Comparison of procedural success between two radial sheaths : Comparison of the 6-Fr Glidesheath Slender to 6-Fr standard sheath.

BACKGROUND: The most common cause of procedural failure in cardiac catheterization using the transradial approach is radial artery spasm. The aim of this study was to compare the procedural success rate of the 6­Fr Glidesheath Slender with the 6­Fr standard sheath in transradial coronary angiography and intervention. METHODS: Patients who underwent percutaneous coronary angiography via the transradial approach through placement of a 6-Fr Glidesheath Slender or a 6-Fr standard sheath for primary radial access were prospectively enrolled in the study. RESULTS: The study included 200 cases: 76 patients undergoing percutaneous coronary angiography with the Glidesheath Slender and 124 patients with the standard sheath. Failed procedures were recorded for 19 patients (9.5%), defined as inability to complete the procedure via the primary access. There was no difference in the percentage of failed cases between the Glidesheath Slender and standard sheath groups (10.5% vs. 8.9%, OR = 1.21, p = 0.8). More cases of spasm were observed in the Glidesheath Slender group compared with the standard sheath group, which was not statistically significant (7.9% vs. 5.7%, OR = 1.43, p = 0.56). Smoking, hyperlipidemia, and age influenced the procedural outcome in the Glidesheath Slender group, while body mass index, sex, and smoking impacted the procedural outcome in the standard sheath group. CONCLUSION: There is no difference in procedural success rates, as defined by the ability to complete the procedure via primary radial access, between the 6­Fr Glidesheath Slender and the 6­Fr standard sheath. Our study suggests that the patient characteristics that elevate the risk of procedural failure for Glidesheath Slender may differ from those for the standard sheath.

Familial transmission of substance use disorders.

BACKGROUND: There is increasing evidence that substance use disorders are familial and that genetic factors explain a substantial degree of their familial aggregation. To perform a controlled family study of probands with several different predominant drugs of abuse, including opioids, cocaine, cannabis, and/or alcohol. METHODS: The subjects for the present study included 231 probands with dependence on opioids, cocaine, cannabis, and/or alcohol and 61 control probands, and their 1267 adult first-degree relatives. Diagnostic estimates were based on semistructured diagnostic interviews and/or structured family history interviews regarding each proband, spouse, and adult first-degree relative. The interview data were reviewed blindly and independently by clinicians with extensive experience in the evaluation and treatment of substance use disorders. RESULTS: There was an 8-fold increased risk of drug disorders among the relatives of probands with drug disorders across a wide range of specific substances, including opioids, cocaine, cannabis, and alcohol, which is largely independent from the familial aggregation of both alcoholism and antisocial personality disorder. There was also evidence of specificity of familial aggregation of the predominant drug of abuse. CONCLUSIONS: Elevation in risk of this magnitude places a family history of drug disorder as one of the most potent risk factors for the development of drug disorders. These results suggest that there may be risk factors that are specific to particular classes of drugs as well as risk factors that underlie substance disorders in general.

Clinical management of the NIDDM patient. Impact of the American Diabetes Association practice guidelines, 1985-1993. Endocrine Fellows Foundation Study Group.

OBJECTIVE: To assess the impact of the American Diabetes Association's (ADA's) standards of care for patients with non-insulin-dependent diabetes mellitus (NIDDM) on practice patterns among university-based endocrine physicians and fellows. RESEARCH DESIGN AND METHODS: This study represents a retrospective chart-based review of 790 patients with NIDDM conducted by endocrine fellows in training at 42 academic institutions. By using an ADA guidelines-based questionnaire, patient management and adherence to the guidelines were assessed by reviewing charts dating > or = 3 years before, the year of, and 3 years after the guidelines' publication. All calculations were performed using the McNemar test, and all P values are two-sided. RESULTS: The ADA standards of care have not had the significant impact in the clinical training setting that was anticipated. Deficiencies were noted in all aspects of the diabetic patient encounter and did not improve significantly following publication of the guidelines, except in the areas of foot care, eye examination, and lipid screening. Major deficiencies exist in areas of quality assurance and chart documentation, and these did not improve over time. CONCLUSIONS: New strategies must be devised to increase awareness and implementation of these guidelines, both to enhance patient care and to improve the training of future diabetes caregivers.

