Antimicrobial activity of myotoxic phospholipases A2 from crotalid snake venoms and synthetic peptide variants derived from their C-terminal region.

A short peptide derived from the C-terminal region of Bothrops asper myotoxin II, a Lys49 phospholipase A(2) (PLA(2)), was previously found to reproduce the bactericidal activity of its parent molecule. In this study, a panel of eight PLA(2) myotoxins purified from crotalid snake venoms, including both Lys49 and Asp49-type isoforms, were all found to express bactericidal activity, indicating that this may be a common action of the group IIA PLA(2) protein family. A series of 10 synthetic peptide variants, based on the original C-terminal sequence 115-129 of myotoxin II and its triple Tyr-->Trp substituted peptide p115-W3, were characterized. In vitro assays for bactericidal, cytolytic and anti-endotoxic activities of these peptides suggest a general correlation between the number of tryptophan substitutions introduced and microbicidal potency, both against Gram-negative (Salmonella typhimurium) and Gram-positive (Staphylococcus aureus) bacteria. Peptide variants with high bactericidal activity also tended to be more cytolytic towards skeletal muscle C2C12 myoblasts, thus limiting their potential in vivo use. However, the peptide variant pEM-2 (KKWRWWLKALAKK) showed reduced toxicity towards muscle cells, while retaining high bactericidal potency. This peptide also showed the highest endotoxin-neutralizing activity in vitro, and was shown to functionally interact with lipopolysaccharide (LPS) using a chimeric bacteria model. The bactericidal and anti-endotoxic properties of pEM-2, combined with its relatively low toxicity towards eukaryotic cells, highlight it as a promising candidate for further evaluation of its antimicrobial potential in vivo.     

Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia.

PURPOSE: To investigate whether allogeneic stem-cell transplantation (allo-SCT) may overcome the negative impact of unmutated VH genes in the outcome of patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: We analyzed the outcome of patients who underwent SCT according to their VH mutational status. RESULTS: Thirty-four patients (14 allo-SCT and 20 autologous SCT [auto-SCT]) presented unmutated VH genes and 16 patients presented mutated VH genes (nine allo-SCT and seven auto-SCT). Tumoral burden pre-SCT was significantly higher in the allo-SCT patients independent of the VH mutational status. The risk of relapse was significantly higher after auto-SCT (5-year risk, 61%; 95% CI, 44% to 84%) than after allo-SCT (5-year risk 12%, 95% CI, 3% to 44%; P < .05). In the unmutated group, 13 of 20 auto-SCT and two of 14 allo-SCT patients experienced disease progression, with a risk of relapse at 5 years of 66% (95% CI, 48% to 93%) v 17% (95% CI, 5% to 60%), respectively (P = .01). CONCLUSION: These results show that allo-SCT may overcome the unfavorable effect of unmutated VH genes in patients with CLL.     

Tolerabilidad y efectividad del citrato de fentanilo oral transmucosa en el tratamiento a largo plazo del dolor irruptivo en pacientes oncológicos: estudio ECODIR

INTRODUCTION: Oral trans-mucosal fentanyl citrate (OTFC) is the one drug specifically developed for the management of breakthrough pain. This study assesses the long-term safety and efficacy of OTFC standard clinical conditions. Patients and methods. Six-month observational study performed on cancer patients with episodes of breakthrough pain. Safety was assessed by recording the advent of adverse events and efficacy by the evaluating the intensity of breakthrough pain. RESULTS: 174 cancer patients were recruited into the study. All adverse reactions reported were mild or moderate. OTFC was significantly faster (time to the commencement of pain relief: 12.7 +/- 11.4 vs 32.7 +/- 18.4 minutes; p < 0.001) and potent (post-treatment pain intensity: 3.4 +/- 1.5 vs 4.3 +/- 1.5; p < 0.001) than the previously-used drugs. CONCLUSIONS: This observational study confirms the good safety profile of OTFC as well as its effectiveness over long-term period treatment of breakthrough pain.     

Epididymal metastases as the first sign of a colon cancer recurrence

Metastastic tumours involving the epididymis are rare and most often found in patients with disseminated disease. It is even more unusual when the metastasis of the epididymis is the first sign of tumour recurrence. We report a case of an asymptomatic recurrent colon carcinoma presenting as metastasis in the epididymis. Although metastatic cancer presenting as an intra-scrotal mass is extremely rare, it should be considered as a possibility in patients who present with a mass involving the testicle or epididymis.     

Population study of Aymara Amerindians for the PCR-DNA polymorphisms HUMTH01, HUMVWA31A, D3S1358, D8S1179, D18S51, D19S253, YNZ22 and HLA-DQα

Allele and genotype frequencies for eight DNA polymorphisms (HUMTH01, HUMVWA31A, D3S1358, D8S1179, D18S51, D19S253, YNZ22 and HLA-DQalpha) were determined in a population sample of Aymara Indians from Bolivia using PCR. No deviations of the observed allelic frequencies from Hardy-Weinberg equilibrium were found for all the systems studied. Significant differences in the allele frequencies were found between the Aymara and Quechua populations only for HUMVWA31A, which suggests a certain degree of genetic differentiation between the two populations.     

