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PubMed2002

Relation of magnetocardiographic arrhythmia risk parameters to delayed ventricular conduction in postinfarction ventricular tachycardia.

Time-domain late field and intra-QRS fragmentation parameters in magnetocardiography (MCG) identify patients prone to VT after myocardial infarction. This study investigated if they are related to slow ventricular conduction and affected by arrhythmia surgery. Twenty-two patients with old myocardial infarction undergoing map-guided subendocardial resection to treat sustained VT were included. Bipolar electrograms were recorded during operation using an epicardial jacket and endocardial balloon electrode array. The time from the QRS onset to the end of local ventricular excitation in each electrogram was measured during sinus rhythm. Multi-channel MCG was recorded before and after operation and filtered QRS duration (QRSd), root mean square amplitude of the magnetic field strength during the last 40 ms of the QRS complex (RMS40), duration of the low amplitude signal < 300 fT (LAS300), fragmentation index M (M), and fragmentation score S (S) were determined. All patients had one or two VT foci localized and resected. MCG parameters correlated with time to the latest end of ventricular excitation; r = 0.45 for QRSd (P = 0.035), r = 0.64 for M (P = 0.001), and r = 0.73 for S (P < 0.001). The correlations were even better in patients with anterior infarction (e.g., r = 0.87 for QRSd, P < 0.001; r = 0.91 for M, P < 0.001). The operation reduced the abnormalities in MCG parameters and 20 of the 21 patients tested postoperatively became noninducible. MCG parameters indicating postinfarction arrhythmia propensity are related to delayed ventricular conduction. Abolition of the arrhythmia substrate reverses the abnormality of these parameters.

Electrocardiography↗

PubMed1994

Reversal of low-molecular-weight heparin anticoagulation by synthetic protamine analogues.

Protamine reversal of unfractionated and low-molecular-weight heparin (LMWH) causes hypotension, bradycardia, pulmonary artery hypertension, and declines in oxygen consumption. Furthermore, protamine incompletely reverses the anti-Xa activity of LMWH. The present study assesses the efficacy and toxicity of three protamine variants having +16 and +18 charges in reversal of LMWH (Logiparin, LHN-1): [+16] P(AK2A2K2)4, [+18] PK(K2A2K2A)3K2AK3, and [+18B] acetyl-PA(K2A2K2A)4K2-amide. The [+18B] compound was made by acetylating and amidating the [+18] to decrease in vivo degradation and to increase the alpha-helix forming propensity. Variants were examined in a canine model (n = 7, each variant) and compared to controls (n = 7, each variant) and compared to controls (n = 7) reversed with standard protamine with a +21 charge. Animals were anesthetized, anticoagulated with LMWH (150 IU factor Xa activity/kg), and reversed with protamine variants (1.5 mg/kg with 100 IU/mg). Blood pressure (BP), heart rate (HR), cardiac output (CO), pulmonary artery pressures, oxygen saturations, and oxygen consumption (VO2) were continuously monitored. Comparisons were undertaken at baseline, after heparin, before variant administration, and for 30 min thereafter. A total toxicity score (TTS) was calculated for each variant, accounting for maximal declines in BP, HR, CO, and VO2 during the first 5 min after reversal. Protamine [+21] was most toxic, TTS -7.6, with the variants being less toxic (P < 0.01, ANOVA): TTS = [+16] -2.8, [+18] -1.3, and [+18B] -4.1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Associations of the dopamine D4 receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients.

