Cytotoxic and proliferative T cell responses in HIV-1-infected Macaca nemestrina.

Macaca nemestrina has been described as an animal model for acute HIV-1 infection. This animal, unlike most infected humans, appears to contain HIV-1 replication. Therefore analysis of HIV-1-specific proliferative and cytotoxic T lymphocyte (CTL) responses following HIV-1 challenge of M. nemestrina may provide information into the role of such responses in both the control of acute HIV infection and protective immunity. Although CD4+ T cell responses to HIV-1 are generally difficult to detect in HIV-1-infected humans, early and persistent CD4+ T cell proliferative responses to HIV-1 antigens were detected in all HIV-1-inoculated M. nemestrina. HIV-1-specific CD8+ CTL responses were evaluated in PBMC by stimulation with autologous cells expressing HIV-1 genes, limiting dilution precursor frequency analysis, and T cell cloning. CTL reactive with gag, env, and nef were present 4-8 wk after infection, and persisted to 140 wk after infection. The presence of both CD4+ and CD8+ T cell responses before and after clearance of HIV-1 viremia is consistent with a role for these responses in the successful control of HIV-1 viral replication observed in M. nemestrina. Further studies of T cell immunity in these animals that resist disease should provide insights into the immunobiology of HIV-1 infection.     

Single centre experience with GORE-HELEX septal occluder for closure of PFO

Several devices are available for percutaneous patent foramen ovale (PFO) closure. Over the past 3 years our planned treatment strategy of PFO closure has been routine use of the GORE-HELEX septal occluder device, followed by 6 months of aspirin therapy. We present the safety and feasibility of routinely using this device for all patients undergoing percutaneous PFO closure, with 3-month transthoracic echocardiogram (TTE) follow up. In total, 75 adult patients (44.0+/-11.7 years; 45.3% male) were referred for PFO closure during the study period. All patients underwent echocardiography prior to PFO closure. In 5 patients no PFO was found, and 1 patient had an atrial secundum defect closed using the Amplatzer septal occluder. Of the 69 remaining patients with PFO, 68/69 (98.6%) underwent closure with the GORE-HELEX device. Six of 69 cases required device retrieval and 5 of 6 were replaced successfully with a second GORE-HELEX device. One of the 6, a large PFO associated with atrial septal aneurysm, was replaced using the Amplatzer septal occluder. There were no major complications. At 3-month follow up, 65/68 (95.6%) had no residual shunt on TTE, and 3 patients had small residual shunts thought to be related to incomplete endothelialisation at 3 months. In conclusion, percutaneous PFO closure using the GORE-HELEX septal occluder device is safe and feasible, with no major peri-procedural complications and excellent short-term results at 3-month follow up.     

Complete genome sequence of Vibrio fischeri: a symbiotic bacterium with pathogenic congeners

Vibrio fischeri belongs to the Vibrionaceae, a large family of marine gamma-proteobacteria that includes several dozen species known to engage in a diversity of beneficial or pathogenic interactions with animal tissue. Among the small number of pathogenic Vibrio species that cause human diseases are Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus, the only members of the Vibrionaceae that have had their genome sequences reported. Nonpathogenic members of the genus Vibrio, including a number of beneficial symbionts, make up the majority of the Vibrionaceae, but none of these species has been similarly examined. Here we report the genome sequence of V. fischeri ES114, which enters into a mutualistic symbiosis in the light organ of the bobtail squid, Euprymna scolopes. Analysis of this sequence has revealed surprising parallels with V. cholerae and other pathogens.     

A randomized trial of nicotine enemas for active ulcerative colitis.

