The parathyroid hormone 2 (PTH2) receptor

The human PTH2 receptor binds and is activated at high potency by PTH and by the recently discovered peptide tuberoinfundibular peptide of 39 residues (TIP39). Rat and zebrafish PTH2 receptors are more weakly activated by PTH, suggesting that TIP39 may be the natural ligand for the PTH2 receptor. Unlike the PTH1 receptor, the PTH2 receptor interacts extremely weakly with parathyroid hormone-related peptide (PTHrP). The PTH2 receptor is strongly coupled to stimulation of cAMP accumulation, and more weakly, in a cell-specific manner to increases in intracellular calcium concentration. A variety of evidence supports the general model of receptor amino terminal sequences binding ligand carboxyl terminal sequences with high affinity, and ligand amino terminal sequences activating the receptor through interaction with the "juxtamembrane" portion of the receptor. The receptor is present at greatest levels in the nervous system. It is expressed in scattered cells in the cerebral cortex and basal ganglia and at relatively high abundance in the septum, midline thalamic nuclei, several hypothalamic nuclei, and the dorsal horn of the spinal cord. Peripherally, expression in pancreatic islet somatostatin cells is most dramatic. Functional hypotheses based on the receptor's distribution are being tested. Recent data support involvement in hypothalamic releasing-factor secretion and pain.     

Concerns of the dry-cleaning industry: a qualitative investigation of labor and management

BACKGROUND: Occupational scientists agree there are hazards associated with dry-cleaning, but do dry-cleaning owners and workers concur? Knowledge of owners' and workers' perceptions can help guide intervention efforts to reduce worker exposure. To better understand these issues, a qualitative study was conducted using focus group methodology and constant comparative analysis. METHODS: Two owner and four worker focus groups were held. RESULTS: Findings suggest that overall, health and safety issues were not of great concern. Owners were primarily concerned with the economic impact of regulations. Workers did express some anxiety about solvent exposure and burns, but most felt that these hazards were "just part of the job." Also, other than the installation of air-conditioning in the shops and the provision of health benefits, workers could not think of ways health and safety on the job could be improved. CONCLUSIONS: These findings will be used to develop comprehensive safety and health interventions (e.g., engineering plus education and training) in dry-cleaning shops.     

Deep levels in bulk LEC single crystal IxGa1-xAs

Bulk single crystals of In_xGa_1-xAs (0.01 <x < 0.12) were successfully grown by the Liquid Encapsulated Czochraski (LEC) technique. These crystals are of high quality and can provide tunable substrate material for epitaxial application, since the lattice constant may be adjusted by varying the composition. Nominally undoped crystals were semi-insulating as grown ifx is less than about 0.05. Semi-insulating crystals with higher In composition can be obtained by chromium doping during crystal growth. The asgrown crystals were studied by 4.2 K photoluminescence spectroscopy (PL) and thermally stimulated current spectroscopy (TSC). Results from PL measurements indicate good crystal quality and impurity control. TSC spectra reveal several bulk traps in undoped and Cr doped semi-insulating samples. The activation energies of these traps decrease as In composition is increased. The amount of change in activation energy is about one third of the bandgap shrinkage due to increased In concentration.     

Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids

We have examined the effects of the macrocyclic lactone protein kinase C (PKC) activator bryostatin 1 on taxol-induced apoptosis and inhibition of clonogenicity in the human monocytic leukemia cell line U937. Exposure of cells to bryostatin 1 (10 nM; 15 hr) after (but not before) a 6-hr incubation with 0.5 microM taxol significantly increased apoptosis and resulted in an approximately 3 log reduction in clonogenicity. Cell cycle analysis revealed that the increase in apoptotic cells following bryostatin 1 treatment occurred primarily in the population undergoing taxol-mediated G2M arrest. The actions of bryostatin 1 were not attributable to potentiation of taxol-induced tubulin stabilization or to a reduction in the intracellular retention of taxol. Following exposure of cells to taxol, the Bcl-2 protein displayed an alteration in mobility that was not modified appreciably by bryostatin 1 treatment. The mobility shift in Bcl-2 protein from cells exposed to taxol followed by bryostatin 1 was eliminated by treatment of lysates with the protein phosphatase 2A (PP2A); the latter effect was blocked by okadaic acid. Treatment of cells with taxol followed by bryostatin 1 did not increase the amount of total Bax (compared with treatment with taxol alone), but did increase the amount of free Bax in the supernatant fraction. Finally, the ability of bryostatin 1 to potentiate taxol-induced apoptosis in U937 cells was mimicked closely by 2'-amino-3'-methoxyflavone (PD98059), a specific inhibitor of the mitogen-activated protein kinase (MAPK) kinase (MEK). Collectively, these findings indicate that bryostatin 1 increases the susceptibility of U937 cells to taxol-induced apoptosis and inhibition of clonogenicity. They also raise the possibility that this phenomenon may involve functional alterations in Bcl-2 and/or other proteins involved in regulation of the cell death pathway.     

