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Biomedical subjects

J E Hall

Publications and source records attributed to J E Hall.

At least 181 records · Page 10Linked to original sources
PubMed1995

Predicting the integrity of vertebral bone screw fixation in anterior spinal instrumentation.

STUDY DESIGN: Using 2-week-old calf lumbar vertebrae as a model for the human adolescent spine, the strength and rigidity of different methods of anterior spinal screw fixation and the use of noninvasive techniques for predicting bone screw stability before surgery and screw insertional torque intraoperatively were investigated. OBJECTIVES: The objectives were to determine what factors most affect the strength and rigidity of screw fixation, to determine the strongest and most rigid type of screw fixation for anterior spinal instrumentation, and to determine if noninvasive measurements of bone density before surgery by dual energy x-ray absorptiometry or quantitative computed tomography and if intraoperative measurement of screw insertional torque can be used to predict the in vivo strength and rigidity of vertebral screw fixation. SUMMARY OF BACKGROUND DATA: Anterior spinal instrumentation is an efficient method to correct spinal deformities in the thoracolumbar and lumbar spine. Fewer vertebrae are instrumented and arthrodesed, allowing for greater spine mobility. The forces transmitted to each vertebra are higher, perhaps accounting for the clinical failure rate of 13-30% at the metal bone interface from screw cut out. METHODS: Quantitative computed tomography and dual energy x-ray absorptiometry were used to assess the bone density of 24, 2-week-old calf lumbar vertebrae. Four different methods of vertebral screw fixation were evaluated: unicortical screw, bicortical screw, bicortical screw and washer, and bicortical screws and staple. The maximal screw insertional torque was measured for each specimen. Each vertebral body-screw construct failed in a mode simulating in vivo screw cut out. The applied moment and rotatory displacement were recorded. Ash density was measured for each vertebral body after removing all hardware. RESULTS: Noninvasive measures of bone density varied linearly with ash density (P < 0.01). Screw insertional torque varied linearly with bone mineral content and bone mineral density (r2 = 0.50) and was correlated with the yield moment for all types of fixation except the staple. Density measured by quantitative computed tomography did not affect rigidity or yield moment. Post hoc analysis showed that the screw-staple construct was the strongest and most rigid form of fixation. CONCLUSIONS: Measurement of bone density before surgery using dual energy x-ray absorptiometry and intraoperative measurement of screw insertional torque can be used to assess the stability of anterior spinal instrumentation. A bicortical screw inserted through a Dwyer-type staple provided the strongest and most rigid form of fixation.

Absorptiometry, Photon↗
PubMed1995

Dicationic diarylfurans as anti-Pneumocystis carinii agents.

Seven dicationic 2,5-diarylfurans have been synthesized, and their interactions with poly(dA-dT) and the duplex oligomer d(CGCCAATTCGCG)2 were evaluated by Tm measurements. The inhibition of topoisomerase II isolated from Giardia lamblia, the inhibition of growth of G. lamblia in cell culture by these furans, and the effectiveness of these compounds against Pneumocystis carinii in the immunosuppressed rat model have been assessed. Strong binding affinities to poly(dA-dT) and to the oligomer were observed for the dicationic furans, and the interaction strength is directly correlated to the biological activity of the compounds. An X-ray structure for the complex of the dicationic amidine derivative, 2,5-bis(4-guanylphenyl)furan (1), with the oligomer demonstrates the snug fit of these compounds with the AATT minor-groove binding site and hydrogen bonds to AT base pairs at the floor of the minor groove. The stronger DNA binding molecules are the most effective inhibitors of topoisomerase II and G. lamblia in cell culture, and there is a correlation for both DNA interaction and topoisomerase II inhibition with the biological activity of these compounds against G. lamblia. Compound 1 is the most effective against P. carinii, it is more active and less toxic than pentamidine on intravenous administration and it is also effective by oral dosage. The results presented here suggest a model for the biological action of these compounds in which the dication first binds in the minor groove of DNA and forms a complex that results in the inhibition of the microbial topoisomerase II enzyme.

