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PubMed2001

Intra- and extra-familial influences on alcohol and drug misuse: a twin study of gene-environment correlation.

AIMS: Genotype-environment correlation refers to the extent to which individuals are exposed to environments as a function of their genetic propensities. These correlations are important in the study of psychopathology because they identify environments that may maintain the expression of underlying genetic liabilities for a disorder. The present study examined the correlation between genetic liabilities for alcohol and drug misuse with perceptions of the social environments of the family of origin and the classroom. DESIGN: Postal survey data were collected from monozygotic and dizygotic twin pairs. SETTING: Twin pairs were recruited from Vancouver, British Columbia, Canada using newspaper advertisements and media stories. PARTICIPANTS: Eighty-five monozygotic and 77 dizygotic twin pairs were recruited from the general population. MEASUREMENTS: Twin pairs completed self-report measures of alcohol and drug misuse contained in the Dimensional Assessment of Personality Pathology, the Family Environment Scale, the Classroom Environment Scale, and the Traumatic Events Questionnaire. FINDINGS: Genetically indexed alcohol and drug misuse scores were regressed on the environmentally indexed FES and CES scales. Genetic liabilities for alcohol and drug misuse were associated with decreased perceived family moral-religious emphases, family cohesion and classroom task orientation and increased perceptions of classroom order and organization (strictness). CONCLUSIONS: Genotype-environment correlations, in particular, moral-religious emphases in the home, appear to be important in the development of substance misuse.

Adolescent↗

PubMed2003

Bone mineral density in patients with Behçet's disease.

Behçet's disease is a complex, multisystemic, inflammatory disorder characterized clinically by recurrent oral and genital ulcerations as well as uveitis, sometimes leading to blindness. The etiology and pathogenesis of this syndrome remain obscure. However, various factors are suspected, including genetic propensity, infectious precipitants, and immunological abnormalities. Considering the chronicity and unclear etiology of the disease, we conducted a prospective investigation of a possible alteration in the bone mineral density of affected persons. Thirty-five patients (18 males and 17 females, mean age 38.02+/-7.93 years) diagnosed with Behçet's disease and 33 sex- and age-matched healthy controls (14 males and 19 females, mean age 40.06+/-7.66 years) were seen on an outpatient basis, and bone densitometry measurements were done from June 2000 to December 2002 at the Mersin University Hospital in Turkey. Postmenopausal women with Behçet's disease and patients receiving oral corticosteroid therapy were excluded from the study. The mean disease duration was 6.68+/-7.05 years. Bone mineral density was measured with dual X-ray absorptiometry at the lumbar spine and right femur. The mean Z scores of the patient and control groups were -0.50+/-1.06 and -0.13+/-0.92 at the lumbar spine, respectively, and 0.38+/-1.07 and 0.45+/-1.20 at the right femur, respectively. No significant differences in bone mineral density values were detected in the groups at either the lumbar (P = 0.15) or right femur (P = 0.82) site. Body mass index and disease duration did not influence bone mineral density, and age had a positive correlation with bone mineral density in patients with Behçet's disease. In conclusion, although it is difficult to draw definite conclusions due to the relatively small sample size, our study confirms that bone mineral density in Behçet's disease was not lower than in healthy subjects.

Adult↗

PubMed2004

Predicting low bone density in children and young adults with quadriplegic cerebral palsy.

