Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV.

Attachment inhibitor (AI) BMS-626529 (fostemsavir) represents a novel class of antiretrovirals which target human immunodeficiency virus type 1 (HIV-1) gp120 and block CD4-induced conformational changes required for viral entry. It is now in phase III clinical trials and is expected to be approved by the U.S. Food and Drug Administration (FDA) in the near future. Although fostemsavir is very potent against HIV in vitro and in vivo, a number of resistant mutants have already been identified. Broadly neutralizing HIV antibodies (bNAbs) can potently inhibit a wide range of HIV-1 strains by binding to viral Env and are very promising candidates for HIV-1 prevention and therapy. Since both target viral Env to block viral entry, we decided to investigate the relationship between these two inhibitors. Our data show that Env mutants resistant to BMS-626529 retained susceptibility to bNAbs. A single treatment of bNAb NIH45-46G54W completely inhibited the replication of these escape mutants. Remarkable synergy was observed between BMS-626529 and CD4 binding site (CD4bs)-targeting bNAbs in neutralizing HIV-1 strains at low concentrations. This synergistic effect was enhanced against virus harboring mutations conferring resistance to BMS-626529. The mechanistic basis of the observed synergy is likely enhanced inhibition of CD4 binding to the HIV-1 Env trimer by the combination of BMS-626529 and CD4bs-targeting bNAbs. This work highlights the potential for positive interplay between small- and large-molecule therapeutics against HIV entry, which may prove useful as these agents enter clinical use.IMPORTANCE As the worldwide HIV pandemic continues, there is a continued need for novel drugs and therapies. A new class of drug, the attachment inhibitors, will soon be approved for the treatment of HIV. Broadly neutralizing antibodies are also promising candidates for HIV prevention and therapy. We investigated how this drug might work with these exciting antibodies that are very potent in blocking HIV infection of cells. These antibodies worked against virus known to be resistant to the new drug. In addition, a specific type of antibody worked really well with the new drug in blocking virus infection of cells. This work has implications for both the new drug and the antibodies that are poised to be used against HIV.

Comparison of the Elecsys HBsAg II Assay and the Architect Assay for Quantification of hepatitis B surface antigen in patients with chronic hepatitis B.

Quantitative hepatitis B surface antigen (HBsAg) is a valuable tool in hepatitis B virus (HBV) disease diagnosis and management for evaluating the effectiveness of antiviral therapy. The aim of the current research was to compare the performances of the Elecsys HBsAg II and Abbott Architect HBsAg assays in chronic hepatitis B (CHB) patients. Between May 2014 and December 2014, 72 CHBs were tested using Abbott Architect HBsAg QT and Roche Elecsys HBsAg II assay. After transformation to log (10) IU/mL, the results of the two assays were compared using the interclass correlation test, the Pearson correlation test and Bland-Altman analyses. We also analyzed all the parameters in on-treatment patients and naive patients with Pearson correlation test. There was a significant overall correlation between the Elecsys and Architect assays. We also analyzed all the parameters in naive and on-treatment patients. There was a significantly good correlation between the two assays in untreated patients and on-treatment patients. In this study, there was a significant correlation between the results of the Elecsys HBsAg II and Abbott Architect HBsAg assays in the overall and naive/on-treatment CHB patients. Additionally, we found that mean HBsAg levels resulting from the Architect assay were higher than those obtained by Elecsys assay.

Cranial imaging findings in neurobrucellosis: results of Istanbul-3 study.

