Emerging patterns in genome organization.
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Animals↗
Biomedical subjects
J Nadeau
Publications and source records attributed to J Nadeau.
Effect of uvulopalatopharyngoplasty on upper airway collapsibility in obstructive sleep apnea.
Previous investigators have demonstrated variable responses to uvulopalatopharyngoplasty (UPP) in patients with obstructive sleep apnea. We hypothesized that this variability is due to either (1) differences in baseline pharyngeal collapsibility preoperatively or (2) differences in magnitude of the decrease in pharyngeal collapsibility resulting from surgery. To determine the relationship between changes in collapsibility and the response to UPP surgery, we measured the upper airway critical pressure (Pcrit) before and after UPP in 13 patients with obstructive sleep apnea. During non-REM sleep, maximal inspiratory airflow (VImax) was quantitated by varying the level of nasal pressure (PN), and Pcrit was determined by the level of PN below which VImax ceased. A positive response to UPP was defined by a greater than or equal to 50% fall in non-REM disordered breathing rate (DBR). In the entire group, UPP resulted in significant decreases in DBR from 71.1 +/- 22.4 to 44.7 +/- 38.4 episodes/h (p = 0.025) and in Pcrit from 0.2 +/- 2.4 to -3.1 +/- 5.4 cm H2O (p = 0.016). Moreover, the percent change in DBR was correlated significantly with the change in Pcrit (p = 0.001). Subgroup analysis of responders and nonresponders demonstrated that significant differences in Pcrit were confined to the responders. Specifically, responders demonstrated a significant fall in Pcrit from -0.8 +/- 3.0 to -7.3 +/- 4.9 cm H2O (p = 0.01), whereas no significant change in Pcrit was detected in the nonresponders (1.1 +/- 1.6 versus 0.6 +/- 2.0 cm H2O. No clinical, polysomnographic, or physiologic predictors of a favorable response were found preoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)
Humans↗
One subunit of the transcription factor NF-Y maps close to the major histocompatibility complex in murine and human chromosomes.
The genes coding for the A and B subunits of the transcription factor NF-Y are assigned by a combination of in situ hybridization and analysis of somatic cell hybrids and recombinant mouse strains. NF-YA is assigned to human chromosome 6p21 and to mouse chromosome 17. NF-YB is assigned to human chromosome 12 and to mouse chromosome 10.
Animals↗
The effects of clonidine hydrochloride versus atenolol monotherapy on serum lipids, lipid subfractions, and apolipoproteins in mild hypertension.
The study objective was to determine the effects of monotherapy with clonidine and atenolol versus placebo on serum lipids, apolipoproteins, and blood pressure in patients with mild primary hypertension. The protocol comprised a double blind, randomized, placebo-controlled 5-month prospective study carried out in an outpatient general internal medicine clinic in a university medical center. There were 92 patients ages 18 to 70, with mild primary hypertension (sitting diastolic blood pressure of greater than 90 mm Hg and less than 105 mm Hg) without significant cardiac, renal, cerebrovascular, hepatic, neoplastic, or hematologic disorders. Patients with severe hyperlipidemia or peripheral vascular disease were also excluded. All factors known to effect serum lipids were held constant throughout the study (i.e., diet, weight, exercise, caffeine, tobacco). Atenolol and clonidine significantly reduced blood pressure when compared with placebo. Atenolol caused significant increases in serum triglycerides and apolipoprotein B (p less than 0.05) and significant reductions in high-density lipoprotein-cholesterol, apolipoproteins A-I and A-II (p less than 0.05). Atenolol also induced a significant adverse effect on all lipid ratios, increasing total cholesterol/high density lipoprotein-cholesterol, low density lipoprotein-cholesterol/high density lipoprotein-cholesterol, apolipoprotein B/apolipoprotein A-I and apolipoprotein B/apolipoprotein A-II ratios and decreasing low density lipoprotein-cholesterol/apolipoprotein-B ratio (p less than 0.05). Clonidine caused significant reductions in high-density lipoprotein-cholesterol, apolipoproteins AI and AII (p less than 0.05 but was neutral on all other lipids, lipid subfractions, and apolipoproteins. Clonidine did not significantly alter any of the lipid ratios.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Effect of high-dose inhaled budesonide on calcium and phosphate metabolism and the risk of osteoporosis.