Many children and young adults with cerebral palsy (CP) have diminished bone mineral density (BMD) and a propensity to fracture with minimal trauma. The aim of this study was to identify variables which are routinely assessed as part of standard clinical care and that might be used to identify those individuals with CP who are most likely to have low BMD. One hundred and seven participants (ages 2 years 1 month to 21 years 1 month; mean age 10 years 11 months, SD 4 years 2 months) with moderate to severe spastic CP were assessed in detail. This included gathering clinical data, taking anthropometric measures of growth and nutrition, as well as dual energy X-ray absorptiometry measures of BMD. Seventeen participants were ambulatory with assistance (Gross Motor Function Classification System [GMFCS] level III), and 90 were capable of little or no ambulation even with assistance (26 GMFCS level IV and 64 GMFCS level V). Weight z score proved to be the best predictor of BMD z score. Declining BMD z scores also correlated with increasing age and greater severity of involvement. It can be predicted, with reasonable reliability, that a 10-year-old non-ambulatory child with quadriplegic CP and a 'typical' weight z score of -2 will have a BMD z score that is at best -2. Prior fractures, use of anticonvulsants, and feeding difficulties further reduce predicted BMD.

Adolescent↗

PubMed2002

Exploring the propensities of helices in PrP(C) to form beta sheet using NMR structures and sequence alignments.

Neurodegenerative diseases induced by transmissible spongiform encephalopathies are associated with prions. The most spectacular event in the formation of the infectious scrapie form, referred to as PrP(Sc), is the conformational change from the predominantly alpha-helical conformation of PrP(C) to the PrP(Sc) state that is rich in beta-sheet content. Using sequence alignments and structural analysis of the available nuclear magnetic resonance structures of PrP(C), we explore the propensities of helices in PrP(C) to be in a beta-strand conformation. Comparison of a number of structural characteristics (such as solvent accessible area, distribution of (Phi, Psi) angles, mismatches in hydrogen bonds, nature of residues in local and nonlocal contacts, distribution of regular densities of amino acids, clustering of hydrophobic and hydrophilic residues in helices) between PrP(C) structures and a databank of "normal" proteins shows that the most unusual features are found in helix 2 (H2) (residues 172-194) followed by helix 1 (H1) (residues 144-153). In particular, the C-terminal residues in H2 are frustrated in their helical state. The databank of normal proteins consists of 58 helical proteins, 36 alpha+beta proteins, and 31 beta-sheet proteins. Our conclusions are also substantiated by gapless threading calculations that show that the normalized Z-scores of prion proteins are similar to those of other alpha+beta proteins with low helical content. Application of the recently introduced notion of discordance, namely, incompatibility of the predicted and observed secondary structures, also points to the frustration of H2 not only in the wild type but also in mutants of human PrP(C). This suggests that the instability of PrP(C) proteins may play a role in their being susceptible to the profound conformational change. Our analysis shows that, in addition to the previously proposed role for the segment (90-120) and possibly H1, the C-terminus of H2 and possibly N-terminus may play a role in the alpha-->beta transition. An implication of our results is that the ease of polymerization depends on the unfolding rate of the monomer. Sequence alignments show that helices in avian prion proteins (chicken, duck, crane) are better accommodated in a helical state, which might explain the absence of PrP(Sc) formation over finite time scales in these species. From this analysis, we predict that correlated mutations that reduce the frustration in the second half of helix 2 in mammalian prion proteins could inhibit the formation of PrP(Sc).

Amino Acid Sequence↗

PubMedDate not supplied

[Linkage analysis of the 15q25-15q22 region in an extended multigenerational family segregating for idiopathic epilepsy].

INTRODUCTION: Linkage analyses provide strong evidence of how genetic factors influence epilepsy, due to the fact that they involve the determination of the cosegregation of specific marker alleles with epilepsy within families. AIMS: Our aim was to determine whether there was some kind of propensity to develop generalised idiopathic epilepsy (GIE) in the 15q22.1-q25.1 region in an extended multigenerational family from the Paisa de Antioquia community, which is a genetic isolate located in Colombia that segregates for GIE and has a strong capacity to detect linkage. PATIENTS AND METHODS: We selected a family containing a number of individuals suffering from epilepsy who visited the Antioquia Neurological Institute. Each affected individual had to have been diagnosed by a neurologist as suffering from non-myoclonic idiopathic epilepsy or from partial idiopathic epilepsy. All patients suspected of suffering from idiopathic epilepsy were submitted to video monitoring in order to characterise seizures electroencephalographically. RESULTS: Of the 106 individuals in this family who were included in the family tree, 76 were genotyped; 15 of them suffered from generalised clonic tonic seizures and six were considered as being possibly affected. Lod score results were significantly negative for all the markers in relation to each of the models under consideration. CONCLUSIONS: The possibility of the genes that code for the a-3, a-5 and b-4 subunits of the neuronal nicotinic acetylcholine receptor (CHRNA3, CHRNA5 and CHRNB4) situated in the 15q region being responsible for the familial aggregation of GIE in this family, as has been suggested in previous studies in other families, was ruled out.

