PubMed Health⌕ Search

Biomedical subjects

E R Brown

Publications and source records attributed to E R Brown.

At least 19 recordsLinked to original sources
PubMed1996

Hydroxyurea therapy in children severely affected with sickle cell disease.

HYPOTHESIS: The major clinical manifestations of sickle cell disease (SCD) are hemolytic anemia, predisposition to infection, and recurrent vaso-occlusive episodes resulting in pain, organ dysfunction, or both. There has been no satisfactory treatment for children with recurrent severe painful episodes caused by SCD. Hydroxyurea is an antimetabolite drug shown in adults with SCD to increase fetal hemoglobin levels and reduce the symptoms of SCD. We hypothesized that hydroxyurea therapy in children with severe (defined as > or = 3 vaso-occlusive events per year) SCD could improve hematologic parameters and reduce vaso-occlusive events. OBJECTIVE: To assess the safety and efficacy of hydroxyurea for the treatment of severe SCD in children. STUDY DESIGN: After obtaining informed consent, we initiated hydroxyurea therapy at a dosage of 10 to 20 mg/kg per day in 15 patients with severe SCD (hemoglobin SS, hemoglobin SS-alpha thalassemia, or hemoglobin S-beta0-thalassemia). Doses were escalated as tolerated. Patients were monitored with bimonthly physical examinations and monthly laboratory measures. To assess the impact of hydroxyurea on clinical symptoms, we recorded the number of inpatient days for each patient during the period of treatment and compared it with the number of inpatient days for the 12- to 24-month period before institution of hydroxyurea therapy, using the subject as his or her own control subject. RESULTS: Thirteen patients received hydroxyurea for a median of 24 months (range, 6 to 39 months). The mean dose of hydroxyurea was 21.4 +/- 5.2 mg/kg. Treatment with hydroxyurea induced statistically significant increases in the total hemoglobin concentration, mean corpuscular volume, and percentage of hemoglobin F, and a decrease in the serum concentration of bilirubin. Toxic effects included three episodes of a reversible myelotoxic reaction, two of which required transfusion of packed erythrocytes. For the entire group, hospitalization decreased from a prehydroxyurea median of 3.9 +/- 2.0 days per month to 1.1 +/- 2.1 days per month of therapy (p = 0.09). For those subjects (n = 10) completing at least 1 year of treatment, the decrease in hospitalization from 4.1 +/- 2.2 to 1.0 +/- 1.7 days per month was significant (p = 0.03). CONCLUSIONS: In this pilot trial, hydroxyurea treatment of severe SCD in children was associated with improved hematologic parameters, acceptable toxic effects, and a trend to reduced hospitalization. Hydroxyurea appears to be a safe and potentially effective agent for the treatment of severe SCD in children. A prospective, controlled trial to investigate the efficacy of hydroxyurea in children is therefore warranted.

Adolescent↗
PubMed1994

Chronic 1,25-dihydroxyvitamin D3-mediated induction of nerve growth factor mRNA and protein in L929 fibroblasts and in adult rat brain.

We have proposed that elevating levels of nerve growth factor (NGF) in the CNS is a rational strategy for treating certain neurodegenerative disorders. The present studies were conducted to determine: (1) if pharmacologically induced levels of NGF could be sustained for an extended time, and (2) if correlations exist between increases in NGF mRNA and NGF protein in L929 cells and in vivo. Short-term treatment of L929 cells with 1,25-dihydroxyvitamin D3 resulted in a two-fold increase in both NGF mRNA and NGF protein. These increases were sustained for up to 48 h with continuous exposure to 1,25-dihydroxyvitamin D3. In rats, 1,25-dihydroxyvitamin D3 (2.5 nmol; i.c.v.) induced NGF mRNA transiently, with peak two-fold increases observed 4 h post-injection. In contrast to L929 cells, 1,25-dihydroxyvitamin D3 did not elicit an increase in NGF protein after a single administration in vivo. However, consistent with long-term exposure in L929 cells, chronic 6 day infusion of 1,25-dihydroxyvitamin D3 resulted in induction of both NGF mRNA and NGF protein in the brain. These results indicate that 1,25-dihydroxyvitamin D3-mediated NGF induction in cultured L929 cells may predict of NGF induction in vivo, suggesting that L929 cells may have utility in studying underlying mechanisms of NGF induction by 1,25-dihydroxyvitamin D3. On the basis of NGF's ability to increase cholinergic function in animal models of cholinergic degeneration, these results are supportive of a role for NGF inducers as potential drugs for neurodegenerative disorders.