Altered release of prostaglandins by opioids contributes to impaired cerebral hemodynamics following brain injury

OBJECTIVES: After fluid percussion brain injury (FPI) in the newborn pig, pial arteries constrict and responses to dilator stimuli, including opioids, are blunted. This study was designed to determine if altered release of prostaglandins contributes to blunted opioid dilation of cerebral arteries in newborn piglets following brain injury. DESIGN: Prospective, in vivo, cerebral hemodynamic animal study. SETTING: University research laboratory. SUBJECTS: Newborn (1- to 5-days old) piglets of either gender. INTERVENTIONS: In anesthetized, newborn, 1- to 5-day-old pigs, a closed cranial window was used to measure pial artery diameter and to collect cortical periarachnoid cerebrospinal fluid (CSF) for determination of 6-keto-PGF1alpha, the stable metabolite of prostaglandin I2 (PGI2) and thromboxane B2 (TXB2), the stable metabolite of TXA2, via radioimmunoassay. FPI of moderate severity (1.9 to 2.3 atmospheres) was produced by using a pendulum to strike a piston on a saline-filled cylinder that was fluid coupled to the brain via a hollow screw inserted through the cranium. MEASUREMENTS AND MAIN RESULTS: Methionine enkephalin (Met) vasodilation was blunted after FPI but was partially restored with indomethacin pretreatment (5 mg/kg i.v.) (8 +/- 1 [SEM] %, 13 +/- 1%, and 20 +/- 1% vs. 1 +/- 1%, 3 +/- 1%, and 5 +/- 1% vs. 7 +/- 1%, 10 +/- 1%, and 15 +/- 1%, respectively, for 10(-10), 10(-8), and 10(-6) M Met during control conditions, after FPI, and after FPI pretreated with indomethacin, n = 6). Similarly, restoration of Met dilation after FPI was observed with SQ 29,548, a TXA2 antagonist. Met-induced 6-keto-PGF1alpha release was blunted following FPI (889 +/- 20, 1130 +/- 33, and 1886 +/- 59 vs. 2630 +/- 36, 2775 +/- 30, and 2825 +/- 36 pg/mL for control, 10(-10), and 10(-6) M Met before and after FPI, respectively, n = 6). In contrast, Met-induced TXB2 release was enhanced after FPI (340 +/- 20, 423 +/- 25, and 473 +/- 30 pg/mL vs. 518 +/- 30, 726 +/- 90, and 901 +/- 35 pg/mL for control, 10(-10), and 10(-6) M Met before and after FPI, respectively, n = 6). Leucine enkephalin- and dynorphin-induced dilation and associated prostaglandin release were similarly altered following FPI. Beta endorphin-induced constriction was enhanced following FPI, and these potentiated responses were blunted after indomethacin or SQ 29,548 pretreatment. CONCLUSIONS: These data show that FPI increases CSF 6-keto-PGF1alpha and TXB2 concentrations. These data suggest that altered release of prostaglandins by opioids contribute to impaired cerebral hemodynamics following FPI in piglets.     

Double free-flap reconstruction of massive defects involving the lip, chin, and mandible

Men develop perioperative ulnar neuropathies more frequently than women. To determine the role of anatomical gender differences in the development of these neuropathies, we performed several studies of the anatomy of the ulnar nerve, cubital tunnel, and elbow region. These studies included detailed dissection of male and female embalmed and unembalmed cadavers, ultrasound measurements of the tissue layers at the elbow, and measurement of various dimensions of the coronoid process of the ulna in multiple skeletal sets. No gross anatomical differences were found between genders regarding the course of the ulnar nerve through the upper limb. However, there was a strikingly larger (2-19 times greater) fat content on the medial aspect of the elbow in women compared to men, and the tubercle of the coronoid process was approximately 1.5 times larger in men (P < or = .002, rank sum test). Our finding suggest that the tubercle of the coronoid process is a likely area for external compression-induced ischemia of the ulnar nerve because the nerve and its arterial supply (the posterior ulnar recurrent artery) are covered at the tubercle only by skin, subcutaneous fat, and a very thin aponeurosis of the flexor carpi ulnaris. Importantly, this tubercle is larger and the nerve and blood vessels passing by it are less protected by subcutaneous fat in men than in women. These two anatomical differences between men and women may contribute to the increased frequency of perioperative ulnar neuropathy induced by external pressure at the medial aspect of the elbow in men.     

