Decreased expression of bcl-2 (p26) in CD8(+) lymphocytes of patients with T-cell lymphoproliferative disorders of large granular lymphocytes

The objective of the present study was to identify the polychlorinated biphenyl congeners of Aroclor 1254 that are responsible for the induction of the cytosolic bioactivation of aromatic amines. Various chlorobiphenyls, ranging from di- to hexa-substituted, were administered to rats and the ability of the hepatic cytosol to bioactivate 2-aminoanthracene and 2-aminofluorene was investigated. These studies revealed that the induction of the cytosolic activation of aromatic amines increased with the increasing extent of chlorination; moreover, planar congeners were more effective inducers of this activity compared to their non-planar isomers. This observation prompted us to investigate whether the cytosolic activation of aromatic amines is associated with the Ah receptor. Treatment of mice with Aroclor 1254 stimulated the cytosolic activation of aromatic amines in C57BL6 mice, an Ah-responsive strain, whereas it had no effect in DBA2 mice, a non-responsive strain. These findings indicate that the bioactivation of aromatic amines by the liver cytosol is linked to the Ah receptor.     

Increased saturated triacylglycerol levels in plasma membranes of human neutrophils stimulated by lipopolysaccharide

Neutrophils isolated from patients with bacterial infections or stimulated in vitro with lipopolysaccharide (LPS) produce a high resolution, lipid-dominated spectrum on 1H-NMR spectroscopy (May et al, 1993. J. Infect. Dis. 168: 386-392). We have investigated the origin of this lipid signal using NMR and chemical analyses of both whole neutrophils and purified plasma membranes. Plasma membranes from neutrophils that had been stimulated with 50 microg/ml LPS exhibited the high resolution 1H-NMR signal, and contained double the triacylglycerol (TAG) content of plasma membranes isolated from resting cells. Chemical analysis of the whole cells indicated that the TAG also increased at the cellular level (1.7-fold) after stimulation with LPS. Diradylglycerol increased 2- to 3-fold in both whole cells and plasma membranes after stimulation, but was only a minor component compared with TAG. The plasma membrane protein/phospholipid ratio increased 2.6-fold, whereas cholesterol (free and esterified) was unchanged. The membranes from LPS-stimulated neutrophils exhibited increased fluidity, as judged by increased merocyanine 540 binding, consistent with a 2-fold reduction in cholesterol/phospholipid ratio. LPS induced a shift in fatty acid content of whole cell polar lipids towards more oleic acid and less palmitic acid, whereas the neutral lipid fraction contained increased amounts of palmitic and stearic acids. The TAG fraction of plasma membrane lipids contained increased amounts of palmitic acid when prepared from cells stimulated with LPS. We conclude that the 1H-NMR signal in LPS-stimulated neutrophils arises from increased amounts of plasma membrane TAG with an elevated content of palmitic acid.     

Vaccination of pregnant macaques protects newborns against mucosal simian immunodeficiency virus infection

Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a rapid, sensitive animal model of human pediatric AIDS. Newborn macaques were readily infected by uncloned SIVmac following oral-conjunctival exposure and had persistently high viremia and rapid development of AIDS. In contrast, when 3 pregnant macaques were vaccinated against SIV, 2 of the newborns that had transplacentally acquired antiviral antibodies were protected against mucosal SIV infection at birth. These results suggest that intervention strategies such as active immunization of human immunodeficiency virus (HIV)-infected pregnant women and anti-HIV immunoglobulin administration may decrease the rate of perinatal HIV infection.     

Tumour suppressor gene mutations in humans and mice: parallels and contrasts

Tumour suppressor genes prevent cancer development. They can be identified by studying humans, but a full understanding of the mechanisms of their action requires the production of animal models. Mice with mutations in tumour suppressor genes can be produced by gene targeting. The phenotypic consequences of tumour suppressor gene mutations in mice and humans show parallels and contrasts, and both can contribute to the elucidation of disease processes.     