Slow metabolic clearance rate of the 20,000-dalton variant of human growth hormone: implications for biological activity.

The 20,000-dalton variant of human GH (hGH) (20 K) exhibits full growth-promoting bioactivity in the rat despite its poor interaction with GH receptors, as compared to the principal 22,000-dalton form of hGH (22 K). To test the possibility that prolonged survival time of 20 K in vivo may contribute to this apparent discrepancy, we compared the MCRs of 22 K and 20 K in the rat by the single injection technique. Both radiolabeled and native 22 K and 20 K were examined in this regard. The MCR of 20 K was 2- to 3-fold lower than that of 22 K, a statistically significant difference (P less than 0.05). The distribution volumes were similar for the two hGH forms and corresponded approximately to the extracellular fluid space. We conclude that the prolonged persistence of 20 K in the circulation may contribute to its higher than expected bioactivity in vivo in the rat.

The metabolic clearance, distribution, and degradation of dimeric and monomeric growth hormone (GH): implications for the pattern of circulating GH forms.

The ratio of oligomeric (big) to monomeric (little) human (h)GH forms in plasma exceeds that in the pituitary gland severalfold. To investigate whether delayed metabolic clearance of oligomers could explain this discrepancy, we measured MCR, distribution volumes, and degradation rates of radio-labeled hGH22K dimer, hGH20K dimer, hGH22K monomer, and hGH20K monomer in the rat. Hormones were injected as a bolus, and disappearance from plasma was followed by immunoprecipitation and trichloroacetic acid precipitation. MCRs of the dimers were significantly lower than those of the corresponding monomers (5-fold in the case of hGH22K, and 2-fold in the case of hGH20K). Both dimers were also degraded at slower rates than the monomers. Distribution volumes for the dimers, although somewhat smaller, were not statistically different from those for the monomers and were consistent with distribution in the extracellular space. We conclude that hGH dimers are relatively protected from degradation and hence cleared more slowly from the blood than hGH monomers. This may lead to their accumulation in the circulation relative to their monomeric counterparts, which may explain their high proportion in plasma as compared to pituitary.

Molecular forms of human growth hormone secreted in vivo: nonspecificity of secretory stimuli.

Several molecular forms of human GH (hGH) are present in blood, but their individual regulation is largely unknown. To examine the factors controlling the secretion of individual hGH variants, the relationship between the mixture of circulating hGH forms and the type of preceding secretory stimulus was studied in 18 normal subjects and 5 acromegalic patients. The stimuli employed were L-dopa, GH-releasing hormone-(1-40), exercise, spontaneous sleep-related and daytime secretory bursts, estrogens, and TRH in the acromegalic patients. Three monomeric hGH forms (22K, 20K, and acidic hGH) were identified in all samples; their mean relative proportions were 76.4%, 15.8%, and 7.9%, respectively. These proportions were similar in all subjects, regardless of stimulus, sex, or presence of acromegaly (P greater than 0.25). We conclude that the release of individual hGH forms is not stimulus specific, but, rather, that the secretory granule contents are released in toto upon somatotroph stimulation.

Molecular forms of circulating growth hormone during spontaneous secretory episodes and in the basal state.

After pharmacological stimulation of the pituitary gland, human GH (hGH) in plasma consists of three or more monomeric molecular forms and several corresponding oligomers. However, the chemical nature of hGH circulating under physiological (stimulated or basal) conditions is not known. In particular, the molecular basis for the GH-like bioactivity of plasma is poorly understood. To gain information on the type(s) of hGH normally found in blood, we extracted hGH from plasma obtained at the time of spontaneous secretory episodes (nocturnal and random release) and during basal periods in 15 normal subjects. Appropriate plasma volumes (30 or 300 ml) were extracted by immunoadsorbent chromatography, and the extracts were analyzed by native polyacrylamide gel electrophoresis at pH 7.5 and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis at pH 10. The plasma hGH pattern at the time of spontaneous secretion was similar to that after pharmacological stimulation and consisted of 22K (principal), 20K, and acidic hGH as well as hGH dimer. In contrast, plasma hGH patterns during basal periods were highly variable and included immunoreactive hGH fragments in addition to the known hGH forms. Components with mol wt of 30K, 16K, and 12K were consistently identified. We conclude that 1) endogenously stimulated hGH secretion results in the same plasma hormone patterns as pharmacological stimuli; 2) several immunoreactive hGH fragments contribute to the heterogeneity of plasma hGH; and 3) hGH fragments may become a dominant part of total immunoreactivity in the basal state.