Chromosomes, Human, Pair 15↗

PubMed2004

Individual coping characteristics, rearing conditions and behavioural flexibility in pigs.

Several studies suggest that classification of piglets early in life based on the degree of resistance they display in a so-called Backtest may be indicative of their coping style at a later age. In the present study behavioural flexibility was investigated in pigs diverging for Backtest response and housing environment during rearing. Pigs were housed either without a rooting substrate (barren housing, B) or in identical pens enriched with deep straw bedding (enriched housing, E) from birth. During the suckling period piglets were subjected to the Backtest. Each piglet was restrained on its back for 1 min and the resistance (i.e. number of escape attempts) was scored. Pigs classified as 'high-resisting' (HR) or as 'low-resisting' (LR) were subjected to a simple (left/right) spatial discrimination (T-maze) task at 8 weeks of age. The effect of a single, subtle intramaze change was determined after acquisition of the task. In addition, pigs were subjected to reversal learning to assess their ability to modulate established behaviour patterns. Housing and its interaction with Backtest classification influenced the behavioural response to the intramaze change: E pigs were considerably more distracted than B pigs. Housing condition affected LR pigs more than HR pigs, as indicated by the interaction effects on various recorded behaviours. These interactions indicate that behavioural responding of pigs with diverging coping characteristics cannot simply be generalised across rearing conditions. Furthermore, HR pigs were less successful in reversal learning than LR pigs, suggesting that they have a higher propensity to develop inflexible behavioural routines.

Adaptation, Psychological↗

PubMed2006

Effects of body condition score at parturition and postpartum supplemental fat on adipose tissue lipogenic activity of lactating beef cows.

Three-year-old Angus x Gelbvieh beef cows nutritionally managed to achieve a BCS of 4 +/- 0.07 (479.3 +/- 36.3 kg of initial BW) or 6 +/- 0.07 (579.6 +/- 53.1 kg of initial BW) at parturition were used in a 2-yr experiment (n = 36/yr) to determine the effects of BCS at parturition and postpartum lipid supplementation on cow adipose tissue lipogenesis. Beginning 3 d postpartum, cows within each BCS were randomly assigned to be fed hay and a low-fat control supplement or supplements with either cracked high-linoleate safflower seeds or cracked high-oleate safflower seeds until d 60 of lactation. Diets were formulated to be isonitrogenous and isocaloric, and safflower seed diets provided 5% DMI as fat. Adipose tissue biopsies were collected near the tail-head region of cows on d 30 and 60 of lactation. Dietary treatment did not affect (P > or = 0.43) adipose tissue lipogenesis. Body condition score at parturition did not affect acetate incorporation into lipid (P = 0.53) or activity of acetyl CoA carboxylase (P = 0.77) or fatty acid synthase (P = 0.18). Lipoprotein lipase activity and palmitate incorporation into triacyl-glycerol tended to be greater (P = 0.06), and palmitate esterification into total acylglycerols was greater (P = 0.01) in cows with a BCS of 4 at parturition. Mean activity of acetyl-CoA carboxylase (P < 0.001), lipoprotein lipase (P = 0.01), and rate of palmitate incorporation into monoacylglycerol (P = 0.02), diacylglycerol (P = 0.001), triacylglycerol (P = 0.003), and total acylglycerols (P = 0.002) were greater at d 30 than d 60, suggesting a greater proclivity for fatty acid biosynthesis and esterification by adipose tissue at d 30 of lactation. Although dietary lipid supplementation did not affect adipose tissue lipogenesis, results suggest that cows with a BCS of 4 at parturition have a greater propensity to deliver exogenously derived fatty acids to the adipocyte surface and incorporate preformed fatty acids into acylglycerols as stored adipocyte lipid. Additionally, cows in early lactation seemed to be able to synthesize and incorporate more fatty acids into stored lipid than cows during peak lactation.

