Effects of short-acting exenatide added three times daily to insulin therapy on bone metabolism in type 1 diabetes.

AIM: To evaluate the efficacy of the short-acting glucagon-like peptide-1 receptor agonist, exenatide, added to insulin therapy in type 1 diabetes on bone mineral density and bone turnover markers. MATERIALS AND METHODS: In a randomized, double-blinded, parallel-group trial, 108 individuals with type 1 diabetes aged 18 years or older on basal-bolus therapy with HbA1c 59-88 mmol/mol (7.5%-10.0%) and body mass index of more than 22.0 kg/m2 were randomized (1:1) to preprandial subcutaneous injection of 10 µg exenatide (Byetta) before breakfast, lunch, and dinner over 26 weeks as add-on treatment to insulin therapy. RESULTS: Exenatide elicited a body weight reduction of 4.4 kg compared with placebo, but no between-group differences in bone mineral density, as assessed by whole-body, hip, lumbar, and forearm dual-energy X-ray absorptiometry following 26 weeks of treatment, were observed. Fasting plasma levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, and amino-terminal propeptide of type I procollagen, a marker of bone formation, were unchanged by exenatide compared with placebo after 26 weeks. CONCLUSIONS: Despite an exenatide-induced body weight reduction, no changes in bone metabolism were observed with exenatide added to insulin therapy in type 1 diabetes after 26 weeks.

Effect of short-acting exenatide administered three times daily on markers of cardiovascular disease in type 1 diabetes: A randomized double-blind placebo-controlled trial.

AIMS: To investigate the effect of adding the short-acting glucagon-like peptide 1 receptor agonist (GLP-1RA) exenatide to insulin treatment on markers of cardiovascular risk in type 1 diabetes. MATERIALS AND METHODS: In a randomized, double-blind, parallel-group trial, 108 individuals with type 1 diabetes aged ≥18 years on multiple daily injection therapy with a body mass index >22.0 kg/m2 and glycated haemoglobin concentration of 59 to 88 mmol/mol (7.5%-10.0%) were randomized (1:1) to preprandial subcutaneous injection of 10 µg exenatide (Byetta®) or placebo three times daily over 26 weeks as add-on treatment to existing insulin therapy. Reported markers of cardiovascular risk were secondary endpoints and were analyzed in a baseline-adjusted linear mixed model in the intention-to-treat population. The primary results of this study, the MAG1C (Meal-time Administration of exenatide for Glycaemic control in type 1 diabetes Cases) trial, were previously reported. RESULTS: Exenatide changed total fat mass by -2.6 kg (95% confidence interval [CI] -3.6; -1.6; P < 0.0001) and lean body mass by -1.1 kg (95% CI -1.9; -0.4; P = 0.01) compared with placebo, as assessed by dual-energy X-ray absorptiometry. Fat mass reductions were similar for central and peripheral fat mass. Exenatide did not change levels of interleukin-2 or -6; tumour necrosis factor-α; C-reactive protein; N-terminal prohormone of brain natriuretic peptide; or 8-oxo-7,8-dihydroguanosine (RNA oxidation marker) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (DNA oxidation marker). CONCLUSIONS: Exenatide added to insulin therapy in type 1 diabetes for 26 weeks resulted in body weight loss primarily from fat mass reduction, but had no effect on biomarkers of cardiovascular disease risk.

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms.

Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy.

Trail Making Test Error Analysis in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Dementia With and Without Depression.

OBJECTIVE: Standard evaluation of the Trail Making Test (TMT) only incorporates completion times. However, the analysis of different error types may provide more insight into underlying cognitive processes and could also increase diagnostic accuracy. This cross-sectional observational study compared three different TMT error types and assessed their diagnostic utility in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's dementia (AD) with or without depression. METHOD: We evaluated 618 outpatients of a memory clinic with SCD (N = 190), MCI (N = 210), or AD (N = 218). Of these, 157 had comorbid depression. TMT completion times, total error rates, and the three error types "sequencing error," "perseverative error," and "proximity error" were examined. RESULTS: Results indicated that patients with MCI or AD committed more errors on TMT B, and specifically more perseverative errors than patients with SCD (p < 0.001). Depression was not associated with any TMT error type. Including TMT errors in models predicting diagnosis group by TMT completion times did not increase predictive accuracy, measured by areas under the curve. CONCLUSIONS: The findings do not indicate any impact of comorbid depression on TMT errors. Moreover, TMT error analysis does not seem to provide additional diagnostic utility for SCD, MCI, and AD diagnoses.

