Bronchiolitis obliterans in systemic lupus erythematosus: beneficial effect of intravenous cyclophosphamide.

A 49 year old white woman with systemic lupus erythematosus and bronchiolitis obliterans was treated with prednisone (1 mg/kg daily), which led to a transitory improvement in pulmonary status. Cyclophosphamide was then added--4 mg/kg daily intravenously for five days, then 2 mg/kg daily orally--and this was followed by a dramatic and prolonged improvement.     

Distribution of α-integrin subunits in fetal polycystic kidney diseases

An alteration in cell/matrix interactions is one of the suggested mechanisms leading to cyst formation in polycystic kidney diseases. Most of these interactions are mediated by β1-integrins, a subfamily of integrin receptors, formed by the association of the β1-chain with different α-subunits. To date, no study on α-integrin subunit distribution during the early stages of cyst development has been reported. Using immunofluorescence, we analyzed the distribution of α-integrin subunits (α1, α2, α3, α5, and α6) and basement membrane proteins in kidneys of fetuses with autosomal dominant (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The distribution was compared with that observed in normal fetal and post-natal kidneys, and in fetal cystic dysplasia and Meckel syndrome. Marked increase in α1-integrin staining was observed in normal and cystic collecting duct cells of both polycystic diseases (PKD), compared with normal and cystic controls. The distribution of integrin subunits α2, α3, and α6 was irregular in cyst epithelial cells of PKD and cystic controls. The increased expression of the α1-subunit specifically observed in PKD collecting duct cells may be an early consequence of the genetic defect in ARPKD. In ADPKD it parallels the reported expression of polycystin, the protein product of PKD1. The irregular expression of α2, α3, and α6 integrin subunits observed in all types of cysts suggests that cell/matrix interactions are altered early and may participate in the development of cysts, perhaps by contributing to the deregulation of cell survival in cystic diseases. Received May 28, 1996; received in revised form October 2, 1996; accepted October 25, 1996     

Lupus vasculitis

Anatomical studies have demonstrated the high incidence of vasculitis in SLE, the appearances of which are variable and non-specific, ranging from necrotizing angiitis which is undistinguishable from periarteritis nodosa, to scarring lesions. Micro-angiitis is easily demonstrated in skin lesions and is also encountered to varying degrees in CNS, renal, cardiac, pulmonary and gastrointestinal localisations. Disease of large vessels is more rare and sometimes causes gangrene of the limbs. In SLE, vasculitis should be distinguished from thrombosis related to lupus anticoagulant and from atherosclerosis favoured by chronic steroid therapy but perhaps initiated by vascular deposits of immune complexes during the acute inflammatory stage. The treatment of lupic angiitis is mainly based on steroid therapy. The results are variable, probably due to the fibrous nature of some of the vascular lesions.     

Mapping the Von Hippel -- Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis

Von Hlppel—Lindau (VHL) disease is a dominantly Inheritedfamillal cancer syndrome In which affected individuals havea greatly increased predisposition to the development of haemangloblastomasof the central nervous system and retina, renal cell carcinomaand phaeochromocytoma. The VHL gene has been mapped to chromosome3p25 -p26 by genetic linkage studies and we have previouslydemonstrated that the VHL gene is tightly linked to the D3S601locus (Zmax = 18.86 at     

An engineered biopolymer prevents mucositis induced by 5-fluorouracil in hamsters

Oral mucositis is a common, treatment-limiting, and costly side effect of cancer treatments whose biological underpinnings remain poorly understood. In this study, mucositis induced in hamsters by 5-fluorouracil (5-FU) was observed after cheek-pouch scarifications, with and without administration of RGTA (RG1503), a polymer engineered to mimic the protective effects of heparan sulfate. RG1503 had no effects on 5-FU-induced decreases in body weight, blood cell counts, or cheek-pouch and jejunum epithelium proliferation rates, suggesting absence of interference with the cytotoxic effects of 5-FU. Extensive mucositis occurred in all of the untreated animals, and consisted of severe damage to cheek pouch tissues (epithelium, underlying connective tissue, and muscle bundles). Only half of the RG1503-treated animals had mucositis, over a mean area 70% smaller than in the untreated animals. Basement membranes were almost completely destroyed in the untreated group but was preserved in the RG1503 group. RG1503 blunted or abolished the following 5-FU-induced effects: increases in matrix metalloproteinase (MMP)-2, MMP-9, and plasmin, and decreases in tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These data indicate that mucositis lesions are related to massive release of proteolytic enzymes and are improved by RG1503 treatment, this effect being ascribable in part to restoration of the MMP-TIMP balance. RG1503 given with cancer treatment might protect patients from mucositis.     

