Background: Obesity is associated with increased cardiovascular morbidity and mortality. A direct effect of isolated obesity on cardiac function is not well established. Objective: To determine the direct effect of different grades of isolated obesity on echocardiographic indices of systolic and diastolic left ventricular function. Methods: 48 obese and 25 normal weight women were studied. They had no other pathological conditions. Obesity was classed as slight (n = 17; body mass index (BMI) 25-29.9 kg/m

Background-Systemic sclerosis (SSc, scleroderma) in either its diVuse or limited skin forms has a high mortality when vital organs are aVected. No treatment has been shown to influence the outcome or significantly aVect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc. Methods-Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being <70% of the predicted value in 18/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56%) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granulocyte colony stimulating factor, alone or in combination. Thirty eight patients had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used haemoimmunoablative doses of cyclophosphamide +/-anti-thymocyte globulin +/-total body irradiation. The median duration of follow up was 12 months (3-55). Results-An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49-255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis. Conclusion-Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkin's lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.

ASCT constitutes a therapeutic option for HL patients after a first relapse. Promising results are observed in patients with low tumour burden at diagnosis, autografted after a long CR and without detectable disease at ASCT. Innovative approaches should be pursued for patients with risk factors at relapse.

These results indicate that the FcgammaRIIIA-158 genotypes confer differential susceptibility to RA in our study population. Further studies to elucidate the role of this polymorphism in the pathogenesis of RA and other autoimmune diseases are warranted.

We investigated the effects of ursodeoxycholic acid (UDCA; 60 g/day/100 g b.wt.) on the impairment induced by maternal obstructive cholestasis during pregnancy (OCP) in the rat placentamaternal liver tandem excretory pathway. A blunted catheter was implanted in the common bile duct on day 14 of pregnancy, and the tip was cut on day 21. [ 14 C]Glycocholate (GC) was then administered through the umbilical artery of "in situ" perfused placenta (placental transfer test) or through the maternal jugular vein (biliary secretion test), and GC bile output was measured. OCP impaired both GC placental transfer and maternal biliary secretion. UDCA moderately improved the latter but had a more marked beneficial effect on GC placental transfer. Histological examination revealed trophoblast atrophy and structural alterations, e.g., loss of apical membrane microvilli in OCP placentas. Gene expression level was investigated by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis. OCP reduced both placental lactogen II (a trophoblastspecific gene) mRNA and the functional amount of epithelial tissue, determined by transplacental diffusion of antipyrin. Using a rapid filtration technique, impairment in the ATP-dependent GC transport across trophoblast apical plasma membranes obtained from OCP placentas was found. UDCA partially prevented all these changes. The expression level of organic anion transporters Oatp1, Oatp2, and Oatp4, and multidrug resistance-associated proteins Mrp1, Mrp2, and Mrp3 in whole placenta were not affected or were moderately affected by OCP but greatly enhanced by UDCA. In summary, UDCA partially prevents deleterious effects of OCP on the rat placenta-maternal liver tandem excretory pathway, mainly by preserving trophoblast structure and function.

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Objective. To investigate the association of the poly(ADP-ribose) polymerase 1 (PARP-1) gene promoter polymorphism with rheumatoid arthritis (RA) predisposition.Methods. An association study with 213 Spanish RA patients and 242 healthy subjects was carried out to investigate the association of all known PARP-1 gene promoter polymorphisms, i.e., a CA microsatellite repeat, a poly(A) n , and 3 single point mutations (C410T, C1362T, and G1672A), with disease susceptibility. Additionally, we analyzed the distribution of PARP-1 polymorphisms in 58 Spanish families with 1 or more affected members.Results Regarding the G1672A variation, although linkage disequilibrium was detected, it did not seem to be part of the conserved haplotypes described. Haplotype B was statistically overrepresented in the RA patient group compared with the healthy subjects (odds ratio 1.42, 95% confidence interval 1.06-1.91, P ‫؍‬ 0.019). In addition, a significant dose effect of PARP-1 haplotype carriage on disease predisposition was observed. Of note, within haplotype B, the PARP-1 CA 97-bp allele was found to be the RA-predisposing marker (odds ratio 2.17, 95% confidence interval 1.27-3.72, P ‫؍‬ 0.003, corrected P < 0.05).Conclusion. Our results demonstrate the existence of 2 unique PARP-1 haplotypes in the Spanish population and provide the first evidence that PARP-1 haplotypes play a role in susceptibility to RA.

Cholestasis of pregnancy induces alterations in bile acid transport by human trophoblast plasma membrane (TPM) vesicles. We investigated whether maternal cholestasis affects the overall ability of the rat placenta to carry out vectorial bile acid transfer from the fetus to the mother.