Dasiglucagon Treatment for Postprandial Hypoglycemia After Gastric Bypass: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Postbariatric hypoglycemia affects >50% of individuals who have undergone Roux-en-Y gastric bypass surgery. Despite the often debilitating nature of this complication, existing treatment options are limited and often inefficient. Dasiglucagon is a stable glucagon analog available in a ready-to-use formulation and was recently shown to mitigate postbariatric hypoglycemia in experimental settings. Here, we aimed to evaluate the hypoglycemic hindering potential of dasiglucagon in an outpatient trial. RESEARCH DESIGN AND METHODS: We conducted a randomized, double-blind, placebo-controlled, crossover, proof-of-concept study at the Center for Clinical Metabolic Research at Gentofte Hospital in Denmark. The study included 24 individuals who had undergone Roux-en-Y gastric bypass surgery (n = 23 women) with continuous glucose monitor-verified postbariatric hypoglycemia (≥15 min at <3.9 mmol/L three or more times per week) randomly assigned to two treatment periods of 4 weeks of self-administered subcutaneous dasiglucagon at 120 µg or placebo. The primary and key secondary outcomes were continuous glucose monitor-captured percentage of time in level 1 and 2 hypoglycemia (<3.9 and <3.0 mmol/L), respectively. RESULTS: Compared with placebo, treatment with dasiglucagon significantly reduced time in level 1 hypoglycemia by 33% (-1.2 percentage points; 95% CI -2.0 to -0.5; P = 0.002) and time in level 2 hypoglycemia by 54% (-0.4 percentage points; 95% CI -0.6 to -0.2; P < 0.0001). Furthermore, dasiglucagon corrected hypoglycemia within 15 min in 401 of 412 self-administrations, compared with 104 of 357 placebo self-administrations (97.3% vs. 29.1% correction of hypoglycemia rate; P < 0.001). Dasiglucagon was generally well tolerated, with mostly mild to moderate adverse events of nausea. CONCLUSIONS: Compared with placebo, 4 weeks of self-administered dasiglucagon effectively reduced clinically relevant hypoglycemia in individuals who had undergone Roux-en-Y gastric bypass surgery.

Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In type 2 diabetes, long-acting GLP-1 receptor agonists lower fasting plasma glucose and improve glycaemic control via their insulinotropic and glucagonostatic effects. In type 1 diabetes, their efficacy as an add-on treatment to insulin therapy is modest. Short-acting GLP-1 receptor agonists also lower postprandial glucose excursions in type 2 diabetes by decelerating gastric emptying rate. We aimed to test the efficacy of a short-acting GLP-1 receptor agonist in type 1 diabetes. METHODS: In the single-centre, parallel-group, randomised, double-blind, placebo-controlled MAG1C trial, patients with type 1 diabetes on multiple daily injection therapy aged 18 years and older with HbA1c 59-88 mmol/mol (7·5-10·0%) and a BMI of more than 22·0 kg/m2 were randomly assigned (1:1) through a computer-generated randomisation list to preprandial subcutaneous injection of 10 µg exenatide (Byetta) or placebo three times daily for 26 weeks as an add-on treatment to usual insulin therapy. Clinically assessed insulin titration was done by study staff. Participants and investigators were masked to treatment allocation. The primary endpoint was between-group difference in HbA1c after 26 weeks. Data were analysed with a baseline-adjusted linear mixed model in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03017352, and is completed. FINDINGS: Between Jan 4, 2017, and Jan 16, 2019, 108 participants were randomly assigned, 54 to exenatide and 54 to placebo; 23 participants discontinued treatment (17 in the exenatide group and six in the placebo group). From a baseline-adjusted mean of 66·4 mmol/mol (95% CI 64·9-67·8 [8·2%, 8·1-8·4]), HbA1c changed by -3·2 mmol/mol (-5·0 to -1·4 [-0·3%, -0·5 to -0·1]) with exenatide and -2·1 mmol/mol (-3·7 to -0·6 [-0·2%, -0·3 to -0·1]) with placebo after 26 weeks (estimated treatment difference of -1·1 mmol/mol (-3·4 to 1·2 [-0·1%, -0·3 to 0·1]; p=0·36). Exenatide increased the number of self-reported gastrointestinal adverse events (primarily nausea [48 events among 37 patients with exenatide, nine with placebo among 9 patients]). Two serious adverse events occurred in the exenatide group, and six occurred in the placebo group (none were considered to be related to the study drug). INTERPRETATION: Short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes. FUNDING: AstraZeneca.