Animals↗
PubMed1995

A method for determining the unitary functional capacity of cloned channels and transporters expressed in Xenopus laevis oocytes.

The Xenopus laevis oocyte is widely used to express exogenous channels and transporters and is well suited for functional measurements including currents, electrolyte and nonelectrolyte fluxes, water permeability and even enzymatic activity. It is difficult, however, to transform functional measurements recorded in whole oocytes into the capacity of a single channel or transporter because their number often cannot be estimated accurately. We describe here a method of estimating the number of exogenously expressed channels and transporters inserted in the plasma membrane of oocytes. The method is based on the facts that the P (protoplasmic) face in water-injected control oocytes exhibit an extremely low density of endogenous particles (212 +/- 48 particles/microns2, mean, SD) and that exogenously expressed channels and transporters increased the density of particles (up to 5,000/microns2) only on the P face. The utility and generality of the method were demonstrated by estimating the "gating charge" per particle of the Na+/glucose cotransporter (SGLT1) and a nonconducting mutant of the Shaker K+ channel proteins, and the single molecule water permeability of CHIP (Channel-like In-tramembrane Protein) and MIP (Major Intrinsic Protein). We estimated a "gating charge" of approximately 3.5 electronic charges for SGLT1 and approximately 9 for the mutant Shaker K+ channel from the ratio of Qmax to density of particles measured on the same oocytes. The "gating charges" were 3-fold larger than the "effective valences" calculated by fitting a Boltzmann equation to the same charge transfer data suggesting that the charge movement in the channel and cotransporter occur in several steps. Single molecule water permeabilities (pfs) of 1.4 x 10(-14) cm3/sec for CHIP and of 1.5 x 10(-16) cm3/sec for MIP were estimated from the ratio of the whole-oocyte water permeability (Pf) to the density of particles. Therefore, MIP is a water transporter in oocytes, albeit approximately 100-fold less effective than CHIP.

Animals↗
PubMed1995

Obesity and hypertension: roles of hyperinsulinemia, sympathetic nervous system and intrarenal mechanisms.

Hypertension is a well-recognized complication of obesity. However, the mechanisms for the development of obesity hypertension are not known. One mechanism proposed is that the hyperinsulinemia present in obese hypertensive patients causes hypertension via sodium retaining and/or sympathetic nervous system stimulatory effects. However, numerous studies in dogs have revealed no evidence for such chronic pressor actions of hyperinsulinemia. This is in close agreement with studies in human insulinoma patients that show marked hyperinsulinemia and normal blood pressure. The appropriateness of the dog as an experimental model is strengthened by reports from our laboratory and others that inducing obesity in dogs reproduces many of the characteristics of obesity in humans, including insulin resistance, hyperinsulinemia, sodium retention, hypertriglyceridemia and hypertension. Recent studies in obese dogs have indicated that significant increases in renal medullary cellularity and intercellular matrix deposition could contribute to the sodium retention and hypertension. Additional evidence suggests that sympathetic nervous system stimulation also may contribute to the elevated blood pressure. However, the mechanisms through which obesity induces these changes and the temporal relationship between these factors and the development of the hypertension remains to be determined.

Animals↗
PubMed1995

Cardiovascular actions of insulin: are they important in long-term blood pressure regulation?

