Biomedical subjects

A LeBlanc

Publications and source records attributed to A LeBlanc.

At least 19 recordsLinked to original sources

PubMed2001

17-beta-estradiol induces an inhibitor of active caspases.

We have shown previously that caspase-6 activity is lethal to human neurons (LeBlanc et al., 1999; Zhang et al., 2000). Here we find that 17-beta-estradiol but not 17-alpha-estradiol prevents caspase-6-mediated neuronal cell death. 17-beta-estradiol-treated neuronal extracts directly inhibit recombinant active caspase-6, caspase-3, caspase-7, and caspase-8 in vitro. We conclude that 17-beta-estradiol induces a caspase inhibitory factor (CIF) that is preventing neuronal apoptosis. The induction of CIF occurs within 10 min of 17-beta-estradiol exposure to neurons, does not require de novo protein synthesis, and involves mitogen-activated protein kinase activation. The effect is antagonized by the estrogen receptor antagonist tamoxifen. In contrast, 17-beta-estradiol does not induce CIF or prevent caspase-mediated cell death in cultured astrocytes. CIF does not act through oxidation of the caspase active site. CIF activity copurifies with proteins of between 12 and 14 kDa in size. Our results indicate that 17-beta-estradiol induces an inhibitor of active caspases through a receptor-mediated nongenomic pathway and provide an additional mechanism for the neuroprotective action of 17-beta-estradiol that is likely highly relevant to the understanding of the role of estrogen against Alzheimer's disease.

Apoptosis↗

PubMed2001

Prion protein protects human neurons against Bax-mediated apoptosis.

The function of the cellular prion protein (PrP) is still poorly understood. We present here an unprecedented role for PrP against Bax-mediated neuronal apoptosis and show that PrP potently inhibits Bax-induced cell death in human primary neurons. Deletion of four octapeptide repeats of PrP (PrPDeltaOR) and familial D178N and T183A PrP mutations completely or partially eliminate the neuroprotective effect of PrP. PrP remains anti-apoptotic despite truncation of the glycosylphosphatidylinositol (GPI) anchor signal peptide, indicating that the neuroprotective form of PrP does not require the abundant cell surface GPI-anchored PrP. Our results implicate PrP as a potent and novel anti-apoptotic protein against Bax-mediated cell death.

Apoptosis↗

PubMed2001

Diffusion-weighted MRI in two cases of familial Creutzfeldt--Jakob disease.

Diffusion-weighted magnetic resonance imaging (DWI) has been described as a useful tool for the diagnosis of sporadic Creutzfeldt--Jakob disease (CJD). To our knowledge, DWI abnormalities have not previously been reported in familial CJD. In two patients with familial CJD associated with distinct mutations at codon 183 and at codon 210 of the prion protein gene, DWI showed a high signal in the basal ganglia and in the cerebral cortex. These abnormalities are similar to those described in sporadic CJD. This observation expands the value of DWI for the diagnosis of some forms of familial CJD. It remains to be investigated whether this finding also holds for CJD associated with other mutations of the prion protein gene.

Adult↗

PubMed2001

Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons.

Estrogen is an active neuroprotectant and is presently investigated as a potential therapy against Alzheimer's disease for women. To determine if male hormones could also be neuroprotective, we investigated the effect of testosterone, methyltestosterone, and epitestosterone at physiological concentrations on primary cultures of human neurons induced to undergo apoptosis by serum deprivation. Serum deprivation significantly induces neuronal apoptosis in a protracted fashion. As expected, physiological concentrations of 17-beta-estradiol and transcriptionally inactive 17-alpha-estradiol protect neurons against apoptosis. Similar to 17-beta-estradiol, physiological concentrations of testosterone are also neuroprotective. Androgen receptors are present at 8 +/- 2 fmol/mg protein in the neuron cultures. The non-aromatizable androgen, mibolerone, is also neuroprotective and aromatase inhibitor, 4-androsten-4-OL-3,17-dione, does not prevent testosterone-mediated neuroprotection. In contrast, anti-androgen, flutamide, eliminates testosterone-mediated neuroprotection. Testosterone analog, methyltestosterone, showed androgen receptor-dependent neuroprotection that was delayed in time indicating that a metabolite may be the active agent. The endogenous anti-androgen, epitestosterone, also showed a slight neuroprotective effect but not through the androgen receptor. These results indicate that androgens induce neuroprotection directly through the androgen receptor. These data suggest that androgens may also be of therapeutic value against Alzheimer's disease in aging males.