BACKGROUND: The VNTR polymorphism in the Dopamine D4 receptor gene (DRD4) has been associated with differential urge for substances across multiple methodologies ranging from neuroimaging to assessment in the natural environment. It is unclear whether the DRD4 gene is a marker for an underlying propensity for greater urge or whether the DRD4 gene differentially moderates the neuroadaptive effects of extended substance use on urge. Examination of the DRD4 in an adolescent sample may provide evidence of a mechanism of this putative relationship. METHOD: Data from a subset of 77 participants in a larger assessment study characterized adolescents for substance-related behaviors by DRD4 genotype. The psychiatrically admitted adolescents were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene (L>or=7 [n=25], S=or<7 [n=52]). Associations of the DRD4 with scores on the SASSI, and ADI were examined as well as selected individual items thought to be most related to the intermediate phenotype of urge. RESULTS: The DRD4 gene was not associated with any DSM-IV substance misuse diagnostic classification. Individual items related to urge were also nonsignificantly related to DRD4 status. Carriers of the long variant of the DRD4 polymorphism were more likely to have used hard drugs within the previous 6 months and scored higher on the self-medication subscale of the ADI compared to short variant homozygotes. DISCUSSION: Preliminary results provide little evidence for the DRD4 VNTR polymorphism to be related to urge-related phenomena in hospitalized adolescents on a psychiatric inpatient unit. The association of the DRD4 gene with hard drug use may support literature linking this gene to impulsivity. Subscale findings may suggest a role of negative affect in previous DRD4 urge findings.

Adolescent↗

PubMed2004

A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial.

This pilot study was undertaken to estimate the acute antipsychotic effect size and side effect propensity of risperidone and olanzapine in the pediatric population, in comparison to haloperidol, a conventional antipsychotic with established efficacy. Risperidone and olanzapine are widely used as first-line treatments to ameliorate psychotic symptoms in youth, but their abilities to specifically treat children and adolescents presenting due to psychotic symptoms have not been rigorously studied. Subjects, selected because of prominent positive psychotic symptoms, were randomly assigned to double-blind, parallel treatment with risperidone, olanzapine, or haloperidol for 8 weeks. The primary outcome was reduction in the Brief Psychiatric Rating Scale for Children total score from baseline to termination. An exploratory, descriptive analysis was done to compare the three treatments. A total of 50 patients, 8-19 years, participated. All treatments reduced symptoms significantly with p-values (corrected for multiple comparisons) of 0.0018 for each of the atypical agents and 0.012 for haloperidol. In all, 88% of subjects treated with olanzapine, 74% treated with risperidone, and 53% treated with haloperidol met response criteria. The primary side effects observed in all patients were mild to moderate sedation, extrapyramidal symptoms, and weight gain. Risperidone and olanzapine acutely reduced psychotic symptoms in this pediatric sample. Exploratory comparisons indicate the magnitude of the antipsychotic response with these atypical agents is comparable to that observed with haloperidol. However, youth treated with risperidone and olanzapine experienced weight gain and extrapyramidal effects that appear more prevalent and severe than reported in adults.

Adolescent↗

PubMed2005

AVPR1a and SLC6A4 gene polymorphisms are associated with creative dance performance.

Dancing, which is integrally related to music, likely has its origins close to the birth of Homo sapiens, and throughout our history, dancing has been universally practiced in all societies. We hypothesized that there are differences among individuals in aptitude, propensity, and need for dancing that may partially be based on differences in common genetic polymorphisms. Identifying such differences may lead to an understanding of the neurobiological basis of one of mankind's most universal and appealing behavioral traits--dancing. In the current study, 85 current performing dancers and their parents were genotyped for the serotonin transporter (SLC6A4: promoter region HTTLPR and intron 2 VNTR) and the arginine vasopressin receptor 1a (AVPR1a: promoter microsatellites RS1 and RS3). We also genotyped 91 competitive athletes and a group of nondancers/nonathletes (n = 872 subjects from 414 families). Dancers scored higher on the Tellegen Absorption Scale, a questionnaire that correlates positively with spirituality and altered states of consciousness, as well as the Reward Dependence factor in Cloninger's Tridimensional Personality Questionnaire, a measure of need for social contact and openness to communication. Highly significant differences in AVPR1a haplotype frequencies (RS1 and RS3), especially when conditional on both SLC6A4 polymorphisms (HTTLPR and VNTR), were observed between dancers and athletes using the UNPHASED program package (Cocaphase: likelihood ratio test [LRS] = 89.23, p = 0.000044). Similar results were obtained when dancers were compared to nondancers/nonathletes (Cocaphase: LRS = 92.76, p = 0.000024). These results were confirmed using a robust family-based test (Tdtphase: LRS = 46.64, p = 0.010). Association was also observed between Tellegen Absorption Scale scores and AVPR1a (Qtdtphase: global chi-square = 26.53, p = 0.047), SLC6A4 haplotypes (Qtdtphase: chi-square = 2.363, p = 0.018), and AVPR1a conditional on SCL6A4 (Tdtphase: LRS = 250.44, p = 0.011). Similarly, significant association was observed between Tridimensional Personality Questionnaire Reward Dependence scores and AVPR1a RS1 (chi-square = 20.16, p = 0.01). Two-locus analysis (RS1 and RS3 conditional on HTTLPR and VNTR) was highly significant (LRS = 162.95, p = 0.001). Promoter repeat regions in the AVPR1a gene have been robustly demonstrated to play a role in molding a range of social behaviors in many vertebrates and, more recently, in humans. Additionally, serotonergic neurotransmission in some human studies appears to mediate human religious and spiritual experiences. We therefore hypothesize that the association between AVPR1a and SLC6A4 reflects the social communication, courtship, and spiritual facets of the dancing phenotype rather than other aspects of this complex phenotype, such as sensorimotor integration.