We investigated the effects of the antiasthmatic inhaled steroid budesonide at low and high dosage (0.6 and 2.4 mg/day) on calcium and phosphate metabolism (Ca, P) in 10 normal adults. Their endogenous production of cortisol dropped with budesonide treatment (p less than or equal to 0.0005), as did androgen production (p less than or equal to 0.003). This was associated with an increase in the renal tubular maximal reabsorption of Ca (p = 0.003) and P (p = 0.03), a decrease in the urinary output of Ca in the fasting morning state (p = 0.03), and an increase in serum P (p = 0.02). However, there was no change in the 24-h urinary excretion of Ca (p = 0.76) or P (p = 0.08) or the serum Ca level (p = 0.19). Similarly, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, parathyroid hormone, and urinary cAMP levels were not affected, indicating that absorption of Ca from the gut was not compromised. Thus, in contrast to the expected effects of oral steroid treatment, inhaled budesonide had no discernible short-term adverse effect on Ca or P metabolism under the conditions of this study, despite purposely using a dosage high enough to partially inhibit adrenocortical function. These data tend to support a broadening of the therapeutic role of budesonide, and possibly other inhaled steroid drugs, to include higher doses and more severe asthmatics. However, additional clinical and metabolic studies are needed to fully clarify the effects of high-dose inhaled steroid therapy on bone.
Absorption↗
Genetic analysis and developmental regulation of testis-specific RNA expression of Mos, Abl, actin and Hox-1.4.
The pattern of Mos proto-oncogene RNA expression in the gonads of the sterile mouse mutants, dominant spotting (W), sex reversal (Sxr), testicular feminization (Tfm), hypogonadal (hpg), quaking (qk), two t-haplotypes, three X-autosomal translocations, and the YPOS strain, is consistent with its presence in haploid spermatids in the testes and in oocytes in the ovaries. In the male-sterile mouse mutants the pattern of expression of the testis-specific transcripts for Abl, actin, and the mouse homeobox Hox-1.4 genes is identical to that observed for Mos. However, during the postnatal onset of normal spermatogenesis we detected differences in the time of the appearance of the four transcripts. We detected Hox-1.4 transcripts at day 20, Mos at day 25, and Abl and actin at day 30, demonstrating a specific regulation of expression of each of these genes during haploid spermatid maturation in the mouse. Furthermore, comparison of Mos, Abl and actin RNA expression in mouse and rat testes revealed species-specific variations in the regulation of gene expression.
Actins↗
Alterations in leukocyte beta-receptor affinity with aging. A potential explanation for altered beta-adrenergic sensitivity in the elderly.
The elderly have reduced beta-adrenergic sensitivity to agonists, but no change in receptor density. We investigated the relation between beta-receptor affinity for agonists and age in beta-receptors on lymphocytes from 20 healthy men 21 to 74 years old. As an index of beta-receptor affinity for agonists, we determined the IC50 of isoproterenol--the concentration of isoproterenol required to inhibit 50 per cent of iodohydroxybenzylpindolol binding in vitro. We found that receptor affinity for agonists was correlated with age and plasma norepinephrine concentration. Twelve subjects (six 21 to 29 years old and six 55 to 74 years old) were also studied in both the supine and upright positions. In samples obtained in the supine position, the proportion of receptors binding agonist with a high affinity was decreased in the older subjects as compared with the young subjects (22 +/- 1 per cent vs. 38 +/- 3 per cent; P less than 0.05). With upright posture and the associated acute elevation of endogenous plasma catecholamines, the proportion of receptors binding agonist with a high affinity was reduced in the young; no such changes were seen in the older subjects. The data suggest that reduced beta-receptor affinity for agonists may be an explanation for altered beta-adrenergic sensitivity in the elderly.
Adrenergic beta-Agonists↗
Leukocyte beta-receptor alterations in hypertensive subjects.
It has been suggested that beta-adrenergic responsiveness is reduced in hypertension. To evaluate a possible alteration in human beta-receptors that might account for diminished beta-adrenergic responsiveness, we studied leukocytes from hypertensive and normotensive subjects after an overnight rest supine, and then after being ambulatory, a maneuver that increases plasma catecholamines approximately twofold. In supine samples, beta-receptor affinity for the agonist isoproterenol was significantly reduced in hypertensives and was associated with a reduction in the proportion of beta-receptors binding agonist with a high affinity from 42 +/- 6% in normotensive subjects to 25 +/- 2% in hypertensives (P less than 0.05). Alterations in beta-adrenergic-mediated adenylate cyclase activity parallelled the differences seen in the beta-receptor affinity for agonist. In normotensive subjects, beta-receptor density and the proportion of receptors binding agonist with high affinity were reciprocally correlated with plasma catecholamines. However, in the hypertensive subjects these correlations were not evident. Thus, our data suggest an alteration in leukocyte beta-receptor interactions in hypertensive subjects, and may represent a generalized defect in beta-receptor function in hypertension.
