Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯的合成

合成了18个O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯类化合物(Ⅰ_1～18)。初步杀螺试验结果表明,其中5个化合物,即Ⅰ_2,3,7,11,12有明显的杀螺增效作用。     

Erregbarkeitszustand des Atemzentrums und Blutreaktion

Ohne ZusammenfassungFür die zahlreichen Anregungen zu dieser Arbeit erlaube ich mir, Herrn Prof.H. Straub vielen Dank auszusprechen.     

Detecting danger--or just another odorant? Olfactory sensitivity for the fox odor component 2,4,5-trimethylthiazoline in four species of mammals

2,4,5-trimethylthiazoline (TMT) is a volatile component of the anal gland secretion of the red fox and elicits behavioral and physiological fear responses in the rat. Using instrumental conditioning paradigms, we determined olfactory detection thresholds for TMT in three rats, a natural prey species of the red fox, and compared their performance to that of three squirrel monkeys, three spider monkeys and four pigtail macaques, all non-prey species of the red fox. We found that the rats were able to discriminate concentrations between 0.04 and 0.10 ppt (parts per trillion) of TMT from the odorless solvent which is by far the lowest olfactory detection threshold for an odorant reported in rats so far. In contrast, the spider monkeys needed 0.14-1.38 ppb (parts per billion), the pigtail macaques 0.41-4.07 ppb, and the squirrel monkeys 4.07-13.80 ppb to detect TMT which does not rank among the lowest olfactory thresholds reported for these three primate species. Thus, these results support the assumption that the behavioral relevance of an odorant may be an important determinant of a species' olfactory sensitivity.     

The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells

We examined whether the synthesis of interleukin-1 or tumor necrosis factor, two cytokines with potent inflammatory activities, is influenced by dietary supplementation with n-3 fatty acids. Nine healthy volunteers added 18 g of fish-oil concentrate per day to their normal Western diet for six weeks. We used a radioimmunoassay to measure interleukin-1 (IL-1 beta and IL-1 alpha) and tumor necrosis factor produced in vitro by stimulated peripheral-blood mononuclear cells. With endotoxin as a stimulus, the synthesis of IL-1 beta was suppressed from 7.4 +/- 0.9 ng per milliliter at base line to 4.2 +/- 0.5 ng per milliliter after six weeks of supplementation (43 percent decrease; P = 0.048). Ten weeks after the end of n-3 supplementation, we observed a further decrease to 2.9 +/- 0.5 ng per milliliter (61 percent decrease; P = 0.005). The production of IL-1 alpha and tumor necrosis factor responded in a similar manner. Twenty weeks after the end of supplementation, the production of IL-1 beta, IL-1 alpha, and tumor necrosis factor had returned to the presupplement level. The decreased production of interleukin-1 and tumor necrosis factor was accompanied by a decreased ratio of arachidonic acid to eicosapentaenoic acid in the membrane phospholipids of mononuclear cells. We conclude that the synthesis of IL-1 beta, IL-1 alpha, and tumor necrosis factor can be suppressed by dietary supplementation with long-chain n-3 fatty acids. The reported antiinflammatory effect of these n-3 fatty acids may be mediated in part by their inhibitory effect on the production of interleukin-1 and tumor necrosis factor.     

Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke

Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP) by single DNA strand breaks which leads to energy depletion and cell necrosis. Deletion or inhibition of PARP protects against ischemic brain injury. Here we examined the neuroprotective effect of PJ34, a novel potent inhibitor of PARP in vitro and in vivo. Serum-free primary neuronal cultures derived from rat cortex (E15-17) and kept in culture for 10 days were exposed to oxygen glucose deprivation (OGD) in vitro. Neuronal injury was quantified by LDH release after 24 h. Pretreatment with 30-1000 nM PJ34 significantly protected from OGD-induced cell injury in a dose-dependent manner. For in vivo experiments SV/129 mice were treated with PJ34 (50 microg) by intraperitoneal injection 2 h before 1 h middle cerebral artery occlusion (MCAo) and again 6 h later. Twenty-three h after reperfusion ischemic injury was significantly decreased compared to vehicle-treated controls (infarct volume reduction of 40%, p<0.05). Similarly, in a rat model of MCAo (2 h occlusion followed by up to 22 h reperfusion), PJ34 administration (10 mg/kg i.v.) significantly reduced infarct size, and the effect of the drug was maintained even if it was given as late as 10 min prior to reperfusion time. PJ34 significantly protected in a 4 h, but not in a 24 h permanent occlusion model. In conclusion, PJ34, a novel, potent inhibitor of PARP exerts massive neuroprotective agents, with a significant therapeutic window of opportunity. The present work strengthens the concept that pharmacological PARP inhibition may be a suitable approach for the treatment of acute stroke in man.     

In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation

Numerous studies have reported altered in vitro cytokine production in various diseases. In the present study we used specific immunoassays to quantitate production of interleukin 1 beta (IL 1 beta), IL 1 alpha, tumor necrosis factor (TNF) and IL 2 from human peripheral blood mononuclear cells (PBMC). The distribution of cell-associated and secreted cytokines was studied in PBMC of 21 individuals; in response to lipopolysaccharide (LPS) the proportion of cell-associated IL 1 beta ranged from 13% to 56%, for IL 1 alpha 29% to 98%, and for TNF 2% to 17%. In a larger cohort of 32 subjects, the total amount of immunoreactive cytokines produced in response to LPS or phytohemagglutinin was normally distributed within the study group. Mean production of IL 1 alpha in response to LPS was 10.1 ng/ml and exceeded production of IL 1 beta (5.6 ng/ml) and TNF (2.2 ng/ml). The distribution pattern was characterized by high intersubject variability extending over two orders of magnitude and the presence of high and low "producers". Production of IL 1 alpha and IL 1 beta correlated (R = 0.69). In contrast, production of IL 1 beta did not correlate with production of TNF or IL 2. Indomethacin present during stimulation of PBMC increased the amount of IL 1 beta produced and showed a high correlation (R = 0.83) compared to cultures without indomethacin. Thus, low production of IL 1 beta in certain subjects appears not to be due to inhibitable levels of cyclooxygenase products. In a retrospective study, PBMC from 12 subjects who had taken oral cyclooxygenase inhibitors during the preceding 7 days produced 43% more IL 1 beta than subjects who did not take these drugs (p less than 0.05). These studies demonstrate that the amount of cytokine synthesized by PBMC (a) is regulated independently for IL 1, TNF and IL 2; (b) correlates for IL 1 beta and IL 1 alpha; (c) is intrinsic for low and high "producers", and (d) production of IL 1 beta increases with the use of oral cyclooxygenase inhibitors.