1. In recent years, there has been considerable interest in the possibility that insulin may have important cardiovascular as well as metabolic actions. Perhaps the best documented cardiovascular effect of insulin is to cause peripheral vasodilation, especially in skeletal muscle. Hyperinsulinaemia also stimulates sympathetic activity and causes antinatriuresis, but these effects may be linked, at least in part, to the metabolic actions of insulin that elicit peripheral vasodilation and a tendency toward hypotension. Normal, fasting levels of insulin appear to have very little influence on peripheral vascular resistance, sympathetic activity or renal sodium excretion. 2. Decreased sensitivity of the peripheral tissues to the metabolic effects of insulin and compensatory hyperinsulinaemia have been postulated to play key roles in the pathophysiology of diseases such as hypertension and atherosclerosis. Although impaired insulin action (insulin resistance) and hyperinsulinaemia often accompany essential hypertension, especially when associated with obesity, there is currently little direct evidence for a cause and effect relationship between insulin resistance, hyperinsulinaemia and increased arterial pressure. Chronic increases in plasma insulin levels in dogs and humans have not been shown to cause hypertension, although hyperinsulinaemia raises blood pressure in rats. 3. Further research is needed to determine whether there are pathophysiological conditions or genetic factors that may predispose humans to a hypertensive effect of hyperinsulinaemia and/or insulin resistance.

Adenosine Triphosphatases↗
PubMed1995

Metabolism is an important route of pentamidine elimination in the rat: disposition of 14C-pentamidine and identification of metabolites in urine using liquid chromatography-tandem mass spectrometry.

This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of 14C-labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22 +/- 2% (mean +/- S.D.) and 25 +/- 4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21 +/- 5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76 +/- 15% (mean +/- S.D.) of the total excreted radioactivity on day 1 and 97 +/- 1% on day 6. HPLC--tandem mass spectometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.

Animals↗
PubMed1995

Reduced parasympathetic control of heart rate in obese dogs.

We investigated why resting heart rate is elevated in dogs fed a high saturated fat diet for 12.7 +/- 1.8 wk. Obese dogs exhibited elevated body weight (59%), blood pressure (14%), and heart rate (25%). Differences in resting heart rate (control, 58 +/- 5 beats/min; obese, 83 +/- 7 beats/min) were abolished after hexamethonium, indicating an autonomic mechanism. Hexamethonium also reduced blood pressure in obese (20 +/- 4 mmHg) but not control (9 +/- 6 mmHg) animals. Propranolol did not affect heart rate in either group, excluding a beta-adrenergic mechanism. Subsequent administration of atropine increased heart rate more in control than in obese dogs (110 +/- 9 vs. 57 +/- 11 beats/min). The sensitivity of the cardiac limb of the baroreflex (Oxford method) was reduced by 46% in the obese group, confirming impairment of the parasympathetic control of heart rate. The standard deviation of blood pressure measurements was normal when expressed as a percentage of the mean arterial blood pressure (control, 11.2 +/- 0.4%; obese, 11.2 +/- 0.5%). Our results indicate that the development of obesity in dogs fed a high saturated fat diet is accompanied by an attenuated resting and reflex parasympathetic control of heart rate.

Animals↗
PubMed1995

Increased hyaluronic acid in the inner renal medulla of obese dogs.

Dogs placed on a high-fat diet develop obesity and hypertension associated with marked sodium retention that is due to increased tubular reabsorption. Previous studies showed that renal interstitial hydrostatic pressure is elevated in obese dogs compared with lean dogs, and histological studies revealed increases in medullary interstitial cells and expansion of the medullary but not the cortical extracellular matrix. This matrix stained intensively with Alcian Blue at pH 2.6, colloidal iron, and periodic acid-Schiff, suggesting increased glycosaminoglycans. The goal of this study was to quantitate medullary glycosaminoglycan content in obese (n = 8) compared with lean (n = 8) dogs. Measurement of total glycosaminoglycan content, estimated from uronic acid content, and of hyaluronate, the most abundant glycosaminoglycan in canine renal medulla, with an enzyme-linked immunosorbent assay indicated that there were no significant differences in total glycosaminoglycan or hyaluronate contents in the outer medulla of obese dogs compared with those in lean dogs. In contrast, in the inner medulla of obese dogs there was a 140% increase in hyaluronate compared with the content in lean dogs (4.3 +/- 0.5 versus 1.8 +/- 0.2 mg hyaluronate per gram wet tissue, respectively; P < .05); however, total glycosaminoglycan content was not significantly different (6.9 +/- 0.7 versus 6.2 +/- 0.5 mg uronic acid per gram wet tissue) in obese and lean dogs. These results suggest a change in the relative proportion of the glycosaminoglycan species in the inner medulla of obese dogs, with a selective increase in hyaluronate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Renal denervation attenuates the sodium retention and hypertension associated with obesity.

