Increased frequency of HLA-DRwl4b(w6)-associated RFLP in Greenlanders of Eskimo origin

HLA-DR typing by the restriction fragment length polymorphism (RFLP) technique of 42 Greenlanders living in northern Jutland, Denmark, revealed a phenotype frequency of 33.3% for HLA-DRw14b(w6), which is significantly different from the frequency of 0.0% observed among 98 Danes of Caucasian origin. When comparing the two populations, the frequency of other HLA-DRB allogenotypes show insignificant variations. Since HLA-DRw14b(w6) is carried by approximately one-third of the Greenlanders tested, this allogenotype may serve as a useful marker in further anthropological and immunogenetic studies.     

Autoimmune associated recurrent abortions

A possible relationship between recurrent spontaneous abortionsand autoimmune abnormalities was studied. Eight serologicalautoimmune or autoimmune-correlated parameters were investigatedin 91 women with unexplained recurrent abortions (3 consecutive,spontaneous abortions) and 89 fertile control women. Five parameterswere seen significantly more frequently in 19 women with atleast one second trimester miscarriage which had been associatedwith severe intrauterine growth regardation (IUGR), than incontrols. Seventeen of these 19 patients (89%) had at leastone positive autoimmune parameter, compared to 15 of 72 patients(21%) with no second trimester abortions with IUGR (P < 0.0001)and 14 (16%) of the controls (P < 0.0001). No single autoantibodycharacterized patients who exhibited a significant accumulationof autoimmune parameters. These findings may suggest that womenwith recurrent abortions, in whom autoimmunity is thought toplay a role, cannot be identified merely by one laboratory assay,such as that for cardiolipin antibodies, but must be definedby positivity of several criteria. Using our own test panel,preliminary clinical and serological criteria have been setup for the definition of an autoimmune-associated recurrentabortion condition. Twenty-three per cent of the patients inour material fulfilled these criteria, and seven out of nineof these women (78%) have to date been treated successfullywith heparin/aspirin during pregnancy.     

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker's myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen's myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.     

Functional coupling between heterologously expressed dopamine D(2) receptors and KCNQ channels

Activation of KCNQ potassium channels by stimulation of co-expressed dopamine D₂ receptors was studied electrophysiologically in Xenopus laevis oocytes and in mammalian cells. To address the specificity of the interaction between D₂-like receptors and KCNQ channels, combinations of KCNQ1–5 channels and D₂-like receptors (D_2L, D₃, and D₄) were investigated in Xenopus oocytes. Activation of either receptor with the selective D₂-like receptor agonist quinpirole (100 nM) stimulated all the KCNQ currents, independently of the subunit combination, indicating a common pathway of receptor-channel interaction. The KCNQ4 current was investigated in further detail and was increased by 19.9±1.6% (n=20) by D_2L receptor stimulation. The effect could be mimicked by injection of GTPS and prevented by injection of Bordetella pertussis toxin, indicating that channel stimulation was mediated via a G protein of the G_i/o subtype. Cells of the human neuroblastoma line SH-SY5Y were co-transfected transiently with KCNQ4 and D_2L receptors. Stimulation of D_2L receptors increased the KCNQ4 current (n=6) as determined in whole-cell patch-clamp recordings. The specificity of the dopaminergic activation of the KCNQ channels was confirmed by co-expression of other neuronal K⁺ channels (BK, K_V1.1, and K_V4.3) with the D_2L receptor in Xenopus oocytes. None of these K⁺ channels responded to stimulation of the D_2L receptor. In the mammalian brain, dopamine D₂ receptors and KCNQ channels co-localise postsynaptically in several brain regions, so modulation of neuronal excitability by dopamine release could in part be mediated via an effect on KCNQ channels.     

Regulation by growth hormone and glucocorticoid of testosterone metabolism in long-term cultures of hepatocytes from male and female rats.