Animals↗
PubMed1994

Differential effects of eicosapentaenoic acid and docosahexaenoic acid on human skin fibroblasts.

To better understand the mode of action of omega 3 fatty acids in cell membranes, human foreskin fibroblasts were grown in serum-free medium supplemented with 50 microM oleic acid linoleic acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), and the effects on membrane composition, fluorescence polarization and enzyme activities were followed. The cells were enriched with EPA and DHA up to 7 and 13% of total lipids, respectively, of which > 95% was associated with phospholipids. In addition, the concentration of 22:5n-3 increased with both EPA and DHA to 7.5, and 2.1% of the total fatty acids, respectively. When compared to controls (oleic acid), cells treated with DHA showed a decrease in cholesterol, phospholipids, arachidonic acid (AA) and free cholesterol/phospholipid ratio (P < 0.05). In the presence of EPA, only decreases in AA and cholesterol were significant (P < 0.05). Membrane fluidity, assessed by fluorescence anisotropy, was increased 16% in cells enriched with DHA (P < 0.05), but showed no change with EPA or linoleic acid. There was an increase in membrane-associated 5'-nucleotidase (+27%) and adenylate cyclase (+19%) activities (P < 0.05), in DHA-enriched, but not in EPA-enriched cells, when compared with oleate controls. The studies show that incorporation of DHA, but not EPA, into cell membranes of fibroblasts alters membrane biophysical characteristics and function. We suggest that these two major n-3 fatty acids of fish oils have differential effects on cell membranes, and this may be related to the known differences in their physiological effects.

5'-Nucleotidase↗
PubMed1994

The incidence of prenatal syphilis at the Boston City Hospital: a comparison across four decades.

OBJECTIVE: To examine the incidence and epidemiologic correlates of congenital syphilis at an inner-city Boston hospital, and draw comparisons with the situation at the same hospital 40 years ago. DESIGN: Chart review and comparison with data collected in 1951. SETTING: Maternity and pediatric services at Boston City Hospital. METHODS: A study conducted in 1951 on the maternity service of Boston City Hospital in which demographic data were collected on all women admitted in labor over a 5-month period was replicated. Serologic testing for syphilis was carried out on these women, and the demographic and medical correlates of positive maternal syphilis serology were examined. This study was repeated exactly 40 years later, using the cord blood screening for syphilis done routinely at delivery and a review of prenatal records. RESULTS: From a group made up largely of married white women in 1951, the study population shifted in 1991 to a group made up mostly of minority women, with 75% unmarried. In 1951, 24 patients were diagnosed with syphilis either before or during the pregnancy, giving a prevalence rate of 2.4%. In 1991, 25 of 647 women were diagnosed with syphilis, for a prevalence rate of 3.9%. The women with positive cord blood serologies had a higher rate of other sexually transmitted diseases and substance abuse. No symptomatic cases of congenital syphilis were seen in 1951 or in 1991, although at least 11 of the 26 infants born to mothers with positive serologies in 1991 received intravenous penicillin therapy. CONCLUSIONS: The continued prevalence of diagnosed syphilis in women at delivery reflects an inner-city epidemic of congenital syphilis that is tied to substance abuse, human immunodeficiency virus, and changing social patterns, as well to older problems of serologic screening, prenatal care, treatment failures, and maternal reinfection. It is essential that screening programs be maintained and improved in this high-risk population, and that infants born to mothers with positive serologies receive full and adequate treatment if there is any doubt at all about their infection status.

Adult↗
PubMed1994

Systemic dexamethasone administration increases septal Trk autophosphorylation in adult rats via an induction of nerve growth factor.