Recent studies have indicated that obesity is associated with hypertension, sodium retention, and increased sympathetic nervous system activity. The purpose of this study was to determine the role of renal nerves in mediating the sodium retention and hypertension associated with obesity. We determined the hemodynamic and renal excretory responses to a high-fat diet in control (n = 6) and bilaterally renal-denervated (n = 7) chronically instrumented dogs. After a control period of 8 days, dogs were placed on a high-fat diet for 5 weeks. In response to a high-fat diet, body weight increased from 19.9 +/- 2.2 to 29.9 +/- 2.4 kg in the control group and from 21.1 +/- 2.0 to 32.4 +/- 1.9 kg in the bilaterally renal-denervated group. Heart rate increased from 81 +/- 8 to 113 +/- 7 beats per minute in the control group and from 79 +/- 7 to 103 +/- 8 beats per minute in the bilaterally renal-denervated group. Arterial pressure increased significantly from 95 +/- 2 to 109 +/- 4 mm Hg in the control group. In contrast, 5 weeks of a high-fat diet in the bilaterally renal-denervated group did not significantly increase arterial pressure (which went from 87 +/- 3 to 90 +/- 4 mm Hg). Furthermore, the decrease in sodium excretion in response to the high-fat diet was significantly greater in the control group than in the bilaterally renal-denervated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Hemodynamic and renal responses to chronic hyperinsulinemia in obese, insulin-resistant dogs.

We previously reported that chronic hyperinsulinemia does not cause hypertension in normal insulin-sensitive dogs. However, resistance to the metabolic and vasodilator effects of insulin may be a prerequisite for hyperinsulinemia to elevate blood pressure. The present study tested this hypothesis by comparing the control of systemic hemodynamics and renal function during chronic hyperinsulinemia in instrumented normal conscious dogs (n = 6) and in dogs made obese and insulin resistant by feeding them a high-fat diet for 6 weeks (n = 6). After 6 weeks of the high-fat diet, body weight increased from 24.0 +/- 1.2 to 40.9 +/- 1.2 kg, arterial pressure rose from 83 +/- 5 to 106 +/- 4 mm Hg, and cardiac output rose from 2.98 +/- 0.29 to 5.27 +/- 0.54 L/min. Insulin sensitivity, assessed by fasting hyperinsulinemia and by the hyperinsulinemic euglycemic clamp technique, was markedly reduced in obese dogs. Insulin infusion (1.0 mU/kg per minute for 7 days) in obese dogs elevated plasma insulin from 42 +/- 12 microU/mL to 95 to 219 microU/mL but failed to increase arterial pressure, which averaged 106 +/- 4 mm Hg during control and 102 +/- 4 mm Hg during 7 days of insulin infusion. Hyperinsulinemia for 7 days in obese dogs elevated heart rate from 116 +/- 8 to 135 +/- 7 beats per minute but caused no significant changes in cardiac output, in contrast to normal dogs (n = 6), in which marked increases in cardiac output (31 +/- 5% after 7 days) and decreases in total peripheral resistance occurred during chronic insulin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Serum follistatin levels in women: evidence against an endocrine function of ovarian follistatin.

