Biomedical subjects

A L Mark

Publications and source records attributed to A L Mark.

At least 19 recordsLinked to original sources

PubMed2001

Does leptin cause functional peripheral sympatholysis?

Leptin is a protein produced by adipocytes. Leptin is known to markedly and rapidly increase sympathetic nerve activity to the kidney and hindlimb of experimental animals. Recent studies suggest that leptin may stimulate endothelial production of nitric oxide, which could oppose sympathetically induced vasoconstriction. We tested the hypothesis that such actions of leptin may produce peripheral functional sympatholysis. In Sprague-Dawley rats, we intermittently stimulated the abdominal sympathetic trunk and measured renal and hindlimb blood flows before and after 3 h of infusion of leptin (1000 microg/kg, n = 7) or vehicle (n = 7). Leptin did not change arterial pressure, heart rate, or renal or hindlimb conductance over the course of 3 h. In addition, leptin did not significantly alter sympathetically mediated vasomotor responses to electrical stimulation, as compared with vehicle. Thus, we conclude that leptin does not change regional blood flows, and that leptin also does not appear to have vascular or neural actions to cause peripheral functional sympatholysis.

Animals↗

PubMed2001

Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure.

Systemic leptin increases energy expenditure through sympathetic mechanisms, decreases appetite, and increases arterial pressure. We tested the hypothesis that the pressor action of leptin is mediated by the central nervous system. The interaction of dietary salt with leptin was also studied. Leptin was infused for 2 to 4 weeks into the third cerebral ventricle of Sprague-Dawley rats. Arterial pressure was measured by radiotelemetry. To control for the effects of leptin on body weight, vehicle-treated rats were pair-fed to the leptin group. Intracerebroventricular infusion of leptin at 200 ng/h in salt-depleted rats caused a reduction in food intake, weight loss, tachycardia, and decreased arterial pressure. Leptin at 1000 ng/h caused further reduction in food intake, weight loss, and tachycardia and prevented the hypotensive effect of weight loss observed in pair-fed, vehicle-treated animals. Intracerebroventricular leptin at 1000 ng/h in high-salt-fed rats also caused a sustained pressor response (+3+/-1 mm Hg), but high-salt intake did not potentiate the pressor effect of leptin. Intracerebroventricular leptin potentiated the pressor effect of air-jet stress. Intravenous administration of the same dose of leptin (1000 ng/h) did not change weight or arterial pressure, suggesting a direct central nervous system action. In contrast, a high dose of intravenous leptin (18 000 ng/h) caused weight loss and prevented the depressor effect of weight loss. In conclusion, this study demonstrates that high-dose leptin increases arterial pressure and heart rate through central neural mechanisms but leptin does not enhance salt sensitivity of arterial pressure. Leptin appears to oppose the depressor effect of weight loss.

Animals↗

PubMed2001

Role of corticotrophin-releasing factor in effects of leptin on sympathetic nerve activity and arterial pressure.

Leptin and corticotrophin-releasing factor increase sympathetic nervous activity to interscapular brown adipose tissue, kidneys, and adrenal glands. Leptin is known to increase hypothalamic corticotrophin-releasing factor. In this study, we tested the hypothesis that leptin-dependent increases in sympathetic nervous activity are mediated through increases in central nervous system corticotrophin-releasing factor activity. We examined the effects of intracerebroventricular administration of corticotrophin-releasing factor and intravenous leptin on sympathetic nervous activity to interscapular brown adipose tissue through multifiber neurography in anesthetized Sprague-Dawley rats pretreated with intracerebroventricular alpha-helical corticotrophin-releasing factor(9-41) (corticotrophin-releasing factor receptor antagonist) or vehicle. Centrally administered corticotrophin-releasing factor substantially increased interscapular brown adipose tissue sympathetic nervous activity. The responses to corticotrophin-releasing factor were substantially attenuated in animals pretreated with alpha-helical corticotrophin-releasing factor(9-41). Leptin-dependent increases in interscapular brown adipose tissue sympathetic nervous activity were significantly inhibited by pretreatment with alpha-helical corticotrophin-releasing factor(9-41). Interestingly, leptin also significantly increased arterial pressure over 6 hours, but this pressor action was not attenuated by the corticotrophin-releasing factor receptor antagonist. These results suggest that corticotrophin-releasing factor may mediate the sympathoexcitatory effect of leptin on thermogenic tissue without altering its cardiovascular actions.