Adult↗

PubMed1998

The association of personality characteristics with parenting problems among alcoholic couples.

This retrospective cross-sectional study explored the associations of personality characteristics with parenting problems among 25 couples, one or both members of which were identified as alcoholics by virtue of their voluntary past completion of a residential program for alcoholics. Most of them (90%) scored lower, indicating their more problematic parental attitudes and behaviors, on all four scales of the Adult-Adolescent Parenting Inventory (AAPI: inappropriate parental expectations of children, lack empathy for children's needs, value physical punishment, and parent-child role reversal) than average "normal" nonalcoholic, nonabusive adults. Such parenting problems were found to be very highly associated with clients' personality characteristics. For example, schizoid, schizotypal, histrionic, and passive aggressive characteristics (DSM-III-R-based) along with a few other personal characteristics of the couples, accounted for nearly all (90.2%, R2 = .902) of their propensity to reverse roles with their children. Findings also suggested that the identified parenting problems among alcoholic couples are amenable to programmatic intervention: the longer couples had participated in aftercare programs offered by the treatment facility the more appropriate and empathetic was their parenting.

Adolescent↗

PubMed2003

Concurrent evaluation of locomotor response to novelty and propensity toward cocaine conditioned place preference in mice.

Neural and physiological factors underlying individual differences in the vulnerability to drug abuse are the major questions remained to be determined. The present study described new methods that concurrently assess the relationship between locomotor response to novelty and conditioned place preference (CPP) for cocaine in mice using a novel activity monitor, SCANET. The activity monitor simultaneously measured the distance traveled and the amount of time spent in each side of a two-compartment CPP chamber, and the latency to the first entry into the other side of the CPP chamber. Mice were divided into two groups according to their locomotor response to the first exposure to the CPP chamber during a preconditioning session; high-responder (HR) and low-responder (LR) mice. Following conditioning sessions, the CPP score was shown to be higher in LR mice than in HR mice, especially at low doses of cocaine. In a separate experiment with SCANET, we measured the latency to the first entry into the white-floored compartment from the black-floored compartment of the CPP chamber as an index of anxiety-like behavior. The latency was significantly prolonged in the LR group as compared with the HR group. Thus, the new methods described here are considered to be useful for examining animal models of drug addiction with respect to anxiety-like behavior.

Animals↗

PubMed2005

Association of depressive symptoms with coagulation factors in young healthy individuals.