Follistatin is a monomeric protein first identified in and isolated from ovarian follicular fluid. Evidence that follistatin might be an ovarian endocrine hormone functioning in a negative feedback fashion to modulate pituitary FSH production is based primarily on in vitro experiments. To examine the possible role of follistatin as an endocrine agent in vivo, we sought to relate circulating levels of follistatin to ovarian activity in women. Therefore, we developed a specific and sensitive homologous RIA using antiserum generated against recombinant human follistatin for the measurement of total follistatin in the presence or absence of activin. Follistatin was measured quantitatively (106 +/- 6% recovery) using calibration standards ranging from 0.4-25 ng/tube and up to 400 microL/tube serum. Furthermore, all of the endogenous follistatin measured in human serum could be removed by adsorption to activin-coated plates. Using this homologous RIA, human follicular fluid (100-600 ng/mL; n = 75) contained 3-150 times more follistatin than serum (4-35 ng/mL), an observation consistent with the notion that serum follistatin originates from the gonad. However, further studies of follistatin levels across the normal menstrual cycle (mean +/- SE, 8.09 +/- 0.73; n = 72 daily samples from 4 women), in pregnant women (17.49 +/- 1.34; n = 8), in daily samples from 20 women undergoing ovarian stimulation by exogenous FSH (9.90 +/- 0.62; n = 119), in postmenopausal women including two ovariectomized individuals (9.57 +/- 0.43; n = 8), and in GnRH-deficient women (9.85 +/- 0.50; n = 6) failed to support the hypothesis that serum levels of follistatin reflect ovarian activity in women. Levels of follistatin measured in serum collected across normal menstrual cycles did not fluctuate. However, the roughly nanomolar concentrations of follistatin measured suggest a physiological role for this protein. Follistatin at nanomolar concentrations may be capable of binding and inactivating circulating activin and perhaps in this way limiting the biological activity of activin to local autocrine or paracrine mechanisms. Measurement of peripheral levels of follistatin apparently represents only a first, albeit crucial, step in the study of the physiological significance of this protein in human reproduction.

Endocrine Glands↗
PubMed1995

Midcycle levels of sex steroids are sufficient to recreate the follicle-stimulating hormone but not the luteinizing hormone midcycle surge: evidence for the contribution of other ovarian factors to the surge in normal women.

The midcycle surge of LH and FSH is critical for final oocyte maturation and ovulation. In normal women, this gonadotropin surge follows a gradual increase in estradiol levels (E) and is concomitant with a small increase in progesterone (P) levels. However, whether sex steroids alone are sufficient to induce the complex neuroendocrine interactions underlying this switch from negative to positive feedback is unknown. In this study, physiological midcycle levels of E, with and without periovulatory levels of P (E+P and E, respectively) were infused into 18 normally cycling women in their early to midfollicular phases. The resulting sex-steroid-induced gonadotropin responses were then compared with 118 spontaneous midcycle surges in 81 normal women. The sex steroid levels achieved by the infusions were within the normal ranges for the spontaneous midcycle surge. However, neither women who received E alone nor those who received E+P had LH responses that achieved those of spontaneous LH surges in the normal menstrual cycle (NMC) [82.7 +/- 16.23 IU/L E (mean +/- SEM), 69.7 +/- 12.01 IU/L E+P vs. 121.7 +/- 6.23 IU/L NMC, P < 0.05 E and P < 0.005 E+P vs. NMC]. In contrast, peak FSH levels evoked by E and P matched the spontaneous FSH peaks (19.0 +/- 2.1 IU/L E, 24.5 +/- 4.0 IU/L E+P vs. 23.3 +/- 0.9 IU/L NMC, P = 0.07 E and P = 0.71 E+P vs. NMC). In conclusion, sex steroids alone do not seem to be sufficient to stimulate the normal midcycle LH surge. We hypothesize that other ovarian factors, which are missing in the midfollicular phase, are required for the generation of the normal midcycle surge of LH.

Adolescent↗
PubMed1995

Insulin resistance, hyperinsulinemia, and hypertension: causes, consequences, or merely correlations?

