TLRs, future potential therapeutic targets for RA

Toll like receptor (TLR)s have a central role in regulating innate immunity and in the last decade studies have begun to reveal their significance in potentiating autoimmune diseases such as rheumatoid arthritis (RA). Earlier investigations have highlighted the importance of TLR2 and TLR4 function in RA pathogenesis. In this review, we discuss the newer data that indicate roles for TLR5 and TLR7 in RA and its preclinical models. We evaluate the pathogenicity of TLRs in RA myeloid cells, synovial tissue fibroblasts, T cells, osteoclast progenitor cells and endothelial cells. These observations establish that ligation of TLRs can transform RA myeloid cells into M1 macrophages and that the inflammatory factors secreted from M1 and RA synovial tissue fibroblasts participate in TH-17 cell development. From the investigations conducted in RA preclinical models, we conclude that TLR-mediated inflammation can result in osteoclastic bone erosion by interconnecting the myeloid and TH-17 cell response to joint vascularization. In light of emerging unique aspects of TLR function, we summarize the novel approaches that are being tested to impair TLR activation in RA patients

Attenuation of leukocyte sequestration by selective blockade of PECAM-1 or VCAM-1 in murine endotoxemia

Background: Molecular mechanisms regulating leukocyte sequestration into the tissue during endotoxemia and/or sepsis are still poorly understood. This in vivo study investigates the biological role of murine PECAM-1 and VCAM-1 for leukocyte sequestration into the lung, liver and striated skin muscle. Methods: Male BALB/c mice were injected intravenously with murine PECAM-1 IgG chimera or monoclonal antibody (mAb) to VCAM-1 ( 3 mg/kg body weight); controls received equivalent doses of IgG2a ( n = 6 per group). Fifteen minutes thereafter, 2 mg/kg body weight of Salmonella abortus equi endotoxin was injected intravenously. At 24 h after the endotoxin challenge, lungs, livers and striated muscle of skin were analyzed for their myeloperoxidase activity. To monitor intravital leukocyte-endothelial cell interactions, fluorescence videomicroscopy was performed in the skin fold chamber model of the BALB/c mouse at 3, 8 and 24 h after injection of endotoxin. Results: Myeloperoxidase activity at 24 h after the endotoxin challenge in lungs (12,171 +/- 2,357 mU/g tissue), livers ( 2,204 +/- 238 mU/g) and striated muscle of the skin ( 1,161 +/- 110 mU/g) was significantly reduced in both treatment groups as compared to controls, with strongest attenuation in the PECAM-1 IgG treatment group. Arteriolar leukocyte sticking at 3 h after endotoxin (230 +/- 46 cells x mm(-2)) was significantly reduced in both treatment groups. Leukocyte sticking in postcapillary venules at 8 h after endotoxin ( 343 +/- 69 cells/mm(2)) was found reduced only in the VCAM-1-mAb-treated animals ( 215 +/- 53 cells/mm(2)), while it was enhanced in animals treated with PECAM-1 IgG ( 572 +/- 126 cells/mm(2)). Conclusion: These data show that both PECAM-1 and VCAM-1 are involved in endotoxin-induced leukocyte sequestration in the lung, liver and muscle, presumably through interference with arteriolar and/or venular leukocyte sticking. Copyright (C) 2004 S. Karger AG, Basel

Differential Susceptibility of Human Cancer Cell Lines to Wild-Type Tanapoxvirus Infection

Tanapoxvirus (TPV) is a member of the genus Yatapoxvirus in the family Poxviridae and is endemic to equatorial Africa. This disease is restricted to human and non-human primates, producing a mild febrile illness characterized by a single or more rarely additional pock-like lesions on the extremities. While there are several studies elucidating the replication cycle and host range of TPV, there is currently no standardized investigation comparing the ability of TPV to successfully replicate in a variety of tumor cell lines. This study examined the cytopathic effect and calculated the efficiency of TPV replication in vitro using 14 different human cancer cell lines. TPV replicates efficiently in some human tumor cells, and is restricted in others when measured by viral titer at 7 days post infection. Results described here clearly demonstrate that TPV replication in one glioblastoma cell line (U-373), and one colorectal cancer cell line (HCT-116) is more productive than in owl monkey kidney cells (OMK). Replication in two renal cancer cell lines (ACHN and Caki-1) is also increased when compared to OMK. TPV infection produced the greatest change in cellular morphology in U-373 cells, and to a much lesser degree in the breast cancer cell lines T-47D and MCF-7, and in the ovarian cancer line SK-OV3. Negligible change was noted in glioblastoma line U-87, breast cancer line MDA-MB-435, osteosarcoma line HOS, melanoma line SK-MEL5, colorectal cancer line COLO205, and prostate cancer line PC3. The cell lines least permissive to TPV replication were the glioblastoma (U-87) and melanoma (SK-MEL5) cell lines

Knowledge and Practice Gaps among Pediatric Nurses at a Tertiary Care Hospital Karachi Pakistan