Adenylyl Cyclases↗
Effects of feeding on the systemic clearance of indocyanine green and propranolol blood concentrations and plasma binding.
In six healthy subjects a 250 g steak significantly increased the systemic clearance of indocyanine green. During a steady-state infusion of propranolol there was a rapid decrease (mean 35%) in blood propranolol concentrations within 5 min of feeding and levels were reduced for 30 min before gradually returning towards the pre-feeding. These results suggest that the systemic clearance of high extraction drugs may be increased immediately following food.
Adult↗
Dynamic regulation of leukocyte beta adrenergic receptor-agonist interactions by physiological changes in circulating catecholamines.
beta-Adrenergic receptors on human mononuclear leukocytes were assessed using [125I]iodohydroxybenzylpindolol binding. Subjects were studied supine and after being ambulatory, a maneuver that increases plasma catecholamines approximately two-fold. beta-Receptor affinity for agonists, measured by the competition of [125I]iodohydroxybenzylpindolol binding by (-)isoproterenol was significantly reduced with ambulation and this reduction was associated with a reduction in the proportion of beta-receptors binding agonist with a high affinity from a mean (+/- SEM) of 42 +/- 5 to 24 +/- 2% (P less than 0.01). In a parallel series, beta-adrenergic-stimulated adenylate cyclase activity was also reduced with postural change from 4.6 +/- 1.1 to 2.4 +/- 0.6 pmol [32P]cAMP/min per mg protein (P less than 0.05) after ambulation. Similar reductions in the proportion of receptors binding agonist with a high affinity were seen after infusion of norepinephrine. We conclude that the maneuver of ambulation reduces leukocyte beta-receptor responsiveness and affinity for agonists, probably by the effect of increased plasma catecholamines mediating an uncoupling of the beta-receptor-adenylate cyclase complex.
Adenylyl Cyclases↗
Vasodilator capacity of forearm vessels in hypertension.
Factors determining vascular resistance were examined in 6 normotensive subjects (NT), 5 with established hypertension (EH) and diastolic pressures greater than 90 mmHg and 7 with borderline hypertension (BH) having pressures intermittently greater than 140/90 mmHg. Using plethysmography, we measured forearm blood flow (FBF), arterial resistance (FAR) and venous compliance (FVC) before and after autonomic blockade with propranolol 0.2 mg/kh, atropine 0.04 mg/kg and phentolamine 15 mg I.V. Subjects with EH had the highest baseline FBF. MAP was increased 18-22% after atropine and propranolol in all 3 groups. Phentolamine decreased MAP -8.9 +/- 2.1% in NT, -6.9 +/-1.2% in BH and -16.5 +/- 1.9% in EH (p less than 0.05). After total blockade, FAR in EH (32.4 +/- 4.8 units) was similar to FAR in TN (31.0 +/- 3.6 units) whereas that in BH remained high (50.2 +/- 3.8 units; p less than 0.01). Baseline FVC was highest in NT, intermediate in BH and lowest in EH and was not altered by autonomic blockade. Non-gravitational exercise for 6 min during upper arm arterial occlusion after autonomic blockade resulted in a residual FAR of 2.3 +/- 0.1 units in NT, 3.8 +/- 0.3 units in BH and 4.2 +/- 1.7 units in EH (p less than 0.01) during reactive hyperemia. Increased FAR in our subjects with BH and EH was probably due to structural vascular alterations. The greater increase in FAR and MAP in EH over that observed in BH has a sympathetic nervous system component.
Atropine↗
Physiological regulation of beta-receptors in man.
Previous studies have shown that pharmacological doses of agonists can down-regulate beta receptors. We have shown that alteration of catecholamines within the physiological range is associated with modulation of beta receptor density. The stimulus used to alter catecholamine concentrations in vivo was change in sodium intake. In addition, administration of the beta blocker, propranolol, raised beta receptor density and the rise in receptor density was proportional to the pretreatment catecholamine concentrations. It appears that beta receptors in vivo are in a chronic state of down regulation and that this degree of down regulation parallels the catecholamine concentrations.
Adrenergic beta-Antagonists↗
Regulation of human leukocyte beta receptors by endogenous catecholamines: relationship of leukocyte beta receptor density to the cardiac sensitivity to isoproterenol.