Resistance to the metabolic effects of insulin and compensatory hyperinsulinemia have been postulated to mediate human essential hypertension, especially when associated with obesity. Evidence supporting this hypothesis has come mainly from epidemiological studies showing correlations between insulin resistance, hyperinsulinemia, and blood pressure, and from short-term studies suggesting that insulin has renal and sympathetic effects that could raise blood pressure if the effects were sustained. However, there have been no studies demonstrating a direct causal relationship between chronic hypertension and insulin resistance or hyperinsulinemia in humans. The few long-term studies that have been conducted in dogs and humans do not support the hypothesis that hyperinsulinemia causes hypertension or potentiates the hypertensive effects of other pressor agents such as angiotensin II or increased adrenergic tone. To the contrary, multiple studies in dogs and in humans suggest that the vasodilator action of insulin tends to reduce blood pressure. Although resistance to insulin's metabolic effects has been suggested to be essential for hyperinsulinemia to cause hypertension, chronic increases in plasma insulin concentrations do not cause hypertension in dogs or humans even in the presence of insulin resistance. Also, recent studies have also shown that the blood pressure-lowering effects of antihyperglycemic agents, initially believed to lower blood pressure by decreasing insulin resistance, may be unrelated to their effects on insulin sensitivity. Obesity appears to be a key factor in accounting for correlations between insulin resistance, hyperinsulinemia, and hypertension, but increased blood pressure in obesity does not appear to be mediated by insulin resistance and hyperinsulinemia. Although insulin resistance and hyperinsulinemia may not be directly linked to hypertension, there is increasing evidence that metabolic abnormalities associated with insulin resistance may increase the risk of cardiovascular disease (e.g., coronary artery disease) associated with hypertension and Type II diabetes. For this reason, further studies of the long-term effects of insulin resistance on cardiovascular, renal, and metabolic functions are needed.

Animals↗
PubMed1995

Childhood scoliosis: clinical indications for magnetic resonance imaging.

We retrospectively reviewed the magnetic resonance imaging studies that had been made for ninety-five patients who had idiopathic scoliosis. We wished to determine if we could identify any criteria that should be met before these studies are performed. The study group included thirty-one male patients and sixty-four female patients. The average age at the time of the imaging study was thirteen years (range, one to twenty-eight years). The average curve was 41 degrees (range, 11 to 95 degrees). Fourteen patients were seen to have an intraspinal abnormality on the imaging study: twelve had a syrinx, one had a syrinx and an astrocytoma of the spinal cord, and one had dural ectasia. Five of the eight patients who were less than eleven years old and who had a left thoracic curve had an intraspinal abnormality on the imaging study, but this combination of factors did not indicate the need for operative intervention. Four of the intraspinal abnormalities in the fourteen patients necessitated neurosurgical intervention; if the criteria for obtaining the imaging study had been restricted to neck pain and headache--particularly with exertion--and neurological findings such as ataxia, weakness, and a cavus foot, these abnormalities would have been diagnosed.

Adolescent↗
PubMed1994

The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence.

BACKGROUND: Although the medical complications associated with multiple-gestation pregnancies have been well documented, little is known about the effects of such pregnancies on the use of health care resources and the associated costs. This is an important issue because of the increasing use of assisted-reproduction techniques, which commonly result in multiple-gestation pregnancies. METHODS: We determined hospital charges and the use of assisted-reproduction techniques (such as induction of ovulation, in vitro fertilization, and gamete intrafallopian transfer) for 13,206 pregnant women (11,986 with singleton pregnancies, 1135 with twin pregnancies, and 85 with more than two fetuses) who were admitted for delivery to Brigham and Women's Hospital, Boston, in 1986 through 1991 and their 14,033 neonates (11,671 singletons, 2144 twins, and 218 resulting from higher-order multiple gestations). RESULTS: After we controlled for variables known to affect hospital charges, the predicted total charges to the family in 1991 for a singleton delivery were $9,845, as compared with $37,947 for twins ($18,974 per baby) and $109,765 for triplets ($36,588 per baby). Assisted-reproduction techniques were used in 2 percent of singleton, 35 percent of twin, and 77 percent of higher-order multiple-gestation pregnancies; such procedures were approximately equally divided between induction of ovulation alone and in vitro fertilization or gamete intrafallopian transfer. CONCLUSIONS: Multiple-gestation pregnancies, a high proportion of which result from the use of assisted-reproduction techniques, dramatically increase hospital charges. If all the multiple gestations resulting from assisted-reproduction techniques, dramatically increase hospital charges. If all the multiple gestations resulting from assisted-reproduction techniques had been singleton pregnancies, the predicted savings to the health care delivery system in the study hospital alone would have been over $3 million per year. Although assisted reproduction provides tremendous benefits to families with infertility, the increased medical risks entailed by multiple-gestation pregnancies and the associated costs cannot be ignored. We suggest that more attention be paid to approaches to infertility that reduce the likelihood of multiple gestation.

