Biomedical subjects

M Wolfe

Publications and source records attributed to M Wolfe.

At least 19 recordsLinked to original sources

PubMed2005

Mixed modelling to characterize genotype-phenotype associations.

We propose using mixed effects models to characterize the association between multiple gene polymorphisms, environmental factors and measures of disease progression. Characterizing high-order gene-gene and gene-environment interactions presents an analytic challenge due to the large number of candidate genes and the complex, undescribed interactions among them. Several approaches have been proposed recently to reduce the number of candidate genes and post hoc approaches to identify gene-gene interactions are described. However, these approaches may be inadequate for identifying high-order interactions in the absence of main effects and generally do not permit us to control for potential confounders. We describe how mixed effects models and related testing procedures overcome these limitations and apply this approach to data from a cohort of subjects at risk for cardiovascular disease. Four (4) genetic polymorphisms in three genes of the same gene family are considered. The proposed modelling approach allows us first to test whether there is a significant genetic contribution to the variability observed in our disease outcome. This contribution may be through main effects of multi-locus genotypes or through an interaction between genotype and environmental factors. This approach also enables us to identify specific multi-locus genotypes that interact with environmental factors in predicting the outcome. Mixed effects models provide a flexible statistical framework for controlling for potential confounders and identifying interactions among multiple genes and environmental factors that explain the variability in measures of disease progression.

Adult↗

PubMed2000

Treatment outcome among child psychiatric outpatients in a community mental health center.

The study evaluated the effectiveness of mental health center treatments for children aged 5-12 years. The Child Behavior Checklist (CBCL) was administered before and after treatment to the parents of the treatment group (N = 71). The results were analyzed and compared to the results of the pretest and posttest CBCL administered to the parents of a matched group of comparison subjects (N = 33). The results showed that the treatment subjects significantly improved on both the externalizing and internalizing scales of the CBCL. The controls showed no significant change between pretest and posttest scores. As a result, it appears that clinic treatments can help clients with measurable problems decrease problematic behaviors. More data is needed to determine whether clinic treatments such as the ones described in this study can substantially help the most seriously disturbed school-age children.

Ambulatory Care↗

PubMed2000

Pulmonary macrophage counts in deceased infants: baseline data for further study of infant mortality.

Infant lung samples were obtained prospectively at autopsy by medical examiner pathologists in five areas of the United States and regardless of the cause of death. Four sections were examined for each case and were taken from the anterior and posterior aspects of the right and left upper lung lobes. Lung sections were stained with HAM-56 immunostain, which is specific for macrophages. Sixty-one cases were evaluated for the study. Three pathologists independently counted the number of macrophages per 40x field (10x ocular) in 10 contiguous fields near the center of each lung section examined. There was good agreement between pathologists on the average number of macrophages observed in each case. The mean macrophage count for all fields counted was 16.5 per 40x field (range 0-136), and the mean for individual cases was 16 (range 6.6-39.4). There was no observed difference between right, left, anterior, and posterior lung sections. There was a tendency for cases certified as sudden infant death syndrome to show lower macrophage counts than those with other causes of death, but the difference was of only marginal statistical significance. Seven of 10 cases in which infants died after a survival period in the hospital had a mean macrophage count greater than the overall mean of 16 per 40x field. These data suggest that mean pulmonary macrophage counts > 16 per 40x field may be a marker for causes of death other than sudden infant death syndrome or that there was a survival interval. These data may be useful as baseline data for further studies of infant mortality possibly involving pathologic changes in the lungs.

Autopsy↗

PubMed1999

Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch.

