Effects of nimodipine on acute cerebral ischemia and reperfusion injury of rats

AIM: To study the effect of nimodipine (Nim) on ischemic cerebral damage. METHODS: The four-vessel occlusion method was performed on rats. Monoamines were measured by fluorospectrophotometry. RESULTS: Intraperitoneal injection of Nim 0.75 and 1.5 mg.kg-1 quickened the recovery of EEG changes to 19 +/- 3 and 17 +/- 4 min (P < 0.01), respectively. Nim reduced the decreases of monoamines (NE, DA, 5-HT, and 5-HIAA) contents after 30-min cerebral ischemia and 1-h reperfusion. CONCLUSION: Nim protects the brain from ischemic damage.     

Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives

We performed a community-based study to investigate the relationship of genetic susceptibility and head injury to Alzheimer's disease (AD) in 138 patients with AD and 193 healthy elderly control subjects. Data concerning presence or absence of dementia and certain exposures were also obtained from 799 first-degree relatives of the patients and 1,238 first-degree relatives of the control subjects. Adjusting for age, gender, and other risk factors, the odds ratio for AD associated with head injury was 3.7 (95% confidence interval [CI], 1.4-9.7). The association was highest for head injuries that occurred after age 70. The risk of AD was higher in first-degree relatives of patients with onset prior to age 70 than in relatives of control subjects (risk ratio [RR] = 2.5; 95% CI, 1.1-5.6). The risk was not increased for relatives of patients with onset of AD at age 70 or older. Compared with relatives without head injury, the risk of AD was increased among both head-injured relatives of patients (RR = 5.9; 95% CI, 2.3-14.8) and head-injured relatives of control subjects (RR = 6.9; 95% CI, 2.5-18.9). Our results are consistent with the hypothesis that severe head injury and genetic susceptibility are associated with AD. Both associations concur with current concepts regarding the role of amyloid in AD. Although we regard head injury, like genetic susceptibility, to be a putative risk factor for AD, the temporal relationship between head injury and AD warrants further investigation.     

Dynamics and thermodynamics of the regulatory domain of human cardiac troponin C in the apo- and calcium-saturated states

The contraction of cardiac and skeletal muscles is triggered by the binding of Ca2+ to their respective troponin C (TnC) proteins. Recent structural data of both cardiac and skeletal TnC in both the apo and Ca2+ states have revealed that the response to Ca2+ is fundamentally different for these two proteins. For skeletal TnC, binding of two Ca2+ to sites 1 and 2 leads to large changes in the structure, resulting in the exposure of a hydrophobic surface. For cardiac TnC, Ca2+ binds site 2 only, as site 1 is inactive, and the structures show that the Ca2+-induced changes are much smaller and do not result in the exposure of a large hydrophobic surface. To understand the differences between regulation of skeletal and cardiac muscle, we have investigated the effect of Ca2+ binding on the dynamics and thermodynamics of the regulatory N-domain of cardiac TnC (cNTnC) using backbone 15N nuclear magnetic resonance relaxation measurements for comparison to the skeletal system. Analysis of the relaxation data allows for the estimation of the contribution of changes in picosecond to nanosecond time scale motions to the conformational entropy of the Ca2+-binding sites on a per residue basis, which can be related to the structural features of the sites. The results indicate that binding of Ca2+ to the functional site in cNTnC makes the site more rigid with respect to high-frequency motions; this corresponds to a decrease in the conformational entropy (TdeltaS) of the site by 2.2 kcal mol(-1). Although site 1 is defunct, binding to site 2 also decreases the conformational entropy in the nonfunctional site by 0.5 kcal mol(-1). The results indicate that the Ca2+-binding sites in the regulatory domain are structurally and energetically coupled despite the inability of site 1 to bind Ca2+. Comparison between the cardiac and skeletal isoforms in the apo state shows that there is a decrease in conformational entropy of 0.9 kcal mol(-1) for site 1 of cNTnC and little difference for site 2.     

Influence of education and occupation on the incidence of Alzheimer's disease

OBJECTIVE: Several cross-sectional studies have found an association between Alzheimer's disease (AD) and limited educational experience. It has been difficult to establish whether educational experience is a risk factor for AD because educational attainment can influence performance on diagnostic tests. This study was designed to determine whether limited educational level and occupational attainment are risk factors for incident dementia. DESIGN: Cohort incidence study. SETTING: General community. PARTICIPANTS: A total of 593 nondemented individuals aged 60 years or older who were listed in a registry of individuals at risk for dementia in North Manhattan, NY, were identified and followed up. INTERVENTIONS: We reexamined subjects 1 to 4 years later with the identical standardized neurological and neuropsychological measures. MAIN OUTCOME MEASURES: Incident dementia. RESULTS: We used Cox proportional hazards models, adjusting for age and gender, to estimate the relative risk (RR) of incident dementia associated with low educational and occupational attainment. Of the 593 subjects, 106 became demented; all but five of these met research criteria for AD. The risk of dementia was increased in subjects with either low education (RR, 2.02; 95% confidence interval [Cl], 1.33 to 3.06) or low lifetime occupational attainment (RR, 2.25; 95% Cl, 1.32 to 3.84). Risk was greatest for subjects with both low education and low life-time occupational attainment (RR, 2.87; 95% Cl, 1.32 to 3.84). CONCLUSIONS: The data suggest that increased educational and occupational attainment may reduce the risk of incident AD, either by decreasing ease of clinical detection of AD or by imparting a reserve that delays the onset of clinical manifestations.     

