Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8.

In humans, inactivating mutations in the gene of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8; SLC16A2) lead to severe forms of psychomotor retardation combined with imbalanced thyroid hormone serum levels. The MCT8-null mice described here, however, developed without overt deficits but also exhibited distorted 3,5,3'-triiodothyronine (T3) and thyroxine (T4) serum levels, resulting in increased hepatic activity of type 1 deiodinase (D1). In the mutants' brains, entry of T4 was not affected, but uptake of T3 was diminished. Moreover, the T4 and T3 content in the brain of MCT8-null mice was decreased, the activity of D2 was increased, and D3 activity was decreased, indicating the hypothyroid state of this tissue. In the CNS, analysis of T3 target genes revealed that in the mutants, the neuronal T3 uptake was impaired in an area-specific manner, with strongly elevated thyrotropin-releasing hormone transcript levels in the hypothalamic paraventricular nucleus and slightly decreased RC3 mRNA expression in striatal neurons; however, cerebellar Purkinje cells appeared unaffected, since they did not exhibit dendritic outgrowth defects and responded normally to T3 treatment in vitro. In conclusion, the circulating thyroid hormone levels of MCT8-null mice closely resemble those of humans with MCT8 mutations, yet in the mice, CNS development is only partially affected.

Antibiotic therapy for preterm premature rupture of membranes - results of a multicenter study.

AIMS: To evaluate whether primary application of mezlozillin in preterm premature rupture of membranes (pPROM) prolongs pregnancy and lowers neonatal morbidity. METHODS: In this prospective, randomized, double blind, placebo-controlled multicenter study a total of 105 pregnant women with pPROM between 24 + 0 and 32 + 6 weeks of gestation were examined receiving i.v. injections of corticoids and tocolytics as well as mezlocillin (3 x 2 g/d) or placebo. Assessed factors were prolongation of pregnancy and neonatal morbidity such as neonatal infection, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). RESULTS: Prolongation of pregnancy by more than 7 days was achieved in 63.8% of the mezlocillin group versus 44.8% of the placebo group (P < 0.05). The babies of mothers treated with anibiotics had fewer neonatal infections, RDS, IVH and NEC. Total morbidity was significantly lowered in the verum group (P = 0.02). CONCLUSIONS: Antibiotic administration following preterm premature rupture of membranes is associated with a prolongation of pregnancy and a reduction of neonatal infectious morbidity.

Structure-activity studies with high-affinity inhibitors of pyroglutamyl-peptidase II.

Inhibitors of PPII (pyroglutamyl-peptidase II) (EC 3.4.19.6) have potential applications as investigative and therapeutic agents. The rational design of inhibitors is hindered, however, by the lack of an experimental structure for PPII. Previous studies have demonstrated that replacement of histidine in TRH (thyrotropin-releasing hormone) with asparagine produces a competitive PPII inhibitor (Ki 17.5 microM). To gain further insight into which functional groups are significant for inhibitory activity, we investigated the effects on inhibition of structural modifications to Glp-Asn-ProNH2 (pyroglutamyl-asparaginyl-prolineamide). Synthesis and kinetic analysis of a diverse series of carboxamide and C-terminally extended Glp-Asn-ProNH2 analogues were undertaken. Extensive quantitative structure-activity relationships were generated, which indicated that key functionalities in the basic molecular structure of the inhibitors combine in a unique way to cause PPII inhibition. Data from kinetic and molecular modelling studies suggest that hydrogen bonding between the asparagine side chain and PPII may provide a basis for the inhibitory properties of the asparagine-containing peptides. Prolineamide appeared to be important for interaction with the S2' subsite, but some modifications were tolerated. Extension of Glp-Asn-ProNH2 with hydrophobic amino acids at the C-terminus led to a novel set of PPII inhibitors active in vitro at nanomolar concentrations. Such inhibitors were shown to enhance recovery of TRH released from rat brain slices. Glp-Asn-Pro-Tyr-Trp-Trp-7-amido-4-methylcoumarin displayed a Ki of 1 nM, making it the most potent competitive PPII inhibitor described to date. PPII inhibitors with this level of potency should find application in exploring the biological functions of TRH and PPII, and potentially provide a basis for development of novel therapeutics.

Oral glucose before venepuncture relieves neonates of pain, but stress is still evidenced by increase in oxygen consumption, energy expenditure, and heart rate.

Oral glucose was recommended as pain therapy during venepuncture in neonates. It is unclear whether this intervention reduces excess oxygen consumption (o(2)), energy loss, or cardiovascular destabilization associated with venepuncture, and whether <2 mL glucose solution is effective. We tested the hypothesis that oral glucose solution attenuates the increases in neonatal oxygen consumption, energy expenditure (EE), and heart rate associated with venepuncture for two different volumes of glucose solution (2 and 0.4 mL). In this prospective, randomized, controlled, double-blind trial, 58 neonates (gestational age, 31-42 wk; postnatal age, 1-7 d) were randomized to 2 mL glucose 30%, 0.4 mL glucose 30%, or 2 mL water by mouth before venepuncture. The videotaped behavioral pain reactions were scored with the Premature Infant Pain Profile. Cry duration, o(2), EE (indirect calorimetry), and heart rate were measured. The 2 mL glucose solution reduced pain score and crying after venepuncture compared with controls [median pain score, 5.5 (interquartile range, 4-9) versus 11 (7-12), p = 0.01; median duration of first cry, 0 s (0-43 s) versus 13 s (2-47 s), p < 0.05, respectively]. The 0.4 mL glucose solution had no effect. The 2 mL glucose solution did not attenuate the o(2) increase during venepuncture (1.5 +/- 0.2 mL/kg min (water) versus 1.7 +/- 0.5 (0.4 mL glucose) versus 1.1 +/- 0.2 (2 mL glucose) (mean +/- SEM) nor EE nor heart rate. We conclude that oral administration of 2 mL glucose 30% before venepuncture reduced pain expression and crying, but did not prevent the rise in o(2), EE, or heart rate. Alternative therapies against the stress of nonpainful handling during venepuncture should be explored.