Presenilin-1 (PS1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both Notch and beta-amyloid precursor protein (APP) within their trans- membrane domains. The activity that cleaves APP (called gamma-secretase) has properties of an aspartyl protease, and mutation of either of the two aspartate residues located in adjacent transmembrane domains of PS1 inhibits gamma-secretase processing of APP. We show here that these aspartates are required for Notch processing, since mutation of these residues prevents PS1 from inducing the gamma-secretase-like proteolysis of a Notch1 derivative. Thus PS1 might function in Notch cleavage as an aspartyl protease or di-aspartyl protease cofactor. However, the ER localization of PS1 is inconsistent with that hypothesis, since Notch cleavage occurs near the cell surface. Using pulse-chase and biotinylation assays, we provide evidence that PS1 binds Notch in the ER/Golgi and is then co-transported to the plasma membrane as a complex. PS1 aspartate mutants were indistinguishable from wild-type PS1 in their ability to bind Notch or traffic with it to the cell surface, and did not alter the secretion of Notch. Thus, PS1 appears to function specifically in Notch proteolysis near the plasma membrane as an aspartyl protease or cofactor.

3T3 Cells↗

PubMed1999

Changes in substance P and calcitonin gene-related peptide binding in the dorsal horn of rat spinal cord following pronase-induced deafferentation.

Quantitative receptor autoradiography was used to evaluate potential alterations in substance P (SP) and calcitonin gene-related peptide (CGRP) binding in the L4 spinal segment of rats following unilateral poisoning of the sciatic nerve with pronase. Ten days after pronase-induced deafferentation there was a significant increase in SP and CGRP binding in the superficial (I-II) and deeper (II-IV) laminae of the dorsal horn ipsilaterally. Densitometric measurements revealed a 50% return towards normal values for SP binding by 90 days postpronase injection in all laminae examined, while the density of CGRP binding showed a partial return towards normal values for laminae III-IV only. These differential responses may be indicative of the mechanisms underlying pronase-induced peripheral neuropathy.

Animals↗

PubMed1999

Cystic fibrosis carrier screening practices in an ethnically diverse region: experience of the Genetic Network of the Empire State, Puerto Rico, and the U.S. Virgin Islands.

We surveyed clinical genetics centers to assess current cystic fibrosis (CF) screening practices with regard to clinical and laboratory aspects. The survey was developed by the CF committee of the Genetics Network of the Empire State, Puerto Rico, and the U.S. Virgin Islands (GENES) to gauge changes in trends following the April, 1997, NIH Consensus Statement recommending the offering of CF carrier screening to all pregnant patients. Thirty-five of 45 Centers (78%) returned the survey, which was mailed in June, 1998. Sixteen centers currently offer population-based screening, whereas 19 centers do not. Reasons cited for not offering testing included the low risk for CF in ethnic groups served, lack of data about test sensitivity in the populations served, and the absence of CF screening policies in the current standards of care. Approximately half (56%) of genetics centers that are offering testing altered their screening policy following the NIH Consensus statement, either by offering screening to patients of higher-risk ethnicities or by offering it to all patients. Less than half of the Centers that offer routine carrier screening offer screening to all patients regardless of ethnicity. This report is an initial step in documenting and understanding the current service practices regarding CF carrier testing in a diverse region. Our conclusions: (1) Screening practices vary widely among genetic centers in the region. (2) The decision to offer routine CF carrier screening is largely based on ethnicity of the patient population served. (3) Methods used to screen pregnant women and their partners in this part of the country reflect the diversity of models employed throughout the United States. (4) CF screening practices in the GENES region have changed significantly following the April, 1997, NIH consensus statement.

Cystic Fibrosis↗

PubMed1998

Ticlopidine-induced neutropenia mimicking sepsis early after intracoronary stent placement.

We report a case of ticlopidine-induced profound neutropenia early in the course of therapy, which was manifest as a febrile systemic illness mimicking sepsis. This clinical presentation was potentially indicative of a contaminated intracoronary stent. The patient's signs and symptoms of illness promptly resolved with removal of ticlopidine, and no infection was documented. Review of indications for ticlopidine use, potential adverse effects, and monitoring recommendations are discussed.

Coronary Angiography↗

PubMed1998

Female exposure to high G: echocardiographic evaluation for chronic changes in cardiac function.

