Relationships among ragweed skin tests and both allergen specific and nonspecific nasal provocation.

Twenty-six patients with ragweed-induced allergic rhinitis were evaluated prior to the onset of seasonal symptoms. Ragweed skin tests and nasal challenges were performed 2 weeks after histamine nasal provocation. A correlation between ragweed skin tests and nasal challenges was detected (r = .4867, P much less than .01). Histamine challenges did not correlate with either of the other variables. A properly performed skin test predicts nasal reactivity to the same allergen. A clinical role for nonspecific nasal provocation could not be determined.     

Complete genomic screen in Parkinson disease: evidence for multiple genes.

CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.     

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.     

The pharmacology of RS-15385-197, a potent and selective α2-adrenoceptor antagonist

1 RS-15385-197 ((8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(methylsul- phonyl)-6H-isoquino [2,1-g][1,6]-naphthyridine) was evaluated in a series of in vitro and in vivo tests as an antagonist at α₂-adrenoceptors.2 RS-15385-197 had a pK_i of 9.45 for α₂-adrenoceptors in the rat cortex (pA₂ in the guinea-pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS-15385-198, had a pK_i of only 6.32 (pA₂ 6.47) indicating a high degree of stereoselectivity. The racemate RS-15385-196 had a pK_i of 9.18.3 RS-15385-197 showed unprecedented α₂ vs. α₁ adrenoceptor selectivity in vitro. In the rat cortex, RS-15385-197 had a pK_i of 9.45 in displacing [³H]-yohimbine and 5.29 in displacing [³H]-prazosin (α₂/α₁ selectivity ratio in binding experiments > 14000). The compound had a pA₂ of 9.72 as a competitive antagonist of the inhibitory effects of UK-14,304 in transmurally-stimulated guinea-pig ileum and 10.0 against BHT-920-induced contractions in dog saphenous vein (DSV); this latter value was unaltered by phenoxybenzamine. An apparent pK_B of 5.9 was obtained against cirazoline-induced contractions in DSV, whilst a pA₂ of 6.05 was obtained against phenylephrine-induced contractions in the rabbit aorta (α₂/α₁ selectivity ratio in functional experiments > 4000).4 RS-15385-197 was highly selective for α₂-adrenoceptors over other receptors: the compound showed low affinity for 5-HT_1A (pK_i 6.50) and 5-HT_1D (pK_i 7.00) receptor subtypes, and even lower affinity (pK_i≤5) for other 5-HT receptor subtypes, dopamine receptors, muscarinic cholinoceptors, β-adrenoceptors and dihydropyridine binding sites. RS-15385-197 was devoid of affinity for the non-adrenoceptor imidazoline binding site, labelled by [³H]-idazoxan, which provides further evidence that these sites are not related to α₂-adrenoceptors. In the DSV, contractile responses to 5-hydroxytryptamine (5-HT) were unaffected by a concentration of 1 μM RS-15385-197.5 RS-15385-197 was non-selective for the α_2A- and α_2B-adrenoceptor subtypes in that the pK_i for the α_2A-adrenoceptor in human platelets was 9.90 and the pK_i for the α_2B-adrenoceptor in rat neonate lung was 9.70. However, RS-15385-197 showed lower affinity for the α₂-adrenoceptor subtype in hamster adipocytes (pK_i 8.38).6 In anaesthetized rats, RS-15385-197 was a potent antagonist of the mydriasis response induced by UK-14,304 or clonidine (AD₅₀ 5 and 7 μg kg^-1, i.v., respectively; 96 μg kg^-1, p.o.) and of UK-14,304-induced pressor responses in pithed rats (AD₅₀ 7 μg kg^-1, i.v.); the compound therefore is both centrally and orally active. Even at a high dose (10 mg kg^-1, i.v.), RS-15385-197 did not antagonize pressor responses to cirazoline in pithed rats, indicating that the selectivity for α₂ vs. α₁-adrenoceptors was maintained in vivo.8 RS-15385-197 is therefore a very potent, selective, competitive α₂-adrenoceptor antagonist, both in vitro and in vivo, is orally active and readily penetrates the brain. It will thus be a powerful pharmacological tool for exploring the various physiological roles of α₂-adrenoceptors.     

Hypotheses: Melatonin/steroid combination contraceptives will prevent breast cancer

Summary The use of the conventional combination oral contraceptives (containing ethinyl-estradiol and a progestin) is associated with reduced risk of ovarian and endometrial cancer. However, prolonged use of these pills before first term pregnancy apparently increases the risk of pre menopausal breast cancer. We propose that the pineal gland hormone melatonin, combined with a progestin, as a new and novel oral contraceptive combination might prevent breast cancer in long term users. This hypothesis is based on the assumption that women have a propensity to develop breast cancer which correlates with number of ovulatory cycles over their lifetime. In evolution, the phylogenetic point at which women became sensitive to breast cancer evolved at a transfer point of the mechanism of ovulation from seasonal ovulation, which is still common in many mammalian species, to the current human pattern of continuous ovulatory cycles. We suggest that melatonin/ovariansteroid contraceptive will restore the lost mechanism of endogenous anovulation, and thus, by preventing continuous epithelial breast cell proliferation, will reduce the risk of breast cancer in long-term users.     

Apolipoprotein E promotes the binding and uptake of β-amyloid into Chinese hamster ovary cells in an isoform-specific manner

The 4 allele of apolipoprotein E gene is a major risk factor for Alzheimer's disease. However, the mechanism by which the E4 isoform of apolipoprotein E increases the risk of Alzheimer's disease is poorly understood. To determine whether the isoform-specific effects of apolipoprotein E may be mediated via clearance of bound β-amyloid, we examined the uptake of β-amyloid 1–40 into Chinese hamster ovary cells in the presence or absence of the apolipoprotein E isoforms E2, E3 and E4. Apolipoprotein E2 and E3 treatments were associated with higher association of β-amyloid with cells as compared to treatment with E4. Heparin blocked the association of β-amyloid with cells, as did an antibody to one of the apolipoprotein E receptors (the low-density lipoprotein receptor-related protein).

Thus, the apolipoproteins E2 and E3, but not E4, may play important roles in the clearance of β-amyloid from the extracellular space via the low-density lipoprotein receptor-related protein.     

The use of indirect composite and ceramic inlays to restore anterior teeth: a clinical case report

A clinical case has been presented utilizing old inlay techniques with new materials. The teeth were restored to proper form, function, and esthetics with a minimal removal of tooth structure. Crowns were not necessary, thereby eliminating a margin near the gingiva, and esthetics were acceptable.