Hepatotoxicity of anticholesterol, cardiovascular, and endocrine drugs and hormonal agents

Drugs in these categories may have effects on several organs in addition to the liver. For example, amiodarone may produce thyroid and corneal injury apart from or in addition to the phospholipidosis seen in the liver. Oral contraceptive steroids remain a rare but important concern for developing hepatic adenomas and possibly hepatocellular carcinoma, as well as a risk factor for developing Budd-Chiari syndrome in long-term users. Among the antihyperlipidemic agents, nicotinic acid, especially the sustained release formulations, may produce severe of even fatal hepatic injury. Increasing numbers of reports of hepatotoxicity from newer beta blockers and angiotensin-converting enzyme inhibitors require ongoing vigilance in patients receiving these medications.     

Convulsions due to increased permeability of the blood-brain barrier in experimental cerebral malaria can be prevented by splenectomy or anti-T cell treatment

Experimental cerebral malaria (ECM) can be induced in C57B1 mice by infection with Plasmodium berghei K173 parasites. Behavioral changes shortly before they die of ECM may reflect disturbance of the integrity of the blood-brain barrier (BBB). Folic acid elicits strong convulsive activity if the permeability of the BBB is increased. Administration of folic acid to mice during development of ECM induced convulsions. Interventions known to prevent fatal outcome from ECM, such as splenectomy or treatment with anti-CD4 or anti-CD8 monoclonal antibodies, also prevented sensitivity to folic acid-induced convulsions. In addition, infected mice with ECM and sensitive to folic acid-induced convulsions, recovered from this sensitivity after treatment with anti-T cell antibodies within 4 h. These data suggest that disturbance of the permeability of the BBB can be reversed and depends on the involvement of T cells.     

Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin

Alterations in triglyceride and cholesterol metabolism often accompany inflammatory diseases and infections. We studied the effects of endotoxin (lipopolysaccharide [LPS]) and cytokines on hepatic sphingolipid synthesis, activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme in sphingolipid synthesis, and lipoprotein sphingolipid content in Syrian hamsters. Administration of LPS induced a 2-fold increase in hepatic SPT activity. The increase in activity first occurred at 16 hours, peaked at 24 hours, and was sustained for at least 48 hours. Low doses of LPS produced maximal increases in SPT activity, with half-maximal effect seen at approximately 0.3 microg LPS/100 g body weight. LPS increased hepatic SPT mRNA levels 2-fold, suggesting that the increase in SPT activity was due to an increase in SPT mRNA. LPS treatment also produced 75% and 2.5-fold increases in hepatic sphingomyelin and ceramide synthesis, respectively. Many of the metabolic effects of LPS are mediated by cytokines. Interleukin 1 (IL-1), but not tumor necrosis factor, increased both SPT activity and mRNA levels in the liver of intact animals, whereas both IL-1 and tumor necrosis factor increased SPT mRNA levels in HepG2 cells. IL- produced a 3-fold increase in SPT mRNA in HepG2 cells, and the half-maximal dose was 2 ng/mL. IL-1 also increased the secretion of sphingolipids into the medium. Analysis of serum lipoprotein fractions demonstrated that very low density lipoprotein, intermediate density lipoprotein, and low density lipoprotein isolated from animals treated with LPS contained significantly higher amounts of ceramide, glucosylceramide, and sphingomyelin. Taken together, these results indicate that LPS and cytokines stimulate hepatic sphingolipid synthesis, which results in an altered structure of circulating lipoproteins and may promote atherogenesis.     

The effect of adrenergic agonists on the systemic response to hemorrhage

An in vivo antitumor screening of extracts of Gomphrena martiana indicated positive activity in the petroleum ether extract, and its further bioactivity-directed fractionation resulted in a lipophilic flavonoid fraction. Upon inoculation of various doses of 5,6,7-trisubstituted flavones on two murine tumor lines, Sarcoma 180 and Ehrlich's carcinoma, a decrease of tumor growth was observed. An in vitro KB cultured cell screen indicated cytotoxicity.