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Biomedical subjects

E M Brown

Publications and source records attributed to E M Brown.

At least 19 recordsLinked to original sources
PubMed1992

Effect of sequential and daily continuous hormone replacement therapy on indexes of mineral metabolism.

BACKGROUND: Continuous regimens of estrogen-progesterone have recently been favored over sequential regimens because of a lower incidence of withdrawal bleeding. To determine whether the beneficial effects of sequential hormonal therapy on bone metabolism are preserved with the newer continuous regimens, we studied indexes of skeletal metabolism and changes in bone mineral density during a 1-year prospective trial. METHODS: Our subjects were randomized to one of three treatment groups: those in group C-2.5 were treated with 0.625 mg of conjugated estrogen with 2.5 mg of micronized medroxyprogesterone acetate daily continuously; group C-5 received 0.625 mg of conjugated estrogen and 5.0 mg of micronized medroxyprogesterone acetate daily continuously; and group S-5 received 0.625 mg of conjugated estrogen on days 1 through 25 and 5 mg of micronized medroxyprogesterone acetate on days 14 through 25. RESULTS: At 1 year, all groups demonstrated a significant decrease in indexes of bone formation turnover, including decrements in alkaline phosphatase levels of 11% to 30% and in osteocalcin levels of 45% to 60%. Intact parathyroid hormone levels rose 10% to 20%, with a concomitant near-significant decrement in ionized calcium levels at 12 months. In addition, there were significant decrements in the 24-hour urinary calcium-creatinine ratios and hydroxyproline-creatinine ratios of 13% to 28%, measures of bone resorption. Linear regression analyses showed that the subjects with the high bone resorption achieved the greatest increment in bone mineral density in response to hormone therapy. CONCLUSION: The daily continuous estrogen-progesterone regimens are as efficacious as sequential hormonal therapy in decreasing indexes of bone turnover and stabilizing bone mineral density of the spine and proximal femur.

Bone Density↗
PubMed1992

Effects of high extracellular calcium concentrations on phosphoinositide turnover and inositol phosphate metabolism in dispersed bovine parathyroid cells.

We previously showed that high extracellular calcium (Ca2+) concentrations raise the levels of inositol phosphates in bovine parathyroid cells, presumably via the G protein-coupled, "receptor-like" mechanism through which Ca2+ is thought to regulate these cells. To date, however, there are limited data showing Ca(2+)-evoked hydrolysis of phosphoinositides with attendant increases in the levels of the biologically active 1,4,5 isomer of inositol trisphosphate (IP3) that would be predicted to arise from such a receptor-mediated process. In the present studies we used HPLC and TLC, respectively, to quantify the high Ca(2+)-induced changes in various inositol phosphates, including the isomers of IP3, and phosphoinositides in bovine parathyroid cells prelabeled with [3H]inositol. In the absence of lithium, high Ca2+ dose dependently elevated the levels of inositol-1,4,5-trisphosphate [I(1,4,5)P3], with a maximal, 4- to 5-fold increase within 5 s; the levels of inositol 1,3,4-trisphosphate [I(1,3,4)P3] first rose significantly at 5-10 s and remained 5- to 10-fold elevated for at least 30 minutes. These changes were accompanied by reciprocal 29-36% decreases in PIP2 (within 5-10 s, the earliest time points examined), PIP (within 60 s), and PI (within 60 s). These results document that, as in other cells responding to more classic "Ca(2+)-mobilizing" hormones, the high Ca(2+)-evoked increases in inositol phosphates in bovine parathyroid cells arise from the hydrolysis of phosphoinositides, leading to the rapid accumulation of the active isomer of IP3. The latter presumably underlies the concomitant spike in the cytosolic calcium concentration (Ca(i)) in parathyroid cells.

