Middle-aged children of Alzheimer parents, a pilot study: stable neurocognitive performance at 20-year follow-up

The objective of this pilot study on a convenience sample of 25 offspring of Alzheimer patients (mean age 61.5 +/- 8.8 years; range, 50-82) was the early detection of neurocognitive decline. This preliminary report appears to be the first one dealing with 20-year follow-up of neurocognitive data of Alzheimer's disease (AD) children. Digit symbol (Wechsler Adult Intelligence Scale) was the only of 11 neurocognitive measures with a significant decline. And that decline between first and last testing (mean = 19.98 +/- 0.30 years) was on raw scores, not scaled scores. Neither parents' age at onset of AD nor autopsy confirmation or offspring APOE-e4 status influenced neurocognitive results. More robust data than currently available are needed to confirm the findings of this first pilot study and to determine both the trajectory of neurocognitive decline in AD and the risks of developing AD faced by children whose parent had the disease.     

Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants

Individual differences in detoxication capacities for specific organophosphorous (OP) compounds are due largely to differences in catalytic efficiency or abundance of the HDL-associated enzyme, paraoxonase (PON1). First, we provide evidence that children less than 2 years of age represent a particularly susceptible population for OP exposure due to low abundance of PON1 and variable onset of plasma PON1 activity. Second, we describe studies examining the neurotoxic effects of chronic, low-level OP pesticide exposure in mice. PON1 knockout (PON1(-/-)) and wild-type mice were exposed chronically (PN4 to PN21) to low levels of chlorpyrifos oxon (CPO). Endpoints included cholinesterase activity, histopathology, gene expression, and behavior. Even at PN4, when PON1 levels were low in wild-type mice, PON1(-/-) mice were more sensitive to inhibition of brain cholinesterase by CPO. At PN22, and persisting as long as 4 months, chronic developmental exposure to 0.18 mg/kg/d or 0.25 mg/kg/d CPO resulted in perinuclear vacuolization of cells in a discrete area of the neocortex and irregular distribution of neurons in the cortical plate, with an increase in the number of affected cells at 0.25mg/kg/d. Third, we describe a transgenic mouse model in which human transgenes encoding either hPON1Q192 or hPON1R192 were expressed at equal levels in place of mouse PON1. The developmental onset of expression followed the mouse time course and was identical for the two transgenes, allowing these mice to be used to assess the importance of the Q192R polymorphism during development. Adult mice expressing hPON1R192 were significantly more resistant than hPON1Q192 mice to CPO toxicity. Our studies indicate that children less than 2 years old, especially those homozygous for PON1Q192, would be predicted to be particularly susceptible to CPO toxicity.     

Periventricular leukomalacia is common after neonatal cardiac surgery

OBJECTIVES: Periventricular leukomalacia is necrosis of the cerebral white matter adjacent to the lateral ventricles and results from injury to immature oligodendroglia. In infants without congenital heart disease, periventricular leukomalacia is associated with an increased incidence of developmental delay and attention deficit/hyperactivity disorder. The incidence of periventricular leukomalacia and the risk factors for development of periventricular leukomalacia after infant cardiac surgery are not known. METHODS: Magnetic resonance imaging of the brain was performed 6 to 14 days after cardiac surgery utilizing cardiopulmonary bypass with or without deep hypothermic circulatory arrest in 105 neonates and infants < or = 6 months of age. RESULTS: Median age at surgery was 6 days (range 1-178), with 82 neonates (age < or = 30 days). Periventricular leukomalacia was found in 44 of the neonates (54%) compared with 1 of 23 infants (4%). Forward logistic regression using age at surgery as a continuous variable identified a model containing longer total support time (cardiopulmonary bypass plus deep hypothermic circulatory arrest), lower systolic blood pressure at cardiac intensive care unit admission postoperatively, lower minimum diastolic blood pressure, and Po(2) in the first 48 hours after surgery. When age at surgery was considered as a dichotomous variable (neonate versus infant), younger age at surgery replaced systolic blood pressure, Po(2), and total support time in the model. Lower minimum diastolic blood pressure was a significant risk factor in both models. CONCLUSIONS: Periventricular leukomalacia was found in >50% of neonates after cardiac surgery but rarely in older infants. Hypoxemia and hypotension in the early postoperative period, particularly diastolic hypotension, may be important risk factors for periventricular leukomalacia.     

Residence,income and cancer hospitalizations in British Columbia during a decade of policy change

BACKGROUND: Through the 1990s, governments across Canada shifted health care funding allocation and organizational foci toward a community-based population health model. Major concerns of reform based on this model include ensuring equitable access to health and health care, and enhancing preventive and community-based resources for care. Reforms may act differentially relative to specific conditions and services, including those geared to chronic versus acute conditions. The present study therefore focuses on health service utilization, specifically cancer hospitalizations, in British Columbia during a decade of health system reform. METHODS: Data were drawn from the British Columbia Linked Health Data resource; income measures were derived from Statistics Canada 1996 Census public use enumeration area income files. Records with a discharge (separation) date between 1 January 1991 and 31 December 1998 were selected. All hospitalizations with ICD-9 codes 140 through 208 (except skin cancer, code 173) as principal diagnosis were included. Specific cancers analyzed include lung; colorectal; female breast; and prostate. Hospitalizations were examined in total (all separations), and as divided into first and all other hospitalizations attributed to any given individual. Annual trends in age-sex adjusted rates were analyzed by joinpoint regression; longitudinal multivariate analyses assessing association of residence and income with hospitalizations utilized generalised estimating equations. Results are evaluated in relation to cancer incidence trends, health policy reform and access to care. RESULTS: Age-sex adjusted hospitalization rates for all separations for all cancers, and lung, breast and prostate cancers, decreased significantly over the study period; colorectal cancer separations did not change significantly. Rates for first and other hospitalizations remained stationary or gradually declined over the study period. Area of residence and income were not significantly associated with first hospitalizations; effects were less consistent for all and other hospitalizations. No interactions were observed for any category of separations. CONCLUSIONS: No discontinuities were observed with respect to total hospitalizations that could be associated temporally with health policy reform; observed changes were primarily gradual. These results do not indicate whether equity was present prior to health care reform. However, findings concur with previous reports indicating no change in access to health care across income or residence consequent on health care reform.     

Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study

In untreated smokers, exposure to cigarette-related cues increases both the intensity of cigarette craving and relative glucose metabolism of the perigenual/ventral anterior cingulate cortex (ACC). Given that treatment with bupropion HCl reduces overall cigarette craving levels in nicotine dependent subjects, we performed a preliminary study of smokers to determine if bupropion HCl treatment attenuates cue-induced cigarette craving and associated brain metabolic activation. Thirty-seven, otherwise healthy smokers (20 untreated and 17 who had received open-label treatment with bupropion HCl) underwent two (18)F-fluorodeoxyglucose positron emission tomography scanning sessions in randomized order--one when presented with neutral cues and the other when presented with cigarette-related cues. Bupropion-treated smokers had smaller cigarette cue-induced increases in craving scores on the Urge to Smoke (UTS) Scale and less activation of perigenual/ventral ACC metabolism from the neutral to the cigarette cue scan than untreated smokers. Thus, in addition to its known effects on spontaneous cigarette craving and withdrawal symptoms, bupropion HCl diminishes cue-induced cigarette craving and appears to attenuate cigarette cue-induced ACC activation. These results are consistent with the known effects of bupropion HCl, including its enhancement of catecholaminergic neurotransmission.     

Symptoms of depression and anxiety (MHI) following acute medical/surgical hospitalization and post-discharge psychiatric diagnoses (DSM) in 839 geriatric US veterans

OBJECTIVE: We addressed the relatively unexplored use of screening scores measuring symptoms of depression and/or anxiety to aid in identifying patients at increased risk for post-discharge DSM-IV Axis I diagnoses. We were unable to find such studies in the literature. METHOD: Elderly veterans without recent psychiatric diagnoses were screened for depression and anxiety symptoms upon admission to acute medical/surgical units using the Mental Health Inventory (MHI). Following discharge, those who had exceeded cut-off scores and had been randomized to UPBEAT Care (Unified Psychogeriatric Biopsychosocial Evaluation and Treatment, a clinical demonstration project) were evaluated for DSM diagnoses. We report on 839 patients, mostly male (96.3%; mean age 69.6 +/- 6.7 years), comparing three groups, i.e. those meeting screening criteria for symptoms of (i) depression only; (ii) anxiety only; and (iii) both depression and anxiety. RESULTS: Despite absence of recent psychiatric history, 58.6% of the 839 patients received a DSM diagnosis post-discharge (21.8% adjustment; 15.4% anxiety; 7.5% mood; and 14.0% other disorders). Patients meeting screening criteria for both depression and anxiety symptoms received a DSM diagnosis more frequently than those meeting criteria for anxiety symptoms only (61.9% vs 49.0%, p = 0.017), but did not differ significantly from those meeting criteria for depressive symptoms only (61.9% vs 56.8%, p = 0.174). Although exceeding the MHI screening cut-off scores for depression, anxiety, or both helped to identify patients with a post-discharge DSM diagnosis, the actual MHI screening scores failed to do so. CONCLUSION: Screening hospitalized medical/surgical patients for symptoms of depression, anxiety, and particularly for the combination thereof, may help identify those with increased risk of subsequent DSM diagnoses, including adjustment disorder.     

Diagnosis of carpal tunnel syndrome: electrodiagnostic and MR imaging evaluation

In clinically classic carpal tunnel syndrome (CTS) without symptoms or signs to suggest other disorders that can mimic CTS, it remains somewhat controversial as to whether performing nerve conduction studies is necessary or cost-effective. MR imaging reliably depicts normal carpal tunnel anatomy. It can also identify pathologic nerve compression and mass lesions, such as ganglion cysts, that compress nerves. Currently, MR imaging is most commonly used to image patients with ambiguous electrodiagnostic studies and clinical examinations. MR diffusion-weighted imaging of peripheral nerves might prove to be the most sensitive imaging sequence for the detection of early nerve dysfunction. Electrodiagnostic studies are likely to remain the pivotal diagnostic examination in patients with suspected CTS for the foreseeable future. With advances in both software and hardware, however, high-resolution MR imaging of peripheral nerves will become faster, cheaper, and likely more accurate, possibly paving the way for an expanded role in the diagnosis of this common syndrome.     

Detection and assignment of mutations and minihaplotypes in human DNA using peptide mass signature genotyping (PMSG): application to the human RDS/peripherin gene

Peptide mass-signature genotyping (PMSG) is a scanning genotyping method that identifies mutations and polymorphisms by translating the sequence of interest in more than one reading frame and measuring the masses of the resulting peptides by mass spectrometry. PMSG was applied to the RDS/peripherin gene of 16 individuals from a family exhibiting autosomal dominant macular degeneration. The method revealed an A-->T transversion in the 5' splice site of intron 2 that is the likely cause of the disease. It also revealed four different minihaplotypes in exon 3 that represent particular combinations of SNPs at four different locations. This study demonstrates the utility of PMSG for identifying and characterizing point mutations and local minihaplotypes that are not readily analyzed by other approaches.