OBJECTIVE: Neuroimaging abnormalities in central nervous system (CNS) brucellosis are not well documented. The purpose of this study was to evaluate the prevalence of imaging abnormalities in neurobrucellosis and to identify factors associated with leptomeningeal and basal enhancement, which frequently results in unfavorable outcomes. METHODS: Istanbul-3 study evaluated 263 adult patients with CNS brucellosis from 26 referral centers and reviewed their 242 magnetic resonance imaging (MRI) and 226 computerized tomography (CT) scans of the brain. RESULTS: A normal CT or MRI scan was seen in 143 of 263 patients (54.3 %). Abnormal imaging findings were grouped into the following four categories: (a) inflammatory findings: leptomeningeal involvements (44), basal meningeal enhancements (30), cranial nerve involvements (14), spinal nerve roots enhancement (8), brain abscesses (7), granulomas (6), and arachnoiditis (4). (b) White-matter involvement: white-matter involvement (32) with or without demyelinating lesions (7). (c) Vascular involvement: vascular involvement (42) mostly with chronic cerebral ischemic changes (37). (d) Hydrocephalus/cerebral edema: hydrocephalus (20) and brain edema (40). On multivariate logistic regression analysis duration of symptoms since the onset (OR 1.007; 95 % CI 1-28, p = 0.01), polyneuropathy and radiculopathy (OR 5.4; 95 % CI 1.002-1.013, p = 0.044), cerebrospinal fluid (CSF)/serum glucose rate (OR 0.001; 95 % CI 000-0.067, p = 0.001), and CSF protein (OR 2.5; 95 % CI 2.3-2.7, p = 0.0001) were associated with diffuse inflammation. CONCLUSIONS: In this study, 45 % of neurobrucellosis patients had abnormal neuroimaging findings. The duration of symptoms, polyneuropathy and radiculopathy, high CSF protein level, and low CSF/serum glucose rate were associated with inflammatory findings on imaging analyses.

Mean platelet volume and red cell distribution width to platelet ratio for predicting the severity of hepatic fibrosis in patients with chronic hepatitis C.

OBJECTIVE: We designed this study to investigate the relationship between the severity of fibrosis and mean platelet volume (MPV), red cell distribution width, and red cell distribution width to platelet ratio (RPR) in patients with chronic hepatitis C (CHC). DESIGN: Overall, 98 biopsy-proven naïve CHC cases were enrolled in the study. Complete blood count variables, including white blood cell, hemoglobin, platelet count, MPV, red cell distribution width, platelet distribution width as well as aspartate transaminase, alanine transaminase, total bilirubin, albumin, and other routine biochemical parameters, were tested. Liver biopsy samples were assessed according to the Ishak scoring system. Data analyses were carried out using SPSS-15 software. Statistical significance was set at a P-value of less than 0.05. RESULTS: Of the 98 cases, 80 (81.6%) were men and 18 (18.4%) were women. Fibrosis scores of 69 cases (70.4%) (group 1) were less than 3, whereas 29 cases had fibrosis scores at least 3 (29.6%) (group 2). Significant differences in MPV and RPR were observed between these two groups (MPV: 8.19±1.002 vs. 8.63±0.67 fl, P<0.05; RPR: 0.0526±0.02 vs. 0.0726±0.02, P=0.001). The areas under the curve of the RPR and MPV for predicting significant fibrosis were 0.705 and 0.670, which was superior to the aspartate transaminase-to-alanine transaminase ratio and aspartate transaminase-to-platelet ratio index scores of the study group. Cut-off values were calculated for diagnostic performance, and the cut-off values for MPV and RPR were 8.5 and 0.07 fl, respectively. CONCLUSION: MPV and RPR values were significantly higher in patients with CHC, associated with severity, and can be used to predict advanced histological liver damage. The use of MPV and RPR may reduce the need for liver biopsy. Further studies are required to determine the relationship between these parameters and the severity of fibrosis in hepatitis C patients.

Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study.

BACKGROUND: Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. AIMS: The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naïve. STUDY DESIGN: A multicenter, retrospective observational study. METHODS: The study was conducted retrospectively on 1214 treatment naïve-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients' data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient's demographic characteristics, baseline viral load, genotype, and fibrosis scores. RESULTS: The mean age of the patients was 50.74 (±0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2/3, age less than 45 years, low fibrosis stage, low baseline viral load and presence of early virological response. SVR rates to each peginterferon were found to be similar in genotype 1/4 although SVR rates were found to be higher for peginterferon alpha-2b in patients with genotype 2/3. The number of patients who failed to complete treatment due to adverse effects was 33 (2.7%). The number of patients failed to complete treatment due to adverse effects was 33 (2.7%). CONCLUSION: Our findings showed that the rate of SVR to dual therapy was higher in treatment-naïve Turkish patients than that reported in randomized controlled trials. Also peginterferon alpha-2a and alpha-2b were found to be similar in terms of SVR in genotype 1 patients.

