No major effect of orciprenaline and propranolol upon ACTH-induced cortisol secretion.

Preclinical research suggests adrenal beta-adrenergic receptors to be involved in the regulation of steroid synthesis. In a group of healthy male volunteers, we compared ACTH-induced cortisol and dehydroepiandrosterone (DHEA) secretion after pre-treatment with orciprenaline, propranolol or placebo. Neither baseline nor ACTH-induced steroid secretion differed between these conditions. Our data do not support the hypothesis that the adrenal beta-receptor plays a major role in steroid secretion in humans.     

Thirty-year follow-up of superior vena cava-pulmonary artery (Glenn) shunts.

The first superior vena cava-pulmonary artery shunt (Glenn shunt) in our series was performed in February 1958. From then through September 1988, 91 patients have undergone this procedure for a wide variety of congenital defects. We here report follow-up data available on all patients. Ages ranged from 2 days to 46 years (mean 6.8). Diagnoses were as follows: tricuspid atresia, 27; single ventricle, 22; tetralogy of Fallot, 14; D-transposition of the great arteries, ventricular septal defect, and pulmonary stenosis, 9; D-transposition, 5; Ebstein's anomaly, 4; pulmonary atresia + intact septum, 4; and others, 6. The hospital mortality rate was 7.7% (one death in the last 53 patients, 1.9%). Five deaths occurred in patients less than 6 months old. There were 20 late deaths (22%) with actuarial survival rates of 84% and 66% at 10 and 20 years, respectively. Pulmonary arteriovenous fistula formation was seen in 18 patients (19.7%), six of whom have undergone therapeutic embolization with improvement in saturation. The prevalence of pulmonary arteriovenous fistula increases with time after shunt. No long-term shunt thrombosis or stricture formation was seen. Fifty percent of shunts were still functioning at 20 years. Palliation was limited because of decrease in blood flow to the contralateral pulmonary artery, collaterals between the inferior and superior venae cavae, and pulmonary arteriovenous fistula formation. Improvement in saturation was obtained in eight otherwise inoperable patients by creation of a right axillary arteriovenous fistula up to 19 years after the Glenn shunt. Three patients had conversion of a Blalock-Taussig shunt to a Glenn shunt with improvement in congestive heart failure. Twenty-six patients have undergone a Fontan procedure with two deaths. Compared with the group having a Fontan procedure without a prior Glenn operation, there was no difference in early or late mortality. Thirty years after a Glenn shunt, the first patient in this series is working full time after having undergone a modified Fontan procedure in 1981. We conclude that the Glenn connection, usually with supplemental procedures to enhance oxygenation, has provided excellent physiologic palliation with low mortality up to 30 years with no late thrombosis or stricture formation. The incidence of pulmonary arteriovenous fistula increases with time and can be effectively treated with embolization. Physiologic repair after the Glenn shunt carries a low mortality. Although currently used infrequently, superior vena cava-pulmonary artery shunting remains a useful method of palliation in selected patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Interleukin 6 Influences Germinal Center Development and Antibody Production via a Contribution of C3 Complement Component

Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell–dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules involved in initial signaling events leading to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were detected on germinal center B cells isolated from the deficient mice suggesting a modification of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6–deficient mice. Indeed, C3 provided an essential stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti–mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from C3–deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes. Adding IL-6 in vitro to IL-6–deficient germinal center cells stimulated cell cycle progression and increased levels of antibody production. These findings reveal that the germinal center produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.     

Hydrosalpinges adversely affect markers of endometrial receptivity

While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.      

Hapten-induced colitis associated with maintained Th1 and inflammatory responses in IFN-gamma receptor-deficient mice

IFN-gamma is a potent pro-inflammatory cytokine thought to be involved in the pathogenesis of Crohn's disease. To further define the role of IFN-gamma in intestinal inflammation, we studied the effects of intra-colonic 2,4,6-trinitrobenzene sulfonic acid (TNBS) instillation in mice with a functionally inactivated IFN-gamma receptor 1 (IFN-gammaR1(- / -)). Our results indicate that IFN-gamma is not necessary for the induction of hapten-induced colitis: after TNBS administration both wild-type and IFN-gammaR1(- / -) mice lost body weight, and the histological features of TNBS-induced colitis were comparable. Colons of IFN-gammaR1(- / -) mice contained a greater number of cells, represented by macrophages and CD4(+) T cells; caudal lymph node cells produced more IFN-gamma and TNF-alpha upon stimulation in vitro. Moreover, IL-18 and IL-12 p40 RNA levels were comparably up-regulated after TNBS treatment in IFN-gammaR1(- / -) wild-type mice. These findings demonstrate that IFN-gamma is dispensable for the development of TNBS-induced colitis. Importantly, the production of Th1 cytokines (e. g. IFN-gamma and TNF-alpha) by caudal lymph node T lymphocytes was enhanced rather than decreased in IFNgammaR1(- / -) mice with no evidence for default Th2 development.     

bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors

Proliferative expansion and apoptotic cell death play prominent roles in T cell development. The molecular control of cell cycle progression and apoptosis appear to be inter-connected since the Bcl-2 protein can inhibit apoptosis and slow cell cycle progression in cortical thymocytes and mature T cells, particularly during the transition from the quiescent state into the cell cycle. Here the impact of bcl-2 transgene expression on CD3-CD4-CD8- T cell progenitors was assessed. Bcl-2 enhanced the survival of these progenitors at all of the four major differentiation stages, CD25- CD44+ (pro-T1), CD25 + CD44+ (pro- T2), CD25 + CD44- (pro-T3) and CD25-CD44- (pro-T4). However, it reduced cell cycling and slowed turnover only in the pro-T4 subset. From an analysis of bcl-2 transgenic mice expressing a TCR transgene or bearing a mutation in the scid or rag-1 gene we conclude that Bcl-2 inhibits proliferation only of T cell progenitors that are activated via the pre- TCR, not those stimulated via c-Kit and the IL-7 receptor.      

Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism

Parathyroid hormone secretion is negatively regulated by a 7- transmembrane domain, G-protein coupled Ca(2+)-sensing receptor. We hypothesized that activating mutations in this receptor might cause autosomal dominant hypoparathyroidism (ADHP). Consistent with this hypothesis, we identified, in two families with ADHP, heterozygous missense mutations in the Ca(2+)-sensing receptor gene that cosegregated with the disorder. None of 50 normal controls had either mutation. We also identified a de novo, missense Ca(2+)-sensing receptor mutation in a child with severe sporadic hypoparathyroidism. The amino acid substitution in one ADHP family affected the N-terminal, extracellular domain of the receptor. The other mutations involved the transmembrane region. Unlike patients with acquired hypoparathyroidism, patients with these mutations had hypercalciuria even at low serum calcium concentrations. Their greater hypercalciuria presumably reflected activation of Ca(2+)-sensing receptors in kidney cells, where the receptor negatively regulates calcium reabsorption. This augmented hypercalciuria increases the risk of renal complications and thus has implications for the choice of therapy.