T cells responsive to myelin basic protein in patients with multiple sclerosis.

Gene mutation in vivo in human T lymphocytes appears to occur preferentially in dividing cells. Individuals with multiple sclerosis (MS) are assumed to have one or more populations of diving T cells that are being stimulated by autoantigens. Mutant T cell clones from MS patients were isolated and tested for reactivity to myelin basic protein, an antigen that is thought to participate in the induction of the disease. The hypoxanthine guanine phosphoribosyltransferase (hprt) clonal assay was used to determine mutant frequency values in MS patients with chronic progressive disease. Eleven of 258 thioguanine-resistant (hprt-) T cell clones from five of the six MS patients who were tested proliferated in response to human myelin basic protein without prior in vitro exposure to this antigen. No wild-type clones from these patients, nor any hprt- or wild-type clones from three healthy individuals responded to myelin basic protein. Thus, T cell clones that react with myelin basic protein can be isolated from the peripheral blood of MS patients.

The efficacy and safety of exenatide once weekly in patients with type 2 diabetes.

INTRODUCTION: Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D). Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit-risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide. Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.

Effect of folate deficiency on mutations at the hprt locus in Chinese hamster ovary cells exposed to monofunctional alkylating agents.

Multiplex PCR amplification of hprt exons from 113 Chinese hamster ovary cell clones selected for resistance to 6-thioguanine was performed to investigate the molecular basis for the synergistic mutagenic effects of nutritional folic acid deficiency and alkylating agents. In cells treated with ethyl methanesulfonate, intragenic deletions were detected in 9 of 46 (19.6%) clones derived from folate-deficient cells, but in none of 16 mutants grown in folate-replete medium. The number of deletions found in mutants generated by N-nitroso-N-ethylurea was low in both folate-deficient (1 of 25; 4%) and folate-replete (1 of 26; 3.8%) cells. Correction of folate deficiency may decrease the frequency of intragenic deletions caused by some alkylating agents.

Increased frequency of specific genomic deletions resulting from in vitro malathion exposure.

Malathion is a widely used pesticide with high potential for human exposure. Epidemiological studies suggest that individuals with chronic environmental exposures to pesticides have increased risks of various hematological malignancies. The genotoxic data to date have been somewhat inconclusive with regard to malathion exposure. We have used a cell cloning assay to study the genotoxicity of in vitro exposure of human T lymphocytes to malathion. We exposed cells in G0 to doses of malathion ranging from 10 to 600 microg/ml. Mutant frequencies of treated samples showed both intra- and interindividual variability and, in some cases, slight significant increases over the controls. Molecular analysis of hprt mutants resulting from both in vitro and an in vivo malathion exposure was performed by genomic multiplex PCR. In seven in vitro experiments (using cells from four different individuals) and one experiment on an individual exposed in vivo, one or more independent mutant(s) containing a partial deletion of exon 3 have been isolated from each individual. In five of the seven mutants, the deleted regions overlap extensively, revealing an area within exon 3 exceptionally prone to deletions upon exposure to malathion, This work provides the first evidence of an association between malathion exposure and specific mutations in human T lymphocytes. Additional work is necessary to determine the underlying molecular mechanism for these deletions and how this may relate to agricultural workers' increased risk of cancer.

Mitochondrial genome damage associated with cigarette smoking.