[Tuberculosis and tularemia as part of the differential diagnosis in cervical lymphadenitis]. / Servikal lenfadenitlerin etiyolojisinde tüberküloz ve tularemi ayirici tanisi

We have read with interest the recently published article entitled "Investigation of the presence of Mycobacterium tuberculosis in the lymph node aspirates of the suspected tularemia lymphadenitis cases" by Albayrak et al. published in Mikrobiyol Bul 2014; 48(1): 129-34. They concluded that tuberculous lymphadenitis (TCL) should be kept in mind in suspected tularemia cases and those patients should also be investigated simultaneously for the presence of TCL. With reference to data provided by the Ministry of Health in Turkey, the number of reported cases of pulmonary tuberculosis in comparison to previous years is currently on decline whereas a gradual increase in extra-pulmonary (specifically cervical TCL) cases has been observed. Besides, as one of the most common causes of cervical lymphadenitis, we are witnessing a marked increase in granulomatous infections which have been part of the evaluated cases of oropharyngeal tularemia in Turkey. In fact, differentiation of the two types of lymphadenitis can be confusing on the basis of clinical and histopathological findings. Thus, investigating the presence of M.tuberculosis in cervical lymph node aspirates of tularemia suspected cases is a vital contribution, specifically in a geographical region that is considered endemic for both diseases. We would therefore like to note the importance of this study and thank the authors for their comprehensive contribution. Contrary to what is noted in the study, cervical lymphadenitis due to acute tonsillopharyngitis unresponsive to penicillin and its derivatives, has been regarded as cervical TCL due to their histopathological appearance and have been treated unnecessarily with long-term antituberculous drugs. There are some publications from Turkey indicating the detection of Francisella tularensis antibodies and nucleic acids in the patients who were histologically diagnosed as TCL. In situations where the exact etiology of cervical lymphadenitis is not determined, treatment is delayed, disease duration is prolonged and patients are forced into visiting multiple physicians and hospitals. In this case uneccessary protocols such as lymph node excision and various surgical procedures are performed to rule out the presence of commonly encountered malignancies like lymphoma. On the other hand, lymph node suppuration is more commonly seen among these group of patients. As a conclusion, tularemia and TCL should be kept in mind as different endemic entities in widespread geographical regions such as Turkey. In particular, early serological and microbiological investigations should be performed for early diagnosis and appropriate treatment in such patients.

High resolution computed tomography findings in smear-negative pulmonary tuberculosis patients according to their culture status.

OBJECTIVE: The aim of this study was to assess the clinical features and high resolution computed tomography (HRCT) findings in smear-negative pulmonary tuberculosis (PTB) and to evaluate the correlation between these parameters and the culture results. METHODS: We retrospectively studied 78 active smear-negative PTB patients. They were divided into two groups according to their culture results. The HRCT findings and clinical features at the beginning of the antituberculosis treatment were reviewed. RESULTS: The mean age was 22.48±3.18 years. Micronodules (87%), large nodules (63%) and centrilobular nodules (62%) were the most common HRCT findings. HRCT findings were observed in the right upper (72%), left upper (56%), right lower (32%), and left lower lobes (29%). Cough (37%) and chest pain (32%) were the most frequent symptoms at presentation. CONCLUSIONS: There were no significant differences in the HRCT findings and clinical features between the two groups. Thus, in cases of smear-negative and culture-negative PTB, the patient with compatible clinical and radiological features should be considered for tuberculosis treatment.