Androgen Antagonists↗

PubMed2001

Normal bone mineral density in cystic fibrosis.

BACKGROUND: Osteoporosis has been reported as a complication of cystic fibrosis (CF). AIMS: To measure bone mineral density (BMD) in non-acutely ill adults and bone mineral content (BMC) in children with CF. METHODS: We analysed data from 28 adults and 13 children with CF. Corticosteroid use was minimal for the year prior to study in both groups. Dual x ray absorptiometry was used to measure total body and regional bone mineral density in adults. In children, whole body BMC was measured. Lean tissue mass (LTM) was also measured in all subjects. There were two control groups: A (matched for LTM and height, in addition to age and gender); and B (matched for age and gender only). RESULTS: There was no difference in whole body or regional BMD density between adult CF patients and control A subjects. Both whole body and regional BMD were significantly lower in adult CF patients than in control B subjects. Total body BMD was correlated with body mass index, LTM, and percent fat in both CF and control subjects. There was no significant correlation between total body BMD or regional BMD and either NIH clinical status scores, or pulmonary function tests in adults. There was no difference in total body BMC between CF children and control A subjects. Total body BMC was significantly lower in CF children than in control B subjects. There was no correlation between pulmonary function results and BMC in children. CONCLUSION: Osteopenia and osteoporosis in CF may be caused more by malnutrition and chronic use of intravenous or oral corticosteroids than by a CF related inherent defect in BMD. Appropriate "normal" data should be selected when determining whether or not osteoporosis is present in a CF patient.

Absorptiometry, Photon↗

PubMed2001

Prion disease resembling frontotemporal dementia and parkinsonism linked to chromosome 17.

OBJECTIVE: To compare the clinical features of a familial prion disease with those of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). BACKGROUND: Prion diseases are not usually considered in the differential diagnosis of FTDP-17, since familial Creutzfeldt-Jakob disease (CJD), the most common inherited prion disease, often manifests as a rapidly progressive dementia. Conversely, FTDP-17 usually has an insidious onset in the fifth decade, with abnormal behavior and parkinsonian features. METHOD: We present the clinical features of 12 patients from a family with CJD associated with a point mutation at codon 183 of the prion protein gene. RESULTS: The mean age at onset was 44.0 +/- 3.7; the duration of the symptoms until death ranged from two to nine years. Behavioral disturbances were the predominant presenting symptoms. Nine patients were first seen by psychiatrists. Eight patients manifested parkinsonian signs. CONCLUSION: These clinical features bear a considerable resemblance to those described in FTDP-17.

Adult↗

PubMed2001

Localization of maximal ST segment displacement in various ischemic settings by orthogonal ECG: Implications for lead selection and the mechanism of ST shift.

BACKGROUND: ST segment deviation conveys crucial information concerning diagnosis, therapy and prognosis during acute coronary syndromes, but the understanding of the genesis of different ST shift polarities and the rationale for optimal lead placement during ischemic monitoring are incomplete. PATIENTS AND METHODS: Ninety-nine continuous recordings were made with orthogonal X, Y and Z leads in 35 patients during ST elevation myocardial infarction (MI), in 30 patients during single vessel, elective coronary angioplasty (PTCA), and in 34 patients with unstable angina or acute non-Q wave MI. Each lead was sampled at 500 Hz, and dominant QRS-T complexes were averaged every 47 s. In PTCA, 10 s averages were analyzed. Trend plots of ST + 60 ms for each lead and ST vector angles phi and theta were constructed and edited. ST shift polarity (depression or elevation) and vector orientation (phi and theta) were noted for the greatest ST shift 50 microV or greater on any lead for each patient. Coronary angiographical data were consulted when available. RESULTS: By constructing polar plots of phi and theta, it was evident that ST depression vectors were confined to a small, lateral cardiac region despite a variety of coronary lesions, while ST elevation vectors were oriented according to the territory of the occluded artery (difference of direction means, P<0.002). CONCLUSION: ST depression in acute coronary syndromes is maximal over the left thorax regardless of coronary lesion location, indicating that the mechanism of ST depression is not fully understood. In ambulatory monitoring where ST depression is expected, a lateral lead may suffice.