BACKGROUND: Depression has been reported to be an independent risk factor for coronary heart disease (CHD). We investigated the association of depressive symptoms with lipids and coagulation factors in young individuals free of CHD. METHODS: We recruited 1073 young healthy individuals candidates for military academies (mean age=18.4+/-0.8 years, males 762) in whom the presence of depressive symptoms was assessed by using the depression scale of Minnesota Multiphasic Personality Inventory test. Total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein (a), fibrinogen, factors VII, VIII and X were measured. RESULTS: The depression score ranged from 22 to 90. The participants were divided into quartiles according to the depression score. Three hundred twenty-two subjects were classified in the upper quartile (score>48) and 269 in the lower quartile (score<37) of the depression score. Factor VII (102.95+/-24 versus 98.5+/-20%) and X levels (92+/-11 versus 89.7+/-10%) were significantly higher in individuals in the upper quartile compared to the lower quartile of the depression score. In a logistic regression model with factor VII as dependent variable (upper versus lower quartile) and depression score, age, gender, body mass index, exercise and smoking as predictor variables, depression was an independent predictor of factor VII levels with an adjusted odds ratio for high levels of factor VII of 1.05 (95% confidence interval 1.008-1.09, p=0.01). Factor VII levels were associated with triglycerides (r=0.21, p=0.001) while factor X with triglycerides (r=0.22, p<0.001) and cholesterol levels (r=0.12, p<0.001). CONCLUSIONS: Depressed mood is associated with a hypercoagulant profile as it is expressed by the higher levels of coagulation factors VII and X. This might partially explain the higher propensity for CHD of people with depressive symptoms.

Adolescent↗

PubMed2006

Expression of the calcium receptor in human breast cancer--a potential new marker predicting the risk of bone metastases.

AIMS: This study investigates whether the calcium-sensing receptor (CaR) is commonly expressed in primary breast cancers. The CaR controls secretion of PTHrP in several breast cancer cell lines and PTHrP is known to stimulate osteolysis during metastatic bone resorption. Whether this could explain the propensity of breast cancers to develop bone metastases has not been explored. METHODS: With Ethical Committee approval, immunohistochemistry was performed using a commercially available antiCaR antibody (AffinityBioReagents, Cambridge, UK) on archived histological sections of primary tumours from patients who died with advanced breast cancer. Intensity of CaR expression was assessed by two independent observers on a 6-point scale. RESULTS: One hundred and eight patients with breast cancer were found to have positive bone scans, 42 patients had died. Of the patients with negative bone scans, 23 had liver or lung metastases. Most patients with strongly expressed CaR (score 4-5 on immunohistochemistry) had bone metastases (13/15 patients) compared with 2/23 patients with normal bone scans (p < 0.001, chi(2) test). Other clinical/pathological markers (ER, PR, c-erb B-2, LN status) were not significantly different between patients with CaR-positive or CaR-negative tumours. CONCLUSIONS: CaR expression is common in a selected group of patients with advanced primary breast cancers. A prospective study should investigate if patients with CaR-positive tumours are more likely to develop bone metastases.

Adult↗

PubMed1999

Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions.

Regulated expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) plays a role in various physiological processes. To determine in vivo how unbalanced expression of these factors can promote or affect the course of pathologies, we knocked out the mouse gelatinase B gene by replacing the catalytic and zinc-binding domains with an antisense-oriented neomycin resistance gene. Adult gelatinase B-deficient mice and wild-type controls could be induced to develop experimental autoimmune encephalomyelitis (EAE) with similar scores for neurologic disease, blood-brain barrier permeability, and central nervous system histopathology. However, whereas diseased control animals showed necrotizing tail lesions with hyperplasia of osteocartilaginous tissue, adult gelatinase B-deficient mice were resistant to this tail pathology. Gelatinase B-deficient mice younger than 4 weeks of age were significantly less susceptible to the development of EAE than were age matched controls and, even as they aged, they remained resistant to tail lesions. These data illustrate that gelatinase B expression plays a role in the development of the immune system and that, in ontogenesis, the propensity to develop autoimmunity is altered by the absence of this MMP.

Age Factors↗

PubMed2001

A genome-wide scan for abdominal fat assessed by computed tomography in the Québec Family Study.

