Budesonide in the treatment of refractory celiac disease

OBJECTIVE: Corticosteroids are used in patients with refractory celiac disease. In order to minimize their systemic side effects, we assessed the role of a locally active sustained release corticosteroid with minimal systemic bioavailability in patients with refractory celiac disease in an open labeled noncontrolled study. METHODS: Patients who received budesonide for refractory celiac disease were classified according to whether they were primarily or secondarily unresponsive to the diet, and whether they had a polyclonal (type I) or clonal (type II) expansion of intraepithelial lymphocytes. The response to budesonide was assessed globally and by reduction in bowel movements. RESULTS: Patients (N = 29, 72% female) received budesonide for a mean of 6.7 +/- 8.5 months, 5 patients (18%) had type II disease (clonal T-cell population); 76% responded to the medication, 55% completely. Response occurred when budesonide was used alone or with oral corticosteroids and/or azathioprine. There was an objective improvement in the number of bowel movements in those that responded. Response occurred in those with either primary or secondary refractory disease and in those with type II disease, irrespective of the presence of microscopic colitis (N = 7). There was no improvement in the duodenal biopsy over the study period and there were no side effects of budesonide. CONCLUSIONS: Budesonide may be of value in the management of refractory celiac disease.     

Poor kidney allograft survival associated with positive B cell – Only flow cytometry cross matches: A ten year single center study

The presence of donor specific antibody (DSA) to class 1 or class 2 HLA as detected respectively in T cell or B cell – only flow cytometry cross matches (FCXMs) are risk factors for renal allograft survival, though the comparative risk of these XMs has not been definitively established. Allograft survival and FCXM data in 624 microcytotoxicity (CDC) XM negative kidney transplants were evaluated. Short and long term allograft survival was significantly less in recipients with T⁻ B⁺ FCXMs (1 year, 74%, 10 year, 58%) compared to T⁺ B⁺ FCXMs (1 year, 84%, 10 year, 68%) and to T⁻ B⁻ FCXM (1 year, 90%, 10 year, 85%). Risk factors were positive FCXM, deceased donor (DD) transplantation and donor age, but not race, gender, recipient age or previous transplant. Recipients with T⁻ B⁺ and T⁺ B⁺ FCXMs were at 4.5 and 2.5 fold greater risk, respectively, of DD allograft failure compared to patients with T⁻ B⁻ FCXMs. The quantitative value of FCXM did not correlate with the duration of graft survival. We conclude that patients with DSA to class 2 HLA have a greater risk of early and late allograft failure compared to patients with DSA to class 1 HLA.     

Mitogenic effect of a factor from rat somatomammotrophs on mammary epithelial cells.

We have previously established a somatomammotroph cell line (rPC0) derived from normal rat pituitary that secretes GH and PRL. In this study we report that conditioned medium from rPC0 cells (CM-rPC0) exhibited a stimulatory effect on the growth of rat mammary epithelial cells in culture. Fractionation of CM-rPC0 revealed that the growth-promoting activity of CM-rPC0 was associated with a fraction eluting from a diethylaminoethyl-Sephacel column at 0.5 M NaCl. The growth-promoting activity of this fraction was abolished by trypsin and was resistant to dithiothreitol treatment. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the predominant components of the 0.5-M NaCl fraction were proteins migrating at the 14-18K region of the gel. The 0.5-M NaCl fraction did not contain immunodetectable GH or PRL. Further fractionation of CM-rPC0 on a heparin-agarose column showed that the growth-promoting activity eluted at 0.9 M NaCl. The two predominant proteins in this fraction had apparent mol wt of 14.5K and 18.2K. Based on the structural and biological properties, several known hormones and growth factors were excluded from consideration as potential candidates responsible for the growth-promoting effect of the 14-18K proteins. It is postulated that this group of 14-18K proteins contains a new factor(s) that affects the growth of mammary epithelial cells.     

Cardiovascular disease and metabolic risk factors in male patients with schizophrenia, schizoaffective disorder, and bipolar disorder

The authors determined whether diagnoses of cardiovascular disease (CVD) and CVD-related conditions differed by psychiatric diagnosis among male Veterans Administration patients from the mid-Atlantic region. Among 7,529 patients (mean age: 54.5 years), the prevalence of diagnoses ranged from 3.6% (stroke) to 35.4% (hypertension). Compared with schizophrenia patients, those with bipolar disorder were 19% more likely to have diabetes, 44% more likely to have coronary artery disease, and 18% more likely to have dyslipidemia, after adjustment. Clinical suspicion for CVD-related conditions, as well as risk-modification strategies, in patients with serious mental illness should incorporate differences in prevalence across specific psychiatric diagnoses.     

Activation of protein kinase B/Akt by urocortin is essential for its ability to protect cardiac cells against hypoxia/reoxygenation-induced cell death

Urocortin (Ucn), is a peptide related to hypothalamic corticotrophin-releasing factor (CRF) and binds with a high affinity to the CRF-R2 beta receptor which is expressed in the heart. Ucn promotes cardiac myocyte survival against hypoxia reoxygenation (HR) injury and this involves activation of the mitogen activated protein kinase pathway (MEK1/2 p42/44 MAPK). In this study we report that Ucn stimulates the phosphorylation of protein kinase B (PKB/Akt) via phosphatidylinositol (PI) 3-OH kinase (PI-3 kinase). To investigate the signalling pathways that mediate the anti-apoptotic and cell survival effect of Ucn in hypoxia reoxygenation (HR), gene based inhibitors of MEK1/2, PI-3 kinase and Akt were over-expressed in rat neonatal cardiac myocytes and cell survival effects against HR were assessed. The dominant negative mutants of the MEK1/2, PI-3 kinase and Akt inhibited Ucn mediated cardioprotection in HR and active PI-3 kinase was itself cardioprotective. In addition, chemical inhibitors of the PI-3 kinase pathway, wortmannin and LY294002 inhibit Ucn mediated cardioprotection in HR in both neonatal and adult cardiac myocytes. Hence the PI-3 kinase/Akt pathway is required in addition to MEK1/2 to mediate Ucn cardioprotection in HR. To our knowledge this is the first report of the activation of the PI-3 kinase/Akt pathway by a member of the CRF family of peptides.     