The activities of 2-, 6 beta-, 7 alpha- and 16 alpha-testosterone hydroxylase and 5 alpha-testosterone reductase were measured in intact hepatocytes from male and female rats cultured for 8 days in a modified Waymouth medium supplemented with 0.1 or 1.0 microM dexamethasone with or without addition of 1 microgram/mL growth hormone. During culture of hepatocytes from female rats the activity of the male-specific 16 alpha-testosterone hydroxylase increased. This increase was significantly inhibited at day 8 by 1 microM dexamethasone as well as by growth hormone. Furthermore, in cultures of hepatocytes from male rats, the activity of the constitutive 16 alpha-testosterone hydroxylase was decreased by 1 microM dexamethasone as well as by growth hormone. The induction of 6 beta-testosterone hydroxylase by dexamethasone was suppressed by growth hormone in hepatocytes from both male and female rats, while the 7 alpha-testosterone hydroxylase activity was unaffected by culture time, hormone additions and gender. The decrease in female-specific 5 alpha-reductase activity with culture time in hepatocytes from female rats was significantly attenuated by growth hormone at 0.1 microM dexamethasone. The effects of growth hormone on testosterone hydroxylase activities in hepatocyte cultures from male and female rats are in accordance with the concept of growth hormone as a "feminization signal". The results suggest that the glucocorticoid-dependent expression of the male constitutive 16 alpha-hydroxylase requires periods of low levels of growth hormone.     

A therapeutic trial of radiation therapy with Vincristine,etoposide, and Procarbazine (VVP) in high grade intracranial gliomas

This study is a combined modality Phase II therapeutic trial to determine the efficacy of the novel combination of VP-16, Vincristine and Procarbazine in addition to postoperative radiation therapy in patients with high grade intracranial gliomas. Thirty three patients (median age 51 years) were entered (27 with glioblastoma multiforme, 6 with anaplastic astrocytoma). Toxicity was manageable with no lethal toxicities. Five of seven life threatening toxicities were hematologic. Median overall survival was 14.2 months. These data suggest this regimen is effective treatment for patients with high grade gliomas.     

Non-capsulated Haemophilus influenzae in the genital flora of pregnant and post-puerperal women.

Non-capsulated Haemophilus influenzae may cause neonatal septicaemia. Genital carriage of this pathogen was studied in 3 mothers of infected neonates and in 2 pregnant women in the first trimester. A carrier state in 2 of the females was terminated by antibiotic therapy after 3 and 7 months, respectively. A previous carrier had no recurrence of H. influenzae in a subsequent pregnancy. A survey of 544 parturient women revealed a carrier rate of 1.8/1,000 (95% confidence limits: 0.1-11). Carriage of non-capsulated H. influenzae is thus rare, and pregnant women may be successfully treated in order to reduce the risk of neonatal infection. There was no evidence of immunodeficiency in women with non-capsulated H. influenzae in the genital tract.     

The effect of hepatectomy on glucose homeostasis in pig and in man.

BACKGROUND/AIMS: The liver is regarded the most important source of glucose production and it is common practice to administer glucose during human liver transplantations to avoid hypoglycaemia. The purpose of this study was to evaluate the importance of extra-hepatic contribution (kidney, gut and muscle) to the glucose homeostasis in the anhepatic pig and in man during the anhepatic phase of human liver transplantations. METHODS: Blood glucose and lactate were monitored in the anhepatic phase in 46 patients undergoing liver transplantation. Arterial-venous differences of lactate, glucose, glycerol, alanine and free fatty acids were measured over kidney, gut and hind leg in 18 pigs made anhepatic. RESULTS: Blood glucose did not change significantly and blood lactate increased only marginally during the anhepatic phase of human orthotopic liver transplantation. In the anhepatic pig, however, blood glucose decreased with a halflife of about 26 min and blood lactate increased. Kidney gluconeogenesis was 0.116+/-0.016 mmol min(-1). Fifty percent of kidney glucose output could be accounted for by lactate- and glycerol uptake. CONCLUSIONS: The results show that in humans extra hepatic gluconeogenesis is sufficient to maintain normal blood glucose in the anhepatic phase of orthotopic liver transplantation, while in the pig this was not the case.