Perinatal vitamin D metabolism. IV. Maternal and cord serum 24,25-dihydroxyvitamin D concentrations.

Fetal and maternal compartments differ in factors shown to regulate 24.25 dihydroxyvitamin D [24,25(OH)2D] metabolism [calcium, phosphorus, and parathyroid hormone (PTH)] such that one might predict that maternal serum 24,25(OH)2D levels are decreased and fetal 24,25(OH)2D concentrations are increased. To evaluate this, 25-hydroxyvitamin D (25OHD), 24,25(OH)2D, calcium, magnesium, calcitonin, and PTH were measured in 24 paired maternal and cord sera. The mean maternal serum 24,25(OH)2D concentration (2.9 +/- 0.26 ng/ml) was significantly lower than that of nonpregnant females (3.9 +/- 0.37 ng/ml). Mean serum PTH and calcitonin levels were, however, normal in maternal sera. The normal elevations of PRL, estrogen, and placental lactogen in serum of pregnant women could possibly decrease 24,25(OH)2D production, as seen in animal experimental systems. There was no correlation (R = -0.25) between 24,25(OH)2D levels in maternal and cord sera, as predicted; however, mean (+/-SE) fetal 24,25(OH)2D (2.5 +/- 0.26 ng/ml) was similar to the mean maternal concentration and significantly below the mean level in normal adults. The low fetal 24,25(OH)2D concentration may be due to 1) decreased 24-hydroxylase capacity of the fetus; 2) regulation by fetal factors other than calcium, phosphorus, and PTH; or 3) increased utilization of 24,25(OH)2D possibly for fetal bone mineralization.     

The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH)

The low grade inflammatory state present in obesity promotes the progression of Non-Alcoholic Fatty Liver Disease (NAFLD). In Non-Alcoholic Steatohepatitis (NASH), augmented hepatic steatosis is accompanied by aberrant intrahepatic inflammation and exacerbated hepatocellular injury. NASH is an important disorder and can lead to fibrosis, cirrhosis and even neoplasia. The pathology of NASH involves a complex network of mechanisms, including increased infiltration of different subsets of immune cells, such as monocytes, T-lymphocytes and neutrophils, to the liver, as well as activation and in situ expansion of liver resident cells such as Kupffer cells or stellate cells. In this review, we summarize recent advances regarding understanding the role of the various cells of the innate and adaptive immunity in NASH development and progression, and discuss possible future therapeutic options and tools to interfere with disease progression.     

Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome

Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43-19-63) was 0.84 (95% confidence intervals, 0.40-1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.     

Isolation of microtubule coils from normal human platelets

The blood platelet is the only human cell known to have a circumferential band of microtubules. However, the mechanisms involved in assembly of the multi-looped coil, its interaction with the cell membrane to support discoid shape, and constriction into tight rings around centrally concentrated organelles in activated platelets are unknown. Separation of the microtubule rings from intact platelets would permit new approaches to solution of these questions. The present study has used simultaneous detergent extraction and fixation to isolate intact microtubule coils in significant numbers from suspended platelets for the first time. Isolated coils closely resembled the circumferential band observed in thin sections of plastic embedded platelets and in platelets prepared by the negative-stain whole-mount method. Enough microtubule coils could be recovered from suspensions of concentrated platelets to permit counting and quantitation on microscope grids. Results of this study will permit new approaches to clarification of the structural physiology of platelet microtubule coils.     

Congenital atresia of the ostium of the left coronary artery. Diagnostic difficulty and successful surgical revascularization in two patients

We report two cases of congenital atresia of the ostium of the left coronary artery. Case 1: a six-month-old infant presenting with serious cardiac insufficiency. A noninvasive diagnosis of dilated myocardiopathy was established and the clinical picture was pharmacologically compensated. When the patient was nine months of age, a hemodynamic study was performed that revealed congenital atresia of the ostium of the left coronary artery; the infant immediately underwent a successful anastomosis of the internal mammary artery with the left coronary artery. Case 2: an eleven-year-old asymptomatic boy with a history of heart murmur from the age of six months on, was referred for surgery with a diagnosis of anomalous origin of the left coronary artery from pulmonary trunk. A definitive diagnosis of atresia of the left coronary ostium was only established during surgery. Successful surgical revascularization with the left internal mammary artery, and left ventricular aneurysmectomy were performed.     