Animals↗
PubMed1992

The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant syndrome of unknown aetiology characterized by lifelong elevation in serum calcium concentration and low urinary calcium excretion. These features suggest that the causal gene is important for maintenance of extracellular calcium homeostasis by the parathyroid gland and kidney. To identify the chromosomal location of FHH gene(s), we clinically evaluated 114 individuals in four unrelated affected families and performed linkage analyses. The disease gene mapped to the long arm of chromosome 3 in each family (combined maximum multipoint lod score = 20.67). We suggest that this is the predominant FHH locus and anticipate that identification of the FHH gene will improve our understanding of the molecular basis for physiologic and pathologic regulation of calcium.

Base Sequence↗
PubMed1992

Microbial flora of the trachea during intubation of patients undergoing upper abdominal surgery.

BACKGROUND: The presence of Haemophilus influenzae in the oropharynx is correlated with the subsequent development of chest infection. The importance of colonisation of the trachea by bacteria at the time of surgery is uncertain. This study investigated the tracheal flora at the time of intubation in 24 patients undergoing elective upper abdominal surgery. METHODS: The bacterial flora of the trachea was sampled in all 24 patients immediately after intubation and immediately before extubation. Patients were assessed postoperatively for the development of chest infection. RESULTS: Bacteria, including H influenzae in five cases, were isolated from the post-intubation brushings of the trachea of 15 patients. The pre-extubation brushings from only four patients yielded growth. Three of five patients developing a chest infection were colonised by H influenzae according to the postintubation brush, compared with two of 19 without chest infections. Before extubation two of five developing chest infections had H influenzae in the trachea but none of 19 without infection. All but one of the patients from whom H influenzae was isolated were smokers. CONCLUSIONS: These results suggest that the increased risk of postoperative chest infection in cigarette smokers may be due in part to colonisation of the trachea by H influenzae at the time of operation.

Adult↗
PubMed1992

A comparison of the effects of concanavalin-A and tetradecanoylphorbol acetate on the modulation of parathyroid function by extracellular calcium and neomycin in dispersed bovine parathyroid cells.

Ca2+ and other polyvalent cations as well as polycations, such as neomycin, produce similar effects on intracellular second messengers and PTH release in dispersed bovine parathyroid cells, but it is unclear whether all of these agents share the same mechanism of action. The lectin Concanavalin-A (Con-A) and the activator of protein kinase-C tetradecanoylphorbol acetate (TPA) blunt the effects of elevated extracellular calcium (Ca2+) concentrations on several aspects of parathyroid function, including PTH release, the cytosolic calcium concentration, and the accumulation of cAMP and inositol phosphates. In the present studies we used these two agents as well as pertussis toxin as probes to investigate further whether neomycin acts on parathyroid cells through the same receptor-like mechanism used by extracellular Ca2+ to regulate parathyroid function. Con-A and TPA both enhanced PTH release by about 2-fold at 0.5-1 x 10(-4) M neomycin, concentrations that inhibited PTH release to an extent (40-50%) similar to that seen with high (1.5-2 mM) Ca2+. Con-A also reduced the inhibition of agonist-stimulated cAMP accumulation by the same concentrations of neomycin. Conversely, Con-A and TPA produced 70-80% decreases in the cytosolic calcium concentration transient and the accumulation of inositol phosphates stimulated by neomycin. The effects of these two agents on neomycin-regulated parathyroid function were similar in magnitude to their actions on the modulation of these same parameters by extracellular Ca2+. Pertussis toxin, however, which we have previously shown to block the inhibitory effects of high Ca2+ and neomycin on cAMP accumulation, had no effect on the inhibition of PTH release by these two agents. These results provide further indirect evidence that polyvalent cations and polycations act on the parathyroid cell through related pathways, which probably involve cell surface moieties containing carbohydrate(s).

Animals↗
PubMed1992

Structure-function relationships for the effects of various aminoglycoside antibiotics on dispersed bovine parathyroid cells.