BACKGROUND: Significant changes in cardiac preload and afterload are generated by a number of factors present during the operation of high performance aircraft. These include high levels of +Gz, positive pressure breathing and anti-G straining maneuvers. Centrifuge subjects are exposed to these same factors in doses that are comparable to their operational counterparts. The question of whether such exposures produce long-term adverse effects on the heart has not been definitively answered. METHODS: In an effort to further address this issue, a longitudinal study was conducted on 18 newly recruited centrifuge panel members (7 males and 11 females) who did not have a previous history of significant high +Gz exposure. In order to document the cumulative long-term effects of high +Gz exposure and G protection measures, baseline echocardiographic studies were conducted prior to any +Gz exposure on the Dynamic Environment Simulator (DES) centrifuge. The echocardiograms were repeated after each panel member completed eight sessions of indoctrination. These follow-up echos were performed after all 18 subjects had been exposed to over 45 min (cumulative) of sustained acceleration > or = 2 G. Each subject served as his/her own control. All studies were evaluated independently by a cardiologist who was blinded to the order in which the studies were performed. Although complete echocardiographic studies were performed, only the parameters identified as significant in prior studies were evaluated. RESULTS: No significant differences were found between the initial and follow-up echo parameters. No significant differences were found between male and female responses. CONCLUSIONS: We found no significant differences in cardiac function after 45 min (cumulative) of exposure to G > or = 2 in men or women. These subjects will be monitored during a longitudinal study throughout their centrifuge subject career.

Aerospace Medicine↗

PubMed1997

Synthesis, metabolism and levels of the neuroactive steroid, 3alpha-hydroxy-4-pregnen-20-one (3alphaHP), in rat pituitaries.

The neuroactive steroid, 3a-hydroxy-4-pregnen-20-one (3alphaHP), is a metabolite of progesterone and a precursor of 3alpha-hydroxy-5alpha-pregnan-20-one (5alphaP3alpha; allopregnanolone). In addition to analgesic and anxiolytic effects by interaction with the GABA(A) receptor complex, 3alphaHP regulates pituitary FSH secretion by rapid non-genomic interaction with the Ca2+-driven cell signaling mechanisms. Since gonadectomy and adrenalectomy do not result in elimination of 3alphaHP, and since there is the possibility of paracrine and/or autocrine regulation of FSH release, the capacity of pituitary cells to regulate levels (by synthesis, metabolism, and storage) of 3alphaHP was examined. Anterior pituitaries from random cycling female rats were incubated, either as fragments or as cultured cells, for 1, 4 or 8 h with 3H- or 14C-labeled progesterone. The steroid metabolites were identified by thin-layer chromatography, autoradiography, high pressure liquid chromatography (HPLC), derivatization and GC/MS. Pituitary cells actively converted progesterone to 3alphaHP along with 5alphaP3alpha, 5alpha-pregnane-3,20-dione, 20alpha-hydroxy-5alpha-pregnan-3-one, 3beta-hydroxy-5alpha-pregnan-20-one, 5alpha-pregnane-3alpha(beta), 20alpha-diols, 20alpha-hydroxy-4-pregnen-3-one, and 4-pregnene-3alpha(beta), 20alpha-diols. The results indicate the presence of the following steroidogenic enzymes in anterior pituitary cells: 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO), 20alpha-HSO, 3beta-HSO, and 5alpha-reductase. The activities of 5alpha-reductase and 3alpha-HSO were approximately equal and greatly exceeded those of the other enzymes. After 8 h of incubation with 100 ng progesterone per pituitary, about 20% of the progesterone was metabolized and 3.18 ng of 3alphaHP had been formed. The accumulation of 3alphaHP increased approximately linearly with the time of incubation. Metabolism studies using [1,2,6,7-(3)H]3alphaHP showed that pituitary cells convert about 29% and 8% of the 3alphaHP to progesterone and 5alphaP3alpha, respectively, in 2 h. Specific radioimmunoassays determined 11.6 and 7.5 ng of 3alphaHP per pituitary, respectively, in 25- and 40-day-old non-cycling female rats; these concentrations of 3alphaHP were about 2-3-fold greater than those of progesterone in the same pituitaries. In older (80-100 days old) cycling rats, the levels of 3alphaHP were about 9.4 and 18.6 ng/pituitary at 13.00 h and 22.00 h, respectively, on the day of proestrus, while the concomitant circulating levels were 13.7 and 5.4 ng/ml. The results indicate a marked capacity of rat pituitary cells to synthesize the neuroactive and FSH regulating steroid, 3alphaHP, from progesterone, and in turn to metabolize 3alphaHP to the neurosteroid, allopregnanolone, and to progesterone. The studies suggest cyclic biosynthetic and metabolic pathways for 3alphaHP and other steroids in the pituitary. They also indicate that the regulation of FSH secretion by 3alphaHP may be (in part, or in whole) via paracrine or autocrine mechanisms.