Nerve growth factor (NGF) maintains cholinergic neurons in various animals models of neurodegeneration and is thus a potential treatment for certain neurodegenerative disorders such as Alzheimer's disease. Because NGF does not cross the blood-brain barrier, we have proposed elevating endogenous levels of NGF in the central nervous system with small molecules that induce NGF expression, as an alternative strategy. The present studies were conducted to determine whether pharmacologically elevated levels of NGF are sufficient to cause subsequent stimulation of its high affinity receptor, as measured by increased levels of Trk phosphorylation. Dexamethasone (0.5-20 mg/kg, intraperitoneally) caused a time- and dose-dependent increase in NGF mRNA and NGF protein in the hippocampus and septum of adult male Sprague-Dawley rats. Exogenously administered NGF (1 microgram, intracerebroventricularly) led to a rapid (30 min) and transient increase in Trk phosphorylation in the septum, which has high levels of NGF-specific TrkA. Similarly, dexamethasone led to an increase in Trk phosphorylation only within the septum. Dexamethasone-mediated Trk phosphorylation was dose and time dependent, with peak increases being observed 12 hr after injection, concurrently with peak increases in NGF protein. These data demonstrate an increase in activation of the high affinity NGF receptor with a compound that elevates levels of NGF in the central nervous system, and they support the strategy of discovering a pharmacological agent that induces NGF as a method for treating neurodegenerative disorders.

Animals↗
PubMed1993

Ultrastructure and permeability of the Schwann cell layer surrounding the giant axon of the squid.

The ultrastructure of the Schwann cell layer surrounding the giant axon of the squid Alloteuthis subulata is described, and the permeability of extracellular compartments assessed by exposure to electron-dense tracers. Morphometric analysis is used to deduce the number, size and shape of the Schwann cells, and the routes for ion flux across the Schwann cell layer. Axons (mean diameter 233 microns) were surrounded by a 1-2 microns thick layer of Schwann cells which were approximately 1 micron thick, approximately 70 microns long and approximately 23 microns wide. There were around 62,000 Schwann cells per cm2 axon surface. The outer (abaxonal) surface of the Schwann cells was invaginated, with evidence for a covering of fine Schwann cells processes; the inner (adaxonal) surface of the Schwann cells was less folded. The percentage area occupied by mesaxonal cleft openings to the axon and to the basal lamina was 0.02% and 1.09% respectively. A system of tubules, the glial tubular system, occupied 3.9% of the Schwann cell volume, and opened to both axonal and basal lamina surfaces, with more elaborate lattice-like clusters towards the basal side of the cell. Tubule openings accounted for 0.26% of the surface area facing the axon and 0.37% of the area facing the basal lamina (where there was greater clustering of openings). The electron dense tracers horseradish peroxidase, ionic lanthanum and tannic acid filled mesaxon clefts, glial tubular system and periaxonal space. If ion flux occurred via the mesaxonal clefts, a theoretical series resistance (Rsth) of > 20 omega cm2, would be predicted, whereas if it occurred via the tubular system, the figure would be < 2 omega cm2, closer to physiological estimates. The results presented show that the glial tubular system is likely to be the major route for ion flux into and across the Schwann cell layer, and for clearance of K+ from the periaxonal space during periods of axonal stimulation. The implications for K+ homeostasis in the axonal microenvironment are discussed.

Animals↗
PubMed1993

Material-specific memory in the intracarotid amobarbital procedure.

We examined material-specific memory in 45 left hemisphere language dominant patients with temporal complex partial seizures (24 right, 21 left) during the intracarotid amobarbital procedure (IAP) by showing eight cards displaying two line drawings of common objects, two printed words, one colored shape, one math expression, one face, and one abstract shape following amobarbital injection (mean = 109.9 mg). We assessed delayed recall and recognition following clearing. Patients with right foci recognized significantly fewer verbally mediated stimuli (words, object drawings, colored shape) with left than with right injection. Patients with left foci recognized a nonverbal stimulus (abstract shape) more poorly following right versus left injection. Discriminant function analysis lateralized 85% of the sample from memory predictors, upheld to 81% on crossvalidation. Material-specific memory remains intact in the hemisphere contralateral to a seizure focus, but wider representation may occur for stimuli normally dominant for the hemisphere with the seizure focus. The IAP significantly lateralizes a seizure focus with use of both types of stimuli.

Amobarbital↗
PubMed1993

A comparison of two immediate-early genes, c-fos and NGFI-B, as markers for functional activation in stress-related neuroendocrine circuitry.