The advancement in medical science has created health care environments that require nursing professionals who posses specialized clinical knowledge and skills to provide care and deal with critically and acutely ill children. This study explored gaps between knowledge and practice as perceived by the registered nurses of pediatric units by further recommending the changes suggested by them. A descriptive exploratory study design under the quantitative research methodology was utilized using universal sampling of all pediatric nurses working at a tertiary care hospital in Karachi, Pakistan. The gaps between knowledge and practice, as perceived by the participants, were categorized into five major categories: (1) medication (34%), (2) skills (28.3%), (3) knowledge (13.36%), (4) handling of code blue and intubations (12.6%), and (5) operating medical devices (11.58%). As a result, anxiety and incompetency were notably seen in the participants which had great amount of impact on the level of care provided to the patients. The implications of the findings for quality patient care were also analyzed

A collaborative review of the current concepts and challenges of anastomotic leaks in colorectal surgery

The reduction of the incidence, detection and treatment of anastomotic leakage (AL) continues to challenge the colorectal surgical community. AL is not consistently defined and reported in clinical studies, its occurrence is variably reported and its impact on longterm morbidity and health-care resources has received relatively little attention. Controversy continues regarding the best strategies to reduce the risk. Diagnostic tests lack sensitivity and specificity, resulting in delayed diagnosis and increased morbidity. Intra-operative fluorescence angiography has recently been introduced as a means of real-time assessment of anastomotic perfusion and preliminary evidence suggests that it may reduce the rate of AL. In addition, concepts are emerging about the role of the rectal mucosal microbiome in AL and the possible role of new prophylactic therapies. In January 2016 a meeting of expert colorectal surgeons and pathologists was held in London, UK, to identify the ongoing controversies surrounding AL in colorectal surgery. The outcome of the meeting is presented in the form of research challenges that need to be addressed

Gene deletion of P-Selectin and ICAM-1 does not inhibit neutrophil infiltration into peritoneal cavity following cecal ligation-puncture

BACKGROUND: Neutrophil infiltration is one of the critical cellular components of an inflammatory response during peritonitis. The adhesion molecules, P-selectin and intercellular adhesion molecule (ICAM)-1, mediate neutrophil-endothelial cell interactions and the subsequent neutrophil transendothelial migration during the inflammatory response. Despite very strong preclinical data, recent clinical trials failed to show a protective effect of anti-adhesion therapy, suggesting that the length of injury might be a critical factor in neutrophil infiltration. Therefore, the objective of this study was to determine the role of P-selectin and ICAM-1 in neutrophil infiltration into the peritoneal cavity during early and late phases of peritonitis. METHODS: Peritonitis was induced in both male wild-type and P-selectin/ICAM-1 double deficient (P/I null) mice by cecal ligation-puncture (CLP). Peripheral blood and peritoneal lavage were collected at 6 and 24 hours after CLP. The total leukocyte and neutrophil contents were determined, and neutrophils were identified with the aid of in situ immunohistochemical staining. Comparisons between groups were made by applying ANOVA and student t-test analysis. RESULTS: CLP induced a severe inflammatory response associated with a significant leukopenia in both wild-type and P/I null mice. Additionally, CLP caused a significant neutrophil infiltration into the peritoneal cavity that was detected in both groups of mice. However, neutrophil infiltration in the P/I null mice at 6 hours of CLP was significantly lower than the corresponding wild-type mice, which reached a similar magnitude at 24 hours of CLP. In contrast, in peritonitis induced by intraperitoneal inoculation of 2% glycogen, no significant difference in neutrophil infiltration was observed between the P/I null and wild-type mice at 6 hours of peritonitis. CONCLUSIONS: The data suggest that alternative adhesion pathway(s) independent of P-selectin and ICAM-1 can participate in neutrophil migration during peritonitis and that the mode of stimuli and duration of the injury modulate the neutrophil infiltration

The management of patients with primary chronic anal fissure: a position paper

Anal fissure is one of the most common and painful proctologic diseases. Its treatment has long been discussed and several different therapeutic options have been proposed. In the last decades, the understanding of its pathophysiology has led to a progressive reduction of invasive and potentially invalidating treatments in favor of conservative treatment based on anal sphincter muscle relaxation. Despite some systematic reviews and an American position statement, there is ongoing debate about the best treatment for anal fissure. This review is aimed at identifying the best treatment option drawing on evidence-based medicine and on the expert advice of 6 colorectal surgeons with extensive experience in this field in order to produce an Italian position statement for anal fissures. While there is little chance of a cure with conservative behavioral therapy, medical treatment with calcium channel blockers, diltiazem and nifepidine or glyceryl trinitrate, had a considerable success rate ranging from 50 to 90%. Use of 0.4% glyceryl trinitrate in standardized fashion seems to have the best results despite a higher percentage of headache, while the use of botulinum toxin had inconsistent results. Nonresponding patients should undergo lateral internal sphincterotomy. The risk of incontinence after this procedure seems to have been overemphasized in the past. Only a carefully selected group of patients, without anal hypertonia, could benefit from anoplasty