20-alpha-Dihydroprogesterone↗

PubMed1997

Acute, nongenomic actions of the neuroactive gonadal steroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on FSH release in perifused rat anterior pituitary cells.

We have previously shown that the gonadal and neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), can selectively suppress gonadotrophin-releasing hormone (GnRH) induced follicle-stimulating hormone (FSH) release from static cultures of anterior pituitary cells during a 4-h incubation period. The actions appeared to be at the level of the gonadotroph membrane and the cell signaling pathway involving Ca2+ and protein kinase C (PKC). In order to investigate further if the effects of 3 alpha HP on FSH release are generated by nongenomic mechanisms, we monitored the short-term effects of 3 alpha HP using dispersed anterior pituitary cells in a low dead-volume perifusion system with short (< or = 5 min) exposures to the steroid. Pulses of GnRH (10(-8) or 10(-7) M) lasting 2-5 min resulted in marked peaks of FSH release, and the variation in FSH amounts released from the cells in a particular column were minimal if the interval between successive GnRH pulses was at least 3-4 h. A 5-min pulse of 3 alpha HP (10(-9) M) administered simultaneously with the GnRH pulse suppressed GnRH-induced FSH release. On the other hand, similar treatment with the stereoisomer 3 beta-hydroxy-4-pregnen-20-one (3 beta HP), had no effect, but progesterone and estradiol pulses augmented the GnRH-induced FSH release. Pretreatment of cells with a 5-min pulse of 3 alpha HP, at 120, 60, or 30 min prior to a GnRH pulse suppressed the GnRH-induced FSH release. The suppression of GnRH-induced FSH release by 3 alpha HP was only partial if the start of the 3 alpha HP pulse occurred 0.5 or 1.0 min after the start of the GnRH pulse, and no suppression occurred if the start of the 3 alpha HP pulse was delayed by 2-5 min. The FSH release elicited by 5-min pulses of the Ca2+ ionophore A23187, the Ca2+ agonist BAY K8644, the PKC activator phorbol 12-myristate 13-acetate (PMA), or phospholipase C (PLC) was suppressed by simultaneous pulses of 3 alpha HP. The suppression of FSH release by 3 alpha HP appeared to be stereospecific, since no suppression was observed with 5 alpha-pregnane-3,20-dione (5 alpha P) or 3 alpha-hydroxy-5 alpha-pregnan-20-one (5 alpha P3 alpha). In separate experiments, cells were treated with pulses of BSA conjugates of 3 alpha HP, 3 beta HP, or progesterone; the 3 alpha HP-BSA, but not the 3 beta HP-BSA or the progesterone-BSA, suppressed the GnRH-induced release of FSH. The results of this study provide the first evidence that 3 alpha HP exerts immediate (nongenomic) and direct effects on GnRH-induced FSH release by interacting at the level of the pituitary gonadotroph membrane and the phosphoinositol cell signaling cascade involving Ca2+.

20-alpha-Dihydroprogesterone↗

PubMed1996

The interaction of a type A retroviral particle and class II human leukocyte antigen susceptibility genes in the pathogenesis of Graves' disease.