To identify chromosomal regions harboring genes influencing the propensity to store fat in the abdominal area, a genome-wide scan for abdominal fat was performed in the Quebec Family Study. Cross-sectional areas of the amount of abdominal total fat (ATF) and abdominal visceral fat (AVF) were assessed from a computed tomography scan taken at L4-L5 in 521 adult subjects. Abdominal subcutaneous fat (ASF) was obtained by computing the difference between ATF and AVF. The abdominal fat phenotypes were adjusted for age and sex effects as well as for total amount of body fat (kilogram of fat mass) measured by underwater weighing, and the adjusted phenotypes were used in linkage analyses. A total of 293 microsatellite markers spanning the 22 autosomal chromosomes were typed. The average intermarker distance was 11.9 cM. A maximum of 271 sib-pairs were available for single-point (SIBPAL) and 156 families for multipoint variance components (SEGPATH) linkage analyses. The strongest evidence of linkage was found on chromosome 12q24.3 between marker D12S2078 and ASF (logarithm of odds [LOD] = 2.88). Another marker (D12S1045) located within 2 cM of D12S2078 also provided evidence of sib-pair linkage with ASF (P = 0.019), ATF (P = 0.015), and AVF (P = 0.0007). Other regions with highly suggestive evidence (P < 0.0023 or LOD > or =1.75) of multipoint linkage and evidence (P < 0.05) of single-point linkage, all for ASF, included chromosomes 1p11.2, 4q32.1, 9q22.1, 12q22-q23, and 17q21.1. Three of these loci (1p11.2, 9q22.1, and 17q21.1) are close to genes involved in the regulation of sex steroid levels, whereas two others (4q32.1 and 17q21.1) are in the proximity of genes involved in the regulation of food intake. This first genome-wide scan for abdominal fat assessed by computed tomography indicates that there may be several loci determining the propensity to store fat in the abdominal depot and that some of these loci may influence the development of diabetes in obese subjects.

Adipose Tissue↗

PubMed2001

Thermodynamic propensities of amino acids in the native state ensemble: implications for fold recognition.

An amino acid sequence, in the context of the solvent environment, contains all of the thermodynamic information necessary to encode a three-dimensional protein structure. To investigate the relationship between an amino acid sequence and its corresponding protein fold, a database of thermodynamic stability information was assembled that spanned 2951 residues from 44 nonhomologous proteins. This information was obtained using the COREX algorithm, which computes an ensemble-based description of the native state of a protein. It was observed that amino acid types partitioned unequally into high, medium, and low thermodynamic stability environments. Furthermore, these distributions were reproducible and were significantly different than those expected from random partitioning. To assess the structural importance of the distributions, simple fold-recognition experiments were performed based on a 3D-1D scoring matrix containing only COREX residue stability information. This procedure was able to recover amino acid sequences corresponding to correct target structures more effectively than scoring matrices derived from randomized data. High-scoring sequences were often aligned correctly with their corresponding target profiles, suggesting that calculated thermodynamic stability profiles have the potential to encode sequence information. As a control, identical fold-recognition experiments were performed on the same database of proteins using DSSP secondary structure information in the scoring matrix, instead of COREX residue stability information. The comparable performance of both approaches suggested that COREX residue stability information and secondary structure information could be of equivalent utility in more sophisticated fold-recognition techniques. The results of this work are a consequence of the idea that amino acid sequences fold not into single, rigidly stable structures but rather into thermodynamic ensembles best represented by a time-averaged structure.

Algorithms↗

PubMed2002

A longitudinal view of triggers and thresholds of suicidal behavior in depression.

