Objective Cognitive Impairment and Progression to Dementia in Women: The Prospective Epidemiological Risk Factor Study.

BACKGROUND: Identification of subjects with a progressive disease phenotype is an urgent need in the pharmaceutical industry where most of the recent clinical trials in Alzheimer's disease have failed. OBJECTIVES: The objective of this study was to identify subgroups of individuals with objective cognitive impairment (OCI), who were most likely to progress to dementia and to identify the risk factors associated with progression. DESIGN: Prospective cohort study. SETTING: Population-based. PARTICIPANTS: 5,380 elderly women from Denmark. MEASUREMENTS: The Short Blessed Test and a category fluency test with animal naming, was used to assess cognitive function, and to classify them into different groups of OCI. RESULTS: OCI was identified in 852 subjects at baseline. The risk of dementia was elevated for OCI subjects as compared to subjects with normal cognition (HR 1.46[1.19-1.79]). The courses of OCI were studied in a sub-cohort who completed the cognitive assessment at both the baseline and the follow-up visit (n = 1,933). Of these subjects 203 had OCI at baseline. The multi-domain subtypes of OCI were associated with progressive OCI. Subjects most likely to progress were older, physically inactive, had a higher level of total cholesterol (>6.5 mmol/L) and had a history of depression as compared to subjects with a non-progressive course of OCI. CONCLUSIONS: In this cohort we identified a risk profile associated with progression from OCI in older women. The degree of impairment at baseline was an important predictor of conversion to dementia, additionally several modifiable risk factors were associated with progression.

Matrix Metalloproteinase Mediated Type I Collagen Degradation - An Independent Risk Factor for Mortality in Women.

Chronic fibro-proliferative diseases are associated with nearly 45% of all deaths in the developed world. Matrix metalloproteinase (MMP) mediated remodeling of the extracellular matrix (ECM) plays an important role in disease development. Degradation of type I collagen is considered having a major role in this matter. C1M is a biomarker measuring type I collagen degradation fragments in blood. The aim of the current study was to investigate whether MMP mediated type I collagen degradation (C1M) was predictive of mortality in a large prospective cohort of Danish women aged 48-89 (n = 5855). Subjects with high serum C1M showed significant increased mortality. The adjusted three year HR was 2.02 [95% CI: 1.48-2.76] for all-cause mortality, 2.32 [95% CI: 1.51-3.56] for cancer and 1.77 [95% CI: 0.98-3.17] for cardiovascular diseases. The adjusted nine year HR was 1.50 [95% CI: 1.28-1.75] for all-cause mortality, 1.49 [95% CI: 1.16-1.90] for cancer and 1.69 [95% CI: 1.27-2.24] for cardiovascular diseases. High MMP-mediated type I collagen degradation was associated with increased mortality. Subjects with high C1M had a 2-fold increase in mortality compared to subjects with low levels of this collagen degradation product.

Binding of 5H-dibenzo[a,d]cycloheptene and dibenz[b,f]oxepin analogues of clozapine to dopamine and serotonin receptors.

Series of 5,11-dicarbo- and 11-carbo-5-oxy-10-(1-alkyl-1,2,3,6-tetrahydro-4 pyridinyl) analogues and a 11-carbo-5-oxy-10-(1-methyl-4-piperidinyl) analogue of the atypical antipsychotic agent clozapine were prepared and tested for binding to the dopamine D-2L and D-4 and serotonin S-2A and S-2C receptors. Some of these analogues were found to have dopamine D-2L and D-4 and serotonin S-2A and S-2C receptor binding activities as high as or higher than those of clozapine, indicating that neither the diazepine structure nor the piperazine ring present in clozapine is essential for high antidopamine activity and or for high dopamine D-4 selectivity (Ki for the dopamine D-2L receptor/Ki for the dopamine D-4 receptor). Increasing in the effective size of the alkyl substituent at the tertiary amine nitrogen atom in the 1,2,3,6-tetrahydro-4-pyridinyl moiety in the 5H-dibenzo[a,d]cycloheptene series reduces the affinity for the dopamine D-4 receptor, but in the dibenz[b,f]oxepin series, no significant change in binding affinity to the dopamine D-4 receptor was observed. Equal or slightly higher affinity for the serotonin S-2A and S-2C receptors was observed for the 10-(1-ethyl-1,2,3,6-tetrahydro-4- pyridinyl) analogues in both series, but for the 10-[1,2,3,6-tetrahydro-1-(2-propenyl)-4- pyridinyl] analogues, any favourable steric factor is overshadowed by an unfavorable electronic effect as a result of change in the basicity of the tertiary amino group in the pyridinyl moiety. Replacement of three of the four nitrogen atoms in clozapine with three carbon or two carbon atoms and an oxygen atom and removal of the chlorine atoms gives 10-(1,2,3,6-tetrahydro-1- methyl-4-pyridinyl)dibenzo[a,d]cycloheptene and 10-(1-methyl-4-piperidinyl)dibenz[b,f]oxepin, each having twice the binding activity to the dopamine D-4 receptor as does clozapine and a dopamine D-4 selectivity equal to that of clozapine.

A proposal for a foster grandmother intervention program to prevent child abuse.

The incidence of child abuse and neglect is epidemic. Many abused children have sustained lifelong injuries. Often they become perpetrators of abuse, continuing the cycle into future generations. Studies have indicated that mothers who are likely to abuse their children can be identified by a predictive method during the prenatal and postpartum periods. Pilot studies have indicated that mothers who are identified by the method and who receive early intervention, consisting of home visits by registered nurses, show a significantly lower rate of verified cases of child abuse. The author proposes a strategy for early intervention to prevent child abuse and neglect and to help infants and children attain their appropriate developmental milestones. The strategy calls for training and employing women from the Foster Grandparent Program. Foster grandmothers would be a valuable resource for high-risk mothers, providing role models for parenting skills in the home setting. Participating foster grandmothers would be trained and supervised in an interdisciplinary team setting. Evaluation of the program would compare the target population of infants and children whose mothers received the proposed intervention with a similar high-risk group that received only traditional interventions.

On the exudation of plasticizers from PVC haemodialysis tubings.

Prompted by a series of hepatitis-like cases in patients on regular haemodialysis treatment, the sets of polyvinylchloride (PVC) test tubings used were submitted to perfusion experiments. The perfusates from four commercially available tubings were also investigated. Diethylphthalate (DEP) could be identified by by IR and PMR spectrometry in the perfusate from the test tubings. UV spectrometry proved the presence of other non-identified substances in the perfusate from both the test tubings and from some of the other tubings.