Continuous intravenous octreotide treatment for acute experimental pancreatitis

BACKGROUND: The efficacy of octreotide, the synthetic analogue of the hormone somatostatin, for the treatment of acute pancreatitis is controversial. Octreotide has been commonly administered in subcutaneous bolus injections; however, continuous intravenous infusion may be advantageous for acute conditions. METHODS: Acute experimental pancreatitis was induced in rats by intraparenchymal injections of 1 ml 10% sodium taurocholate, and octreotide (1 microg/kg/h, dissolved in physiological solution, intravenously was started 4 h later and continuously infused for 48 h. Physiological solution infusions, in identical volumes, were used in the controls. The following parameters were examined: mortality; macroscopic and histological damage; hematocrit; plasma pH; acid-base balance; serum glucose; calcium, and amylase. RESULTS: Octreotide treatment had a striking effect on mortality: 8.3 versus 91.6% in the treatment and control groups, respectively (p < 0.001). Octreotide also ameliorated pancreatic edema and intestinal dilatation, and had significant beneficial effects on histopathological damage and the biochemical alterations which are associated with acute pancreatitis. CONCLUSIONS: Continuous intravenous octreotide infusion is a potentially efficacious therapeutic method for acute pancreatitis.     

Inhibition of tissue plasminogen activator activity by aspirin in vivo and its relationship to levels of tissue plasminogen activator inhibitor antigen, plasminogen activator and their complexes

The observation that aspirin inhibits the increment in tissue plasminogen activator (t-PA) activity induced by venous occlusion of the forearm became controversial with the publication of several nonconfirmatory studies. The current study was performed to confirm the original observation and determine the mechanism by which aspirin suppresses the incremental t-PA activity induced by venous occlusion. Aspirin (650 mg/d X 2) caused no change in resting levels of t-PA antigen (t-PA:Ag) or activity, plasminogen activator inhibitor 1 antigen (PAI-1:Ag), or activity or t-PA-PAI-1 complexes. In contrast, aspirin reduced the increments induced by venous occlusion as follows: t-PA:Ag by 45% (P = .001); t-PA activity (euglobulin lysis time, ELT) by 43% (P = .006); and t-PA activity (alpha 2-plasmin inhibitor-plasmin complexes, PIPC) by 41% (P = .003). The inhibition of incremental t-PA activity measured as ELT or PIPC was linearly correlated with the inhibition of incremental t-PA:Ag (respectively, r = .75, P less than .02; r = .67, P less than .05). Aspirin had no effect on the increment in PAI-1:Ag induced by venous occlusion, but similar to the effect on t- PA:Ag, aspirin induced a 51% inhibition of the increment in t-PA-PAI-1 complex formation. Aspirin did not alter the ability of alpha 2-plasmin inhibitor to bind plasmin, nor the ability of plasma to support the fibrin-catalyzed generation of plasmin by t-PA, nor the subsequent formation of PIPC. Aspirin inhibits the t-PA activity induced by venous occlusion primarily by inhibiting the release of t-PA antigen.     

Detection of residual lymphoma cells by polymerase chain reaction in peripheral blood is significantly less predictive for relapse than detection in bone marrow

Polymerase chain reaction (PCR) amplification of the t(14;18) has been shown to be a highly sensitive method to detect minimal residual disease in patients with non-Hodgkin's lymphoma (NHL) whose tumors bear this translocation. The ideal tissue source to detect residual lymphoma would be from a previously involved lymph node. However, lymphoid tissue is rarely available once patients achieve complete remission. Although PCR amplification has been used to detect residual lymphoma cells in both bone marrow (BM) and peripheral blood (PB) of patients in complete remission, it is presently unknown whether BM and PB are equivalent tissue sources to detect residual disease. In the present study, we compared the clinical utility of the detection of residual lymphoma in both the BM and the PB of patients with advanced-stage non- Hodgkin's lymphoma before, at the time of, and after high-dose therapy and autologous BM transplantation (ABMT). The detection of residual lymphoma in either the BM or PB was associated with decreased disease- free survival. However, in the present study, 44% of patients who relapsed had no evidence of circulating lymphoma cells in their PB. At the time of BM harvest, PCR-detectable residual lymphoma cells were detected in 211 of 212 patients; although, in a subset of these patients analyzed, lymphoma cells were detected in the peripheral blood of only 49% of patients. When residual lymphoma cells within the autologous BM are infused into the patient these cells are rapidly detectable circulating in the PB in the patient. These cells continue to circulate during the immediate posttransplant period and be detectable in the PB in the majority of patients who are infused with marrow containing residual lymphoma. We conclude that BM is a more informative tissue source than PB in detecting minimal residual disease at the time of and after ABMT, and that contamination of PB early after ABMT appears to be the consequence of reinfusion of lymphoma cells within autologous marrow.