We previously showed that the polycationic aminoglycoside antibiotic neomycin mimics the effects of high extracellular calcium (Ca2+) concentrations on several aspects of parathyroid function. In the present studies we examined the actions of several additional aminoglycosides on dispersed bovine parathyroid cells to investigate the relationship between antibiotic structure and function in eliciting Ca(2+)-like effects on intracellular second messengers and PTH release. Of the antibiotics tested, those with six amino groups (neomycin-B and -C) were most potent in inhibiting dopamine-stimulated cAMP accumulation, showing IC50 values (the concentration producing a half-maximal inhibitory effect) of 7.7 x 10(-5) and 1.5 x 10(-4) M. Gentamicin-C, paromomycin, and tobramycin, which have five amino groups, were less potent, with IC50 values of 4 x 10(-4), 10(-3), and 3.3 x 10(-4) M, respectively, while gentamicin-B, kanamycin, and ribostamycin, with four amino groups, were least potent (respective IC50 values, 2.0, 2.9, and 3 x 10(-3) M). These antibiotics showed a similar order of potency for inhibiting PTH release, with a close correlation between their IC50 values for modulating cAMP accumulation and PTH release (r = 0.98; P less than 0.001). Finally, they showed qualitatively similar potencies for eliciting transient increases in the cytosolic free Ca2+ concentration arising from the release of Ca2+ from intracellular stores. Neomycin-B and -C both acted at 10(-4) M; gentamicin-C, paromomycin, and tobramycin evoked free intracellular Ca2+ spikes at 1.4 x 10(-4) to 6.3 x 10(-4) M; and gentamicin-B, kanamycin, and ribostamycin had little or no effect at 7 x 10(-4) M, the highest concentration tested. Thus, a variety of aminoglycoside antibiotics mimic the effects of Ca2+ and other polyvalent cations on parathyroid function. Their relative potencies are closely related to the total number of amino groups on the molecule, with a 5- to 6-fold increase in potency for each additional amino group between four and six.

Animals↗
PubMed1992

Lower serum ionized calcium and abnormal calciotropic hormone levels in preeclampsia.

Relative hypocalciuria has been reported in women with preeclampsia. However, there has been no systematic explanation for this finding. We measured serum and urinary calcium and serum calciotropic hormones in third trimester women with preeclampsia (n = 12, gestational hypertension and proteinuria) and with normotensive pregnancies (n = 24) to try to explain these changes. We confirmed that the women with preeclampsia have a relative hypocalciuria (2.9 +/- 0.7 vs. 6.5 +/- 0.2 mmol/day, P less than 0.01). Preeclamptic women also had lower serum ionized calcium than normotensive third trimester pregnant women (1.20 +/- 0.01 vs. 1.26 +/- 0.01 mmol/L, P less than 0.02). Intact PTH levels were significantly higher in preeclamptic women (29.9 +/- 4.3 vs. 15.4 +/- 1.3 ng/L, P less than 0.01) and a significant inverse relationship was observed between PTH and both urine calcium (r = -0.60, P less than 0.0001) and serum ionized calcium (r = -0.36, P less than 0.05). We measured vitamin D metabolites in a subgroup of both normotensive and preeclamptics. Preeclamptic and normotensive pregnant women had equivalent levels of 25-hydroxyvitamin D [25(OH)D]; however, preeclamptics had significantly lower 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels (172.1 +/- 18.5 vs. 219.6 +/- 12.7 pmol/L, P less than 0.05). Lower 1,25-(OH)2D may contribute to suboptimal intestinal absorption of calcium during a time of increased calcium demand resulting in lower ionized calcium, increased PTH, and hypocalciuria in preeclampsia. Abnormalities in calcium homeostasis may contribute to the increased vascular sensitivity documented in preeclampsia.

Adult↗
PubMed1992

Interrelationships between the renin-angiotensin-aldosterone and calcium homeostatic systems.