We have investigated the level of mitochondrial DNA (mtDNA) damage and deletions in bronchoalveolar lavage tissues from smokers and nonsmokers using quantitative, extra-long PCR and a "common" mtDNA deletion assay. Smokers had 5.6 times the level of mtDNA damage, 2.6 times the damage at a nuclear locus (beta-globin gene cluster), and almost 7 times the level of a 4.9-kb mtDNA deletion compared to nonsmokers, although the latter increase was not significant. Although both genomes (mitochondrial and nuclear) showed significantly increased levels of DNA damage in smokers (mtDNA P = 0.00072; beta-globin P = 0.0056), the relative differences were greatest in the mtDNA. Damage to the mtDNA may inhibit oxidative phosphorylation and, therefore, potentially cause or contribute to chronic lung disease and cancer. Consequently, the mtDNA may be a sensitive biomarker for environmentally induced genetic damage and mutation.

V(D)J recombinase-like activity mediates hprt gene deletion in human fetal T-lymphocytes.

Studies from several laboratories worldwide have developed a large database for in vivo hypoxanthine-guanine phosphoribosyltransferase gene mutations in human T-lymphocytes. Sufficient differences have been found thus far between the spectrum for spontaneous mutations in adults and that observed in the fetus to suggest fundamental differences in in vivo mutagenic mechanisms at these two life stages. In adults, only approximately 15% of hypoxanthine-guanine phosphoribosyltransferase mutations have structural alterations on Southern blots, while in the fetus 75% of mutations show alterations of which one-half are deletions of exons 2 and 3. We have now sequenced the breakpoint sites for these specific deletions in 18 mutant lymphocyte clones isolated from 13 normal newborns. Three classes of deletions were found. Each class had the same intron 1 breakpoint but a different intron 3 breakpoint. These mutations have all the signatures of a V(D)J recombinase-mediated event (a 5' consensus heptamer, 3' consensus heptamer and nonamer, nibbling, non-germline-encoded nucleotides, P-nucleotides). At the 3' breakpoint of the most common class (comprising 83% of the mutants) a perfect heptamer can be created by postulating a hairpin loop which could attain a Z-DNA configuration. This feature may indicate recombinase preference for certain DNA structures. These results implicate the V(D)J recombinase in illegitimate events causing mutation in this housekeeping gene during T-cell development. Inactivation of genes involved in the control of growth and differentiation (e.g., tumor suppressor genes) by this mechanism may have important implications for cancer development.

Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure.

BACKGROUND: Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. METHODS AND RESULTS: This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators.

BACKGROUND: We determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. METHODS AND RESULTS: One hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) who had a pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

Decreased coronary flow reserve after transient myocardial ischemia in dogs.

The effect of a transient (15 min) period of regional ischemia on coronary flow reserve in the postischemic myocardium was studied in 24 open chest dogs. Coronary flow was measured with electromagnetic flow probes, and flow reserve was determined during reactive hyperemia after 30 s coronary occlusions and during intracoronary infusions of adenosine. Measures of flow reserve after 15 min of ischemia were made after coronary flow returned to basal levels and flow reserve was then monitored for 1 h. All measures of coronary flow reserve were significantly reduced after transient ischemia: peak flows during reactive hyperemia and intracoronary adenosine infusions decreased by 20 and 24%, respectively, the peak/basal flow ratio by 16% and the repayment/debt ratio by 54%; minimal coronary vascular resistance during reactive hyperemia and intracoronary adenosine increased by 29 and 33%, respectively. Abnormal flow reserve was present for at least 1 h. No changes in flow reserve were detected in control animals over the same time period. Thus, a transient period of myocardial ischemia significantly decreases coronary flow reserve for a prolonged period of time. This "vascular stunning" must be considered when flow reserve is used to assess the functional significance of a coronary stenosis and could be the cause of variable exercise tolerance in patients with angina pectoris.

Randomized, double-blind, placebo-controlled trial of tissue plasminogen activator in unstable angina.