Adipose Tissue, Brown↗

PubMed2001

Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation?

Leptin decreases appetite and increases sympathetic nerve activity and arterial pressure. Recent reports suggest that leptin may also have peripheral vasodilator actions that would tend to reduce arterial pressure. We tested the hypothesis that the direct vascular actions of leptin oppose sympathetically mediated vasoconstriction. We evaluated the effects of intravenous leptin (1 mg/kg over 3 hours) on arterial pressure and mesenteric, hindlimb, and renal blood flows in conscious rats. We then tested whether blockade of nitric oxide or the sympathetic nervous system would unmask a pressor or depressor effect of leptin, consistent with direct vascular actions. Acute intravenous administration of leptin alone did not change arterial pressure or regional blood flows. This was despite a significant increase in lumbar sympathetic nerve activity. Administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester significantly increased arterial pressure and caused vasoconstriction. However, leptin did not have any significant effect on hemodynamics in the presence of N(G)-nitro-L-arginine methyl ester despite continued sympathoactivation. alpha-Adrenoceptor blockade with prazosin alone or combined with yohimbine significantly decreased arterial pressure and caused vasodilation. Again, leptin did not have any effect on arterial pressure or regional blood flow in the presence of sympathetic blockade. These data demonstrate that leptin does not have vasodilator actions in vivo at concentrations that are sufficient to increase sympathetic nerve activity. The absence of a pressor effect of leptin-induced sympathetic activation may merely reflect the brief duration of leptin administration. These data support the concept that the chronic hemodynamic actions of leptin are likely to be related to sympathetic activation.

Adrenergic alpha-Antagonists↗

PubMed2001

Clinician scientist training program: a proposal for training medical students in clinical research.

There is national alarm about a decline in the number of clinician scientists. Most of the proposed solutions have focused on housestaff and junior faculty. We propose a new national program for training medical students in clinical research. This program, coined "Clinician Scientist Training Program" (CSTP), would consist of a combined degree program in medicine (MD) and clinical research (eg, masters in translational research or masters in clinical epidemiology). Students could enroll in the program at any stage during medical school. After 3 years of medical school, students would spend at least 2 years in a combined didactic and mentored clinical research training program and then complete medical school. Students could elect to pursue more prolonged clinical research training toward a combined PhD and MD. The CSTP is designed to meet six critical challenges: 1) engage students early in clinical research training; 2) provide a didactic clinical research curriculum; 3) expose students to several years of mentored clinical research training; 4) promote debt prevention by providing tuition payments during medical education and a stipend during clinical research training; 5) facilitate prolonged exposure to a community of peers and mentors in a program with national and institutional identity and respect; and 6) permit enrollment in the program as students enter medical school or at any stage during medical school. If the success of the Medical Scientist Training Program in training medical students in basic research is a guide, the CSTP could become a linchpin for training future generations of clinician scientists.

Humans↗

PubMed1999

Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice.