Acetyl-CoA Carboxylase↗

PubMed2001

Novel COL1A1 mutation (G559C) [correction of G599C] associated with mild osteogenesis imperfecta and dentinogenesis imperfecta.

A genotype-phenotype analysis of a three-generation family segregating for an autosomal-dominant osteogenesis imperfecta (OI) variant is reported here. The family was ascertained through the presentation of a proband concerned about discoloration of her teeth, found to be dentinogenesis imperfecta (DGI). Examination of 36 family members identified 15 individuals with DGI. Linkage studies were performed for genetic markers from candidate intervals known to contain genes responsible for DGI on chromosomes 4q, 7q, and 17q. Conclusive evidence for linkage of DGI was obtained to genetic markers on chromosome 17q21-q22 (DLX-3, Z(max) = 5.34, theta = 0.00). All DGI-affected family members shared a common haplotype, which was not present in individuals without DGI. Haplotype analysis sublocalized the gene to a 5-cM genetic interval that contained the collagen 1 alpha 1 (COL1A1) gene. More than 150 different COL1A1 gene mutations have been associated with various forms of OI, and five of these have been associated with DGI and type IV OI. After excluding these five mutations, mutational analysis was performed on the remaining exons including intron--exon boundaries, which resulted in identification of a Gly559Cys mutation in exon 32, present in all DGI-affected family members. Clinical features segregating with this G559C mutation included hyperextensible joints, joint pain and an increased propensity for bone fractures with moderate trauma. This is the first report of joint pain associated with a COL1A1 mutation and DGI. The mild skeletal features and reduced penetrance of the non-dental findings illustrate the importance of genetic evaluations for families with a history of DGI.

Amino Acid Substitution↗

PubMed2004

Linkage of serum creatinine and glomerular filtration rate to chromosome 2 in Utah pedigrees.

BACKGROUND: Serum creatinine and creatinine clearance are used as indicators of renal function and may indicate a propensity for development of end-stage renal disease. Identifying genes related to future decreases in renal function could be important in assessing risk and defining abnormal mechanisms amenable to preventive measures. Although creatinine clearance is a better measure of renal function than serum creatinine, proper and complete urine collections in large population studies are sometimes problematic. This can lead to a loss in power to detect linkage. Therefore, in this study we also investigated serum creatinine and estimated glomerular filtration rates (GFR), both of which are more reliably measured. METHODS: Linkage was tested in a genome scan using 49 large Utah pedigrees examined three times over 10 years to detect regions harboring genes related to reduced renal function. RESULTS: Heritability of serum creatinine ranged from 25% to 31% across three examinations, and heritability of GFR ranged from 37% to 42%. The highest log of the odds (LOD) score for serum creatinine was found on chromosome 2 at 145 cM on the Marshfield map (D2S1334). Consistent nonparametric linkage for serum creatinine was found for all three examinations (LOD = 3.15, 2.75, and 2.00, respectively). Estimates of GFR also showed linkage to this region. CONCLUSIONS: The consistency of linkage to chromosome 2 over longitudinally repeated measurements increases the likelihood that this region harbors a gene influencing phenotypic variation in serum creatinine and GFR. Identification of this gene could help to predict which individuals are most likely to progress to renal disease.

Adult↗

PubMed2000

Difference in incidence of spontaneous mutations between Herpes simplex virus types 1 and 2.