Genetic aspects of uveal melanoma: a brief review

Uveal melanoma usually occurs sporadically in the absence of obvious genetic predisposing factors. However, in rare patients, there is a suggestion that there may be genetic predisposition. Rare occurrences of familial uveal melanoma are believed to be inherited in an autosomal dominant mode. There are a few clinical conditions that can predispose to or be associated with uveal melanoma, including ocular melanocytosis, neurofibromatosis type I, and familial atypical mole and melanoma syndrome. Nonrandom cytogenetic changes in uveal melanoma are characterized by monosomy 3, trisomy 8, and structural or numerical abnormalities of chromosome 6. Alterations of chromosome 9p are less frequently observed. CDKN2 gene, a cutaneous melanoma predisposition gene, is probably not a uveal melanoma predisposition gene as evidenced by the lack of somatic mutations involving this gene in uveal melanoma samples and the absence of germline mutations in familial uveal melanoma patients. Transgenic mouse models developed using a tyrosinase promoter tagged with a mutated ras gene or SV40-Tag oncoprotein develop retinal pigment epithelium tumors that resemble uveal melanoma. We propose that uveal melanoma cases be categorized on genetic basis according to a new classification system. This classification scheme will help to identify and uniformly categorize uveal melanoma patients with genetic predisposition. Such patients offer unique opportunities for studying the genetic aspects of uveal melanoma and, therefore, appropriate tissue samples should be obtained from them for molecular genetic studies. Further studies are needed to fully understand the genetic aspects of uveal melanoma.     

Systemic iron metabolism and mortality from Parkinson's disease

Six measures of systemic iron metabolism were used to predict mortality among 103 patients with Parkinson's disease and 353 controls followed in a longitudinal study. Adjusting for gender, education, ethnicity, presence of dementia, and extrapyramidal signs, transferrin receptor concentration was strongly associated with mortality in patients with PD but not controls. This increase in serum transferrin receptor concentration before death suggests that the previously observed perturbation in iron metabolism continues throughout the disease course.     

The catalytic subunit of Dictyostelium cAMP-dependent protein kinase -- role of the N-terminal domain and of the C-terminal residues in catalytic activity and stability

The C subunit of Dictyostelium cAMP-dependent protein kinase (PKA) is unusually large (73 kDa) due to the presence of 330 amino acids N-terminal to the conserved catalytic core. The sequence following the core, including a C-terminal -Phe-Xaa-Xaa-Phe-COOH motif, is highly conserved. We have characterized the catalytic activity and stability of C subunits mutated in sequences outside the catalytic core and we have analyzed their ability to interact with the R subunit and with the heat-stable protein-kinase inhibitor PKI. Mutants carrying deletions in the N-terminal domain displayed little difference in their kinetic properties and retained their capacity to be inhibited by R subunit and by PKI. In contrast, the mutation of one or both of the phenylalanine residues in the C-terminal motif resulted in a decrease of catalytic activity and stability of the proteins. Inhibition by the R subunit or by PKI were however unaffected. Sequence-comparison analysis of other protein kinases revealed that a -Phe-Xaa-Xaa-Phe- motif is present in many Ser/Thr protein kinases, although its location at the very end of the polypeptide is a particular feature of the PKA family. We propose that the presence of this motif may serve to identify isoforms of protein kinases.     

Christian's spondylo-digital syndrome: second familial case

We studied a mother and daughter with skeletal dysplasia which was characterized clinically by proximal and distal flexion contractures in the phalanges, and by brachydactyly, clinodactyly and ulnar and radial subdislocations of the fingers. Radiologically, the 2nd metacarpal in the daughter was seen to be longer than the other metacarpals, with bone carpal fusion, and flexion contractures of the fingers in both hands. Thoraco-lumbar xyphorotoscoliosis and malformed vertebrae with dyssegmentation of L2-L3, T12 and L1 with cuneiform shape, asymmetry of the pelvic bones and exostotic lesions in the proximal third of the tibia and the distal third of the femur were also noted. The clinical and radiological characteristics were compatible with the syndrome described by Christian et al. in 1975 and called the second metatarsal syndrome. The purpose of this paper was to present a second corroborative familial case and to propose another name: Christian's spondylo-digital syndrome.