OBJECTIVE: Recent advances in understanding the neuroendocrine pathways regulating appetite, metabolism and body weight afford an opportunity to explore further the mechanisms by which obesity influences arterial pressure. ob/ob(Lep(ob)/Lep(ob)) mice have a mutation in the ob gene and are leptin-deficient. Leptin possesses pressor actions and has been shown to increase arterial pressure when infused chronically or over-expressed transgenically. In contrast, agouti yellow obese(Ay) mice have overexpression of an agouti peptide that blocks melanocortin receptors. Stimulation of melanocortin receptors by alpha-melanocyte-stimulating hormone decreases arterial pressure. DESIGN AND METHODS: This study measured arterial pressure in leptin-deficient ob/ob mice, agouti yellow obese mice and their lean controls to test the hypothesis that the effects of obesity on arterial pressure are importantly influenced by the genetic and neuroendocrine mechanisms causing the obesity. We measured arterial pressure directly in conscious ob/ob mice (n = 14), agouti yellow obese mice (n = 6) and the same number of lean littermates. RESULTS: Body weight was nearly twice as high in ob/ob mice as in their lean controls, but mean arterial pressure was significantly lower in ob/ob mice (92+/-3 mmHg) compared with their lean controls (106+/-2 mmHg; P = 0.00017). In contrast, mean arterial pressure was significantly higher in agouti yellow obese mice (124+/-3 mmHg) than in their lean controls (99+/-1 mmHg; P = 0.000002) despite the fact that the agouti mice had milder obesity. CONCLUSIONS: This study prompts three conclusions: (1) leptin-deficient ob/ob mice and agouti yellow obese mice have contrasting blood pressure responses to obesity, (2) obesity does not invariably increase arterial pressure in mice, and (3) the arterial pressure response to obesity may depend critically on the underlying genetic and neuroendocrine mechanisms.

Animals↗

PubMed1999

Hyperinsulinemia produces cardiac vagal withdrawal and nonuniform sympathetic activation in normal subjects.

The exact mechanisms for the decrease in R-R interval (RRI) during acute physiological hyperinsulinemia with euglycemia are unknown. Power spectral analysis of RRI and microneurographic recordings of muscle sympathetic nerve activity (MSNA) in 16 normal subjects provided markers of autonomic control during 90-min hyperinsulinemic/euglycemic clamps. By infusing propranolol and insulin (n = 6 subjects), we also explored the contribution of heightened cardiac sympathetic activity to the insulin-induced decrease in RRI. Slight decreases in RRI (P < 0.001) induced by sevenfold increases in plasma insulin could not be suppressed by propranolol. Insulin increased MSNA by more than twofold (P < 0.001), decreased the high-frequency variability of RRI (P < 0.01), but did not affect the absolute low-frequency variability of RRI. These results suggest that reductions in cardiac vagal tone and modulation contribute at least in part to the reduction in RRI during hyperinsulinemia. Moreover, more than twofold increases in MSNA occurring concurrently with a slight and not purely sympathetically mediated tachycardia suggest regionally nonuniform increases in sympathetic activity during hyperinsulinemia in humans.

Adrenergic beta-Antagonists↗

PubMed1999

State-of-the-art-lecture: Obesity-induced hypertension: new concepts from the emerging biology of obesity.

offsity is associated with an increased risk of hypertension. In the past 5 years there have been dramatic advances into the genetic and neurobiological mechanisms of obesity with the discovery of leptin and novel neuropeptide pathways regulating appetite and metabolism. In this brief review, we argue that these mounting advances into the neurobiology of obesity have and will continue to provide new insights into the regulation of arterial pressure in obesity. We focus our comments on the sympathetic, vascular, and renal mechanisms of leptin and melanocortin receptor agonists and on the regulation of arterial pressure in rodent models of genetic obesity. We suggest 3 concepts. First, the effect of obesity on blood pressure may depend critically on the genetic-neurobiological mechanisms underlying the obesity. Second, obesity is not consistently associated with increased blood pressure, at least in rodent models. Third, the blood pressure response to obesity may be critically influenced by modifying alleles in the genetic background.

Animals↗

PubMed1999

Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic.