Adolescent↗
PubMed1994

Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women.

To investigate the contribution of hypothalamic gonadotropin-releasing hormone (GnRH) secretion to the midcycle gonadotropin surge in the human, the response of luteinizing hormone (LH) to competitive GnRH receptor blockade achieved by administration of a range of doses of a pure GnRH antagonist was used to provide a semiquantitative estimate of endogenous GnRH secretion. The LH response to 5, 15, 50, and 150 micrograms/kg s.c. of the NAL-GLU GnRH antagonist ([Ac-D-2Nal1,D-4ClPhe2,-D-Pal3,Arg5,D-4-p-met hoxybenzoyl-2-aminobutyric acid6,D-Ala10]GnRH, where 2Nal is 2-naphthylalanine, 4ClPhe is 4-chlorophenylalanine, and 3Pal is 3-pyridylalanine) was measured in normal women in the early and late follicular phases of the menstrual cycle, at the time of the midcycle LH surge and in the early luteal phase. LH decreased in a dose-response fashion after administration of the GnRH antagonist in all cycle phases (P < 0.0001). When this suppression was expressed as maximum percent inhibition, there was no difference in response during the early and late follicular and early luteal phases. However, at the midcycle surge, there was a leftward shift of the dose-response curve with significantly greater suppression of LH at the lower antagonist doses in comparison to the other cycle phases (P < 0.005), but no difference at the highest dose. Thus, we draw the following conclusions. (i) There is a consistently greater degree of LH inhibition by GnRH antagonism at the midcycle surge at submaximal degrees of GnRH receptor blockade than at other phases of the menstrual cycle in normal women. (ii) This leftward shift of the dose-response relationship to GnRH receptor blockade suggests that the overall amount of GnRH secreted at the midcycle surge is less than at other cycle stages. (iii) These data confirm the importance of pituitary augmentation of the GnRH signal at the time of the midcycle gonadotropin surge in the human.

Adolescent↗
PubMed1994

Switch in gap junction protein expression is associated with selective changes in junctional permeability during keratinocyte differentiation.

Gap junctional communication provides a mechanism for regulating multicellular activities by allowing the exchange of small diffusible molecules between neighboring cells. The diversity of gap junction proteins may exist to form channels that have different permeability properties. We report here that induction of terminal differentiation in mouse primary keratinocytes by calcium results in a specific switch in gap junction protein expression. Expression of alpha 1 (connexin 43) and beta 2 (connexin 26) gap junction proteins is down-modulated, whereas that of beta 3 (connexin 31) and beta 4 (connexin 31.1) proteins is induced. Although both proliferating and differentiating keratinocytes are electrically coupled, there are significant changes in the permeability properties of the junctions to small molecules. In parallel with the changes in gap junction protein expression during differentiation, the intercellular transfer of the small dyes neurobiotin, carboxyfluorescein, and Lucifer yellow is significantly reduced, whereas that of small metabolites, such as nucleotides and amino acids, proceeds unimpeded. Thus, a switch in gap junction protein expression in differentiating keratinocytes is accompanied by selective changes in junctional permeability that may play an important role in the coordinate control of the differentiation process.

Animals↗