High levels of beta receptor agonist have previously been shown to down-regulate beta receptor density on circulating leukocytes in man; however, the factors controlling receptor density under physiological conditions have not previously been defined. To determine whether beta receptor density is normally down-regulated by circulating, physiological levels of catecholamines we have examined the relationship between receptor density and catecholamine levels. Urinary epinephrine and norepinephrine were significantly reciprocally correlated to lymphocyte receptor density. A similar relationship existed between beta receptor density and supine plasma epinephrine, norepinephrine, upright epinephrine, and norepinephrine levels. Change in sodium intake from 10 to 400 meq/d caused a 52% increase in lymphocyte and a 48% increase in polymorphonuclear beta receptor density. The changes in receptor density were accompanied by an increase in the sensitivity to isoproterenol measured as a fall in the dose of isoproterenol required to raise the heart rate by 25 beats per minute. Beta receptor density on both lymphocyte and polymorphonuclear cells was significantly correlated to the cardiac sensitivity to isoproterenol. Propranolol administration resulted in an increase in the density of beta receptors on lymphocyte and polymorphonuclear cells that correlated with the subject's pretreatment catecholamine levels. These findings, therefore, suggest that physiological levels of catecholamines normally down-regulate beta receptors in man and that blockade of this down-regulation by propranolol allows receptor density to increase.
Adult↗
Laser Raman scattering. A molecular probe of the contractile state of intact single muscle fibers.
The 500 to 1,800-cm-1 region of the Raman spectra of intact single muscle fibers from the giant barnacle are dominated by bands caused by the protein component of the fibers. The frequency and the intensity of the conformationally sensitive bands indicate that the contractile proteins adopt a predominantly alpha-helical structure and are not affected when the contractile state of the fibers is changed from relaxed to contracted by addition of ATP and Ca. However, the contraction induces a decrease of the scattering intensity of some of the Raman bands caused by the acidic and tryptophan side chains, showing that these amino acids are involved during the generation of tension.
Adenosine Triphosphate↗
Acebutolol and hydrochlorothiazide in essential hypertension.
Acebutolol (ABL) and hydrochlorothiazide (HCT) were compared in patients with mild to moderate essential hypertension and low or normal peripheral renin activity. ABL reduced mean supine blood pressure from 151/97 to 140/87 mm Hg and HCT reduced the mean supine blood pressure from 153/98 to 143/92 mm Hg. ABL reduced heart rate from 73 to 67 beats/min; during HCT therapy it rose from 74 to 77 beats/min. Although the same proportion of patients achieved normal diastolic pressures with ABL (11/19) and with HCT (10/19), tension-time indices were lower during ABL than during HCT therapy. The average daily dose was 621 mg of ABL and 168 mg of HCT. Stimulated peripheral renin activity increased with HCT and was the same or lower with ABL. ABL did not induce adverse effects on serum potassium or uric acid. ABL was as effective in lowering blood pressure HCT but induced larger reductions in tension-time index as a result of the lowerered heart rate.
Acebutolol↗
Histocompatibility-2 system in wild mice. X. Frequencies of H-2 and Ia antigens in wild mice from Europe and Africa.
In this study, data are presented on serologic H-2 typing of 320 wild mice collected in several parts of Europe and Egypt. The sample was typed for 39 class I (K, D) and 16 class II (Ia) antigens. The phenotype frequencies of class I and class II antigens showed high variability in their distribution among different areas, ranging from absence or presence in low frequency in one area to presence in about one-half of the mice in another area. The average phenotypic frequency of class I private antigens was 6.3%; at least 60% of class I alleles (blanks) could not be identified with the available reagents. The data suggest that there might be more than 100 alleles for each class I locus, H-2K and H-2D. The average phenotypic frequencies of Ia-1 private antigens was 10.8%. About 75% of Ia-1 alleles (blanks) could not be identified. The number of Ia-1 alleles was estimated to be in the range of 20 to 50.
Alleles↗
Antihypertensive efficacy of propranolol given twice daily.
The therapeutic efficacy of propranolol in four and two daily doses was compared in 63 treated hypertensive patients in a multicentre trial. After 3 months of a stable diastolic blood pressure while receiving propranolol four times a day the patients were switched to a twice-a-day regimen, the drug being given at 8 am and 8 pm, with the same total daily dose, for 3 more months. Blood pressures and heart rates were measured at 8 am, 12 noon, 4 pm and 8 pm at 4-week intervals. There were no significant changes in mean blood pressure after the change to the twice-a-day regimen, although some patients reported new side effects. Compliance appeared to be unaffected.
Adolescent↗