We have previously reported that over 85% of patients with Graves' disease have detectable serum antibodies against a human intracisternal type A retroviral particle (HIAP), which are not present in age- and gender-matched controls, suggesting a role for HIAP in triggering the autoimmune process leading to Graves' disease. To investigate the interaction of this viral particle with genetic factors, 35 members of 3 kindreds, selected because of a high family prevalence of Graves' disease (a total of 11 members affected), were examined for clinical signs of thyroid dysfunction, goiter, and opthalmopathy. Thyroid function tests and autoimmune serological profiles were also obtained. In addition, subjects were tested for the presence of antibodies against HIAP by means of immunoblot analysis of their sera, and their human leukocyte antigen (HLA) class II alleles were determined by DNA methodology. Molecular genetic analyses enabled the detection of postulated HLA susceptibility haplotypes in each family. These families had 8, 4, and 5 members, respectively, with such apparent susceptibility genes and 11, 5, and 9 members, respectively, with immunological evidence of retroviral exposure. In the presence of both factors (codetected in a total of 15 members of the 3 kindreds), the incidence of Graves' disease was 100%, 67%, and 80%, respectively. One additional member of family B and 3 in family C with both viral and genetic susceptibility factors were found to have serological abnormalities and/or goiter and ocular signs consistent with evolving or preclinical Graves' disease. In families A and C, tight linkage between HLA haplotypes and Graves' disease was demonstrated in a manner consistent with recessive inheritance. The association between the occurrence of both anti-HIAP-I antibody positivity and HLA susceptibility and the presence of Graves' disease was highly significant (P < 0.001). The pathogenesis of Graves' disease in these families appears to be attributable to the interaction between the immune response to an intracisternal type A retroviral particle and immunogenetic susceptibility, leading to the autoimmune processes that underlie Graves' disease, with subsequent development of the characteristic features of the illness. Data from these families suggest that both of these factors are necessary for final disease expression. These results imply that serological evidence of retroviral exposure together with genetic HLA susceptibility are the two major predisposing factors underlying the pathogenesis of Graves' disease. Further studies will establish whether prospective identification of persons at risk for Graves' disease is possible by this means.

Adult↗

PubMed1996

Hematopoietic growth factors: Part I.

The recent production of recombinant human growth factors has expanded the neonatal clinician's armamentarium for treating sepsis and anemia of prematurity (AOP). Agents that may prove useful in the premature neonate include recombinant human erythropoietin (rh-EPO), granulocyte colony-stimulating factor (rhG-CSF), and CSF). Within the neonatal population, research utilizing these agents is still relatively new. Appropriate clinical trials are still needed to elucidate the optimal dosing regimen for both rhG-CSF and rh-EPO, as are studies to address the issue of long-term safety. Use of rhG-CSF in sepsis and of rh-EPO for AOP is still considered experimental, but in instances where conventional treatments are not proving beneficial, these agents may provide a therapeutic alternative. Their potential for improving care of the premature neonate must also be assessed.

Anemia, Neonatal↗

PubMed1996

Hematopoietic growth factors: Part II.

Anemia of prematurity (AOP) affects almost all infants that are born prematurely. Excessive phlebotomy in the NICU setting has exacerbated this condition. Until recently, erythrocyte transfusion has been the only therapy for AOP. Recombinant human erythropoietin (rh-EPO) has been shown to be effective in reducing erythrocyte transfusions in premature infants with AOP. Various studies have utilized rh-EPO as a treatment modality or as prophylaxis for AOP. The results of these studies have shown that rb-EPO is a complementary strategy along with restriction of phlebotomy and less liberal transfusion policies, to decreasing the number of transfusions that an infant may need. Trials are necessary to document the cost-effectiveness of rh-EPO as well as its long term effects on the premature infant.

Anemia, Neonatal↗

PubMed1995

Retrospectively measured individual differences in childhood sex-typed behavior among gay men: correspondence between self- and maternal reports.

Male sexual orientation is strongly associated with childhood sex-typed behavior, but there are also marked within-orientation differences. Gay men show increased variance compared to heterosexual men on retrospective measures of childhood sex-typed behavior. Individual differences among gay men for their degree of sex-typed behavior may have important implications. However, there has been little attention given to the reliability or validity of retrospective measures of such differences that are most common. Gay men and their mothers completed questionnaires assessing the men's sex-typicality during childhood. Results of structural modeling analyses found that mothers' and sons' reports were significantly associated, both regarding the general level of sex-typed behavior and the specific behaviors, supporting the validity of retrospectively measured individual differences for those characteristics.

