Search PubMed⌕ Search

Biomedical subjects

H A Pearson

Publications and source records attributed to H A Pearson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Invasive pneumococcal infections in children infected with HIV are not associated with splenic dysfunction.

OBJECTIVES: Children infected with HIV-1 are more likely to acquire infections associated with the encapsulated bacterial pathogens of childhood than their non-HIV-infected peers. The goal of the current study was to determine what proportion of community-acquired, invasive pneumococcal disease in HIV-infected children could be attributed to splenic dysfunction, as measured by enumerating the number of pocked red blood cells (RBCs) in peripheral blood. METHODS: Splenic reticuloendothelial function was assessed semiquantitatively by examining the morphology of the RBCs of 84 children born to HIV-infected mothers using phase interference microscopy. Surveillance of medical records, and a review of the Yale-New Haven Hospital Clinical Microbiology computerized database, revealed that all of the bacterial cultures of blood and cerebrospinal fluid from these patients were positive. RESULTS: Of the 84 children assessed, 70 were infected with HIV (median age 66 months) and 14 were uninfected seroreverters (controls). Sixty-one of the 70 HIV-infected children met the CDC criteria for moderate or severe immunodeficiency and/or moderate or severe symptomatic conditions. Seventeen of the 70 HIV-infected children experienced 23 invasive bacterial infections. Streptococcus pneumoniae was responsible for all 23 infections. The median age at the time of first infection among these 17 subjects was 20 months (range, 10-58 months). There were no episodes of invasive bacterial infections in the remaining 53 HIV-infected children nor among the 14 controls. All 84 children studied, including those with invasive pneumococcal disease, had normal proportions (i.e., < 2%) of pocked erythrocytes in peripheral blood. CONCLUSION: Splenic dysfunction, as measured by the pocked RBC count, does not account for the increased occurrence of invasive pneumococcal disease found in children infected with HIV.

AIDS-Related Opportunistic Infections↗
PubMed1996

The changing profile of homozygous beta-thalassemia: demography, ethnicity, and age distribution of current North American patients and changes in two decades.

BACKGROUND: The age of patients with homozygous beta-thalassemia is increasing because of better treatment and decreased births. A countering influence is immigration of ethnic groups with a high prevalence of thalassemia. METHODS: a questionnaire sent to 48 North American centers requested information about current patients with homozygous beta-thalassemia: age, clinical severity, and ethnicity. An 83% response was obtained. Twelve reference hospitals that participated in similar surveys in 1972 and 1984 were included. RESULTS: Five hundred eighteen patients with homozygous beta-thalassemia represent most North American patients. Four hundred forty-three (86%) of these had transfusion-dependent thalassemia major (TM); 75 (14%) had thalassemia intermedia (TI). Sixty-two percent were of Greek and Italian ancestry. There were approximately equal numbers of patients with TM in 5-year intervals between 0 and 25 years of age. Thereafter, the numbers of patients fell sharply. The mean age (+/- SD) of the patients with TM was 16.1 +/- 9.2 years. Striking differences were seen in Italian and Greek patients compared with those of other ancestries. Sixty-six percent of the 271 Italian and Greek patients with TM were older than 16 years of age, whereas 77% of the 172 patients of other ethnic groups with TM were younger than 15 years of age. The mean age of the 75 patients with TI was greater than that of the patients with TM. Seventy-three percent of African-American patients had TI, compared with 0% of Southeastern Asian patients. Comparisons of patients with TM from the 12 reference hospitals for two decades show increasing mean ages of TM patients (1973, 11.4 +/- 6.7 years; 1985, 14/2 +/- 7.3 years; and 1993, 16.1 +/- 9.2 years). CONCLUSIONS: There are probably only 750 to 1000 patients with homozygous beta-thalassemia in North America. Only about 15 to 20 new cases are diagnosed each year. The increasing mean age and age distribution indicate that modern therapies are effective, but immigration of non-Mediterranean ethnic groups with thalassemia has resulted in more, younger patients. TM is increasingly becoming a disease of young adults.

Adolescent↗
PubMed1995

Characterization of Ca2+ channel currents in cultured rat cerebellar granule neurones.