[Two imported and relapsed of Plasmodium vivax malaria cases and primaquine prophylaxis]. / Dis kaynakli Iki Relaps Plasmodium vivax Olgusu ve Proflakside Primakin.

Malaria is a worldwide infection causing serious health and financial problems. Turkey is in the elimination phase, and malaria cases have been observed in patients who have come from abroad recently. In this study, 2 relapsed Plasmodium vivax (Pv) cases that returned from Afghanistan to our country at least 6 months ago were presented. The first case had received irregular chemoprophylaxis during travel, 6 months after returning to Turkey occurred malaria clinic. The second case had not received chemoprophlaxis during his travel, and he had experienced 2 previous episodes of malaria. He had used inappropriate anti-malarial drugs before returning to Turkey. Two separate incubation periods for P. vivax and P. ovale have been described. One of them is defined as late infection, or relapse, which is maturation of dormant bacilli in the liver, known as the hypnozoite stage. We thought that relapses of Pv infection could result from activation of hypnozoites in these cases. These 2 cases were treated with chloroquine and primaquine. The purpose of presenting these 2 cases is that primaquine should be considered for primer prophylaxis in short travels, especially after traveling to endemic areas, and the patient's relapse should be considered.

[The management of therapeutic failure in a falciparum malaria patient under oral arthemether-lumefantrine therapy]. / Falsiparum sitmali bir vakada oral artemisin-lümefantrin tedavi basarisizliginin yönetimi.

Malaria is a parasitic infection characterized by anemia, splenomegaly and periodic fever. This infection has a tendency to cause serious complications. Falciparum malaria could occur in our country as an imported case due to increasing intercontinental travel opportunities. The World Health Organisation (WHO) recommends arthemether combination treatment as a first line choice. Here we report a Turkish case admitted to the hospital with high fever, sweating and fatigue. He had been in Uganda for 6 months without prophylaxis. Plasmodium falciparum with an intense parasitic load was diagnosed. We started arthemether-lumefantrine combination therapy immediately. 18 days after his discharge he was readmitted with the same complaints and parasitemia was detected once again. This time, we treated him with the quinine-tetracycline combination regime for 7 days. Within 48 hours the patient was afebrile and the blood smear was negative. Falciparum malaria must be considered in infection emergencies for febrile patients especially with any travel history. For an initial therapy, arthemetherlumefantrine combination is a successful choice of treatment. Even with adequate treatment of arthemether-lumefantrine combination, the problems of recurrence (recrudescence or reinfection) could occur due to treatment failure. For the possibility of recurrence, close monitoring of patients is very important in the critical course after adequate treatment.

Antibiotherapy with and without bone debridement in diabetic foot osteomyelitis: A retrospective cohort study.

BACKGROUND AND OBJECTIVE: The treatment of diabetic foot osteomyelitis (DFO) is a controversial issue, with disagreement regarding whether the best treatment is surgical or conservative. The purpose of this study was to compare the outcome of patients with DFO who were treated with antibiotherapy alone and those who underwent concurrent minor amputation. METHODS: Hospital records of patients who were diagnosed as having DFO within a 2-year study period were retrospectively reviewed. Patients were divided into two groups: those who received antibiotherapy alone and those who underwent concurrent minor amputation. Groups were compared in terms of duration in hospitalization, antibiotherapy, and wound healing. RESULTS: Thirty seven patients were included in the study. These comprised patients who received antibiotherapy alone (ABG, n=15) and patients who underwent concurrent minor amputation (AB-MAG, n=22). Hospitalization duration was 37.2 (± 16.2) days in ABG and 52.8 (± 40.2) days in AB-MAG (p = 0.166). Mean duration of antibiotherapy was 45.0 (± 21.7) days in ABG and 47.7 (± 19) days in AB-MAG (p = 0.689). Wound healing duration was 265.2 (± 132.7) days in ABG and 222.6 (± 85.9) days in AB-MAG (p = 0.243). None of the outcome measures were significantly different between ABG and AB-MAG. CONCLUSIONS: Our results have shown similar outcomes for both patient groups who received antibiotherapy alone and who underwent concurrent minor amputations. Considering the small sample sizes in this study, it is important to confirm these results on a larger scale.