Angina, Unstable↗

PubMed2000

Selective and protracted apoptosis in human primary neurons microinjected with active caspase-3, -6, -7, and -8.

We have shown previously that caspase-6 is activated in serum deprivation-mediated human neuronal cell death and correlates with increased production of Alzheimer's disease (AD) amyloid beta peptide (Abeta). Here, we show by direct microinjection of recombinant active enzymes that caspase-6 (>0.5 pg/cell) induces a protracted course of apoptosis in neurons in a caspase-specific, dose- and time-dependent manner in the presence of serum. Only transient activation of caspase-6 is required to initiate apoptosis. Caspase-6 induces apoptosis directly without the activation of other caspase effectors. Doses of caspase-6 of <0.25 pg/cell induce only 20% cell death within 16 d but render neurons vulnerable to oxidative stress, indicating that caspase activation affects neurons despite the absence of cell death. Caspase-3 induces neuronal apoptosis in 20% of the cells, whereas caspase-7 or -8 do not induce apoptosis. In contrast, astrocytes undergo apoptosis within 24 hr when microinjected with caspase-3 but not caspase-6, -7, or -8. These results show cell type-specific vulnerability to caspases in the CNS. The results suggest that activation of caspases in human neurons does not lead to an immediate and rapid process of cell death but provokes a protracted form of apoptosis. Activation of caspases in human neurons may participate in the long-term overproduction of Abeta and other potential toxic fragments resulting from caspase-mediated proteolysis. These results are consistent with the protracted and age-dependent nature of AD.

Alzheimer Disease↗

PubMed2000

Predicting state Medicaid home and community based waiver participants and expenditures, 1992-1997.

PURPOSE: The study examined trends and predictors of state Medicaid home and community based waiver participants and expenditures from 1992 to 1997 to identify factors of interest to policy makers and clinicians. DESIGN AND METHODS: HCFA Form 372 data were collected from state officials for each waiver for each year. Two separate regression analyses were conducted to examine the effects of sociodemographic, economic, political, policy, and health services on state waiver participants and expenditures. RESULTS: State waiver participants were positively associated with those aged 85 and over, personal income, residential care beds, and inpatient users and negatively with home health regulation and nursing home beds. State waiver expenditures were positively associated with democratic governors, personal income, home health reimbursement methods, Medicaid eligibility, home health agencies, and Medicare home health users. IMPLICATIONS: The factors policy makers might consider changing include increasing the number of residential care beds and home health agencies, removing certificate of need for home health care, using Medicare home health reimbursement methods for Medicaid, and raising the Medicaid eligibility criteria. In some states with low nursing home occupancy rates, reducing the supply of nursing home beds may also be considered. All of these approaches would be controversial and should be based on additional cost-effectiveness analysis.

Age Factors↗

PubMed2000

Muscle volume, MRI relaxation times (T2), and body composition after spaceflight.

Postflight changes in muscle volume, calf muscle transverse relaxation time, and total body composition were measured in 4 crewmembers after a 17-day mission and in 14-16 crewmembers in multiple shuttle/Mir missions of 16- to 28-wk duration. During the 17-day mission, all muscle regions except the hamstrings significantly decreased 3-10% compared with baseline. During the shuttle/Mir missions, there were significant decreases in muscle volume (5-17%) in all muscle groups except the neck. These changes, which reached a new steady state by 4 mo of flight or less, were reversed within 30-60 days after landing. Postflight swelling and elevation of calf muscle transverse relaxation time persisted for several weeks after flight, which suggests possible muscle damage. In contrast to the 17-day flight, in which loss in fat, but not lean body mass, was found (25), losses in bone mineral content and lean body mass, but not fat, were seen after the longer shuttle/Mir missions. The percent losses in total body lean body mass and bone mineral content were similar at approximately 3.4-3.5%, whereas the pelvis demonstrated the largest regional bone loss at 13%.

Adult↗

PubMed2000

Louisiana Rural Health Access Program.