Blood pressure is affected by both sodium and calcium intake. To determine if there is an interaction between the regulatory mechanisms for these two cations, eight normal male volunteers received the following 1-h infusions on three different days: 1) angiotensin II (AII), 2) the synthetic 1-34 amino terminal fragment of human PTH [hPTH(1-34)], and 3) AII and hPTH(1-34) together. Blood samples were obtained at t = 0 and every 20 min during each infusion and urine was collected for 3 h both before and after the start of each infusion. Infusion of AII produced an increase in intact PTH from 18 +/- 2 to 31 +/- 4 ng/L (P < 0.05), most likely in response to a small decrease in serum ionized calcium (1.25 +/- 0.01 to 1.23 +/- 0.01 mmol/L, P < 0.05). Urinary excretion of calcium was unchanged. Infusion of hPTH(1-34) at 200 U/h increased N-terminal PTH levels (18 +/- 3 to 268 +/- 42 ng/L, P < 0.05), decreased tubular reabsorption of phosphate (0.92 +/- 0.03 to 0.82 +/- 0.11, P < 0.05), and increased urinary cAMP (0.18 +/- 0.02 to 0.53 +/- 0.05 nmol/L of glomerular filtrate, P = 0.0001). hPTH(1-34) infusion suppressed endogenous intact PTH (18 +/- 3 to 14 +/- 2 ng/L, P < 0.005) and increased PRA from 0.14 +/- 0.02 to 0.32 +/- 0.05 ng/(L.s) (P < 0.05) without a change in serum ionized calcium which suggests direct effects of hPTH(1-34) on the parathyroid glands and the juxtaglomerular apparatus. The effects of AII and hPTH(1-34) were antagonistic with little change in serum ionized calcium, intact PTH, or PRA when both were infused together. These interrelationships between the major hormonal systems controlling sodium and calcium homeostasis suggest a mechanism underlying the close association of calcium and sodium in the regulation of blood pressure.

Adult↗
PubMed1992

Tertiary hyperparathyroidism during high phosphate therapy of familial hypophosphatemic rickets.

We report the development of severe tertiary hyperparathyroidism in three girls treated for familial hypophosphatemic rickets and characterize parathyroid function in vivo and in vitro. All patients had been previously treated with relatively large doses of inorganic phosphorus (125 mm/day) and ergocalciferol or calcitriol for several years and had radiographic evidence of long-standing hyperparathyroidism. Even in the presence of extremely elevated PTH levels, oral phosphate lowered serum calcium levels in vivo and further stimulated PTH secretion. Profound multiglandular parathyroid hyperplasia was found in each patient at surgery. Examination of the secretory characteristics of the excised parathyroid tissue revealed that either relatively high calcium concentrations were generally needed to suppress PTH secretion or PTH secretion was not suppressible. Caution is recommended when relatively large doses of phosphate are used to treat familial hypophosphatemic rickets.

Calcitriol↗
PubMed1992

Murine splenic null cell compartment contains distinct haemopoietic subpopulations: enlargement of a myeloid and an undifferentiated subset with the development of splenomegaly in New Zealand black mice.

We have previously reported that non-T, non-B 'null' cells increase with age in New Zealand Black (NZB) mice resulting in splenomegaly. Using a panel of monoclonal antibodies recognizing lineage-specific cell surface antigens we demonstrate four distinct subsets within this null cell compartment: (1) undifferentiated; (2) T lineage with undetectable Thy-1.2; (3) myeloid/erythroid; and (4) a pre-B/plasma cell type. All four subsets also occur in non-autoimmune mice. The frequency of these populations are similar in the young mice of all the strains examined, although the total number of null cells is higher in NZB. The elevation of null cells in young NZB mice is controlled by a single dominant gene in the genetic cross with New Zealand White (NZW) mice and does not appear closely related to the subsequent development of autoimmune disease. The proportion of myeloid/erythroid null cells increases with age in NZB as splenomegaly develops.

