New areas for therapeutic intervention in the treatment of rheumatic disease.

Anti-rheumatic therapy has been targeted against the symptoms arising from chronic inflammation of the joint. This has resulted in the extensive use of non-steroidal anti-inflammatory drugs. It is now becoming apparent that these agents have no beneficial effect on disease progression. This mini review concentrates on the formation and maintenance of pannus, the granulomatous tissue responsible for cartilage and bone erosion. This reveals a number of possible therapeutic targets. Protease inhibitors could be used to interfere with the degradatory processes. The diverse functions of endothelial cells suggest oedema formation, cell accumulation and supply of nutrients to the granulomatous tissue could all be targeted by appropriate therapy. Alternatively the immune processes that control pannus formation and state of activation could be regulated by interfering with antigen presentation and the cytokine network.     

Characterization of bortezomib-adapted I-45 mesothelioma cells

Background  

Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy.     

Secondary pharyngeal tuberculosis

Secondary tuberculosis of pharynx is a rare condition as pharynx is not a common site for clinically manifest tuberculosis. A rare and unusual case of secondary oropharyngeal tuberculosis in a 40 years male patient, who presented with an ulceroproliferative lesion of oropharynx extending to nasopharynx and laryngopharynx is being reported.     

Candidaemia: a 10-year study in an Indian teaching hospital

Retrospective evaluation of candidaemia patients was performed in an Indian teaching hospital over a 10-year period. The incidence of patients with candidaemia increased eleven-fold in the second half of the study period (55 patients) compared with the first half (5 patients). Haematological malignancies (11 patients), neonatal septicaemia (9), cardiac abnormalities and cardiac surgery (9) were the commonest underlying diseases in these patients. Candida albicans (50%), C. guilliermondii (17%), C. tropicalis (15%) and C. parapsilosis (8%) were the most common fungal pathogens isolated from blood culture. Therapy with two or more antibiotics (92%), corticosteroid administration (25%), intravascular catheter use for over 24 h (78%) and neutropenia (48%) were the accountable predisposing factors. Prolonged hospitalization (mean average 22.2 days as compared with 11.2 days in other patients) was an added risk factor in these patients.     

Loss of LFA-1, but not Mac-1, protects MRL/MpJ-Fas(lpr) mice from autoimmune disease

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex-mediated tissue injury. Many different adhesion molecules are thought to participate in the development of SLE; however, few studies have directly examined the contributions of these proteins. Here we demonstrate that LFA-1 plays an essential role in the development of lupus in MRL/MpJ-Fas(lpr) mice. Mice deficient in LFA-1, but not Mac-1, showed significantly increased survival, decreased anti-DNA autoantibody formation, and reduced glomerulonephritis. The phenotype of the LFA-1-deficient mice was similar to that observed in beta(2) integrin-deficient (CD18-null) MRL/MpJ-Fas(lpr) mice, suggesting a lack of redundancy among the beta(2) integrin family members and other adhesion molecules. These studies identify LFA-1 as a key contributor in the pathogenesis of autoimmune disease in this model, and further suggest that therapeutic strategies targeting this adhesion molecule may be beneficial for the treatment of SLE.     

Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.     

Degradation of dipalmitoyl phosphatidylcholine by isolated rat granular pneumocytes and reutilization for surfactant synthesis.

We investigated metabolic utilization of exogenous (modelled after lung surfactant) phospholipids by granular pneumocytes in primary culture. Cells were incubated for 21, 65, and 140 min with [3H-methyl]dipalmitoylphosphatidylcholine (DPPC) containing liposomes prepared from synthetic lipids. Radioactivity in cellular phosphatidylcholine (PC) declined steadily to 50% of the total trypsin-resistant cell-associated radioactivity. The proportion of radioactivity increased with time in cytidine-5'-diphosphate-choline and phosphorylcholine, which suggested reutilization of choline for PC synthesis. Cells incubated with liposomes for 2 h revealed that of the total cell-associated radioactivity, 7% was in lamellar bodies and 10% in the microsomal fraction. The lipid-associated radioactivity was 24% in "soluble," 96% in lamellar bodies, and 92% in the microsomal fraction. Percent of total PC label recovered in disaturated PC of microsomal fractions decreased (slope = -5.27%/h) with time of incubation (r = 0.67). Incubation of cells with liposomes containing ([3H-methyl]choline-[14C]palmitoyl) DPPC led to altered isotope ratios in both lamellar bodies and microsomes. These observations indicate that granular pneumocytes degrade exogenous PC and resynthesize PC from degradation products.     

Enzyme studies in GM2 gangliosidiosis,and their application in prenatal diagnosis

Assay of hexosaminidase A and B enzymes in four cases with developmental regression and cherry red spot on fundus examination confirmed that three cases had Tay-Sachs disease, and one case had Sandhoff disease. Prenatal diagnosis was carried out by hexosaminidase enzyme assay in amniotic fluid and cells in one family, and chorionic villus sample in the second family. The fetus was diagnosed to be unaffected in one, and affected in the other family. Assay of hexosaminidase A and B is useful for specific diagnosis of GM₂ gangliosidosis, and for prenatal diagnosis to reduce the burden of these disorders.