Leptin plays an important role in regulation of body weight through regulation of food intake and sympathetically mediated thermogenesis. The hypothalamic melanocortin system, via activation of the melanocortin-4 receptor (MC4-R), decreases appetite and weight, but its effects on sympathetic nerve activity (SNA) are unknown. In addition, it is not known whether sympathoactivation to leptin is mediated by the melanocortin system. We tested the interactions between these systems in regulation of brown adipose tissue (BAT) and renal and lumbar SNA in anesthetized Sprague-Dawley rats. Intracerebroventricular administration of the MC4-R agonist MT-II (200 to 600 pmol) produced a dose-dependent sympathoexcitation affecting BAT and renal and lumbar beds. This response was completely blocked by the MC4-R antagonist SHU9119 (30 pmol ICV). Administration of leptin (1000 microg/kg IV) slowly increased BAT SNA (baseline, 41+/-6 spikes/s; 6 hours, 196+/-28 spikes/s; P=0.001) and renal SNA (baseline, 116+/-16 spikes/s; 6 hours, 169+/-26 spikes/s; P=0.014). Intracerebroventricular administration of SHU9119 did not inhibit leptin-induced BAT sympathoexcitation (baseline, 35+/-7 spikes/s; 6 hours, 158+/-34 spikes/s; P=0.71 versus leptin alone). However, renal sympathoexcitation to leptin was completely blocked by SHU9119 (baseline, 142+/-17 spikes/s; 6 hours, 146+/-25 spikes/s; P=0.007 versus leptin alone). This study demonstrates that the hypothalamic melanocortin system can act to increase sympathetic nerve traffic to thermogenic BAT and other tissues. Our data also suggest that leptin increases renal SNA through activation of hypothalamic melanocortin receptors. In contrast, sympathoactivation to thermogenic BAT by leptin appears to be independent of the melanocortin system.

Adipose Tissue, Brown↗

PubMed1998

Short tandem repeat polymorphic markers for the rat genome from marker-selected libraries.

In an effort to generate a genome-wide set of high-quality polymorphic markers for the rat, we used the marker-selection method, which has already been proven useful for the development of markers, especially for the human genome. Small-insert (300-900 bp) rat genomic libraries were constructed with an estimated complexity of three genome equivalents and enriched for short tandem repeat sequences (STRs). The enriched libraries were found to contain 45% (CA)n and 27% (GATA)n, representing at least a 50-fold enrichment over unselected small insert genomic libraries. A subset of 2160 STR-containing clones, primarily of the (GATA)n class of repeats, were sequenced. PCR primers flanking the repeats were synthesized from some of the sequences from the (CA)n and (GATA)n classes of STRs and tested for polymorphism in a panel of eight inbred rat strains. This strategy yielded 147 polymorphic markers, which mapped with high odds to all chromosomes by linkage in three F2 populations. The integration of these STR markers with other rat genetic markers and mapping reagents will facilitate the mapping of disease genes in the rat and the identification of loci associated with complex mammalian phenotypes.

Animals↗

PubMed1998

Risk stratification with pre-hospital discharge exercise technetium-99m sestamibi myocardial tomography in men after acute myocardial infarction.

BACKGROUND: Exercise thallium-201 imaging early after acute myocardial infarction (MI) may provide information concerning risk of future cardiac events. The prognostic value of exercise technetium-99m sestamibi (MIBI) single-photon emission computed tomography in such patients has not been established. METHODS AND RESULTS: Submaximal exercise stress testing with MIBI tomography was done before hospital discharge in 134 consecutive men after acute MI. Patients were monitored for occurrence of late cardiac events (nonfatal MI or cardiac death). Coronary revascularization was done in 31 patients (23%) < or = 3 months after testing. Nonfatal MI or cardiac death occurred in 30 (23%) of the overall group of 133 patients monitored (mean 35+/-19 months) and in 25 (25%) of the 102 patients treated medically. A history of congestive heart failure, failure to reach 85% of age-predicted maximal heart rate, and an isolated fixed MIBI defect were associated with significantly increased risk (p < 0.05) of a late cardiac event in both groups of patients. A reversible MIBI defect was not associated with increased risk. In a multivariable Cox proportional hazards model, only a history of congestive heart failure (relative risk 4.2, 95% confidence interval [CI] 1.7 to 10.4, p < 0.002) and an isolated fixed MIBI defect (relative risk 2.1, 95% CI 1.1 to 4.3, p < 0.05) were independent predictors of increased risk in the total group of 133 patients. In the 102 patients treated medically, only a history of congestive heart failure (relative risk 4.9, 95% CI 1.9 to 13.1) and achievement of 85% of age-predicted maximal heart rate (relative risk 0.13, 95% CI 0.02 to 0.9) were independent predictors of risk. CONCLUSIONS: Early post-MI submaximal exercise testing with MIBI tomography provides limited prognostic information for late cardiac events. An isolated fixed MIBI defect is associated with increased risk but not as strongly as other variables, particularly a history of congestive heart failure.