Louisiana Rural Health Access is part of a Robert Wood Johnson Foundation project to address primary and preventive medical care for indigent, uninsured people residing in underserved rural parishes. This 15-month grant funds the development of a pilot program to improve access to health care in Acadia, Evangeline, Iberia, Lafayette, St Landry, St Martin, St Mary, and Vermilion parishes. Led by representatives from the Department of Health and Hospitals and the Louisiana State University Health Sciences Center, team committees designed the program's innovative use of telemedicine, loan development, network integration, and community involvement. A benefit of the program will be to measure the outcomes of each objective in order to determine which intervention works best. This information will be invaluable for the design of a five-year rural health care development plan.

Capital Financing↗

PubMed1999

Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease.

Neuronal cell death, neurofibrillary tangles, and amyloid beta peptide (Abeta) deposition depict Alzheimer's disease (AD) pathology, but neuronal loss correlates best with dementia. We have shown that increased production of Abeta is a consequence of neuronal apoptosis, suggesting that apoptosis activates proteases involved in amyloid precursor protein (APP) processing. Here, we investigate key effectors of cell death, caspases, in human neuronal apoptosis and APP processing. We find that caspase-6 is activated and responsible for neuronal apoptosis by serum deprivation. Caspase-6 activity precedes the time of commitment to neuronal apoptosis by 10 h, indicating possible activity without subsequent apoptosis. Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Abeta. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Abeta-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons. A pulse-chase experiment reveals a precursor-product relationship between Capp6.5, intracellular Abeta, and secreted Abeta, indicating a potential alternate amyloidogenic pathway. Caspase-6 proenzyme is present in adult human brain tissue, and the p10 active caspase-6 fragment is detected in AD brain tissue. These results indicate a possible alternate pathway for APP amyloidogenic processing in human neurons and a potential implication for this pathway in the neuronal demise of AD.

Adult↗

PubMed1999

Trace element content of commercial shampoos: impact on trace element levels in hair.

Popular shampoos were screened for their contents in trace elements, using ICP-MS detection in a semi-quantitative mode. Hair samples from volunteers were analyzed before and after hair washing with selected shampoos to demonstrate the effect of the contamination and the impact on occupational medicine. While some shampoos showed high levels of certain elements, the degree of contamination on the hair was found to be negligible. Only one shampoo tested, formulated with selenium sulfide, was found to seriously contaminate the hair.

Hair↗

PubMed1999

Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation.

The amyloid-beta precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer's disease brains and colocalization of its APP cleavage product with A beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.

Acute Disease↗

PubMed1999

T2 vertebral bone marrow changes after space flight.

Bone biopsies indicate that during immobilization bone marrow adipose tissue increases while the functional cellular fraction decreases. One objective of our Spacelab flight experiment was to determine, using in vivo volume-localized magnetic resonance spectroscopy (VLMRS), whether bone marrow composition was altered by space flight. Four crew members of a 17 day Spacelab mission participated in the experiment. The apparent cellular fraction and transverse relaxation time (T2) were determined twice before launch and at several times after flight. Immediately after flight, no significant change in the cellular fraction was found. However, the T2 of the cellular, but not the fat component increased following flight, although to a variable extent, in all crew members with a time course for return to baseline lasting several months. The T2 of seven control subjects showed no significant change. Although these observations may have several explanations, it is speculated that the observed T2 changes might reflect increased marrow osteoblastic activity during recovery from space flight.

Adult↗

PubMed1999

Evaluation of the contamination of marine algae (Seaweed) from the St. Lawrence River and likely to be consumed by humans.

The goal of the study was to assess the contamination of marine algae (seaweeds) growing in the St. Lawrence River estuary and Gulf of St. Lawrence and to evaluate the risks to human health from the consumption of these algae. Algae were collected by hand at low tide. A total of 10 sites on the north and south shores of the St. Lawrence as well as in Baie des Chaleurs were sampled. The most frequently collected species of algae were Fucus vesiculosus, Ascophyllum nodosum, Laminaria longicruris, Palmaria palmata, Ulva lactuca, and Fucus distichus. Alga samples were analyzed for metals (As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, and Zn), iodine, and organochlorines. A risk assessment was performed using risk factors (e.g., RfD of the U.S. EPA, ADI of Health Canada, etc.). In general, concentrations in St. Lawrence algae were not very high. This was especially true for mercury and the organochlorines, concentrations of which were very low or below detection limits. Consequently, health risks associated with these compounds in St. Lawrence algae were very low. Iodine concentration, on the other hand, could be of concern with regard to human health. Regular consumption of algae, especially of Laminaria sp., could result in levels of iodine sufficient to cause thyroid problems. For regular consumers, it would be preferable to choose species with low iodine concentrations, such as U. lactuca and P. palmata, in order to prevent potential problems. Furthermore, it would also be important to assess whether preparation for consumption or cooking affects the iodine content of algae. Algae consumption may also have beneficial health effects. Scientific literature has shown that it is a good source of fiber and vitamins, especially vitamin B12.