Plasma "big" and "big-big" growth hormone (GH) in man: an oligomeric series composed of structurally diverse GH monomers.

Human GH (hGH) immunoreactivity in plasma can be separated into three species of different molecular size by gel filtration (little, big, and big-big hGH). In contrast to pituitary high mol wt GH forms, the molecular nature of the big hGH forms in blood is not known. Therefore, we purified these hGH size isomers from the plasma of L-dopa-stimulated normal subjects and acromegalic patients. Plasma was chromatographed on Sephadex G-100, and fractions containing big-big, big, and little hGH were generated. hGH was extracted and concentrated from these fractions by immunoadsorbent chromatography and analyzed by polyacrylamide gel electrophoresis (PAGE), sodium dodecyl sulfate-PAGE, and isoelectric focusing. The resulting gel profiles indicated that the majority (70%) of big and big-big hGH was converted to little hGH during extraction and storage. The remainder migrated as distinct species with mol wt of approximately 45, 62, 80, and 110 K in sodium dodecyl sulfate-PAGE. These forms could be converted almost completely to little hGH by sulfhydryl reduction. Little hGH (both native and converted from big forms) was composed of several monomeric hGH species, namely the 22 K form (principal), the 20 K variant, and at least one acidic form. All hGH size isomers contained the same monomeric building blocks, although in somewhat different proportions. Big hGH, e.g. was particularly rich in 20K. No abnormal or previously unrecognized hGH forms were identified as components of big or big-big hGH. Binding of hGH to plasma proteins could not be demonstrated. We conclude that 1) plasma big and big-big hGH represent an oligomeric series composed of 22K (major), 20K, and one or more acidic hGH monomers, 2) the majority of these oligomers are noncovalently associated, with a smaller fraction consisting of monomers linked by disulfide bridges.

Circulating growth hormone forms after stimulation of pituitary secretion with growth hormone-releasing factor in man.

Human GH (hGH) in the circulation of acromegalic patients and pharmacologically stimulated normal subjects consists of several monomeric and oligomeric molecular forms. However, little is known about the nature of plasma hGH under physiological conditions. We examined the molecular composition of plasma hGH secreted in response to synthetic human pancreatic tumor GRF-(1-40) (hpGRF-40), a peptide closely resembling or identical to hypothalamic GRF. The peptide (10 micrograms/kg) was injected iv into six normal men, and blood was obtained 30 min later. Plasma hGH was characterized by gel filtration and by polyacrylamide gel electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and isoelectric focusing after extraction from plasma by immunoadsorbent chromatography. At least 53% of hGH eluted as little (monomeric) hGH, 27% as big (dimeric) hGH, and 20% or less as big-big (oligomeric and spurious) hGH during gel filtration. Among the monomeric forms, the 22,000-dalton form was predominant (83%), with smaller quantities of the 20,000-dalton variant (11%), and one or more unidentified acidic forms (N alpha-acetylated, deamidated, or cleaved hGH) (6%) also present. The molecular composition of plasma hGH secreted in response to hpGRF-40 is similar to that released after pharmacological stimuli or that circulating in acromegaly.

A specific growth hormone-binding protein in human plasma: initial characterization.