Adult↗

PubMed1998

Sympathetic nerve activity and insulin sensitivity in normotensive offspring of hypertensive parents.

Insulin resistance and elevated sympathetic nerve activity (SNA) are observed in young borderline hypertensive humans. A positive family history of hypertension (FH) is a strong risk factor for developing hypertension. To assess whether insulin resistance and increased sympathetic tone precede the onset of hypertension, we studied 17 young adults with and 17 without a documented family history of hypertension. Subjects were matched for age (33+/-0.4 years in FH positive and 32+/-0.5 years in FH negative; mean+/-SE) and body mass index (BMI, 25+/-1 kg/m2 in both FH positive and FH negative subjects). We measured blood pressure (BP), heart rate (HR), muscle sympathetic nerve activity (MSNA, microneurography), forearm blood flow, and insulin sensitivity (total glucose uptake determined by an euglycemic/hyperinsulinemic clamp using stable isotope tracer infusion), and calculated forearm vascular resistance (FVR). Mean BP and HR were similar in both groups (86+/-3 mm Hg and 61+/-2 beats/min, and 85+/-2 mm Hg and 62 +/-2 beats/min, respectively, in FH positive and negative respectively, P = ns). Baseline MSNA (24 +/-3 bursts/min in FH positive v 20+/-3 bursts/min in FH negative, P = ns) and total glucose uptake [0.104+/-0.014 mg/(kg x min x microU insulin/mL) in FH positive v 0.095+/-0.014 mg/(kg xmin x microU insulin/mL) in FH negative, P = ns] did not differ between the groups. Sympathetic and vascular responses to insulin were also similar in both groups. The increase in MSNA was 10+/-2 bursts/ min in FH positive and 10+/-1 bursts/min in FH negative, P = ns. Thus, age- and weight-matched offspring with and without a FH of hypertension did not vary in MSNA or insulin sensitivity. These findings suggest that in the absence of obesity and high arterial pressure, a FH of hypertension may not be accompanied by decreased insulin sensitivity or increased MSNA.

Adult↗

PubMed1998

Linkage of infantile Bartter syndrome with sensorineural deafness to chromosome 1p.

Bartter syndrome (BS) is a family of disorders manifested by hypokalemic hypochloremic metabolic alkalosis with normotensive hyperreninemic hyperaldosteronism. We evaluated a unique, inbred Bedouin kindred in which sensorineural deafness (SND) cosegregates with an infantile variant of the BS phenotype. Using a DNA-pooling strategy, we screened the human genome and successfully demonstrated linkage of this unique syndrome to chromosome 1p31. The genes for two kidney-specific chloride channels and a sodium/hydrogen antiporter, located near this region, were excluded as candidate genes. Although the search for the disease-causing gene in this family continues, this linkage further demonstrates the genetic heterogeneity of BS. In addition, the cosegregation of these phenotypes allows us to postulate that a single genetic alteration may be responsible for the SND and the BS phenotype. The identification and characterization of this gene would lead to a better understanding of the normal physiology of the kidney and the inner ear.

Bartter Syndrome↗

PubMed1998

Cardiovascular consequences of obesity: role of leptin.