Animals↗
PubMed1991

Polyarginine, polylysine, and protamine mimic the effects of high extracellular calcium concentrations on dispersed bovine parathyroid cells.

We investigated the effects of the basic peptides polyarginine, protamine, and polylysine on dispersed bovine parathyroid cells. All three peptides produced a dose-dependent inhibition of dopamine-stimulated cAMP accumulation, with half-maximal inhibition at 4 x 10(-8), 1.5 x 10(-7), 3 x 10(-7), and 2 x 10(-6) M, respectively, for polyarginine, protamine, and two preparations of polylysine of molecular weights 10,200 and 3800. The inhibition of cAMP accumulation was reversible and was blocked by preincubating the cells overnight with 0.5 micrograms/ml of pertussis toxin. The same peptides also inhibited PTH release at similar concentrations, markedly stimulated the accumulation of inositol phosphates at two- to threefold higher concentrations, and produced transient increases in the cytosolic Ca2+ concentration (Cai) in fura-2-loaded parathyroid cells. The polylysine-evoked spike in Cai persisted despite the removal of extracellular Ca2+, indicating that it arose from intracellular Ca2+ stores. Exposure of the cells to elevated extracellular magnesium (Mg2+) concentrations elicited a similar spike in Cai but blocked the Cai transient in response to subsequent addition of polylysine, or vice versa. Thus, Mg2+ and polylysine mobilize Ca2+ from the same intracellular store(s). These results indicate that highly basic peptides closely mimic the effects of polyvalent cations on parathyroid function, suggesting that both agents may regulate parathyroid function via similar biochemical pathways.

Animals↗
PubMed1991

An energetic evaluation of a "Smith" collagen microfibril model.

An energy minimized three-dimensional structure of a collagen microfibril template was constructed based on the five-stranded model of Smith (1968), using molecular modeling methods and Kollman force fields (Weiner and Kollman, 1981). For this model, individual molecules were constructed with three identical polypeptide chains [Gly-Pro-Pro)n, (Gly-Prop-Hyp)n, or (Gly-Ala-Ala)n, where n = 4, 12, and 16) coiled into a right-handed triple-helical structure. The axial distance between adjacent amino acid residues is about 0.29 nm per polypeptide chain, and the pitch of each chain is approximately 3.3 residues. The microfibril model consists of five parallel triple helices packed so that a left-handed superhelical twist exists. The structural characteristics of the computed microfibril are consistent with those obtained for collagen by X-ray diffraction and electron microscopy. The energy minimized Smith microfibril model for (Gly-Pro-Pro)12 has an axial length of about 10.2 nm (for a 36 amino acid residue chain), which gives an estimated D-spacing (234 amino acids per chain) of approximately 66.2 nm. Studies of the microfibril models (Gly-Pro-Pro)12, (Gly-Pro-Hyp)12, and (Gly-Ala-Ala)12 show that nonbonded van der Waals interactions are important for microfibril formation, while electrostatic interactions contribute to the stability of the microfibril structure and determine the specificity by which collagen molecules pack within the microfibril.

Amino Acid Sequence↗
PubMed1991

Oropharyngeal flora and chest infection after upper abdominal surgery.

The oropharyngeal flora was determined before and after operation in 127 patients undergoing upper abdominal surgery. Swabs of the oropharynx were obtained on the day before operation and on the first, third, and fifth postoperative days. Isolation of Haemophilus influenzae, Streptococcus pneumoniae, and coliforms was noted. In the 108 patients with the full series of throat swabs the incidence of oropharyngeal colonisation by H influenzae was 16% and was unchanged after operation. S pneumoniae was present in only 5.6 (six patients) before operation and the incidence fell to 1.9% (two patients). There was a transient rise in coliform colonisation postoperatively. Twenty four patients developed a chest infection. In eight a bacterial cause was established, in six H influenzae and in two S pneumoniae. There was a significant relation between the carriage of H influenzae before operation and development of a chest infection. H influenzae was also found more often in cigarette smokers. The presence of S pneumoniae or coliform organisms before surgery was not related to the development of infection. The high incidence of postoperative chest infection in cigarette smokers appears to be due in part to preoperative colonisation of the oropharynx by H influenzae.