Human (h) GH in plasma exists as a series of size isomers, which are in part explained by the presence of hGH oligomers. However, certain aspects of circulating large mol wt hGH, such as its high relative proportion compared to that in the pituitary, are poorly understood. To explore whether binding of hGH to plasma protein(s) could contribute to the phenomenon of large mol wt hGH, we incubated freshly prepared monomeric [125I]hGH or biosynthesized [3H]hGH with normal human plasma or serum at pH 7.4 for various time periods at 22 and 37 C. Plasma radioactive hGH patterns were then analyzed simultaneously with unincubated tracer hGH by Sephadex G-100 and G-200 chromatography. We found that part of the radioactivity was converted to a component with an apparent mol wt of 85,000, suggesting binding to a plasma protein(s). This phenomenon was inhibited in a dose-dependent fashion by unlabeled hGH. Saturation/Scatchard analysis indicated an association constant (Ka) of 2-3 X 10(8) M-1 and a maximum binding capacity of 20 ng hGH/ml plasma. Binding was rapid, reversible, and specific. A number of polypeptide hormones, including human placental lactogen, hPRL and rat GH, did not inhibit hGH binding. However, the 20K variant of hGH interacted weakly with the plasma binding component (Ka, 1.2 X 10(7) M-1; maximum binding capacity, 450 ng/ml). The binding component was heat labile and could be partially purified by gel permeation chromatography and affinity chromatography on a hGH-Sepharose column. Its estimated mol wt is 60,000-65,000, and it appears to bind one molecule of hGH to form a complex of 80,000-85,000 mol wt. The binding component is neither albumin nor an immunoglobulin. Under physiological conditions, a minimum of 15-18% of circulating hGH is presumably bound to this plasma component. We conclude that a specific, high affinity, low capacity binding protein for hGH with mol wt of 60,000-65,000 exists in normal and hypopituitary human plasma. hGH complexed with this protein forms part of big-big hGH. The biological significance of this binding protein remains to be investigated.

Consistency of atypical antipsychotic superiority to placebo in recent clinical trials.

BACKGROUND: The use of control placebos in clinical trials of new antipsychotic medications is increasingly under examination. The active controlled equivalence study could offer a potential alternative design. First, however, it must be clear that any proposed standard control agent has been consistently superior to placebo in previous studies. METHODS: Through a Freedom of Information Act request, we identified nine placebo-controlled trials of risperidone, olanzapine, or quetiapine. RESULTS: Meta-analysis indicated that the pooled estimate of the true population effect size +/- SE was 0.46 +/- 0.06 for categorical response rates and >0.53 +/- 0.07 for the continuous Brief Psychiatric Rating Scale change score outcome measure. If the desired detectable effect size is set very conservatively at a 95% confidence lower bound for the estimate of true effect size, statistical power for random samples of 80 per group drawn from a population of subjects similar to that of the nine meta-analyzed studies is.67 for categorical response rates and >.82 for the continuous measure, based on one-sided alpha =.05. CONCLUSIONS: These data suggest substantial confidence that a therapeutic dose of an atypical antipsychotic will be statistically superior to placebo in an adequately sized randomized trial, when reporting a continuous measure as the principal outcome.

Comorbidity of depression in children and adolescents: models and evidence from a prospective high-risk family study.

Despite abundant research demonstrating the magnitude of comorbidity and its importance in understanding childhood psychopathology, there has been limited empirical research designed to examine the nature and causes of comorbidity among youth. This article reviews the current literature on the magnitude and mechanisms of depressive comorbidity and presents data to exemplify the application of high-risk and longitudinal study designs to investigate patterns and explanations for comorbidity. A prospective family study of offspring at high and low risk for the development of anxiety was used to examine the specificity of familial comorbidity of depression and anxiety and the longitudinal stability of "pure" and comorbid disorders over an 8-year period. Findings suggest some specificity of familial expression, as well as longitudinal specificity, of depression and anxiety. The onset of depression follows the onset of most anxiety subtypes, suggesting the sequential nature of depressive comorbidity. Evaluation of mechanisms for comorbidity is important for the identification of homogeneous syndrome categories that will inform research designed to gain understanding of the pathogenesis of mood or anxiety disorders.

Predictors of differential response to clozapine and haloperidol. Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.

