Genetic association signal near NTN4 in Tourette syndrome

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10⁻³) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry‐matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10⁻⁴) remained significant after Bonferroni correction. Meta‐analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10⁻⁷). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case–control status (p = 0.042), suggesting that many of these variants are true TS risk alleles. Ann Neurol 2014;76:310–315     

Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene

PURPOSE: To report posterior chorioretinal atrophy (PCRA) and correlate the vitreous phenotype with inheritance of the disease mutation in a family with vitreoretinal dystrophy. DESIGN: Prospective observational case series. METHODS: Twenty-four members of a family with 14 affected individuals were examined, and genetic linkage analysis was performed at the COL2A1, COL11A1, and Wagner disease loci. The vitreous phenotype was prospectively graded as optically empty with retrolenticular membrane, fibrillar, or normal. Ocular ultrasonography and optical coherence tomography (OCT) were performed on selected individuals to study the vitreous structure and vitreoretinal interface. RESULTS: The 6-year-old proband had PCRA and optically empty vitreous without systemic features, suggestive of Wagner disease. The family history was negative for systemic disease, except for one cousin with cleft palate. However, when examined, clinical features of the 14 affected subjects included 5 with small chin, 4 with at least submucosal cleft palate, and 9 with a myopic refractive error greater than 5 diopters. Lens opacity or previous cataract extraction was found in 13 family members. All affected individuals in whom the vitreous could be examined had an optically empty vitreous with retrolental membrane. Posterior chorioretinal atrophy was found in eight of the affected subjects. The finding was not limited to highly myopic subjects, nor did all the high myopes have PCRA. Ultrasonography and OCT revealed vitreous adherent to the retina, but without apparent retinal distortion or edema of the macula. Significant linkage was established to the COL2A1 locus; the other loci were excluded. A single nucleotide insertion mutation (c.2012 2013insC) was identified in exon 34, leading to a downstream premature stop codon in the COL2A1 gene. CONCLUSIONS: Although posterior chorioretinal atrophy and vitreoretinal degeneration have been classically associated with Wagner disease, we demonstrate its presence in a family with typical Stickler syndrome. On the basis of clinical, ultrasonographic, and OCT studies, the etiology of PCRA in this family does not seem to be attributable to vitreomacular traction or myopia. The vitreous findings in this large family confirm reports that mutations in the COL2A1 gene lead to the optically empty vitreous with retrolenticular membrane phenotype.     

Significance of secondary ultrasonographic endometrial thickening in postmenopausal tamoxifen-treated women

BACKGROUND: Ultrasonography has a limited value in endometrial assessment for identification of endometrial pathologies in postmenopausal tamoxifen-treated patients. METHODS: We compared the rate of endometrial pathologies and the mean +/- SD of endometrial thickness diagnosed after the first and second transvaginal ultrasonographic studies performed on 55 postmenopausal tamoxifen-treated patients with secondary endometrial thickening (Group I). This rate was also compared with 46 similar patients without secondary thickening (Group II). We also compared the mean +/- SD of endometrial thickness detected in various ultrasonographic studies, as well as various clinical features. RESULTS: A significantly higher rate of endometrial pathologies, including two cases of endometrial cancer identified in gynecologically asymptomatic patients (3.6%), was diagnosed in Group I after the second study compared with the first study (52.7% and 9.1%, respectively; P = 0.001) and compared with those diagnosed after the second study in Group II (30.4%; P = 0.03). There was a significant increase (74.7 +/- 115%) in endometrial thickness after the second study compared with the first study performed on Group I (10.7 +/- 5.53 mm and 16.59 +/- 5.53 mm, respectively; P = 0.0001) and a significant difference in endometrial thickness demonstrated in the second study performed on Groups I and II (16.59 +/- 5.53 mm and 11.4 +/- 3.91 mm, respectively; P = 0.001).There were no significant differences in the time elapsed since the diagnosis of breast carcinoma and from the beginning of tamoxifen treatment to the performance of the first ultrasonographic study as well as the time elapsed between the first and second studies performed. CONCLUSIONS: A significant increase (> 50%) in secondary endometrial thickening, measured ultrasonographically, in postmenopausal tamoxifen-treated patients, is associated with a high rate of endometrial pathologies, including endometrial cancer.     