The promoter regions of the rat corticotropin-releasing factor (CRF), oxytocin (OT), and vasopressin (AVP) genes contain sequences similar to the cis-acting response element identified for NGFI-B, an immediate-early gene structurally related to the steroid hormone receptor superfamily. Combined immuno- and hybridization histochemical approaches were used to determine whether challenges that influence the synthesis and secretion of CRF, OT, and/or AVP result in altered expression in neurosecretory neurons of NGFI-B and another immediate-early gene, c-fos, which is widely used as a marker for functionally activated neurons. NGFI-B mRNA was found to be expressed at constitutively high levels in the telencephalon, but not in the endocrine hypothalamus, of unperturbed controls; basal levels of c-fos expression were uniformly low throughout the CNS. NGFI-B and c-fos mRNAs, and Fos protein, were induced with a similar time course and in similar neuroendocrine cell types in response to acute hypotensive hemorrhage (15% reduction in blood volume), intravenous injection of interleukin-1 beta (IL-1 beta; 1.87 micrograms/kg), chronic salt loading (7 d maintenance on 2% saline), and acute bilateral adrenalectomy. c-fos mRNA and Fos protein were readily demonstrable in afferent pathways that have been implicated as mediating the neuroendocrine responses in the three stress paradigms; these include medullary catecholaminergic cell groups in response to IL-1 beta and hemorrhage, and cell groups lining the lamina terminalis in response to salt loading. Challenge-specific induction of NGFI-B expression was detectable in these extrahypothalamic cell groups, though with a lesser sensitivity than that required to reveal NGFI-B induction in the hypothalamus, or c-fos expression in these related afferents. These results establish NGFI-B as a useful adjunct to c-fos, for revealing synaptic and/or transcriptional activation in the magno- and parvocellular neurosecretory systems. Differences in the sensitivity of the two markers in revealing functionally related activation in extrahypothalamic regions speak to general issues concerning the use of immediate-early genes in mapping functional circuitry in the CNS.

Adrenalectomy↗
PubMed1992

Program and staff characteristics in successful treatment.

Women come to drug treatment with lower self-esteem (Regan et al. 1984), more social isolation, and more difficult life situations than men. Women are more likely to present with mental health comorbidity such as depression (Regan et al. 1982). Treatment programs modeled on outcome research on male patients may not yield strategies that are successful with women. Only in the past decade has research been undertaken into the specific population characteristics of women in drug treatment. Programs must be designed with a clear understanding of women's psychological makeup and particular life stress, including the need to care for their children and the reality of physical and sexual abuse. Drug treatment often unmasks a variety of psychosocial problems that, if not adequately addressed by the drug treatment program, may result in relapse into drug use. Many women live in poverty and are inadequately educated, two factors that can interfere with reintegration of the recovered addict into the community. Thus, the drug treatment program, to provide successful long-term outcomes with respect to drug use, must provide long-term aftercare that includes attention to the variety of social, medical, and emotional problems faced by women who use drugs.

Female↗
PubMed1991

Morphology and electrical properties of Schwann cells around the giant axon of the squids Loligo forbesi and Loligo vulgaris.

The first successful dye-fills of Schwann cells around the split giant axon of Loligo show them to be spindle-shaped cells ca. 600 microns long and 20 microns wide lying parallel to the axonal axis. There are some 50,000 Schwann cells per cm2 of axonal membrane. Only a small part (ca. 6% of each Schwann cell membrane) is in contact with the periaxonal space, the remainder is overlain by adjacent Schwann cells, or applied to the basal lamina. The mean membrane potential of the Schwann cells in artificial seawater (ASW) varies from around -40 mV in fresh split-axon preparations to around -60 to -70 mV after 1-2 h; this hyperpolarization is not seen in preparations dissected and maintained in Ca2(+)-free ASW. Electrical- and dye-coupling (abolished by prior octanol treatment) is present between Schwann cells, but is weaker in cells with lower (less negative) membrane potentials. The implications for potassium homeostasis around the axon are briefly discussed.

Animals↗
PubMed1991

Sexually dimorphic distribution of substance P in specific anterior pituitary cell populations.