BACKGROUND: Recurrent brief depressive disorder (RBD) and major depressive disorder (MDD) share the same diagnostic picture of full-blown depression and are both associated with increased suicide attempt rates. However, longitudinal diagnostic shifts from RBD to MDD or vice versa, called "combined depression" (CD), have demonstrated a substantially higher risk of suicide attempts in epidemiologic and clinical studies. Following the stress-diathesis model of suicidal behavior, we compared possible triggers and thresholds for suicidal behavior among patients with RBD, MDD, and CD. RBD and MDD diagnoses were based on DSM-IV criteria. Furthermore, the goal of this study was to determine if impulsivity as an underlying factor could explain high suicide attempt rates in CD. METHOD: A structured clinical interview evaluating comorbid Axis I and II disorders and RBD and a battery of instruments assessing suicidal behavior were administered to 101 patients with RBD (N = 27), MDD (N = 33), or CD (N = 41). RESULTS: Patients with CD showed significantly higher (p < .05) scores on measures of suicidal behavior in comparison with RBD and MDD patients. Together with comorbid substance abuse and marital status, CD was among the highest-ranking risk factors for suicide attempts. Impulsivity was identified as a major underlying factor, predicting 80.7% of suicide attempts. CONCLUSION: CD seems to be an important clinical risk factor for the prediction of suicide attempts, similar to risk factors such as substance use disorders and borderline personality disorder. All of these factors share the same diathesis for increased impulsivity and suicidal ideation, which could explain comorbidity and suicidal behavior. The coexistence of a greater propensity for suicidal ideation and impulsivity in RBD might also explain why such patients are more prone to attempt suicide, even if they do not, in the case of RBD, meet the duration criteria for MDD.

Adult↗

PubMed2002

Significance of planum temporale and planum parietale morphologic features in neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is associated with learning disabilities and cognitive impairment in childhood and adolescence. Individuals with NF-1 have a propensity for brain hyperintensities on T2-weighted magnetic resonance images, macrocephaly, and optic gliomas. Few clear relationships between these central nervous system abnormalities and cognitive function, however, have been found in this population. OBJECTIVES: To determine whether planum temporale (PT) and planum parietale (PP) morphologic features are associated with learning disabilities in NF-1. PATIENTS AND METHODS: We measured and compared the surface area, gray matter volume, and asymmetry of the PT and PP on T1-weighted MRIs from 24 children and adolescents with NF-1 and an equal number of controls. Relationships between these measurements and cognitive and academic achievement scores were examined. RESULTS: The left PT in boys with NF-1 was significantly smaller in both surface area and gray matter volume compared with girls with NF-1 and controls. Boys with NF-1 also showed greater symmetry between the left and right hemispheres in this region compared with girls with NF-1 and controls, who showed a pattern of left greater than right asymmetry of the PT. Intelligence-based discrepancy scores of reading and math achievement, which are commonly used to define learning disabilities, were significantly related to PT asymmetry in the NF-1 group as a whole. Less leftward asymmetry of the PT was associated with poorer reading and math achievement in relation to intellectual test scores. CONCLUSIONS: The high susceptibility of individuals with NF-1 to develop reading and other learning disabilities seems to be related to the development of the sylvian fissure. These results provide further support for the hypothesized association between sylvian fissure morphologic features and learning disabilities.

Adolescent↗

PubMed2003

Graded atmospheric oxygen level effects on performance and ascites incidence in broilers.

The effects of graded atmospheric O2 concentration (12, 14, 16, 18, and 20.6%) on chick performance and propensity to develop ascites were investigated using commercial male broilers. Chicks were housed in calorimetry chambers for 2 wk with incoming air diluted with N to provide the desired O2 concentration at thermoneutral (TN) ambient temperature. Day 14 body weight, weight gain, feed consumption, and gain-to-feed ratio increased (P < 0.01) as O2 concentration incrementally rose from 12 to 20.6%. Body weight was 138 g for the lowest atmospheric O2 level compared to 371 g for 20.6% O2. The greatest treatment difference occurred between the 12 and 14% O2 concentrations. Growth depression appeared related to feed consumption. Ascites heart ratio (AHR), ascites score (AS), right ventricular mass (RVM), and hematocrit (HCT) all increased (P < 0.01) as O2 concentration decreased. Blood HCT appeared to be a more sensitive indicator of physiological change attributable to atmospheric O2 than AHR, AS, or RVM. The data reported herein suggests that 19.6% atmospheric O2 is the minimal allowable level for housing birds within a relatively stress-free, TN environment to avoid cardiac and HCT changes related to ascites.

Altitude↗

PubMed2002

Endpoints in prostate cancer clinical trials.