Phenotypic,ethologically based resolution of spontaneous and D(2)-like vs D(1)-like agonist-induced behavioural topography in mice with congenic D(3) dopamine receptor "knockout"

Uncertainty as to the functional role of the D(3) dopamine receptor, due primarily to a paucity of selective agonists or antagonists, is being addressed in mice with targeted gene deletion ("knockout") thereof. This study describes, for the first time, the phenotype of congenic D(3)-null mice. Initially, 129/Sv x C57BL/6 D(3)-null mice were backcrossed 14 times onto C57BL/6; they were then assessed using an ethologically based approach which resolves all topographies of behaviour within the mouse repertoire. The ethogram of D(3)-null mice, on comparison with wildtypes, was characterised by no alteration in any topography of behaviour over an initial period of exploration; subsequent assessment over several hours revealed only increased rearing among females due to delayed habituation. Low doses of the selective D(2)-like agonist RU 24213 (0.016-0.25 mg/kg) inhibited topographies of exploratory behaviour; this effect was diminished in D(3)-null mice only when investigated following prolonged habituation, and then only for certain topographies of behaviour, primarily sniffing and rearing. High doses of RU 24213 (0.1-12.5 mg/kg) induced stereotyped sniffing and "ponderous" locomotion, while the selective D(1)-like agonist SK&F 83959 (0.016-2.0 mg/kg) promoted characteristic grooming syntax; these effects did not differ materially between the genotypes. When examined topographically on an essentially congenic C57BL/6 background (<0.005% 129/Sv), the resultant phenotype indicated essential conservation of the mouse ethogram, high-dose D(2)-like stimulatory effects, and D(1)-like stimulatory effects in the absence of D(3) receptors. A role for D(3) receptors in inhibitory processes appeared topographically circumscribed and only when baseline levels of behaviour were low.     

Pulse pressure and cardiovascular disease-related mortality: follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT)

Context  The sixth Joint National Committee (JNC-VI) classification system of blood pressure emphasizes both systolic blood pressure (SBP) and diastolic blood pressure (DBP) for cardiovascular disease risk assessment. Pulse pressure may also be a valuable risk assessment tool. Objective  To compare relationships of SBP, DBP, and pulse pressure, separately and jointly, with cardiovascular disease-related mortality in men. Design and Setting  Data from the Multiple Risk Factor Intervention Trial (MRFIT), which screened men aged 35 to 57 years from 1973 through 1975 at 22 US centers, was used to assess cardiovascular disease-related mortality through 1996. Participants  A total of 342 815 men without diabetes or a history of myocardial infarction were divided into 2 groups based on their age at MRFIT screening (35- to 44-year-olds and 45- to 57-year olds). Participant blood pressure levels were classified into a JNC-VI blood pressure category based on SBP and DBP (optimal, normal but not optimal, high normal, stage 1 hypertension, stage 2-3 hypertension), and pulse pressure was calculated. Main Outcome Measure  Cardiovascular disease-related mortality. Results  There were 25 721 cardiovascular disease-related deaths. Levels of SBP and DBP were more strongly related to cardiovascular disease than pulse pressure. Relationships of SBP, DBP, and pulse pressure to cardiovascular disease-related mortality varied within JNC-VI category. Concordant elevations of SBP and DBP were associated with a greater risk of cardiovascular disease-related mortality for both age groups of men. Among men aged 45 to 57 years, higher SBP and lower DBP (discordant elevations) also yielded a greater risk of cardiovascular disease-related mortality. Conclusion  In both age groups, cardiovascular disease risk assessment was improved by considering both SBP and DBP, not just SBP, DBP, or pulse pressure separately.      

Inflammation, proinflammatory mediators and myocardial ischemia-reperfusion Injury

Ischemic myocardium must be reperfused to terminate the ischemic event; otherwise the entire myocardium involved in the area at risk will not survive. However, there is a cost to reperfusion that may offset the intended clinical benefits of minimizing infarct size, postischemic endothelial and microvascular damage, blood flow defects, and contractile dysfunction. There are many contributors to this reperfusion injury. Targeting only one factor in the complex web of reperfusion injury is not effective because the untargeted mechanisms induce injury. An integrated strategy of reducing reperfusion injury in the catheterization laboratory involves controlling both the conditions and the composition of the reperfusate. Mechanical interventions such as gradually restoring blood flow or applying postconditioning may be used independently in or conjunction with various cardioprotective pharmaceuticals in an integrated strategy of reperfusion therapeutics to reduce postischemic injury.