Current management of calculi in horseshoe kidneys

OBJECTIVES: To assess treatment options for calculi in horseshoe kidneys and the impact of extracorporeal shockwave lithotripsy (ESWL) on the management of renal stones. MATERIAL AND METHODS: From June 1971 to January 1998, 52 patients with horseshoe kidneys and calculi received treatment at our Urologic Stone Unit. There were 40 men (77%) and 12 women (23%). Average patient age was 41 years (range: 10-70 years). Clinical onset, treatment received and outcome were evaluated retrospectively. A successful outcome was defined as a patient without residual calculi or with fragments <0.4 cm in size. RESULTS: Clinical onset was mainly low back pain in 37 patients (71%). Eighty-nine stones were treated, i.e. an average of 1.7 treatments per patient. Before the ESWL era (May 1987), we performed two heminephrectomies, 16 pyelolithotomies, 12 pyelolithotomies combined with ureteropyeloplasty and one percutaneous nephrolithotomy. Since the advent of ESWL, seven pyelolithotomies and three pyelolithotomies combined with ureteropyloplasty have been done. ESWL was used to treat 48 calculi. In three cases the patient was placed in the prone position due to difficulties in stone focusing. In 37 cases (77%) patients were either rendered stone-free or had residual fragments <0.4 cm in size. Urinary diversion for obstruction was carried out in two cases (4%). CONCLUSIONS: At present ESWL is the first-choice treatment for calculi in horseshoe kidneys. It involves no significant focusing difficulties and is associated with a low incidence of obstructive complications. Open surgery is indicated in cases of stone-related pyeloureteral stenosis and in the presence of calculi >2-2.5 cm in size.     

Systemic oxidative stress in children with cystic fibrosis with bacterial infection including Pseudomonas Aeruginosa

IntroductionOxidative stress (OS) occurs in cystic fibrosis (CF).ObjectiveThe objective of this work is to evaluate the influence of bacterial infection on biomarkers of OS (catalase [CAT], glutathione peroxidade [GPx], reduced glutathione [GSH]), markers of oxidative damage (protein carbonyls [PC], thiobarbituric acid reactive substances [TBARS]), together with the nutritional status and lung function in children with CF.MethodsCross‐sectional study including CF group (CFG, n = 55) and control group (CG, n = 31), median age: 3.89 and 4.62 years, respectively. CFG was distributed into CFG negative bacteriology (CFGB−, n = 27) or CFG positive bacteriology (CFGB+, n = 28), and CFG negative Pseudomonas aeruginosa (CFGPa−, n = 36) or CFG positive Pseudomonas aeruginosa (CFGPa+, n = 19).ResultsCompared with CG, CFG (P = .034) and CFGB+ (P = .042) had lower body mass index‐for‐age z‐score; forced expiratory volume in the first second was lower in CFGB+ and CFGPa+ (both P < .001). After adjusting for confounders and compared with CG: CFG showed higher TBARS (P ≤ .001) and PC (P = .048), and lower CAT (P = .004) and GPx (P = .003); the increase in PC levels was observed in CFGB+ (P = .011) and CFGPa+ (P = .001) but not in CFGB− (P = .510) and CFGPa− (P = .460).ConclusionsThese results indicate a systemic OS in children with CF. The presence of bacterial infection particularly Pseudomonas aeruginosa seems to be determinant to exacerbate the oxidative damage to proteins, in which PC may be a useful biomarker of OS in CF.     

IL-24 intrinsically regulates Th17 cell pathogenicity in mice

In certain instances, Th17 responses are associated with severe immunopathology. T cell–intrinsic mechanisms that restrict pathogenic effector functions have been described for type 1 and 2 responses but are less well studied for Th17 cells. Here, we report a cell-intrinsic feedback mechanism that controls the pathogenicity of Th17 cells. Th17 cells produce IL-24, which prompts them to secrete IL-10. The IL-10–inducing function of IL-24 is independent of the cell surface receptor of IL-24 on Th17 cells. Rather, IL-24 is recruited to the inner mitochondrial membrane, where it interacts with the NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 13 (also known as Grim19), a constituent of complex I of the respiratory chain. Together, Grim19 and IL-24 promote the accumulation of STAT3 in the mitochondrial compartment. We propose that IL-24–guided mitochondrial STAT3 constitutes a rheostat to blunt extensive STAT3 deflections in the nucleus, which might then contribute to a robust IL-10 response in Th17 cells and a restriction of immunopathology in experimental autoimmune encephalomyelitis.     

Role of 5-lipoxygenase pathway in the regulation of RAW 264.7 macrophage proliferation

Arachidonic acid (AA) metabolites control cell proliferation, among other physiologic functions. RAW 264.7 macrophages can metabolise AA through the cyclooxygenase and lipoxygenase (LOX) pathways. We aimed to study the role of AA-metabolites derived from 5-LOX in the control of RAW 264.7 macrophage growth. Our results show that zileuton, a specific 5-LOX inhibitor, and nordihydroguaiaretic acid (NDGA), a non-specific LOX inhibitor, inhibit cell proliferation and [(3)H]-thymidine incorporation in a concentration-dependent fashion. Growth inhibition induced by NDGA can be explained by an apoptotic process, while zileuton does not seem to induce apoptosis. Moreover, these treatments delay the cell cycle, as analysed by flow cytometry. On the other hand, the leukotriene (LT) B(4) receptor antagonist U-75302, the LTD(4) receptor antagonists LY-171883 and MK-571, and the cysteinyl-LT receptor antagonist REV-5901 also inhibit cell proliferation and [(3)H]-thymidine incorporation in a concentration-dependent manner, and delay the RAW 264.7 cell cycle. However, these antagonists did not induce annexin V staining, caspase activation or DNA fragmentation. Furthermore, we demonstrated that exogenous addition of LTB(4) or LTD(4) revert the cell growth inhibition induced by zileuton or the leukotriene receptor antagonists mentioned above. Finally, we observed that LTB(4) and LTD(4), in the absence of growth factors, have pro-proliferative effects on macrophages, and we obtained preliminary evidences that this effect could be through mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, our results show that the interaction between LTB(4) and LTD(4) with its respective receptor is involved in the control of RAW 264.7 macrophage growth.