Mortality indicators in pneumococcal meningitis: therapeutic implications.

BACKGROUND: The aim of this study was to delineate mortality indicators in pneumococcal meningitis with special emphasis on therapeutic implications. METHODS: This retrospective, multicenter cohort study involved a 15-year period (1998-2012). Culture-positive cases (n=306) were included solely from 38 centers. RESULTS: Fifty-eight patients received ceftriaxone plus vancomycin empirically. The rest were given a third-generation cephalosporin alone. Overall, 246 (79.1%) isolates were found to be penicillin-susceptible, 38 (12.2%) strains were penicillin-resistant, and 22 (7.1%) were oxacillin-resistant (without further minimum inhibitory concentration testing for penicillin). Being a critical case (odds ratio (OR) 7.089, 95% confidence interval (CI) 3.230-15.557) and age over 50 years (OR 3.908, 95% CI 1.820-8.390) were independent predictors of mortality, while infection with a penicillin-susceptible isolate (OR 0.441, 95% CI 0.195-0.996) was found to be protective. Empirical vancomycin use did not provide significant benefit (OR 2.159, 95% CI 0.949-4.912). CONCLUSIONS: Ceftriaxone alone is not adequate in the management of pneumococcal meningitis due to penicillin-resistant pneumococci, which is a major concern worldwide. Although vancomycin showed a trend towards improving the prognosis of pneumococcal meningitis, significant correlation in statistical terms could not be established in this study. Thus, further studies are needed for the optimization of pneumococcal meningitis treatment.

Nosocomial infection characteristics in a burn intensive care unit: analysis of an eleven-year active surveillance.

AIMS: The objective of this study was to describe nosocomial infection (NI) rates, risk factors, etiologic agents, antibiotic susceptibility, invasive device utilization and invasive device associated infection rates in a burn intensive care unit (ICU) in Turkey. METHODS: Prospective surveillance of nosocomial infections was performed according to Centers for Disease Control and Prevention (CDC) and National Healthcare Safety Network (NHSN) criteria between 2001 and 2012. The data was analyzed retrospectively. RESULTS: During the study period 658 burn patients were admitted to our burn ICU. 469 cases acquired 602 NI for an overall NI rate of 23.1 per 1000 patient days. 109 of all the cases (16.5%) died. Pseudomonas aeruginosa (241), Acinetobacter baumannii (186) and Staphylococcus aureus (69) were the most common identified bacteria in 547 strains. CONCLUSION: Total burn surface area, full thickness burn, older age, presence of inhalation injury were determined to be the significant risk factors for acquisition of NI. Determining the NI profile at a certain burn ICU can lead the medical staff apply the appropriate treatment regimen and limit the drug resistance. Eleven years surveillance report presented here provides a recent data about the risk factors of NI in a Turkish burn ICU.

Differential diagnosis of cervical lymphadenitis mimicking malignancy due to tularemia: our experiences.