The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1

OBJECTIVE: To delineate the clinical features in patients with the autosomal recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) and to determine the location of the involved gene. METHODS: Eight affected individuals (ages 2-15 years) with CACP from 4 consanguineous kindreds were clinically evaluated. Four patients are newly described and 4 have been reported previously. Findings were compared with those in 21 other previously reported cases. DNA obtained from the 8 affected patients and their available siblings and parents was used in a genome-wide search for linkage. RESULTS: Congenital camptodactyly and childhood-onset noninflammatory arthropathy were present in all affected patients. Seven patients developed bilateral coxa vara deformity, and 1 developed coxa magna with cystic erosions. Two of the patients also had symptoms or signs of pericarditis. A genome-wide search for linkage identified homozygosity for a series of genetic markers on human chromosome 1q in all affected patients. The marker D1S191 yielded a maximum logarithm of the odds ratio (LOD score) of 3.3 at theta = 0. The CACP gene lies within a 1.9-cM candidate interval defined by the markers D1S2107 and D1S222. CONCLUSION: The principal features of the CACP syndrome are congenital or early-onset camptodactyly and childhood-onset noninflammatory arthropathy. Coxa vara deformity or other dysplasia associated with progressive hip disease may develop over time. Clinical pericarditis may also occur. A locus responsible for causing CACP syndrome is assigned to a 1.9-cM interval on human chromosome 1q25-31 by homozygosity mapping. This now facilitates the identification of the responsible gene and permits testing for locus homogeneity in other CACP kindreds.     

Dietary xylitol protects against weakening of bone biomechanical properties in ovariectomized rats

The effects of dietary xylitol (xyl) on bone biomechanical properties in ovariectomized rats (ovx) were studied. Forty-two 3-mo-old female Wistar rats were divided into three groups of 14. Rats in two groups were ovariectomized, while those in the control group underwent a sham operation. All rats received a basal diet, and half of the ovx were given an additional 10 g/100 g dietary xyl supplementation. Three months later the rats were killed and their tibias, femurs and humeri were prepared. The tibias were used for analyses of bone density and trabecular bone volume (BV/TV) and for the three-point bending test. The femurs were used for the torsion test and for the loading test of the femoral neck. The humeri were used for analyses of bone ash weight and bone concentrations of calcium and phosphorus. Dietary xyl gave a significant protection against ovariectomy-caused decline of tibial stress in the three-point bending test, of femoral shear stress in the torsion test, and of stress of the femoral neck, without affecting bone elasticity values. Xyl restricted the ovariectomy-caused reduction in bone density, in bone ash weight and in concentrations of bone calcium and phosphorus. Furthermore, trabecular bone loss in ovx was significantly suppressed by dietary xyl. These results indicate that a 10% dietary supplementation of xyl in ovx has a protective effect against the weakening of bone biomechanical properties. This is related to greater BV/TV and maintained bone mineral content.     

The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus

The British Isles Lupus Assessment Group (BILAG) index is a computerized index for measuring clinical disease activity in systemic lupus erythematosus (SLE), which was developed according to the principle of the physician's 'intention to treat'. The index allocates separate alphabetic scores to each of eight organ-based systems; a total score is not calculated. This study demonstrated good between-rater reliability for the BILAG index for each organ-based system. There was no evidence of bias between observers. The BILAG index had good overall sensitivity (87%) and specificity (99%) when compared with the 'gold standard' criterion (starting or increasing disease-modifying therapy). There were high positive predictive values overall (80%), and for each organ-based system, with the exception of the neurological system.     

An audit of fatal acute pancreatitis

Acute pancreatitis has a mortality of about 10%: this figure has not changed over the last 20 years. A retrospective audit of fatal acute pancreatitis was performed in a teaching hospital with a catchment population of about 750,000 patients to examine patient characteristics. Using Hospital Activity Analysis code 577.0, all fatal cases of acute pancreatitis were studied in a six-year period 1987-93. Additionally, all post mortem diagnoses of acute pancreatitis were traced. The overall post mortem rate in Nottingham at the time of the study was about 35%. All available records, X-ray and biochemical data were studied and appropriate information recorded and analysed for 65 fatal cases. Only 15% were post mortem diagnoses, lower than in previous series; 72% had respiratory and 67% had renal complications. Only 34% had been admitted to the intensive care unit. A third of patients had had surgery; 67% of these was some form of external drainage. Of the 14 patients with proven gallstone pancreatitis only three had endoscopic retrograde cholangiopancreatography; 42% of patients had idiopathic disease. Not all the patients diagnosed ante mortem had the full biochemical predicted severity criteria analysed: pO2 and calcium analysis was performed in about 80%. Pre-mortem diagnoses of pancreatitis was achieved more frequently than in other comparable series.