Alcohol drinking and risk of hospitalization for heart failure with and without associated coronary artery disease

Myocardial damage from heavy alcohol intake can cause the heart failure (HF) syndrome, but the relation of lighter alcohol intake to HF has rarely been studied. We examined the risk of HF hospitalization among 126,236 subjects who supplied data about alcohol during health examinations from 1978 to 1985. Among 2,594 subjects who were subsequently hospitalized for HF, record review established an association between coronary artery disease (CAD) and HF (CAD-HF) in 1,559 patients. Among the remaining 1,035 subjects who had HF (non-CAD-HF), we attempted determination of preponderant etiologic and contributory factors. Analyses used Cox models that were controlled for 7 covariates, with usual alcohol intake studied categorically compared with that in subjects who did not drink alcohol. Heavier drinkers (> or =3 drinks/day) but not light to moderate drinkers had increased risk of non-CAD-HF; e.g., relative risk for subjects who reported > or =6 drinks/day was 1.7 (95% confidence interval 1.1 to 2.6). This association of non-CAD-HF with heavy drinking was limited to subsets with cardiomyopathy or of unclear preponderant etiology. Alcohol drinking was inversely related to risk of CAD-HF (e.g., at 1 to 2 drinks/day, relative risk 0.6, 95% confidence interval 0.5 to 0.7), with consistency across subgroups of age, gender, ethnicity, education, smoking status, interval to diagnosis, and presence or absence of baseline heart disease or systemic hypertension. Moderate drinking was inversely related to non-CAD-HF only in subjects who had diabetes mellitus (n = 252). In conclusion, heavy, but not light, alcohol drinking is associated with increased risk of non-CAD-HF and that apparent protection by alcohol drinking against CAD-HF risk provides confirmation of a protective effect of alcohol against CAD.     

In vitro and in vivo responses to interleukin 12 are maintained until the late SIV infection stage but lost during AIDS

The in vitro proliferative responses of macaque peripheral blood mononuclear cells (PBMCs) to IL-12 appeared similar before and early after SIV infection, whereas macaque PBMCs sampled during symptomatic stages of SIV infection showed markedly decreased responses. IL-12 was administered to SIVmac239-infected rhesus macaques either during the asymptomatic or the AIDS stage of infection in efforts to evaluate the effect of this cytokine on immune responses, viral loads, and hematopoietic functions in vivo. IFN-gamma secretion levels induced during the asymptomatic or early symptomatic phase were similar to preinfection induced levels, whereas in later AIDS stages this response was lost. The constitutive levels of other measured cytokines were not affected by IL-12 administration in vivo. The frequency and activity of circulating NK cells were markedly enhanced at early stages but not at symptomatic stages of SIV infection. pCTL frequencies were enhanced at early symptomatic stages but not at late AIDS stages. Despite its immunomodulatory effect, IL-12 did not seem to exacerbate or inhibit the replication of SIV in vivo, or the frequency of circulating infected lymphocytes. IL-12 administration was associated with a significant yet subclinical and transient decrease in hematocrit and hemoglobin levels without evidence of hemolysis, hemodilution, or reduction in the frequency of colony-forming unit potential of bone marrow CD34+ cells. This phenomenon may be explained by a functional inhibition of differentiation rather than an altered generation of bone marrow precursors. Thus, these results suggest that IL-12 may benefit HIV-1-infected patients only as long as their immune system retains its capability to respond to cytokine stimulation.     

Cardiotrophin-1 (CT-1) can protect the adult heart from injury when added both prior to ischaemia and at reperfusion

OBJECTIVES: To determine whether the cytokine cardiotrophin-1 (CT-1) can protect the adult heart against ischaemia/reperfusion when added either prior to ischaemia or at reperfusion. BACKGROUND: CT-1 has previously been shown to protect cultured embryonic or neonatal cardiocytes from cell death. To assess the therapeutic potential of CT-1, it is necessary to determine whether this effect can be observed in adult cardiac cells both in culture and most importantly in the intact heart. METHODS: We examined the protective effect of CT-1 both in cultured adult rat cardiocytes and in the rat intact heart. In both cases, the cardiac cells were exposed to hypoxia/ischaemia followed by reoxygenation/reperfusion and CT-1 was administered either prior to hypoxia/ischaemia or at reoxygenation/reperfusion. RESULTS: CT-1 has a protective effect in reducing ischaemic damage in the intact heart ex vivo as assayed by infarct size to area at risk ratio (20% compared to 35%). Similar protective effects against cell death were noted in adult cells in vitro. Both in vitro and ex vivo CT-1 can exert a protective effect when added at the time of reoxygenation/reperfusion as well as prior to the hypoxic/ischaemic stimulus (cell death reduced from 50 to 20% in TUNEL assay, infarct size to zone at risk ratio reduced from 35 to 20%). These protective effects are blocked by an inhibitor of the p42/p44 MAPK pathway. CONCLUSION: CT-1 can protect adult cardiac cells both in vitro and in vivo when added both prior to or after the hypoxic/ischaemic stimulus. The potential therapeutic benefit of CT-1 when added at the time of reperfusion following ischaemic damage is discussed.