Abdomen↗
PubMed1991

Cytosolic calcium responses of single rMTC 44-2 cells to stimulation with external calcium and potassium.

Few endocrine tissues can detect changes in the extracellular Ca2+ concentration within the physiological range and modify their hormone secretion accordingly. A rat cell line of C-cell origin (rMTC 44-2) secretes calcitonin and neurotensin in response to small increases in external Ca2+. To better understand the mechanism of extracellular Ca2+ sensing in this cell type, we studied single fura-2-loaded rMTC 44-2 cells perfused with increasing concentrations of Ca2+ and K+. In the basal state (Ca2+ = 0.5 mM), cytosolic Ca2+ levels were 53 nM, with 27% of the cells having spikes or oscillations. With elevation of the external Ca2+ to between 0.5 and 4 mM, 84% of the cells showed a rapid (less than 5 s) rise in cytosolic Ca2+ to values 2- to 10-fold higher than basal levels. Most of the responding cells exhibited complex patterns of cytosolic Ca2+ fluctuations, including oscillations with frequencies varying from less than 1/min to as many as 6/min. When averaged over time, the cytosolic Ca2+ of individual cells showed a dose-dependent response with changes in external Ca2+, resembling the relationship between extracellular Ca2+ and calcitonin secretion. With continued or repeated stimulation, the spike amplitude often declined. These cytosolic Ca2+ responses were attenuated in the presence of the Ca(2+)-channel blockers cadmium and nifedipine. Cytosolic Ca2+ responses to perfusion with elevated K+ (20 mM) were similar in waveform to those seen with Ca2+ stimulation. Most cells displayed cytosolic Ca2+ changes in response to both ionic secretagogues when stimulated with external Ca2+ or K+.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Circulating levels of biologically active and immunoreactive intact parathyroid hormone in human newborns.

We evaluated circulating levels of biologically active and immunoreactive intact parathyroid hormone [iPTH-(1-84)] in 47 newborns at birth and eight hypocalcemic preterm infants during the first 10 d of life. Use of two sensitive detection systems, the cytochemical bioassay and an immunoradiometric assay specific for intact parathyroid hormone, enabled us to compare plasma concentrations of PTH-like bioactivity (bioPTH) and iPTH-(1-84). Mean umbilical venous plasma bioPTH was elevated in nondiabetic term and preterm newborns [22.5 +/- 3.1 (+/- SEM) and 15.8 +/- 2.5 ng-equiv/L, respectively] compared with normal adult subjects (9.8 +/- 2.6 ng-equiv/L; p less than 0.01). Umbilical bioPTH was suppressed in five term infants of diabetic mothers (2.6 +/- 0.4 ng-equiv/L). In contrast, iPTH-(1-84) was low in term and preterm nondiabetic infants' and term infants of diabetic mothers' umbilical samples (5.4 +/- 1.5, 4.3 +/- 1.5, and 2.4 +/- 1.0 ng/L, respectively). Umbilical venous bioPTH was highly correlated with the magnitude of the transplacental calcium gradient (r = 0.90; p less than 0.05). In eight preterm infants studied longitudinally, by 24-36 h of life, declining plasma total and ionized calcium (1.71 +/- 0.04 and 0.78 +/- 0.03 mmol/L, respectively) were accompanied by a significant rise in both bioPTH (41.2 +/- 6.3 ng-equiv/L) and iPTH-(1-84) (56.3 +/- 11.6 ng/L). These data indicate that the 3rd trimester fetoplacental circulation contains levels of bioPTH several-fold higher than those of immunoreactive intact hormone. We also conclude that even hypocalcemic preterm newborn infants can significantly elevate circulating levels of PTH.

Adult↗