL or body-cavity-based lymphoma) but not with other lymphomas. This paper reports on an AIDS patient without obvious malignant effusion in body cavities but with a cutaneous lymphoma where HHV-8 and Epstein-Barr virus (EBV) were detected by PCR and electron microscopy. Both viruses were also detected in all the cells of a malignant cell line (BBG1) established from the patient's peripheral blood mononuclear cells. As in PEL and PEL-derived cell lines, both the tumor and the lines lacked B-antigen expression in immunological studies but were of the same B origin as shown by clonal immunoglobulin gene rearrangements. In contrast to other co-infected cell lines, BBG1 and subclones spontaneously expressed the HHV-8 lytic antigens p40, p27, p60 and the EBV transforming latent antigen EBNA2. These data suggest that the clinical and biological features of HHV-8-and EBV-associated lymphomas could be wider than has been described to date in PEL particularly with the in vivo presence of circulating malignant dually-infected cells engaged in a spontaneous HHV-8 lytic infection.

Prevention of EBV-induced B-lymphoproliferative disorder by ex vivo marrow B-cell depletion in HLA-phenoidentical or non-identical T-depleted bone marrow transplantation.

HLA-mismatched bone marrow transplantation (BMT) is hampered by three major complications: graft rejection, acute graft-versus-host disease (aGVHD) and delayed immune reconstitution. Infusion of anti-LFA1 plus anti-CD2 monoclonal antibodies (MAb), combined with ex-vivo T-cell depletion of the graft, was efficient in preventing graft rejection and aGVHD. Nevertheless, disease-free survival was limited by the high frequency of lethal infections, including EBV-induced lymphoproliferative disease (BLPD), which originates mostly from donor B cells, with an incidence of 5-30%. To decrease the rate of this complication, ex-vivo B-cell depletion was attempted. This study compares a group of 19 patients who received a T- and B-cell-depleted marrow from an HLA-mismatched related donor with a retrospective control group of 19 patients, who had received T-cell-depleted marrow by the same method. The level of T-cell depletion was similar in the two groups. For B-cell depletion, two different methods were compared. The median number of B cells infused in the study group was 0.46/kg. Engraftment and aGVHD incidence were similar in the two groups. No EBV donor-derived BPLD occurred in the study group, compared with seven in the control group, four of whom died because of EBV-BPLD. Event-free survival was significantly different between the two groups. We conclude that ex-vivo B-cell depletion of the graft may be a useful means of preventing EBV-BPLD, and warrants further study on a larger group of patients.

Different distribution of H1-H2 Epstein-Barr virus variant in oropharyngeal virus and in biopsies of Hodgkin's disease and in nasopharyngeal carcinoma from Algeria.

In a previous study of Epstein-Barr virus (EBV) strains in North African nasopharyngeal carcinoma (N PC) biopsies, we have found that the viral strain present was of A/F/W'-I'/Xhol kept/H1-H2 type, while the strain associated with Chinese NPC was the A/"f"/W'I'/Xhol lost/H type. Using the restriction fragment length polymorphism (RFLP) and PCR-RFLP methods, the present study analyzed the H1-H2 variant in different clinical samples from Algeria, including the saliva of healthy EBV-positive individuals and patients with NPC or Hodgkin's disease (HD), as well as HD biopsies and lymphoblastoid cell lines (LCLs) established from the oropharyngeal virus-infected cells. Our results demonstrate that, in contrast to the H1-H2 variant found in NPC biopsies, the H genotype was dominant in HD biopsies. Moreover, H genotype was also dominant in the oropharynx of healthy EBV-positive individuals, of patients with NPC and with HD. Our results clearly indicate that in North Africa the EBV strain present of NPC biopsies is different from that shed in the oropharynx. This may suggest a specific distribution of the H1-H2 variant in the NPC epithelial tumor, whereas the H genotype is dominant in HD biopsies and in the oropharynx. The specific association of both viral strains with these 2 distinct diseases in North Africa may reflect a difference in tumorigenicity.

Non-Hodgkin's lymphoma of the heart in patients infected with human immunodeficiency virus.

A case of HIV-associated cardiac non-Hodgkin's lymphoma (NHL) is described, and the epidemiologic and clinicopathologic features of 21 cases previously reported in the literature are analyzed. All patients were homosexual males, and the cardiac NHL was the first acquired immune deficiency syndrome-defining condition in the majority. Patients were referred with nonspecific clinical findings including dyspnea and tachycardia, but rapid progression of cardiac dysfunction was frequent after symptoms appeared. Echocardiography constitutes the most useful noninvasive procedure in the diagnosis of cardiac NHL. Most of the patients had disseminated diseased at initial presentation; pathologically, the lymphomas were of B lymphocyte origin and of high-grade subtypes. Prognosis of HIV-associated cardiac NHL is generally poor, although clinical remission has been observed with combination chemotherapy. Cardiac lymphomas in HIV-associated patients are typically high-grade and often disseminate early. Although the prognosis is poor, patients in whom dissemination has not occurred could have longer survival under systemic chemotherapy.