1. High-threshold voltage-gated calcium channel currents (IBa) were studied in cultured rat cerebellar granule neurones using the whole-cell patch clamp technique with 10 mM Ba2+ as the charge carrier. The putative P-type component of whole-cell current was characterized by utilizing the toxin omega-agatoxin IVA (omega-Aga IVA) in combination with other blockers. 2. omega-Aga IVA (100 nM) inhibited the high voltage-activated (HVA) IBa by 40.9 +/- 3.4% (n = 27), and the dissociation constant Kd was 2.7 nM. Maximal inhibition occurred within a 2-3 min time course, and was irreversible. The isolated omega-Aga IVA-sensitive current was non-inactivating. 3. omega-Aga IVA exhibited overlapping selectivity with both N- and L-channel blockers; omega-conotoxin GVIA (omega-CTX GVIA) (1 microM) and the dihydropyridine (-)-202-709 (1 microM), respectively. Together these toxins reduced the omega-Aga IVA-sensitive component to just 4.5 +/- 1.4% (n = 3). Thus only a small proportion of the current can be unequivocally attributed to P-type current. Inhibition of the HVA IBa by omega-Aga IA also reduced the proportion of omega-Aga IVA-sensitive current to 28.0 +/- 3.2% (n = 3). 4. Application of omega-Aga IVA and a synthetic form of funnel-web toxin, N-(7-amino-4-azaheptyl)-L-argininamide (sFTX-3.3; 10 microM), produced an additive block of the HVA IBa. Consequently these two toxins do not act on the same channel in cerebellar granule neurones. 5. omega-Aga IVA inhibition of low voltage-activated (LVA) IBa was studied in the ND7-23 neuronal cell line. omega-Aga IVA (100 nM) reduced the LVA current by 41.3 +/- 3.2% (n = 17) in a fully reversible manner with no shift in the steady-state inactivation of the channel. 6. A component of current insensitive to N-, L- and P-channel blockers remained unclassified in all our studies. This component, and also that remaining following block by omega-Aga IVA and omega-Aga IA, exhibited relatively rapid, although incomplete, inactivation compared to the other currents isolated in this study. 7. In conclusion, omega-Aga IVA inhibits a component of current in cultured cerebellar granule neurones which overlaps almost completely with that inhibited by L- and N-channel blockers. In addition, a large component of whole-cell current in these neurones still remains unclassified.

Animals↗
PubMed1995

Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial.

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta-thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.

Adult↗
PubMed1995

Ca/calmodulin-dependent kinase II inhibitor KN62 attenuates glutamate release by inhibiting voltage-dependent Ca(2+)-channels.

The effect of KN62 (1-[N,O-bis(5-isoquinolinesulphonyl)-N -methyl-L-tyrosyl]-4-phenylpiperazine), a putative inhibitor of Ca/calmodulin-dependent kinase II (Ca/CaM-K II), on glutamate release from isolated nerve-terminals (synaptosomes) was examined. The drug caused a potent inhibition of KCl- and 4-aminopyridine-evoked glutamate release from isolated nerve-terminals (synaptosomes). Examination of the effect of the inhibitor on Ca(2+)-influx revealed that the diminution of glutamate release could be attributed to a decrease in cytosolic Ca. A direct effect of KN62 on synaptosomal Ca(2+)-channels was confirmed in experiments where Ba, which does not support CaM-dependent processes, was used in place of Ca. Additionally, whole-cell patch-clamping of cerebellar granule neurones directly demonstrated inhibition of Ca-currents by KN62. We therefore suggest that, in cellular systems, conclusions based on the use of KN62 as a Ca/CaM-K II blocker may be ambiguous and should be viewed with caution unless the effect of the drug on Ca-influx has also been quantified. The effect of KN62 on Ca(2+)-influx appears to be specific to slowly-or non-inactivating conductances, and therefore presents KN62 as a potentially useful tool in this context.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Pediatrics.

Cases of serious H influenzae type b infection have become unusual. Pediatric endocrinologists will probably advocate intensive insulin therapy for almost all adolescents with IDDM. The prone sleeping position should be avoided for most infants.

Pediatrics↗
PubMed1994

Low- and high-voltage-activated calcium channel currents and their modulation in the dorsal root ganglion cell line ND7-23.

