Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants

We have previously reported the pattern of cellular expression of tumor necrosis factor receptors (TNFR) in human kidney and their altered expression in transplant rejection. We have extended our studies to examine the expression of Silencer of Death Domains (SODD), a protein that binds to the cytoplasmic portion of TNFR1 to inhibit signaling in the absence of ligand. In normal human kidney SODD is expressed in glomerular endothelial cells where it colocalizes with TNFR1. During acute rejection both SODD and TNFR1 are lost from glomeruli, but we found strong expression of SODD on the luminal surface of tubular epithelial cells. This occurs in the absence of detectable TNFR1 expression, suggesting that SODD could interact with other proteins at these sites. Several other members of the TNF superfamily, including Fas and death receptors (DR)-3, -4, and -5, also contain intracellular death domains, but SODD only interacts with the death domain of DR3. We therefore studied the expression of DR3 in human kidney, and report that this death receptor is up-regulated in renal tubular epithelial cells and endothelial cells of some interlobular arteries, in parallel with SODD, during acute transplant rejection. In less severe rejection episodes, DR3 and SODD were more focally induced, generally at sites of mononuclear cell infiltrates. In ischemic allografts, eg, with acute tubular necrosis but no cellular rejection, DR3 was induced on tubular epithelial cells and on glomerular endothelial cells. These data confirm that TNF receptor family members are expressed in a regulated manner during renal transplant rejection, and identify DR3 as a potential inducible mediator of tubular inflammation and injury.     

Protective effect of Diosmin against benzo(a)pyrene‐induced lung injury in Swiss Albino Mice

Diosmin, a naturally occurring flavonoid commonly present in citrus fruit, is known to exhibit anti‐inflammatory, antimutagenic, antioxidant, and free radical scavenging as well as blood lipid lowering activities among others. Diosmin has also been used for the treatment of various diseases including diabetes mellitus and Alzheimer's disease. Our study explores the role of Diosmin in pulmonary toxicity (lung injury) induced by environmental contaminant benzo(a)pyrene [B(a)P]. Swiss Albino Mice (SAM) were administered with either Diosmin 100 or 200 mg/kg body weight daily for 14 days and then challenged with a single dose of B(a)P. On the 15th day, animals were sacrificed; lung tissues and blood were collected for molecular analysis. B(a)P administration in mice induced the thickening of lung epithelium, damaged alveolar architecture, and promoted inflammatory cell infiltration in the lung tissues. Also, B[a]P significantly increased the expression of NF‐kB, COX‐2, IL‐6, Bax, cleaved caspase 3, and cleaved PARP proteins and decreased antioxidant enzyme levels. Diosmin‐100 and Diosmin‐200 significantly attenuated the damage to lung epithelium, alveolar architecture, and reduced inflammatory cell infiltration in the lung tissues of mice. Diosmin significantly (P < .05) attenuated the levels of oxidative stress markers: lactate dehydrogenase and xanthine oxidase. A decrease in expression of NF‐kB, COX‐2, IL‐6, Bax, cleaved caspase 3, and cleaved PARP proteins in mice was challenged with B[a]P. Diosmin thus could be a promising therapeutic adjuvant against B[a]P‐induced oxidative stress and lung damage.     

Enterococcus faecalis: a multicenter study on antibiotic resistance]

676 E. faecalis strains were listed over a period of 2 years from the Charles Nicolle hospital of Tunis (167 strains), the Habib Bourguiba hospital of Sfax (350 strains) and the National Centre of Bone marrow Transplantation of Tunis (159 strains). Antibiotic sensibility study was realized by the method of the antibiogram, E-test method and the search of penicillinase by cefinase. E. faecalis resulted essentially from services of onco-haematology (24%), external consultations (23%), surgery (18%) and medicine (15%). These strains were isolated especially from urines (54%), coprocultures (15%), bloodcultures (11%) and from pus (9%). Resistance acquired with these strains is raised for erythromycin, tetracyclin and chloramphenicol (81% to 86%), followed by high level resistance to gentamicine (37%). 0.1% of E. faecalis strains have a low level resistance to amoxicillin without production of penicillinase. No resistance to vancomycin was observed.     

Nanoparticle Albumin-bound Paclitaxel Plus Carboplatin Induction Followed by Nanoparticle Albumin-bound Paclitaxel Maintenance in Squamous Non–Small-cell Lung Cancer (ABOUND.sqm): A Phase III Randomized Clinical Trial

BackgroundWe evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non–small-cell lung cancer.Patients and MethodsPatients with treatment-naive squamous non–small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m² on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m² (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS).ResultsOverall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator’s discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC).ConclusionsThe results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.     

Will the implementation of the 2007 National Institute for Health and Clinical Excellence (NICE) guidelines on childhood urinary tract infection (UTI) in the UK miss significant urinary tract pathology?

What's known on the subject? and What does the study add? Most centres continue to investigate children extensively after a urinary tract infection. These investigations are invasive, time consuming and expensive and despite their widespread application they have not had a significant impact on the rates of chronic renal failure secondary to infection. Despite this evidence the National Institute for Health and Clinical Excellence (NICE) guidelines generated significant controversy that abnormalities would be missed, placing children at increased risk of renal injury, thus reducing their implementation. Significant underlying abnormalities of the urinary tract will not be missed if the NICE guidelines are followed. This will reduce the unpleasant investigations that children will be subjected to and it should lead to considerable cost savings. The NICE guidelines are safe and should be widely implemented.

OBJECTIVE

• ? To investigate whether the implementation of the August 2007 National Institute for Health and Clinical Excellence (NICE) guidelines would miss significant urinary tract pathology in children with urinary tract infection (UTI).

PATIENTS AND METHODS

• ? All ultrasound (US) performed in children aged >6 months, during the year 1 August 2006 to 31 July 2007 for UTI, were retrospectively studied.
• ? Each US scan in the study population of 346 was categorised dependent on whether it was appropriate or inappropriate to have been performed under the new guidelines and whether the US scan was normal or abnormal.
• ? The records of each patient with an inappropriate abnormal US scan were re‐analysed to see if patient management was affected by the US scan.
• ? In 2011 patients with an original inappropriate abnormal US scan were re‐evaluated to identify if any had presented with further urinary pathology.

RESULTS

• ? In accordance with the NICE guidelines patients were divided by age.
• ? Children aged 0.5–3 years: 78/95 (82%) US scans were inappropriate of which 12 (15%) were abnormal and four of these had a further documented UTI. After careful assessment of the US abnormalities it was judged that only one would have benefited from the initial US scan.
• ? Children aged >3 years: 146/251 (58%) US scans were inappropriate of which 21(14%) were abnormal and six of these (29%) had a further documented UTI. After careful assessment of the US abnormalities it was judged that only three of 21 (14%) would have benefited from the initial US scan.

CONCLUSIONS

• ? The vast majority of anomalies detected on the inappropriate US scans were of little clinical significance.
• ? It is difficult to identify any patient who would have been truly disadvantaged if the US scan had not been performed after the initial UTI.
• ? The NICE guidelines are safe to follow.