1. Several mechanisms have been implicated in the association between obesity and hypertension, including salt-sensitivity, insulin resistance and sympathetic activation. Obese animals and humans exhibit exaggerated blood pressure responses to increases in salt intake. 2. Although insulin resistance is common in obesity, it is clear that abnormal insulin action is not the sole or sufficient cause of hypertension in obesity. Obesity is associated with increased activity of the sympathetic nervous system. Sympathetic blockade has been reported to attenuate sodium retention and hypertension in experimental models of obesity. 3. The mediators responsible for salt sensitivity, insulin resistance and sympathetic activation in obesity remain unclear. 4. The novel protein hormone leptin is produced almost exclusively by adipose tissue and acts in the central nervous system through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. 5. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, renal and endocrine function. We have shown that leptin increases sympathetic nerve activity to kidney, hindlimb and adrenal gland, in addition to brown adipose tissue. 6. Despite this sympathoexcitatory action, acute systemic administration of leptin does not acutely increase arterial pressure or heart rate in anaesthetized animals. This may reflect opposing antihypertensive actions of leptin. For example, leptin increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin increases systemic insulin sensitivity, even in the absence of weight loss. 7. In conclusion, leptin may act as a mediator linking body adiposity with changes in insulin action, sympathetic neural outflow and renal sodium excretion. Alterations in leptin generation or action may, in part, underlie the sympathetic, endocrine and renal consequences of obesity.

Animals↗

PubMed1998

The treatment of heart failure: the role of neurohumoral activation.

Neurohumoral activation refers to increased activity of the sympathetic nervous system, renin-angiotensin system, vasopressin and atrial natriuretic peptide. It is now known that neurohumoral activation contributes to the transition from ventricular dysfunction to clinical heart failure, and is an independent predictor of poor prognosis in heart failure. Although the treatment of heart failure has traditionally focused on drugs to improve ventricular function, there is increasing evidence that therapeutic modulation of neurohumoral activation is a key to successful treatment of heart failure. For example, there is mounting evidence that angiotensin converting enzyme inhibitors (the unquestioned cornerstone for treatment of heart failure), beta receptor blockers, digitalis, and endurance exercise training exert their benefit in heart failure in large part through neurohumoral modulation. This observation--discussed in this brief review--highlights the concept that compensatory neurohumoral activation to decreased cardiac function may itself contribute to the development of heart failure and its poor prognosis.

Adrenergic beta-Antagonists↗

PubMed1997

Receptor-mediated regional sympathetic nerve activation by leptin.

Leptin is a peptide hormone produced by adipose tissue which acts centrally to decrease appetite and increase energy expenditure. Although leptin increases norepinephrine turnover in thermogenic tissues, the effects of leptin on directly measured sympathetic nerve activity to thermogenic and other tissues are not known. We examined the effects of intravenous leptin and vehicle on sympathetic nerve activity to brown adipose tissue, kidney, hindlimb, and adrenal gland in anesthetized Sprague-Dawley rats. Intravenous infusion of mouse leptin over 3 h (total dose 10-1,000 microg/kg) increased plasma concentrations of immunoreactive murine leptin up to 50-fold. Leptin slowly increased sympathetic nerve activity to brown adipose tissue (+286+/-64% at 1,000 microg/kg; P = 0.002). Surprisingly, leptin infusion also produced gradual increases in renal sympathetic nerve activity (+228+/-63% at 1,000 microg/kg; P = 0.0008). The effect of leptin on sympathetic nerve activity was dose dependent, with a threshold dose of 100 microg/kg. Leptin also increased sympathetic nerve activity to the hindlimb (+287+/-60%) and adrenal gland (388+/-171%). Despite the increase in overall sympathetic nerve activity, leptin did not increase arterial pressure or heart rate. Leptin did not change plasma glucose and insulin concentrations. Infusion of vehicle did not alter sympathetic nerve activity. Obese Zucker rats, known to possess a mutation in the gene for the leptin receptor, were resistant to the sympathoexcitatory effects of leptin, despite higher achieved plasma leptin concentrations. These data demonstrate that leptin increases thermogenic sympathetic nerve activity and reveal an unexpected stimulatory effect of leptin on overall sympathetic nerve traffic.

