Interleukin-1beta and TNF-alpha act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones.

We hypothesized that pro-inflammatory cytokines can act locally in the growth plate to impair longitudinal growth. In a model of cultured fetal rat metatarsal bones, we found that IL-1beta and TNF-alpha act in synergy to inhibit longitudinal growth, an effect linked to decreased proliferation and increased apoptosis of growth plate chondrocytes. IGF-I could partially reverse all these effects. INTRODUCTION: Children with chronic inflammatory conditions, such as Crohn's disease or rheumatoid arthritis, experience impaired longitudinal growth. The inflammatory process itself, which includes upregulation of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and TNF-alpha, is believed to be at least partly responsible for the poor growth in these patients. This study aimed to clarify whether these cytokines can act locally in the growth plate to suppress longitudinal growth and whether any negative effects can be reversed by insulin-like growth factor-I (IGF-I). MATERIALS AND METHODS: The effects of cytokines on longitudinal bone growth were studied in fetal (day E20) rat metatarsal bones kept in culture. After a 7-day culture, the bones were sectioned, and chondrocyte proliferation was assessed by bromodeoxyuridine (BrdU) incorporation and apoptosis by TUNEL. RESULTS: When added separately, IL-1beta and TNF-alpha impaired longitudinal bone growth only at a high concentration (100 ng/ml each; p < 0.05 versus control). In contrast, when added in combination, IL-1beta and TNF-alpha potently inhibited growth at far lower concentrations (from 3 ng/ml each; p < 0.001 versus control) and also decreased chondrocyte proliferation and increased apoptosis. Growth failure induced by the combination of IL-1beta and TNF-alpha (10 ng/ml each) could be counteracted by anti-IL-1beta (100 ng/ml; p < 0.001), anti-TNF-alpha (100 ng/ml; p < 0.001), or IGF-I (100 ng/ml; p < 0.01). IL-6 did not affect longitudinal growth even when added in combination with IL-1beta or TNF-alpha (10 ng/ml each). CONCLUSIONS: We show that IL-1beta and TNF-alpha act in synergy to locally suppress longitudinal growth, an effect that can be partially reversed by IGF-I. Although growth hormone (GH)/IGF-I may improve longitudinal growth in children with chronic inflammatory diseases, our results suggest that the inflammatory process itself must be targeted to achieve normal growth.     

Long-Term and Oncologic Outcomes of Robotic Versus Laparoscopic Liver Resection for Metastatic Colorectal Cancer: A Multicenter,Propensity Score Matching Analysis

World Journal of Surgery - To assess long-term oncologic outcomes of robotic-assisted liver resection (RLR) for colorectal cancer (CRC) metastases as compared to a propensity-matched cohort of...     

Concurrent pleural infiltration by chronic lymphocytic leukemia and adenocarcinoma of unknown primary site diagnosed by effusion cytology

Synchronous malignancies in a pleural effusion are rare. A case of concurrent pleural infiltration by adenocarcinoma of unknown primary site and chronic lymphocytic leukemia (CLL) is presented in this case study, which was diagnosed by effusion cytology. Pleural effusion is not an uncommon complication in patients with B‐CLL. Even in a pleural effusion rich in monoclonal lymphocytes, the presence of a second cancer must be excluded because this can be the main cause of mortality. The role of cytology in such cases is of paramount importance. Diagn. Cytopathol. 2014;42:151–155. © 2012 Wiley Periodicals, Inc.     

Total versus selective hepatic vascular exclusion in major liver resections

BACKGROUND: Total hepatic vascular exclusion (THVE) and selective hepatic vascular exclusion (SHVE) are two effective techniques for bleeding control in major hepatic resections. Outcomes of the two procedures were compared. METHODS: Patients undergoing major liver resection were randomly allocated to the THVE and SHVE groups. Intraoperative hemodynamic changes and the postoperative course of the two groups were compared. RESULTS: During vascular clamping, the THVE group showed a significant elevation in pulmonary vascular resistance, systemic vascular resistance, intrapulmonary shunts, and a significant reduction in cardiac index, compared with the SHVE group (P <0.05). Patients undergoing THVE received more crystalloids and blood, showed more severe liver, renal and pancreatic dysfunction, and had a longer hospital stay than the SHVE group (P <0.05). CONCLUSIONS: Both techniques are equally effective in bleeding control in major liver resections. THVE is associated with cardiorespiratory and hemodynamic alterations and may be not tolerated by some patients. SHVE is well tolerated with fewer postoperative complications and shorter hospitalization time.     

Structure-guided discovery of novel aminoglycoside mimetics as antibacterial translation inhibitors

We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.     

Clinical efficacy of distigmine bromide in the treatment of patients with underactive detrusor

Purpose: The aim of this study was to assess the clinical efficacy of distigmine bromide, an anti-cholinesterase agent, deemed to improve detrusor function thereby restoring normal voiding patterns in patients suffering from detrusor underactivity. Materials and methods: A total of 27 patients (11 men and 16 women) with poor detrusor function were included in the study. The diagnosis was established using pressure-flow studies. All patients received distigmine bromide at a dose of 5 mg three times daily for 4 weeks and re-attended for a follow-up urodynamic investigation. The results of baseline pressure-flow studies were compared to those after completion of treatment. Results: Treatment with distigmine bromide resulted in a statistically significant reduction of residual volume and percent residual volume, obviating the need for intermittent self-catheterisation in 11 patients. In addition, maximum flow rate and detrusor pressure at maximum flow increased, although not significantly. The drug was generally well tolerated by the majority of patients. Conclusion: Distigmine bromide shows clinical efficacy in patients with poor detrusor function and may therefore be used alternatively in selected cases.     

Urinary transforming growth factor-beta1 excretion in renal allograft recipients during the early post-transplantation period

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1), the major fibrogenic growth factor, is implicated in the pathogenesis of renal scarring in experimental and clinical nephropathies as well as in chronic allograft nephropathy. In this study we examined the pattern of changes of TGF-beta1 excretion in the urine and the sites of TGF-beta1 expression in the kidney of transplanted patients during the early post-transplantation period. METHODS: Eighteen renal allograft recipients were included in the study. In all patients urinary TGF-beta1 levels were determined by ELISA in sequential measurements during the first two postoperative months and compared to that of 14 healthy subjects. The renal expression of TGF-beta1 protein was studied in 4 patients that underwent a biopsy of the transplanted kidney at the same period. All patients were treated with prednisolone, cyclosporin, and mycophenolate mofetil. RESULTS: Urinary TGF-beta1 levels were increased during the first postoperative days. Although they were gradually reduced during the first two post-operative months, they remained significantly higher compared to those of normal subjects (580 +/- 148 ng/24 h vs. 310 +/- 140 ng/ 24 h p < 0.01). The decline of urinary TGF-beta1 excretion followed that of serum creatinine. TGF-beta1 protein expression was identified within the cytoplasm of tubular epithelial cells of transplanted patients. CONCLUSIONS: Elevated urinary TGF-beta1 levels are observed during the early post-transplantation period in renal allograft recipients and are maintained high even after restoration of renal function to normal.