BACKGROUND: We sought to identify baseline predictors of response to clozapine. METHODS: Data were from a 15-site randomized clinical trial comparing clozapine and haloperidol in hospitalized patients with refractory schizophrenia (n = 423). Three-month outcomes were analyzed with the full sample (n = 368 due to attrition). Because of crossovers, analyses of 12-month outcomes were conducted with crossovers excluded (n = 291). Clinical predictors included age, race, diagnosis (current substance abuse, paranoid subtype of schizophrenia, or depressive syndrome), severity of symptoms, quality of life, age at onset of schizophrenia, extrapyramidal symptoms, and VA compensation payment. Multiple regression analysis was used to examine the interaction of treatment condition and each of these variables in predicting outcomes for symptoms, quality of life, side effects, and days hospitalized. RESULTS: Patients with higher quality of life at baseline (p = .04) and higher symptoms (p = .02) had relatively smaller declines in hospital days at 6 months. In the 12-month sample patients with higher levels of symptoms had greater symptom reductions at 12 months (p = .03) and greater improvement in quality of life (p = .004). CONCLUSIONS: Although high levels of symptoms were associated with greater improvement on clozapine, these findings are not robust enough to suggest that any specific, clinically defined subgroup of refractory patients should be preferentially targeted for clozapine treatment.

Impact of clozapine on completed suicide.

OBJECTIVE: Clozapine has been found to be superior to typical neuroleptics in ameliorating the symptoms of refractory schizophrenia. This study evaluated clozapine's effect on the rate of death due to suicide. METHOD: All patients over a 4-year period who initiated treatment with clozapine while hospitalized within the Department of Veterans Affairs (VA) system (N=1,415) were matched with a schizophrenic control group (N=2,830) by propensity scoring-a widely accepted statistical method that has been used relatively little in psychiatric research. Centralized VA databases and a national death registry were used to identify all deaths within the two groups, along with listed causes, for the 3 years after discharge. RESULTS: Veterans exposed to clozapine while inpatients were significantly less likely to die during the follow-up period than those in the control group, but this was entirely attributable to the much lower rate of death due to respiratory disorders in the clozapine group. There were no significant differences in rates of suicide or accidental death. CONCLUSIONS: These results fail to support the hypothesis that clozapine treatment is associated with significantly fewer deaths due to suicide.

Association between migraine and stroke in a large-scale epidemiological study of the United States.

OBJECTIVE: To examine the association between stroke and migraine in an epidemiological study. DATA SOURCES AND DESIGN: The National Health and Nutrition Examination Survey baseline and first follow-up data were used to investigate cross-sectional and longitudinal associations between headache/migraine and stroke. SETTING: Study participants from a national probability sample of the civilian noninstitutionalized population of the United States. MAIN OUTCOME MEASURE: Self-reported physician diagnosis of stroke. RESULTS: After controlling for established risk factors for stroke (hypertension, diabetes, heart disease, and gender), both migraine and severe nonspecific headache were associated with a significantly increased risk for stroke reported at follow-up. The risk for stroke associated with migraine decreased as the age at stroke increased. CONCLUSIONS: Our results strengthen previous evidence regarding a nonrandom association of both headache and migraine with stroke, particularly among young women. To our knowledge, this is the first systematic examination in a large-scale prospective epidemiological study of men and women with sufficient statistical power to test the association between migraine and stroke in women. Severe headache and migraine should be considered as risk factors for the development of stroke, particularly in the absence of other well-established stroke risk factors. Further investigation is required to identify the putative mechanisms underlying comorbidity of migraine and stroke.

Atherosclerosis in diabetes: the role of hyperinsulinemia.

Non-insulin-dependent diabetes (NIDDM) is a major cause of premature morbidity and mortality among adults. Macrovascular disease of coronary and peripheral vessels is the primary cause of death in these patients. Numerous experimental and epidemiologic studies have suggested that hyperinsulinemia accelerates the development of atherosclerosis. In experimental models, insulin promotes diet-induced lesion development and overrides lesion regression and estrogen protection against atherosclerosis. Local hyperinsulinemia induced by selected arterial infusion accelerates atherosclerosis in the perfused artery. Insulin has been shown to stimulate subintimal smooth muscle and fibroblast cells in culture, and to increase the uptake and local synthesis of lipid by these cells. Insulin may also induce inhibition of fibrinolysis. Several prospective studies performed on nondiabetic patients show that either fasting or postprandial insulin levels are a sensitive predictor of the development of coronary disease independent of other risk factors. Two recent studies in NIDDM patients confirm this finding and suggest that glycemic control may not be a significant factor in the development of macrovascular disease. Diseases of carbohydrate tolerance, ie, NIDDM, impaired glucose tolerance, obesity, are frequently associated with elevated circulating insulin levels, either physiologically or secondary to treatment. Given the high prevalence of cardiovascular disease in these populations, modifying therapy to minimize hyperinsulinemia should be an important consideration in a treatment program. Use of oral agents such as glipizide or gliclazide, which induce less diurnal hyperinsulinemia, may be advantageous when compared to traditional oral agent or insulin therapy.