Action Potentials↗

PubMed1997

Sympathetic and vascular effects of short-term passive smoke exposure in healthy nonsmokers.

BACKGROUND: The physiological effects of cigarette smoking have been widely studied; however, little is known about the effects of acute exposure to sidestream smoke (passive smoking). We examined the effects of sidestream smoke on muscle sympathetic nerve activity (MSNA) and forearm vascular resistance (FVR) at rest and during stressful stimuli, including the cold pressor test (CPT), sustained handgrip (SHG), and mental stress (MS). METHODS AND RESULTS: In 17 healthy nonsmokers, blood pressure (BP), heart rate (HR), forearm blood flow (venous occlusion plethysmography), FVR, and MSNA (obtained through direct intraneural recordings) were measured before and during inhalation of sidestream smoke in one session (n = 16) and before and during vehicle (air) inhalation in another session (n = 17) on a separate day. The order of sessions was randomized between subjects. Responses to CPT, SHG, and MS were measured before and after inhalation of smoke or vehicle (ie, twice during each session). After 15 minutes' exposure to sidestream smoke, plasma nicotine and carboxyhemoglobin levels increased to 0.77 +/- 0.11 ng/mL and 0.36 +/- 0.04% (mean +/- SEM, P < .05), respectively. Sidestream smoke, but not vehicle inhalation, increased resting MSNA from 23 +/- 2 to 28 +/- 2 bursts/min (P < .05). FVR increased with passive smoking, but this increase was not significantly different from the change in FVR with vehicle. Plasma norepinephrine and epinephrine, BP, and HR were not changed significantly by sidestream smoke. The responses of MSNNA, BP, HR, and FVR to the stressful stimuli were not potentiated by sidestream smoke, except for an increased BP response to the CPT (P < .05). CONCLUSIONS: Acute short-term passive (sidestream) smoke exposure elicits a modest increase in MSNA in healthy non-smokers but does not change HR, BP, or FVR.

Adult↗

PubMed1997

Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint.

Familial hypomagnesemia with secondary hypocalcemia (HSH) (MIM 307600) was studied in three inbred Bedouin kindreds from Israel. The three kindreds, one extended and two nuclear families, contained 13 affected individuals, 11 males and two females. Assuming that the individuals affected with hypomagnesemia shared a chromosomal region inherited from a common ancestor, we used a DNA pooling strategy in a genome-wide search for loci which show homozygosity for shared alleles in affected individuals. DNA samples from affected individuals within a single kindred were pooled and used as the template for PCR amplification of short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected siblings and parents were used as controls. A shift towards homozygosity was observed in the affected DNA pool compared with the control pools with D9S301 (GATA7D12). Genotyping of individual DNA samples with D9S301 and several flanking markers confirmed linkage to chromosome 9 with maximum LOD scores of 3.4 (theta = 0.05), 3.7 (theta = 0) and 2.3 (theta = 0) for the three families. We have identified a 14 cM interval on chromosome 9 (9q12-9q22.2), flanked by proximal marker D9S1874 and distal marker D9S1807, within which all affected individuals from the three kindreds are homozygous for a shared haplotype. The disease segregates with a common affected haplotype in the three families, suggesting that hypomagnesemia is caused by a common ancestral mutation in these families. Although HSH has been previously reported to be X linked, these linkage data demonstrate that the disorder is an autosomal recessive disease in these kindreds. Mapping of a chromosomal breakpoint in a somatic cell line established from a patient with HSH and a balanced X;9 translocation placed the chromosomal breakpoint in a 500 kb region flanked by D9S1844 and D9S273. Identification of the gene responsible for hypomagnesemia will provide insight into the regulation of this essential cation.

Arabs↗