Fracture of ceramic/ceramic/polymer trilayers for biomechanical applications

Fracture damage in trilayers consisting of outer and inner brittle layers bonded to a compliant (polycarbonate) substrate and subjected to concentrated surface loading is analyzed. The principal mode of fracture is radial cracking at the undersurface of the inner (core) layer, even in the strongest of core ceramics--other damage modes, including radial cracking in the outer (veneer) layer, are less invasive in these all-brittle coating systems. Tests on simple trilayer structures fabricated from glasses, sapphire, and dental ceramics are used to examine the dependence of the critical load for radial fracture in terms of relative outer/inner layer thickness and modulus, and inner layer strength. An explicit relation for the critical load, based on a flexing plate model in which the outer/inner bilayer is reduced to an "equivalent" monolithic coating with "effective" composite modulus, is used to examine these dependencies. The theoretical relation describes all the major trends in the critical load data over a broad range of variables, thus providing a sound basis for trilayer design. Relevance of the analysis to dental crowns and other biomechanical applications is a central theme of the study.     

Sustained plasma TNF-alpha and HIV-1 load despite resolution of other parameters of immune activation during treatment of tuberculosis in Africans

OBJECTIVE: To determine the impact of treatment of tuberculosis on plasma HIV-1 load in African subjects and to correlate viral load with response to treatment and changes in immune activation. DESIGN: Clinical and microbiological responses, immune activation parameters and plasma HIV-1 load were determined in 20 patients with pulmonary tuberculosis and HIV-1 coinfection in Ghana, West Africa during the first 3 months of anti-tuberculosis treatment. METHODS: Plasma HIV-1 load and markers of immune activation were determined by commercially available assays. Human leukocyte antigen (HLA)-DR incorporation into the HIV-1 envelope was measured by using an immunomagnetic capture technique. RESULTS: Treatment of tuberculosis resulted in significant improvements in weight and haemoglobin, a high sputum smear conversion rate and marked reductions in mean plasma tumour necrosis factor (TNF) receptor-1, interleukin-6 and C-reactive protein. Furthermore, incorporation of host HLA-DR into the HIV-1 envelope decreased; this also suggested a reduction in immune activation of the cells supporting viral replication. However, of importance with regard to AIDS pathogenesis, neither mean plasma TNF-alpha nor HIV-1 load decreased significantly. CONCLUSIONS: The failure of HIV-1 plasma load to decline significantly during the initial months of anti-tuberculosis treatment is associated with high, sustained systemic levels of TNF-alpha. The dissociation between the sustained levels of plasma TNF-alpha and the major reductions in other, diverse immune activation parameters may represent dysregulation of cytokine production in these African patients.     

Intravenous digital subtraction renal angiography: use in screening for renovascular hypertension

Intravenous digital subtraction renal angiography (DSRA) has been compared with conventional angiography only in small, selected series of hypertensive patients. The authors prospectively examined with intravenous DSRA 94 patients at increased risk for renovascular hypertension and compared these studies with conventional angiography. A stenosis of at least one main renal artery was identified with intravenous DSRA in 22 patients and confirmed in 20 patients. No significant stenoses were seen with conventional angiography in any of the 64 patients in whom lesions were not seen with intravenous DSRA. Since inadequate DSRA studies were considered positive for renal artery stenosis, the sensitivity of intravenous DSRA was 100% (25 of 25); specificity, 93% (64 of 69); positive predictive value, 83% (25 of 30); and negative predictive value, 100% (64 of 64). The authors conclude that intravenous DSRA is a sensitive test for identifying stenosis of the main renal arteries and is appropriate to use as a screening test among patients at increased risk for renovascular hypertension.     

Causes of jaundice during hepatic artery infusion chemotherapy

Jaundice develops in many patients with liver metastases from colorectal adenocarcinoma during hepatic arterial infusion chemotherapy (HAIC). The usual cause is thought to be hepatotoxicity from the chemotherapeutic agent or biliary obstruction from progressive neoplastic disease. The authors evaluated the abdominal computed tomography and ultrasound examinations performed on 49 patients who were jaundiced during long-term HAIC. In only one patient was diffuse intrahepatic biliary dilatation caused by an obstructing mass in the porta. Two patients had metastatic hepatic lesions causing focal biliary obstruction. Intrahepatic dilatation without an obstructing mass occurred in 20 patients. Percutaneous or endoscopic cholangiograms were commonly interpreted prospectively as showing extrinsic compression by metastases, but no mass was confirmed on imaging studies. Seven patients had focal intrahepatic ductal dilatation from stricture without an associated mass. The remaining 19 patients had normal-caliber ducts; their jaundice was caused by chemical hepatitis. This series suggests that the most common causes of jaundice in these patients are chemical hepatitis and common bile duct stricture, complications of intraarterial chemotherapy, rather than neoplastic obstruction. Stricture formation may be confused with extrinsic compression on direct cholangiograms.     

Translational development of splice-modifying antisense oligomers

Introduction: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention.

Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints.

Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.     

New world mucosal and cutaneous leishmaniasis: an emerging health problem among British travellers

BACKGROUND: Mucosal leishmaniasis (ML) is an important complication of new world cutaneous leishmaniasis (CL) caused by species of the Leishmania Viannia subgenus. Previous reports of ML among travellers to Latin America are few. AIMS: To determine the annual number of cases of CL due to L. Viannia species diagnosed at this institution and to correlate this with changing patterns of travel. Secondly, to document the clinical presentation, diagnosis, treatment and outcome of ML at this institution. DESIGN: Retrospective observational study. METHODS: Data were collected from a clinical database, laboratory records, patient case notes and an international passenger survey. RESULTS: Between 1995 and 2003, the annual number of cases of CL (total 79) steadily increased from 4 per year to 18 per year; the estimated number of travellers from the UK to Latin America increased 3.5-fold. Six cases of ML were diagnosed among British travellers in 1995 (1), 1997 (1) and 2002 (4). These infections were acquired in Bolivia (3), Colombia (2) and Belize (1). Nasopharyngeal symptoms developed 0-15 months after returning to the UK. Four patients had concurrent CL at diagnosis. Diagnosis of ML was delayed up to 6 months from the onset of symptoms. Mucosal biopsies from all 6 patients were PCR-positive for L. (Viannia) DNA; microscopy and culture were less sensitive. ML relapsed in one patient following treatment. DISCUSSION: Increasing travel to Latin America from the UK was associated with an increasing number of diagnoses of L. Viannia CL. ML is likely to emerge as a more frequently imported infection among such travellers. Familiarity with these diseases is important for prompt diagnosis and optimal management.