Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study.

BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Resolving the structure of ionized helium in the intergalactic medium with the far ultraviolet spectroscopic explorer.

The neutral hydrogen (H I) and ionized helium (He II) absorption in the spectra of quasars are unique probes of structure in the early universe. We present Far-Ultraviolet Spectroscopic Explorer observations of the line of sight to the quasar HE2347-4342 in the 1000 to 1187 angstrom band at a resolving power of 15,000. We resolve the He II Lyman alpha (Lyalpha) absorption as a discrete forest of absorption lines in the redshift range 2.3 to 2.7. About 50 percent of these features have H I counterparts with column densities N(H I) > 10(12.3) per square centimeter that account for most of the observed opacity in He II Lyalpha. The He II to H I column density ratio ranges from 1 to >1000, with an average of approximately 80. Ratios of <100 are consistent with photoionization of the absorbing gas by a hard ionizing spectrum resulting from the integrated light of quasars, but ratios of >100 in many locations indicate additional contributions from starburst galaxies or heavily filtered quasar radiation. The presence of He II Lyalpha absorbers with no H I counterparts indicates that structure is present even in low-density regions, consistent with theoretical predictions of structure formation through gravitational instability.

Schild regression analysis of antidepressant and bicuculline antagonist effects at the GABAA receptor.

We showed previously that antidepressants inhibit GABA-stimulated 36Cl- uptake in rat cerebral cortex. In this study Schild analysis was used to determine if antidepressants are competitive antagonists or allosteric modulators at GABAA receptors. GABA concentration-response curves for 36Cl- uptake in rat cerebral cortex were generated in the absence or presence of different concentrations of the following antidepressants: amitriptyline, amoxapine, mianserin, and also the GABAA receptor antagonist, bicuculline. The pA2 values for amitriptyline, amoxapine, mianserin, and bicuculline were 4.2 +/- 0.2, 5.5 +/- 0.3, 4.4 +/- 0.1 and 6.2 +/- 0.6, respectively. The respective Schild slope values were 0.7 +/- 0.1, 0.6 +/- 0.03, 0.7 +/- 0.2 and 1.0 +/- 0.3. All slope values for antidepressants differed from unity. The maximum effect produced by GABA to stimulate chloride influx was decreased by both antidepressants and bicuculline. It is concluded that neither the antidepressants studied nor bicuculline are pure competitive GABA antagonists at the GABAA receptor-chloride-ionophore complex in the rat cerebral cortex.

Clivus and cervical spinal osteomyelitis with epidural abscess presenting with multiple cranial neuropathies.

A 65-year-old diabetic man with a history of otitis was admitted with headache, neck and shoulder pain and cranial nerve abnormalities including sixth, seventh and twelfth nerve palsies, hearing loss and ptosis. Lumbar puncture revealed an elevated CSF protein and pleocytosis. Imaging procedures demonstrated osteomyelitis of the clivus that involved the epidural space and extended within the prevertebral space to the cervical spine. The patient improved after treatment with antibiotics and immobilization of the neck. This case illustrates the importance of recognizing infections of the clivus in patients with cranial nerve abnormalities.

Bidirectional effect of beta-carboline agonists at the benzodiazepine-GABAA receptor chloride ionophore complex on GABA-stimulated 36Cl- uptake.

beta-Carboline agonists produced a left shift of the GABA concentration-chloride uptake curve or a reduction in the maximal increase in GABA-stimulated 36Cl- uptake depending on their concentration. The enhancement of the GABA effect occurs only at lower beta-carboline and GABA concentrations and is smaller for the partial agonist ZK 9126 compared to the full agonist ZK 93423. The opposite effect, inhibition of GABA-stimulated chloride conductance, is observed only at higher concentrations of beta-carboline agonists and GABA. The reduction of the GABA maximal response by the partial agonist ZK 91296 is greater than by the full agonist ZK 93423. The transformation of GABA-stimulated 36Cl- uptake data to specific chloride influx (36Cl- uptake per nM of GABA) reveals that the GABA concentration-response curve consists of three parts characterized by differences in the molar effectiveness of GABA relative to the GABA concentration. The molar effectiveness of GABA is a measure of the sensitivity of the GABAA receptor chloride ionophore complex and shows adaptive changes by this complex to increasing concentrations of GABA and/or beta-carboline. We conclude from our data that the change from GABA-sensitive to GABA-insensitive conformation of the GABAA receptor occurs with increasing concentrations of GABA and/or beta-carboline. Both conformations maintain positive heterotropic cooperativity with beta-carboline binding sites, one responsible for positive and the other responsible for negative effects of beta-carboline agonists on chloride uptake.

Chronic treatment with amitriptyline alters the GABA-mediated uptake of 36Cl- in the rat brain.

Amitriptyline inhibits the GABA-mediated uptake of 36Cl- in membrane vesicles prepared from the cerebral cortices of drug-naive and saline-treated rats. In contrast, chronic in vivo treatment with amitriptyline affects an increase in the GABA-stimulated uptake of chloride ions in its presence. The benzodiazepine receptor antagonist ZK 93426 blocks the capacity of amitriptyline to augment the uptake of 36Cl- by 30 microM GABA. There is a possibility that there are two distinct effects of amitriptyline's action in the rat forebrain. The first is evident in vesicles from drug-naive animals and the second only after chronic treatment with this antidepressant. The authors discuss the pertinence of this finding to the mechanism of action of amitriptyline.

Bright light does not alter muscarinic receptor binding parameters.

Seasonal Affective Disorders (SADs) are disorders of mood characterized by recurrent episodes of illness with a fixed relationship to season. Winter depression is characterized by recurrent onset of depression in the fall or winter followed by spontaneous recovery in the spring. This syndrome is responsive to treatment with bright light. The pathophysiology of depressive disorders may involve central muscarinic mechanisms. This possibility led to a series of physiological studies. The authors now report that contrary to expectation, treatment with bright light did not decrease the density of muscarinic receptors in either the hypothalamus or striatum.

The interaction of a benzodiazepine receptor antagonist (Ro15-1788) with GABA and GABA receptor antagonists at the GABA(A) receptor chloride-ionophore complex.

The effect of the GABA(A) receptor antagonists bicuculline and SR 95531 was compared with that of the antidepressants amoxapine and amitriptyline on GABA-stimulated (36)CL(?) uptake using membrane vesicles from the rat cerebral cortex. The interaction of Ro15-1788 with these drugs and the effect of Ro15-1788 on GABA-stimulated uptake of (36)Cl(?) were also investigated. GABA(A) receptor antagonists and the antidepressants inhibited 30 ?M GABA-mediated uptake of (36)Cl(?) with the rank order of potency of SR 95531 > bicuculline > amoxapine > amitriptyline. Ro15-1788 potentiated the effect of these inhibitors on 30 ?M GABA-stimulated chloride uptake. Ro15-1788 alone did not alter the effect of 30 ?M GABA on (36)Cl(?) uptake. However, it did inhibit the (36)Cl(?) uptake produced by 100 ?M GABA, and enhanced (36)Cl(?) uptake mediated by 10 ?M GABA. The data show variations in the apparent intrinsic efficacy of Ro15-1788 at the chloride channel with respect to different experimental conditions. It is suggested that the activity of Ro15-1788 depends on changes in the conformational state of benzodiazepine-GABA(A) receptor chloride-ionophore complex produced by GABA and GABA receptor antagonists.