The dorsal root ganglion-neuroblastoma cell line ND7-23 expresses low-voltage-activated calcium channel currents, and also expresses high-voltage-activated currents in about 50% of differentiated cells. Calcium channel currents were recorded with Ba2+ as the charge carrier. Low-voltage-activated currents were maximally activated at -30 mV and completely inactivated at holding potentials of -60 to -50 mV. omega-Conotoxin GVIA produced a reversible inhibition of low-voltage-activated currents, whereas the inhibition of high-voltage-activated current was largely irreversible. Dihydropyridine antagonists did not inhibit low-voltage-activated currents, whereas they inhibited a sustained, high-voltage-activated current. Low-voltage-activated currents were inhibited to a greater extent than high-voltage-activated currents by Ni2+ (100 microM) and by phenytoin (10 microM). Bradykinin (0.1 microM), baclofen (2 microM) and internal guanosine-5'-O-3-thiotriphosphate (100 microM) inhibited low-voltage-activated currents without affecting their kinetics of activation. Two classes of low-voltage-activated current were distinguished by their kinetics of inactivation. In the majority of cells, currents were slowly inactivating with a time-constant of inactivation of about 50 ms. They also exhibited a sustained component to the current, representing about 20% of the peak current. This component could be distinguished pharmacologically from high-voltage-activated current. The remainder of cells expressed a rapidly and completely inactivating current, with a time-constant of inactivation of about 20 ms. Two distinct single channel currents were observed in these cells, from cell-attached patch measurements, one had a single channel conductance of 7.9 pS, and the ensemble average current showed some inactivation. It is likely that this channel subtype underlies the low-voltage-activated current. The other showed long openings in the presence of a dihydropyridine agonist, had a conductance of 23.1 pS, and was non-inactivating.

Ammonium Chloride↗
PubMed1994

Thalassemia major in Connecticut: a 20-year study of changing age distribution and survival.

There has been a near doubling of the mean age (10.7 to 19.0 years) of Yale-New Haven Hospital patients with transfusion-dependent homozygous beta thalassemia between 1973 and 1994. This change is, in part, a result of improved transfusion procedures and effective chelation therapy with deferoxamine mesylate. A concomitant trend has been a decrease in the number of births of new cases resulting in fewer thalassemia major patients less than 10 years of age in 1985 and 1994 compared to a decade earlier. Identification of individuals at risk of having children with thalassemia major by extensive screening for heterozygous thalassemia and the availability of prenatal diagnosis may have contributed to this change. Thalassemia major has become a disease of adolescents and young adults. The increasing age has resulted in "new" issues in thalassemia major patients such as sexuality and marriage as well as economic problems involving health-care insurance and employment.

Adolescent↗
PubMed1993

Non-competitive antagonism of calcium by magnesium ions at the K(+)-depolarised mouse neuromuscular junction.

The effect of raising the external Ca2+ concentration on miniature end-plate potential (m.e.p.p.) frequency was measured in the K(+)-depolarised mouse phrenic nerve/hemidiaphragm preparation in the presence of a range of Mg2+ concentrations. With increasing external Mg2+, a plot of external Ca2+ concentration vs. m.e.p.p. frequency was shifted to the right and the maximum frequency attained was reduced. A Schild plot of the data gave a slope factor close to two. These data suggest a non-competitive antagonism of Ca2+ by Mg2+ under these conditions.

Animals↗
PubMed1993

Inhibition of omega-conotoxin-sensitive Ca2+ channel currents by internal Mg2+ in cultured rat cerebellar granule neurones.

The effects of changing the intracellular concentrations of either free Mg2+ ions ([Mg2+]i) or Mg(2+)-bound adenosine triphosphate ([Mg.ATP]i) on Ca2+ channel currents were assessed in cultured rat cerebellar granule neurones using the whole-cell patch-clamp technique. Raising [Mg2+]i from 0.06 mM to 1.0 mM inhibited Ca2+ channel currents by approximately 50%. The action of omega-conotoxin GVIA (omega-CgTX), a selective inhibitor of "N"-type Ca2+ channels was also investigated. With increasing [Mg2+]i, the proportion of current irreversibly blocked by omega-CgTX was reduced, and was negligible (approximately 5 pA of current) in the presence of [Mg2+]i values of 0.5 mM or greater. Block of the omega-CgTX-sensitive current accounted for the reduction in total current by concentrations of [Mg2+]i to 0.5 mM. Raising [Mg2+]i had no effect on the rate of decay of Ca2+ currents, but did produce a negative shift in current activation, possibly due to a non-specific interaction with negative surface charge. Altering [Mg.ATP]i from 0.3 to 5.0 mM caused a twofold increase in the size of currents without affecting the proportion of current sensitive to omega-CgTX. [Mg2+]i was also effective in inhibiting the Ca2+ channel current following potentiation by increasing [Mg.ATP]i. These data suggest that omega-CgTX-sensitive current in these cells is selectively inhibited by internal Mg2+ whereas both omega-CgTX-sensitive and -resistant components of current are potentiated by internal Mg.ATP. The mechanism by which Mg2+ inhibits "N"-type channels is unclear, but may involve an open channel block.