BACKGROUND & AIMS: Ulcerative colitis (UC) is largely a disease of nonsmokers in which transdermal nicotine improves the symptoms but often causes adverse events (AEs). Nicotine enemas cause fewer AEs and were used as supplemental treatment for active UC. METHODS: We treated 104 patients with active UC with either 6-mg nicotine enemas or placebo enemas for 6 weeks in a randomized double-blind study. Patients continued their oral therapy, if any, for UC: 68 patients were taking mesalamine, 15 patients were taking prednisolone, and 12 patients were taking thiopurines during the study. Clinical, sigmoidoscopic, and histologic assessments were made at baseline and at the end of the study and symptoms were recorded daily on a diary card. The primary end point was induction of clinical remission and clinical improvement also was measured by the UC disease activity index. After the study, patients then used nicotine enemas daily for 4 weeks and sigmoidoscopy with a biopsy examination was repeated. AEs and salivary cotinine levels were monitored throughout the study. RESULTS: Clinical remission was achieved in 14 of 52 (27%) patients on active treatment and 14 of 43 (33%) patients on placebo (P = .55). The UC disease activity index improved by 1.45 points in the active group and by 1.65 points for those on placebo (P = .88). Only 1 patient discontinued treatment because of an AE (abdominal pain). In the 47 patients taking mesalamine only, active treatment conferred benefit that was not statistically significant; disease remission occurred in 9 of 25 patients on active therapy and 4 of 21 patients on placebo (P = .20). CONCLUSIONS: Six-milligram nicotine enemas were well tolerated but were not found to be efficacious for active UC.     

CVID-associated TACI mutations affect autoreactive B cell selection and activation

Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6–expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications.     

Association between neutrophil-lymphocyte ratio and lymph node metastasis in gastric cancer: A meta-analysis

Introduction and Aim:The prognostic role of neutrophil to lymphocyte ratio (NLR) has been explored extensively in the literature. The aim of this meta-analysis was to evaluate the link between NLR and lymph node metastasis in gastric cancer. A method for increasing specificity and sensitivity of pre-treatment staging has implications on treatment algorithms and survival.Search Strategy:The relevant databases were searched as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart. After selection, 12 full text articles that met the inclusion criteria were included for quantitative analysis. 2 × 2 squares were generated using lymph node positive/negative, and NLR high/low data. The effect size for each study was calculated using the DerSimonian–Laird random effects model. P values were calculated using the chi-square method. Finally publication bias was evaluated. All statistics were calculated using R Studio.Results:Meta-analysis showed a 1.90 times (odds ratio, with 95% CI 1.52–2.38) increase in risk of positive lymph node status with high neutrophil to lymphocyte ratio. This has significant implications for cancer screening and staging, as NLR is a highly reproducible, cost-effective, and widely available prognostic factor for gastric cancer patients. Additionally, high or low NLR values may have implications for management pathways. Patients with lymph node metastasis can be offered neoadjuvant chemotherapy, avoiding salvage therapy in the form of adjuvant chemoradiotherapy, which is poorly tolerated.Conclusion:This meta-analysis shows an association between NLR and positive lymph node status in gastric cancer patients with implications for staging, as well as preoperative personalisation of therapy.     

Frustration Intolerance Beliefs: Their Relationship with Depression, Anxiety, and Anger, in a Clinical Population

Beliefs regarding the toleration of frustration and discomfort are often described as underlying psychological disturbance, and represent a fundamental concept in Rational Emotive Behavior Therapy (REBT). Nevertheless, there has been little systematic analysis of the content of these beliefs, which are often treated as a unidimensional construct. This paper investigates the relationship between a multidimensional Frustration Discomfort Scale (FDS) and measures of depressed mood, anxiety, and anger, in a clinical population. Results indicated that FDS sub-scales were differentially related to specific emotions, independent of self-esteem and negative affect. The entitlement sub-scale was uniquely associated with anger, discomfort intolerance with depressed mood, and emotional intolerance with anxiety. These results supported the validity of the FDS, the importance of distinguishing between frustration intolerance dimensions, and of separating these beliefs from those related to self-worth.Copies of the Frustration Discomfort Scale are available from the author on request