Adolescent↗

PubMed1995

Memory and vigilance training to improve social perception in schizophrenia.

Previous research has suggested that social cue recognition in schizophrenia may be significantly associated with visual vigilance and verbal memory. Therefore, we predicted that subjects who participated in a cognitive rehabilitation program that incorporated vigilance and memory training strategies would show significantly better social cue recognition than subjects participating in vigilance training alone. Forty subjects with a DSM-III-R diagnosis of schizophrenia or schizoaffective disorder were randomly assigned to either a vigilance-alone or a vigilance-plus-memory training condition. Results showed that subjects in the vigilance-plus-memory condition were able to identify social cues in the videotaped training materials significantly better than subjects in the vigilance-alone condition. This difference was evident in an independent measure of social cue recognition and was present at a 48 h follow-up. Implications for future development of cognitive rehabilitation for schizophrenia were discussed.

Attention↗

PubMed1995

Deafferentation-induced expression of GAP-43, NCAM, and NILE in the adult rat dorsal horn following pronase injection of the sciatic nerve.

The expression of growth-associated protein 43 (GAP-43), neural cell adhesion molecule (NCAM), and nerve-growth-factor-inducible large external glycoprotein (NILE) in the adult rat dorsal horn was examined at several survival times after unilateral pronase injection of the sciatic nerve. Pronase injection produces a permanent major loss of sciatic primary afferents in the dorsal horn, and there is a later sprouting of saphenous afferents into the sciatic territory. Small-diameter myelinated and nonmyelinated saphenous afferents sprout within the superficial dorsal horn, and larger, myelinated afferents sprout within the deep dorsal horn. In the present study, GAP-43 and NCAM immunoreactivity increased in the superficial dorsal horn by 10 days after injection. By 20 days, the increase spread into the deep dorsal horn; NCAM returned to normal after 1-2 months, but GAP-43 persisted up to 4 months. NILE immunoreactivity appeared in laminae I and II by 10 days and increased up to 30 days; by 2 months no NILE remained. NILE never spread into the deeper dorsal horn, regardless of survival time. These data suggest a correlation in the expression of both NCAM and NILE with the sprouting of fine-diameter sprouting afferents in laminae I and II, and of NCAM expression with the sprouting of larger-diameter afferents in the deep dorsal horn.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

PubMed1993

Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study.

PURPOSE: Previous reports of chemotherapy in patients with adrenal cancer have described responses to cisplatin (CDDP). Because of these reports of good results, a phase II trial that used CDDP with and without mitotane (o,p'DDD) was initiated. PATIENTS AND METHODS: Patients with metastatic or residual adrenocortical carcinoma with objectively measurable disease or biochemical abnormalities were divided into good-risk and poor-risk categories. The latter received CDDP 100 mg/m2 intravenously, and the former received 75 mg/m2. o,p'DDD was administered at a 1,000-mg dose orally four times a day along with cortisone acetate and Florinef (fludrocortisone acetate; Bristol-Myers Squibb Co, Princeton, NJ). RESULTS: Of a total of 42 patients entered onto the study, 37 were eligible. Twenty-nine patients received good-risk and eight received poor-risk doses of CDDP. Functioning tumors were present in 45% of patients. Objective responses were noted in 30% (11 of 37) patients (95% confidence interval, 16% to 50%). Response duration was 7.9 months, and the median time to response was 76 days. The median survival of the 37 eligible patients was 11.8 months, and a significant survival advantage was found for patients who underwent prior surgical removal of their primary tumor or bulky disease, who had a performance status of 0 or 1, or who had synchronous metastatic disease. Toxicity of the CDDP and o,p'DDD combination was moderate to severe, and the most common side effects were gastrointestinal, renal, and neurologic. CONCLUSION: The regimen of CDDP and o,p'DDD has activity in patients with adrenocortical carcinoma; however, the toxicity of this treatment was moderate to severe.

Adolescent↗

PubMed1992

A world apart.

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Diarrhea, Infantile↗