Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients

BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS: Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.     

The thiamin, riboflavin and pyridoxine status of patients on emergency admission to hospital.

The aim of this study was to assess the prevalence of thiamin, riboflavin and pyridoxine deficiencies at admission to an acute hospital. One hundred and twenty adult patients were selected at random from those admitted via the Accident and Emergency department over 3 days. Comparisons were made with a group of 80 healthy blood donors sequentially attending a local transfusion centre. The alcohol intake of 500 patients admitted sequentially via the same Accident and Emergency department was also assessed. Erythrocyte transketolase (ETK), glutathione reductase (EGR) and aspartate aminotransferase (EAA) coenzyme activation assays were used to determine thiamin, riboflavin and pyridoxine deficiencies. The prevalences of deficiency states in the inpatient group were 21, 2.7 and 32% for thiamin, riboflavin and pyridoxine deficiencies respectively with 49.2% being deficient in one or more vitamin. The mean alcohol intake in the group of patients in whom this was assessed was 9.7 units per week compared with 10 units per week amongst blood donors.     

Anti-inflammatory activity of c(ILDV-NH(CH2)5CO), a novel, selective, cyclic peptide inhibitor of VLA-4-mediated cell adhesion.

1. Small, N- to C-terminal cyclized peptides containing the leucyl-aspartyl-valine (LDV) motif from fibronectin connecting segment-1 (CS-1) have been investigated for their effects on the adhesion of human T-lymphoblastic leukaemia cells (MOLT-4) to human plasma fibronectin in vitro mediated by the integrin Very Late Antigen (VLA)-4 (alpha4beta1, CD49d/CD29). 2. Cyclo(-isoleucyl-leucyl-aspartyl-valyl-aminohexanoyl-) (c(ILDV-NH(CH2)5CO)) was approximately 5 fold more potent (IC50 3.6+/-0.44 microM) than the 25-amino acid linear CS-1 peptide. Cyclic peptides containing two more or one less methylene groups had similar potency to c(ILDV-NH(CH2)5CO) while a compound containing three less methylene groups, c(ILDV-NH(CH2)2CO), was inactive at 100 microM. 3. c(ILDV-NH(CH2)5CO) had little effect on cell adhesion mediated by two other integrins, VLA-5 (alpha5,beta1, CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule-1 (LFA-1, alphabeta2, CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule-1) at concentrations up to 300 microM. 4. c(ILDV-NH(CH2)5CO) inhibited ovalbumin delayed-type hypersensitivity or oxazolone contact hypersensitivity in Balb/c mice when dosed continuously from subcutaneous osmotic mini-pumps (0.1-10 mg kg(-1) day(-1)). Maximum inhibition (approximately 40%) was similar to that caused by the monoclonal antibody PS/2 (7.5 mg kg(-1) i.v.) directed against the alpha4 integrin subunit. 5. c(ILDV-NH(CH2)5CO) also inhibited oxazolone contact hypersensitivity when dosed intravenously 20 h after oxazolone challenge (1-10 mg kg(-1)). Ear swelling was reduced at 3 h and 4 h but not at 1 h and 2 h post-dose (10 mg kg(-1)). 6. Small molecule VLA-4 inhibitors derived from c(ILDV-NH(CH2)5CO) may be useful as anti-inflammatory agents.     

High resolution CT of the lungs in acute disseminated tuberculosis and a pediatric radiology perspective of the term “miliary”

High resolution CT (HRCT) of the lungs in six children with acute disseminated tuberculosis was evaluated. There was a wide variation in the HRCT appearances. This covered differences in size, distribution and concentration of nodular opacities. Coalescence of nodules and the presence of intestitial thickening was variable. The recognition of acute disseminated tuberculosis is important for diagnosis and has prognostic implications. The use of the term acute disseminated tuberculosis rather than miliary tuberculosis is advocated.     

Recent advances in diagnosis and management of pulmonary hypertension in chronic lung disease

Pulmonary hypertension with elevated pulmonary vascular resistance is a common cardiovascular complication associated with increased morbidity and mortality in preterm infants with chronic lung disease. Injury to the developing pulmonary circulation results in structural and functional abnormalities of the pulmonary vasculature. Animal studies have demonstrated that disruption of angiogenesis may contribute to the failure of normal alveolarisation in chronic lung disease. Levels of vascular endothelial growth factor in bronchoalveolar lavage fluid are lower in infants with chronic lung disease compared to preterm controls. Supplemental oxygen is commonly used to prevent and treat pulmonary hypertension, although optimal arterial oxygen saturation levels remain uncertain. Other vasodilators such as inhaled nitric oxide appear promising, but as yet have not been evaluated in the form of randomised controlled trials. Further studies are required to investigate the long-term effectiveness of pulmonary vasodilator therapy.     

Rapid diagnosis of glucocorticoid suppressible hyperaldosteronism in infants and adolescents

Glucocorticoid suppressible hyperaldosteronism (GSH) is an uncommon form of dominantly inherited hypertension. Presentation with hypertension and complications such as stroke in early life are well recognised. The use of a simple genetic test carried out on blood or placenta facilitates the detection of infants and children with GSH before the development of hypertension, allowing prompt treatment of hypertension if it occurs, and an opportunity to study the effects of growth and environmental influences on the progression of the condition.     

Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients

Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis (P value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.