Environmental Exposure↗

PubMed1999

Hepatic insulin resistance and defects in substrate utilization in cystic fibrosis.

Patients with cystic fibrosis (CF)-related diabetes (CFRD) have clinical features of both type 1 and type 2 diabetes. Past studies have documented peripheral insulin resistance in CF, and some studies have noted high hepatic glucose production (HGP) in CF patients. We hypothesized that patients with CF, similar to patients with type 2 diabetes, have hepatic insulin resistance. Cystic fibrosis is a catabolic condition, yet the etiology of catabolism is poorly understood. De novo lipogenesis is energy wasteful and precludes ketogenesis. Patients with CFRD rarely develop ketogenesis, despite insulin deficiency. We speculated that CF patients have de novo lipogenesis, and therefore evaluated substrate utilization in CF. Using [6,6-2H2]glucose and a three-step hyperinsulinemic-euglycemic clamp, we measured HGP in 29 adult CF subjects and 18 control volunteers. Using indirect calorimetry, we measured lipid oxidation, oxidative glucose metabolism, and resting energy expenditure at baseline and at high levels of insulin. All subjects were characterized by oral glucose tolerance testing (OGTT) and National Diabetes Data Group criteria. The CF subjects had increased HGP when compared with control subjects (CF, 3.5+/-0.6; control, 2.5+/-0.5 mg x kg(-1) x h(-1); P = 0.002). Baseline HGP correlated with glucose levels obtained 2 h after a glucose load given for OGTT (r = 0.69, P = 0.001). Suppression of HGP by insulin was significantly less in all CF subgroups than in control subjects at peripheral insulin levels of 16 and 29 microU/ml. At peripheral insulin levels of 100 microU/ml and 198 microU/ml, there was no difference in insulin suppression of HGP between CF and control subjects. At baseline, there was no significant difference between control and CF subjects for glucose or lipid oxidation. During maximum insulin stimulation, there was a greater tendency for nonoxidative glucose metabolism in all CF subjects. The CF subjects with abnormal glucose tolerance also had de novo lipogenesis. Our results indicate that CF patients have several defects in substrate utilization, including de novo lipogenesis. Furthermore, these results suggest that high hepatic glucose production and hepatic insulin resistance contribute to the high incidence of abnormal glucose tolerance in CF.

Adolescent↗

PubMed1999

Argyremia in septal cauterization with silver nitrate.

OBJECTIVE: The purpose of this study was to demonstrate silver absorption in blood and hair specimens after septal cauterization with silver nitrate and to discuss the potential toxicity of silver. METHOD: A prospective study of 11 volunteers without any known occupational exposure to silver products or past history of septal cauterization with silver nitrate was undertaken. Subjects were recruited in an academic tertiary care centre from October 1996 to September 1997. The study population consisted of five patients with anterior epistaxis and six healthy volunteers without any bleeding problem. Cauterization was done with one or two silver nitrate applicators directly on the bleeding vessel or Kiesselbach's area. Blood was sampled before cauterization and at specified times after application, while hair strands were sampled only 3 months later. Measurements of silver concentration in whole blood and in hair segments were obtained by inductively coupled plasma mass spectrometry. RESULTS: Silver concentrations in whole blood increased significantly after cauterization (p = .02). The measured peak level seemed to correlate with the number of applicators used. No significant increase in silver concentration was observed in hair samples. CONCLUSIONS: Effective silver absorption occurs with only one or two silver nitrate applicators. Hair has not been as reliable as whole blood to document an acute and fragmentary exposure. The indiscriminate use of silver nitrate is a potential source of silver intoxication.

Absorption↗