Big growth hormone forms in human plasma: immunochemical evidence for their pituitary origin.

Large molecular weight (oligomeric) forms of human growth hormone (hGH) are present in both pituitary extracts and plasma, but the origin of the plasma forms is not known. We used a monoclonal anti-hGH antibody (No. NA-71), previously employed to characterize hGH oligomers in pituitary extracts, to examine circulating hGH oligomers. This monoclonal antibody discriminated between monomeric and polymeric hGH forms in the pituitary. Plasma from normal subjects and acromegalic patients was fractionated by Sephadex G-100 chromatography and fractions were assayed by a monoclonal radioimmunoassay (RIA) using antibody NA-71 and by a polyclonal RIA. The oligomeric plasma hGH fraction showed decreased immunoreactivity in the monoclonal RIA, similar to that observed with pituitary oligomers. The immunopotency ratios of the various plasma hGH size isomers, as determined in the two RIAs, were virtually identical to those of pituitary hGH size isomers. We conclude that circulating hGH oligomers are immunochemically indistinguishable from pituitary hGH oligomers, and thus are most likely derived from pituitary stores.

Secretory patterns of growth hormone during basal periods in man.

Human growth hormone (hGH) concentrations in plasma often fall to levels not detectable by RIA. These so-called basal levels prevail during the greater part of the day. Since hGH is involved in the homeostasis of several metabolic processes, it is important to examine its exact plasma concentration and secretory pattern during basal periods. We used an immunoadsorbent technique to extract hGH from large plasma samples to precisely measure basal hGH concentrations and their variation with time. Blood samples (20 mL) were drawn from 12 normal subjects in the fasted and rested state every 15 minutes over a three-hour period. Plasma hGH levels varied over three orders of magnitude (range, 34 to 60,000 pg/mL). During basal periods, episodes of secretory pulses, of moderate sustained secretion, and of complete secretory inactivity occurred. Women had significantly higher overall hGH levels as well as basal hGH levels than men, but no significant sex difference in the pulse frequency during basal periods could be detected in the limited time allotted for study. No convincing relationship was noted between variations in plasma glucose and the secretory pattern of hGH, or vice versa. We conclude that hGH is secreted in an episodic fashion during basal periods. Conceptually, basal and stimulated hGH secretion may be viewed as extremes of a continuous spectrum of pituitary activity, basal hGH levels are lower than heretofore appreciated, the known tendency of women to higher hGH levels is also evident in the basal range, and oscillations in plasma glucose do not affect the microsecretory pattern of hGH, nor are endogenous hGH pulses followed by acute changes in glycemia.

Association between psychiatric disorders and the progression of tobacco use behaviors.

OBJECTIVE: To examine the progression of tobacco use and the patterns of comorbidity of tobacco use and psychiatric disorders. METHOD: The authors conducted analyses of prospective and retrospective reports, collected from 1988 to 1998, of a sample of high- and low-risk youths identified on the basis of the presence or absence of a parental history of substance abuse or dependence. RESULTS: A parental history of substance use disorders was associated with regular tobacco use and nicotine dependence, but not with experimentation for all youths. Individual and composite psychiatric diagnoses were strongly associated with nicotine dependence, but not with regular use or experimentation. While the presence of an affective disorder and drug abuse/dependence generally increased the risk for co-occurring nicotine dependence, analyses based on the temporal onset of disorders showed that it was the initiation of alcohol or drug use that predicted the progression to nicotine dependence. For low-risk youths, oppositional defiant disorder was the single psychiatric risk factor that predicted the transition to nicotine dependence. CONCLUSIONS: This study adds to the accumulating evidence that has implicated comorbid psychiatric disorders in the etiology and subsequent course of nicotine dependence. In addition, family history may represent an important indicator of an increased risk for nicotine dependence.