Substance P (SP) immunoreactivity is detectable in the rat pituitary by RIA; however, immunolocalization has been difficult. We used a sensitive immunogold silver-enhancement staining technique to cytochemically locate SP in the gland. SP-immunoreactive (SP-ir) cells were seen in anterior pituitary (AP), and occasional SP-ir fibers and terminals were seen in both AP and posterior pituitary. Colocalization studies showed the vast majority of SP-ir cells in the male AP to be also immunoreactive for growth hormone (GH). These GH/SP-ir cells represent approximately 23% of the somatotroph population in the male. SP-ir cells did not colocalize with lactotrophs, gonadotrophs, or corticotrophs; however, rare thyroid-stimulating hormone/SP-ir cells were found in the male AP. Comparisons of pituitaries from males and females revealed that females have 70% fewer SP-ir cells and that only approximately 6% of the somatotrophs in the female express SP. This sexual dimorphism is diminished in 6-day ovariectomized rats because this treatment increases the GH/SP-ir cell population 3-fold. This result suggests that the previously reported estrogen-induced decrease in SP gene and peptide expression in the pituitary occurs, at least in part, in a subpopulation of somatotrophs. To test this hypothesis, distribution of SP-ir cells was examined in pituitaries from estrogen- and oil-treated ovariectomized rats. Estrogen reduced the percentage of somatotrophs with SP immunoreactivity by 70% compared with ovariectomized oil-treated controls, indicating that estrogen most likely regulates SP levels in the pituitary by acting on a subpopulation of somatotrophs to suppress SP expression. Estrogen does not appear to alter SP immunoreactivity that is detected in the additional population of SP cells that colocalize with thyroid-stimulating hormone. These SP-expressing thyrotrophs were seen 6-fold more frequently in the female than in the male pituitary, regardless of steroid status. These studies reveal that males have more total SP-ir cells in the AP than do females and that there is a sexually dimorphic pattern of SP distribution in the gland. Males have a higher percentage of SP-ir GH cells, whereas females have more SP-ir thyrotrophs than do males. Identification of independently regulated SP-ir somatotroph and thyrotroph populations provides a basis for investigating the roles of SP in autocrine or paracrine regulation of pituitary hormone secretion.

Animals↗
PubMed1991

Interictal cognitive changes in epilepsy.

There is little evidence for significant intellectual deterioration in well-controlled seizure disorders. With recurrent convulsive seizures, the picture is less clear and depends on severity, type, age of onset, and frequency of toxic levels of antiepileptic drugs (see Table 1). In the interictal state, deficits in verbal language and memory have been observed, especially in patients with complex partial seizure foci in the left (dominant) hemisphere. The memory deficits appear to affect new learning and retention of material; the verbal deficits are more subtle, affecting word-finding, verbal fluency, and comprehension abilities. Both of these changes may either go unnoticed by the patient in day to day activities or be attributed to the effects of antiepileptic medication. Antiepileptic drugs can also affect interictal cognitive functioning. The worst of these appears to be phenobarbital; phenytoin has an intermediate effect; valproic acid and carbamazepine as single agents seem to produce fewer adverse effects. However, individual patients may be particularly sensitive to cognitive side effects of certain drugs. Finally, attention deficits and slowing of cognitive processes, either chronically or intermittently, appear to affect all seizure patients to some extent. The syndrome is more prominent in frontal or generalized seizure patterns. The intermittent nature of these disturbances has been emphasized in recent research on subclinical interictal spike-wave electrical phenomena.

Anticonvulsants↗
PubMed1991

Community action for health promotion: a strategy to empower individuals and communities.

Health status is directly affected by environmental conditions and by personal health-related behaviors, and it is indirectly affected by environmental conditions that themselves influence health behaviors. A comprehensive approach to health promotion, therefore, should encourage individuals to adopt and maintain personal behaviors that would prevent disease and promote health; discourage health-damaging personal behaviors by individuals and facilitate people engaging in health-promoting behaviors; and eliminate health hazards from the physical and social environment and make that environment more health-promoting. This comprehensive approach would require social and community action to change environmental conditions as well as efforts to change individual behavior. A model of health promotion interventions is developed within which community action plays a central role. The author then presents a model of community organization to influence public policy to achieve health promotion goals. The community organization model, previously tested in comparative case-study research, is illustrated with examples drawn from appropriate health promotion programs.

Community Health Services↗