Angiographic, angioscopic and pathologic reports have recently demonstrated a high incidence of intracoronary thrombus in patients with unstable angina. To determine if thrombolysis could be beneficial when combined with maximal medical therapy, 40 patients with rest angina, angiographically documented coronary artery disease and pacing-induced ischemia were randomly assigned to intravenous recombinant tissue-type plasminogen activator (rt-PA, 150 mg/8 h) or placebo in a prospective double-blind trial. All patients received nitrates, a beta-adrenergic blocking agent, a calcium channel blocker, aspirin and heparin. Pacing thresholds for ischemia and quantitative coronary stenosis were measured before and after infusion of the study medication. Intracoronary thrombus was identified angiographically before infusion of the study medication in 16 patients; 7 received rt-PA and 9 received placebo. The ischemic pacing threshold in patients treated with rt-PA increased from 112 +/- 4 beats/min at baseline to 127 +/- 5 beats/min (p = 0.007) by the end of the infusion versus an insignificant change in patients who received placebo (from 116 +/- 4 to 119 +/- 4 beats/min, p = NS). In patients with intracoronary thrombus, the ischemic pacing threshold increased 26 +/- 7 beats/min with rt-PA treatment versus 0 +/- 3 beats/min with placebo (p = 0.004). In contrast, in patients without thrombus, there was no difference in ischemic pacing threshold increments between treatment groups (7 +/- 11 beats/min for rt-PA versus 6 +/- 5 beats/min for placebo, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative measurement of coronary flow during medical revascularization (thrombolysis or angioplasty) in patients with acute infarction.

This study quantitatively evaluated the change in myocardial blood flow resulting from medical revascularization in patients with acute anterior myocardial infarction. Changes in great cardiac vein flow were measured using a thermodilution technique in 13 patients with acute infarction; 3 received intracoronary streptokinase and 10 percutaneous transluminal angioplasty. Average great cardiac vein flow during left anterior descending coronary artery occlusion was 62 +/- 6 ml/min and increased to 70 +/- 7 ml/min (p = 0.039) after arterial recanalization. There was significant individual variability in the great cardiac vein flow increments that was highly predictive of functional recovery as expressed by the change in ejection fraction at 7 to 10 days (r = 0.93, p = 0.0008). Incremental great cardiac vein flow was inversely correlated with the degree of residual stenosis and the duration of ischemia (r = 0.88, p = 0.0007). Patients with residual stenosis less than or equal to 50% had a significantly larger increase in great cardiac vein flow (14 +/- 5 ml/min) than did those with residual stenosis greater than 50% (0 +/- 2 ml/min, p = 0.026). Neither preinterventional left ventricular ejection fraction, hemodynamics nor age predicted incremental great cardiac vein flow. Therefore, quantitative measurements of great cardiac vein flow during medical revascularization in patients with an acute anterior myocardial infarction demonstrate variable reflow that is physiologically significant. A high grade residual stenosis and prolonged period of ischemia limit large increases in flow and prevent functional recovery. This study emphasizes the fact that recanalization in itself cannot be used as an indicator of the success of interventions designed to produce myocardial reperfusion.

Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: results of the Studies of Left Ventricular Dysfunction (SOLVD) Registry. The SOLVD Investigators.

OBJECTIVES: The aim of this study was to determine the differences in neurohumoral responses between patients with pulmonary congestion with and without impaired left ventricular ejection fraction. BACKGROUND: Previous studies have established the presence of neurohumoral activation in patients with congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to the impairment in systolic contractility. METHODS: The 898 patients recruited into the Studies of Left Ventricular Dysfunction (SOLVD) Registry substudy were examined to identify those patients with pulmonary congestion on chest X-ray film who had either impaired (< or = 45%, group I) or preserved (> 45%, group II) left ventricular ejection fraction. Plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were measured in these two groups of patients and compared with values in matched control subjects. RESULTS: Distribution of the New York Heart Association symptom classification was the same in the two groups of patients. Compared with control subjects, patients in group II with pulmonary congestion and preserved ejection fraction had no activation of the neurohumoral mechanisms, except for a small but statistically significant increase in arginine vasopressin and plasma renin activity. Compared with patients in group II, those in group I with pulmonary congestion and impaired ejection fraction had significant increases in plasma norepinephrine (p < 0.002), plasma renin activity (p < 0.02) and atrial natriuretic peptide levels (p < 0.0007). When we controlled for baseline differences between groups I and II, the between-group differences in plasma norepinephrine (p < 0.02) and atrial natriuretic peptide (p < 0.002) remained significant. However, plasma renin activity was not significantly different between groups I and II. When the effects of diuretic agents and angiotensin-converting enzyme inhibitors were adjusted, patients with lower ejection fraction were found to have significantly higher plasma norepinephrine and atrial natriuretic peptide levels. CONCLUSIONS: The results point to the importance of the decrease in left ventricular ejection fraction as one of the mechanisms for activation of neurohormones in patients with heart failure.

Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: a report from the Registry of Studies of Left Ventricular Dysfunction. SOLVD Investigators.

OBJECTIVES: This study examined the relation between neurohumoral activation and severity of left ventricular dysfunction and congestive heart failure in a broad group of patients with depressed left ventricular function who were not recruited on the basis of eligibility for a therapeutic trial. BACKGROUND: Previous studies have established the presence of neurohumoral activation in patients with severe congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to an impairment in left ventricular function. METHODS: From the 6,273 patients recruited into the Studies of Left Ventricular Dysfunction Registry (SOLVD), a subgroup of 859 patients were randomly selected, and their plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were correlated with clinical findings, New York Heart Association functional class, left ventricular ejection fraction and drug use. RESULTS: There was a weak but significant correlation between ejection fraction and an increase in plasma norepinephrine (rho = -0.18, p < 0.0001), plasma renin activity (rho = -0.24, p < 0.0001) and arginine vasopressin (rho = -0.12, p < 0.003). The only exception was atrial natriuretic peptide, which showed the best correlation to ejection fraction (rho = -0.37, p < 0.0001). Deterioration in functional class was associated more with increases in atrial natriuretic peptide (p = 0.0003) and plasma renin activity (p = 0.0003) and less with an increase in plasma norepinephrine. Of the clinical variables, elevated jugular venous pressure and third heart sound (S3) gallop were significantly associated with increased levels of plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. We then compared the relation of neurohormones with clinical signs, functional status, ejection fraction and drug therapy and controlled for mutual interactive effects. After adjustment, a decrease in ejection fraction was still significantly related to an increase in plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. In contrast, only a difference between functional classes I and III/IV was associated with an increase in plasma renin activity and atrial natriuretic peptide levels. CONCLUSIONS: Neurohumoral activation in patients with heart failure is related to severity of left ventricular functional depression, and this relation is independent of functional class or concomitant drug therapy.

Vital Genes That Flank Sex-Lethal, an X-Linked Sex-Determining Gene of DROSOPHILA MELANOGASTER.

The X-chromosome:autosome balance in D. melanogaster appears to control both sex determination and dosage compensation through effects on a maternally influenced sex-linked gene called Sex-lethal (Sxl; 1-19.2). To facilitate molecular and genetic analysis of Sxl, we attempted to determine the locations of all ethyl methanesulfonate (EMS)-mutable genes vital to both sexes in the region between 6E1 and 7B1. This area includes approximately 1 cM of the genetic map on each side of Sxl and was reported by C. B. Bridges to contain 26 salivary gland polytene chromosome bands. The region appears rather sparsely populated with genes vital to both sexes, since the 122 recessive lethal mutations we recovered fell into only nine complementation groups. From one to 38 alleles of each gene were recovered. There was a preponderance of embryonic lethals in this area, although the lethal periods of loss-of-function mutations included larval, pupal and adult stages as well. Since the screen required that mutations be recessive and lethal to males, our failure to recover new Sxl alleles was the result expected for a gene with a female-specific function. An attempt was made to identify recessive male-specific lethals in this region, but none were found. Precise map positions were determined for eight of the nine vital genes. An interesting feature of the map is the location of Sxl in the middle of a 0.6- to 0.7-cM interval that appears to be devoid of genes vital to both sexes. The genetic location was determined of breakpoints near Sxl for all available chromosome rearrangements. Sxl is most likely located just to the left of band 7A1. We determined the relationship of our EMS-induced mutations in these nine genes to alleles induced by others. From this we conclude that the various genes appear to differ significantly from each other in their relative sensitivity to mutation by EMS vs. X rays.