Prostate cancer is an extraordinarily heterogeneous disease with a variety of prognostic factors influential in determining ultimate patient outcomes. However, the vast majority of men harboring pathologic evidence of prostate cancer are not clinically diagnosed with this disease. Selected patients, particularly those with low clinical stage and low Gleason scores, may have extremely prolonged time until disease progression and cancer-specific death. Because of the potential for a prolonged natural history, factors, such as age and comorbidities, are often critical in evaluating clinical trial outcomes. Patients with more aggressive disease (higher clinical stage or Gleason score) have less prolonged natural histories. Careful examination of inclusion and exclusion criteria and the presence of clinical or pathologic staging are necessary for proper interpretation of clinical trials. Although surrogate endpoints, such as prostate-specific antigen and pathologic state, are commonly used to assess the effectiveness of therapeutic interventions, the relations between these surrogates and more relevant clinical endpoints have not always been well defined. Although certain endpoints are generalizable (overall survival and cancer-specific survival), clinical stage and treatments dictate the appropriateness of many other clinical trial endpoints. Both disease-related and treatment-related endpoints are important, given the propensity for various interventions to alter quality of life. Prospective randomized trials with adequate follow-up time and the assessment of clinically meaningful endpoints will offer the best opportunity to evaluate the effectiveness of various interventions used in this disease.

Biomarkers, Tumor↗

PubMed1995

The association between childhood irritability and liability to substance use in early adolescence: a 2-year follow-up study of boys at risk for substance abuse.

The aim of this investigation was to determine whether irritability, defined as the propensity to experience and express anger following actual or perceived provocation, is a component of the liability to alcohol and drug abuse. Sons of substance abusing fathers (n = 40) and normal fathers (n = 56) were studied when they were 10-12 years of age and followed-up 2 years later. Hierarchical regression analysis revealed that resting salivary cortisol concentration, impulsivity and family discord measured when the subjects were 10-12 years of age explained 35% of the variance on a scale measuring irritability 2 years later. At follow-up, when the boys were 12-14 years of age, it was observed that irritability scale scores and family discord were the only variables that accounted for significance variance on a scale measuring coping via alcohol and drug use. Latency and amplitude of the N1 and P3 event-related potentials of an auditory oddball task, measured at age 10-12, were not associated with drug use at age 12-14. These results indicate that family dysfunction, stress state of the child, and low behavioral self-control additively account for a significant proportion of variance on irritability scale scores 2 years later, and that this trait, in conjunction with family discord, is associated with substance use as a coping response by early adolescence.

Adolescent↗

PubMed1987

Medical versus early surgical therapy in patients with triple-vessel disease and mild angina pectoris: a CASS registry study of survival.

Results of coronary artery bypass grafting were evaluated in 856 nonrandomized patients in the Coronary Artery Surgery Study (CASS) registry with mild angina (Canadian Cardiovascular Society Classes I and II) and three-vessel disease, defined as 70% or more stenosis in the proximal or middle segment of the three major coronary arteries. There were 413 patients with medical therapy and 443 with early operation. Patients with delayed operation were kept in the medical group for analysis. Six-year survival adjusted for left ventricular (LV) function and number of proximal stenoses was 67% for medical and 84% for surgical patients (p less than 0.0001). Patients with normal LV function had equal survival with medicine or surgical intervention. Those with mild or moderate LV dysfunction (CASS LV wall motion score 6 to 9 and 10 to 15, respectively) and at least one proximal stenosis (the dominant right coronary artery) had increased probability of being alive at six years with surgical treatment. In patients with severe LV impairment (LV score higher than 15) and in those whose only proximal stenosis of 70% or more (in three-vessel disease) was located in the left anterior descending coronary artery, increased survival with surgical treatment could not be demonstrated. This is a nonrandomized observational study with the limitations of such studies: the need to adjust for differences in baseline traits between medical and surgical groups and the possibility of an unrecognized imbalance in baseline characteristics. In a Cox analysis of variables influencing outcome, early surgical treatment was an independent predictor of survival with 43% the risk of medical treatment (95% confidence range: 29 to 62%). Adjustment by propensity analysis to reduce selection bias from known differences in baseline variables did not alter results.

Angina Pectoris↗