Adenosine Triphosphate↗
PubMed1993

Ca2+ currents in cerebellar granule neurones: role of internal Mg2+ in altering characteristics and antagonist effects.

Using the whole-cell patch-clamp technique, Ca2+ channel currents were measured in cultured rat cerebellar granule neurones in the presence of 10 mM Ba2+. Two different solutions were used to fill patch pipettes, one containing mainly tetraethylammonium acetate (TEA-Ac solution), and the other mainly caesium and HEPES (Cs-HEPES solution). Under these two different intracellular conditions markedly different Ca2+ channel currents were recorded. When TEA-Ac solution was used intracellularly, small, Cd(2+)-sensitive inward currents (approx. -55 pA) that were inhibited by the dihydropyridine antagonist (-)-202-791 and the GABAB agonist (-)-baclofen were observed. These currents were insensitive to the Ca2+ channel clocking toxins omega-conotoxin GVIA (omega-CgTX) and omega-agatoxin IVA and were enhanced by the dihydropyridine agonist (+)-202-791. In contrast, when the Cs-HEPES solution was used, currents were 2-3 times larger (approx. -130 pA), inhibited by (-)-202-791, omega-CgTX and omega-agatoxin IVA but were unaffected by (-)-baclofen. Furthermore, both (+)-202-791 and Bay K8644 in the presence of Cs-HEPES solution produced only a transient enhancement that was followed by an inhibition. Analysis of steady-state inactivation revealed two components of current in both cases, with similar voltage dependencies. The factor(s) giving rise to these differences were investigated in terms of current amplitude and responses to (-)-baclofen and omega-CgTX and were found to be mainly due to the concentrations of Mg2+ and ATP added to the patch pipette solutions. Furthermore, free internal Mg2+ concentrations of greater than 0.2 mM selectively inhibited omega-CgTX-sensitive Ca2+ channels. Preliminary evidence indicates that the same may be true of omega-Aga IVA-sensitive P-type current. These data suggest that the N-type Ca2+ channels in these cells are preferentially inhibited by intracellular Mg2+ and this may provide an explanation for discrepancies between the results of different groups investigating Ca2+ channel currents in similar cell types.

Adenosine Triphosphate↗
PubMed1993

Correction of hyperinsulinemia by glyburide treatment in nondiabetic patients with thalassemia major.

Hyperinsulinemia and insulin resistance precede the development of diabetes in patients with thalassemia major on hypertransfusion/desferoxamine therapy. To examine whether these early metabolic defects could be reversed, seven nondiabetic patients with thalassemia (17 +/- 4 y) were studied for 12 mo before and during 12 mo of low-dose treatment with glyburide (1.25 to 3.75 mg/d), a second-generation oral hypoglycemic agent. Plasma glucose responses to oral glucose (1.75 g/kg body weight) were normal before and after glyburide. Plasma insulin responses were markedly increased before glyburide therapy (area under insulin response curve 86 +/- 15 and 96 +/- 15 versus 40 +/- 5 nmol/min/L in normal controls, p < 0.001). However, insulin responses to glucose fell significantly after 3 mo of glyburide (to 52 +/- 7 nmol/min/L, p < 0.05 versus pretreatment) and were normalized after 12 mo (42 +/- 7 nmol/min/L, p = NS versus controls). The rate of insulin-stimulated glucose metabolism during euglycemic insulin clamps (40 mU/m2/min) was low in the patients before treatment (163 +/- 10 versus 215 +/- 17 mg/m2/min in controls, p < 0.05) and increased to 205 +/- 30 mg/m2/min after 3 mo of glyburide. The treatment was well tolerated. In conclusion, in nondiabetic, hyperinsulinemic, thalassemic patients, chronic glyburide therapy normalizes insulin responses to oral glucose. To the extent that insulin hypersecretion contributes to the development of diabetes in thalassemia, glyburide therapy may provide a means of postponing this complication of the disease.

Adolescent↗