Characterization of the growth hormone receptor in human dermal fibroblasts and liver during development.

Human tissues express growth hormone receptors (hGHR) by the 3rd mo of gestation. We assessed developmental changes in hGHR function in fibroblasts and liver, testing binding and hormonal response. Fetal cells showed low but reproducible hGH binding. No age-related changes occurred in fibroblasts (9 wk-34 yr). In contrast, there was a fourfold increase in hGH binding in postnatal liver, with a sixfold increase in hGHR mRNA. Both full-length and truncated hGHR mRNAs were detected in all livers. Cross-linking revealed a larger hGH/receptor complex in fetal liver. Fetal hepatocytes produced 10 times more insulin-like growth factor (IGF)-II than IGF-I, and responded to hGH (150 ng/ml) with a significant increase in IGF-II. Fetal hepatocytes secreted three IGF-binding proteins (IGFBPs), including IGFBP1, but not IGFBP3. hGH did not alter fetal hepatocyte IGFBPs but stimulated glucose uptake. Exposure of fibroblasts to hGH decreased hGH binding only in >1-yr postnatal fibroblasts, whereas treatment with dexamethasone (100-400 nM) increased binding only in postnatal cells. Thus, although fetal hepatocytes and fibroblasts possess functional hGHR, these receptors (and/or their signaling pathways) are immature or have adapted to the in utero environment.

Novel combinations with oxaliplatin.

Oxaliplatin (Eloxatin) is a novel antineoplastic platinum derivative that may exert its cytotoxic effects by blocking DNA replication/transcription, thus resulting in cell death in proliferating cells, as well as apoptosis. Oxaliplatin is often more potent than other platinums such as cisplatin (Platinol) in vitro, and shows greater efficacy in preclinical studies against many tumor cell lines, including some that are resistant to cisplatin and carboplatin (Paraplatin). Oxaliplatin is approved for use with the fluoropyrimidines in the treatment of metastatic colorectal cancer in Asia, Latin America, and Europe. In light of the broad efficacy of oxaliplatin in several solid tumors and the encouraging preclinical data on combination therapy with novel agents (e.g., thymidylate synthase inhibitors, epidermal growth factor-receptor antagonists, microtubule interactive agents), this article will review the published literature on novel combinations that have been tested in the laboratory and/or the clinic.

The activation of glutamate receptors by kainic acid and domoic acid.

The neurotoxins kainic acid and domoic acid are potent agonists at the kainate and alphaamino-5-methyl-3-hydroxyisoxazolone-4-propionate (AMPA) subclasses of ionotropic glutamate receptors. Although it is well established that AMPA receptors mediate fast excitatory synaptic transmission at most excitatory synapses in the central nervous system, the role of the high affinity kainate receptors in synaptic transmission and neurotoxicity is not entirely clear. Kainate and domoate differ from the natural transmitter, L-glutamate, in their mode of activation of glutamate receptors; glutamate elicits rapidly desensitizing responses while the two neurotoxins elicit non-desensitizing or slowly desensitizing responses at AMPA receptors and some kainate receptors. The inability to produce desensitizing currents and the high affinity for AMPA and kainate receptors are undoubtedly important factors in kainate and domoate-mediated neurotoxicity. Mutagenesis studies on cloned glutamate receptors have provided insight into the molecular mechanisms responsible for these unique properties of kainate and domoate.

Atrioventricular conduction in sick sinus syndrome.

With the increasing recognition of the pacemaker syndrome and with the availability of newer methods of pacing therapy, the status of the atrioventricular (AV) conduction in patients with Sick Sinus Syndrome (SSS) becomes crucial in the choice of mode of pacing. At the Philippine Heart Center, from April 1983 to November 1986, the sinus and AV node function studies of 46 patients who, by electrophysiological studies had sinus node dysfunction (SND)-SN recovery time (SNRT) greater than 1400 msec, were reviewed. These were arbitrarily classified according to duration of SNRT into: Group A--borderline SND, SNRT from 1,401 to 1,499 msec (n = 4); Group B--mild SND, SNRT from 1,500 to 2,499 msec (n = 25); Group C--moderate SND, SNRT from 2,500 to 3499 msec (n = 6); Group D--severe SND, SNRT of 3,500 m and above (n = 11). Out of the 46, 14 (30%) had concomittant AVN dysfunction (AVND)--antegrade block rate less than 130 beats per minute (BPM). The percentage occurrence of AVND was noted as follows: Group A--25% (1/4); Group B--28% (7/25); Group C--50% (3/6); Group D--27% (3/11). Out of the 14 patients with concomittant AVND, 5(35%) had antegrade block rate less than 100 BPM, 3 in Group B and 2 in Group D. The study shows that AVND occurs in only 30% of SSS patients. Its occurrence and severity has no bearing on the degree of SND. In these, antegrade block was at a rate higher than 100 BPM in the majority of patients.(ABSTRACT TRUNCATED AT 250 WORDS)