BACKGROUND: Tularemia is a disease caused by a Gram-negative coccobacillus Francisella tularensis. This bacterium may cause different types of clinical pictures owing to acquisition route and entrance site, such as ulceroglandular, oropharyngeal, glandular, pneumonic, typhoid and ocular forms. Oropharyngeal tularemia (OPT) is the most common form of tularemia in some regions. OPT may cause tonsillopharyngitis followed by cervical lymphadenopathies (LAPs). Without treatment LAP may persist for several months and may mimic other diseases causing cervical LAPs. MATERIALS AND METHODS: A total of six cases of OPT, five male and one female, between 21 and 31 years old, diagnosed serologically and clinically recorded in GATA Haydarpasa Training Hospital were included in this study. Detailed story including the region they lived for last 6 months, their occupation, family and neighborhood story with similar complaints were obtained. Patient data were also obtained from manually written patients files and electronical patient file system. Formalin fixed paraffin embedded tissue blocks of all biopsy material were submitted for polymerase chain reaction (PCR) study for F. tularensis. RESULTS: A total of six cases with head and neck mass following a story of tonsillopharyngitis admitted to different clinics including infectious diseases, ear-nose-throat and internal medicine in our tertiary care hospital. Physical examination revealed immobile, hard, conglomerated unilateral cervical lymphadenopathy in all cases. Histopathological examination revealed granulomatous inflammation in four cases. Acute suppurative inflammatory changes were also seen in two cases. Large necrotic areas mimicking casseifying necrosis were seen in two cases. PCR amplification of F. tularensis genom from isolated deoxyribonucleic acids was successful in five cases. CONCLUSION: Tularemia should be kept in mind in patients with tonsillopharyngitis not responding to penicillins and beta lactam antibiotics. Furthermore, persisting LAPs mimicking tumor with or without the story of previously experienced sore throat or tonsillopharyngitis in past few days or weeks should be evaluated for glandular or OPT. At this point, easily applicable serological tests such as tularemia micro-agglutination tests will confirm the diagnosis of OPT. However, if lymph node were already sampled to exclude especially malignancy or T cell lymphoma, tularemia PCR test may be used to make a certain diagnosis.

Mortality indicators in community-acquired pneumonia requiring intensive care in Turkey.

BACKGROUND: Severe community-acquired pneumonia (SCAP) is a fatal disease. This study was conducted to describe an outcome analysis of the intensive care units (ICUs) of Turkey. METHODS: This study evaluated SCAP cases hospitalized in the ICUs of 19 different hospitals between October 2008 and January 2011. The cases of 413 patients admitted to the ICUs were retrospectively analyzed. RESULTS: Overall 413 patients were included in the study and 129 (31.2%) died. It was found that bilateral pulmonary involvement (odds ratio (OR) 2.5, 95% confidence interval (CI) 1.1-5.7) and CAP PIRO score (OR 2, 95% CI 1.3-2.9) were independent risk factors for a higher in-ICU mortality, while arterial hypertension (OR 0.3, 95% CI 0.1-0.9) and the application of non-invasive ventilation (OR 0.2, 95% CI 0.1-0.5) decreased mortality. No culture of any kind was obtained for 90 (22%) patients during the entire course of the hospitalization. Blood, bronchoalveolar lavage, and non-bronchoscopic lavage cultures yielded enteric Gram-negatives (n=12), followed by Staphylococcus aureus (n=10), pneumococci (n=6), and Pseudomonas aeruginosa (n=6). For 22% of the patients, none of the culture methods were applied. CONCLUSIONS: SCAP requiring ICU admission is associated with considerable mortality for ICU patients. Increased awareness appears essential for the microbiological diagnosis of this disease.

Hepatitis B virus reactivation in a juvenile rheumatoid arthritis patient under treatment and its successful management: a complicated case.

Juvenile rheumatoid arthritis is a common chronic inflammatory disease in the childhood and it can differentiate rarely into spondiloarthropaties. It is one of the important causes of chronic pain and disability. Some of the drugs used for the treatment have immunosupressive activity. One of the serious side-effects of immunosupressive treatment is activation of opportunistic pathogens. Hepatitis B virus (HBV) is one of these pathogens, and the rate of carriers in the population is considerably high. It can cause liver damage and death if reactivated. Thus, the management of oppotunistic pathogens becomes a complex issue when treating rheumatic diseases with immunosupressive drugs. In this case report, we present a juvenile rheumatoid arthritis patient whose liver enzymes raised while he was under treatment and afterwards HBV reactivation was determined as the cause. When reactivation was detected, we started controlled antiviral therapy. We achieved successful clinical and laboratory results after adding biological agents to the treatment. Careful evaluation of the patients who have indication for immunosuppressive agents and regular follow-up in case of infection may be protective from severe morbidity and/or mortality.