Western equine encephalomyelitis virus infection affects the life table characteristics of Culex tarsalis (Diptera: Culicidae)

The life table attributes of Culex tarsalis Coquillett females infected experimentally by feeding on 4 and 6 log10 plaque-forming units (PFU) of western equine encephalomyelitis virus (WEEV) per milliliter of heparinized chicken blood were compared with an uninfected control group. Females continually were offered 10% sucrose and an oviposition substrate and daily a blood meal through a biomembrane feeder. Mortality (dead females) and fecundity (female eggs per female) were monitored daily until all females died. Overall, 94% of 198 females in the two virus-infected groups were positive for WEEV at death when tested by plaque assay; the average body virus titer at death did not differ between groups. WEEV infection significantly altered the life table characteristics of Cx. tarsalis. Life expectancy at infection in days (ex), reproductive effort in female eggs per female per generation (Ro), and generation time (T) in days for the infected cohorts were significantly lower than for the uninfected controls, whereas the reproductive rate (rc) in female eggs per female per day was higher for infected than uninfected cohorts. In agreement with the WEEV infection data that showed similar body titers, there were few differences between the life table parameters for the 4 and 6 log10 PFU treatment groups. Greatest differences were observed for survivorship between days 17-40 when virus titers in infected dying females were greatest. Our data extend recent studies that indicate mosquito infection with encephalitis viruses has a cost of reduced life expectancy and fitness.     

Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH(2)- and carboxyl-terminal interaction

Partial androgen insensitivity with sex phenotype variation in two unrelated families was associated with missense mutations in the androgen receptor (AR) gene that disrupted the AR NH(2)-terminal/carboxy terminal interaction. Each mutation caused a single amino acid change within the region of the ligand-binding domain that forms activation function 2 (AF2). In one family, the mutation I737T was in alpha helix 4 and in the other F725L was between helices 3 and 4. Neither mutation altered androgen binding as determined by assays of mutant AR in the patient's cultured genital skin fibroblasts or of recombinant mutant receptors transfected into COS cells. In transient cotransfection assays in CV1 cells, transactivation with the AR mutants at low concentrations of DHT was reduced several fold compared with wild-type AR but increased at higher concentrations. Defects in NH(2)-terminal/carboxy terminal interactions were identified in mammalian two hybrid assays. In similar assays, there was reduced binding of the p160 coactivators TIF2/SRC2 and SRC1 to the mutant AR ligand binding domains (LBD). In the family with AR I737T, sex phenotype varied from severely defective masculinization in the proband to a maternal great uncle whose only manifestation of AIS was severe gynecomastia. He was fertile and passed the mutation to two daughters. The proband of the F725L family was also incompletely masculinized but was raised as a male while his half-sibling by a different father was affected more severely and reared as a female. These studies indicate that the function of an AR AF2 mutant in male development can vary greatly depending on the genetic background.     

Expression and characterization of recombinant mouse beta 2-microglobulin type a in insect cells infected with recombinant baculoviruses.

The murine beta 2-microglobulina cDNA was cloned into pAc373 and pVL941 transfer vectors and introduced via homologous recombination into the genome of Autographa californica nuclear polyhedrosis virus downstream of the polyhedrin promoter. Both types of recombinant baculoviruses were isolated and used to infect Spodoptera frugiperda (Sf9) lepidopteran cells. beta 2m was synthesized at a substantially higher rate in cells infected with the pVL941-derived virus than when the pAc373-based virus was used. beta 2m was secreted into the culture medium where it accumulated and, under the best conditions, reached an approximate level of 10 micrograms/10(6) cells. Pulse-chase experiments after metabolic labelling with 35S-methionine followed by immunoprecipitation showed that beta 2m was stable, but that the secretion process in infected cells was relatively slow. Recombinant beta 2m was endowed with biological activity and was indistinguishable from that produced by mouse cells in 2D gel analysis. beta 2m was purified to near homogeneity from serum-free culture medium conditioned by recombinant baculovirus-infected cells by using an immunoaffinity column. The use of the insect cell/baculovirus expression system should constitute a suitable source of mouse beta 2m and should aid experiments aimed at unraveling its interactions with mouse class I histocompatibility molecules.