Spontaneous mutations within the herpes simplex virus (HSV) genome are introduced by errors during DNA replication. Indicative of the inherent mutation rate of HSV DNA replication, heterogeneous HSV populations containing both acyclovir (ACV)-resistant and ACV-sensitive viruses occur naturally in both clinical isolates and laboratory stocks. Wild-type, laboratory-adapted HSV type 1 (HSV-1) strains KOS and Cl101 reportedly accumulate spontaneous ACV-resistant mutations at a frequency of approximately six to eight mutants per 10(4) plaque-forming viruses (U. B. Dasgupta and W. C. Summers, Proc. Natl. Acad. Sci. USA 75:2378-2381, 1978; J. D. Hall, D. M. Coen, B. L. Fisher, M. Weisslitz, S. Randall, R. E. Almy, P. T. Gelep, and P. A. Schaffer, Virology 132:26-37, 1984). Typically, these resistance mutations map to the thymidine kinase (TK) gene and render the virus TK deficient. To examine this process more closely, a plating efficiency assay was used to determine whether the frequencies of naturally occurring mutations in populations of the laboratory strains HSV-1 SC16, HSV-2 SB5, and HSV-2 333 grown in MRC-5 cells were similar when scored for resistance to penciclovir (PCV) and ACV. Our results indicate that (i) HSV mutants resistant to PCV and those resistant to ACV accumulate at approximately equal frequencies during replication in cell culture, (ii) the spontaneous mutation frequency for the HSV-1 strain SC16 is similar to that previously reported for HSV-1 laboratory strains KOS and Cl101, and (iii) spontaneous mutations in the laboratory HSV-2 strains examined were 9- to 16-fold more frequent than those in the HSV-1 strain SC16. These observations were confirmed and extended for a group of eight clinical isolates in which the HSV-2 mutation frequency was approximately 30 times higher than that for HSV-1 isolates. In conclusion, our results indicate that the frequencies of naturally occurring, or spontaneous, HSV mutants resistant to PCV and those resistant to ACV are similar. However, HSV-2 strains may have a greater propensity to generate drug-resistant mutants than do HSV-1 strains.

Drug Resistance, Microbial↗

PubMedDate not supplied

Interresidue contacts in proteins and protein-protein interfaces and their use in characterizing the homodimeric interface.

The environment of amino acid residues in protein tertiary structures and three types of interfaces formed by protein-protein association--in complexes, homodimers, and crystal lattices of monomeric proteins--has been analyzed in terms of the propensity values of the 20 amino acid residues to be in contact with a given residue. On the basis of the similarity of the environment, twenty residues can be divided into nine classes, which may correspond to a set of reduced amino acid alphabet. There is no appreciable change in the environment in going from the tertiary structure to the interface, those participating in the crystal contacts showing the maximum deviation. Contacts between identical residues are very prominent in homodimers and crystal dimers and arise due to 2-fold related association of residues lining the axis of rotation. These two types of interfaces, representing specific and nonspecific associations, are characterized by the types of residues that partake in "self-contacts"--most notably Leu in the former and Glu in the latter. The relative preference of residues to be involved in "self-contacts" can be used to develop a scoring function to identify homodimeric proteins from crystal structures. Thirty-four percent of such residues are fully conserved among homologous proteins in the homodimer dataset, as opposed to only 20% in crystal dimers. Results point to Leu being the stickiest of all amino acid residues, hence its widespread use in motifs, such as leucine zippers.

Amino Acid Motifs↗

PubMed2002

Fibrin glue fixation of a digital osteochondral fracture: case report and review of the literature.

Surgical treatment options for digital osteochondral fractures are limited by the small amount of bone available for fixation and the propensity for digital stiffness with the introduction of hardware. Fibrin sealant is used in a variety of clinical settings as a biologic bonding agent and may circumvent the drawbacks of traditional fixation or simple excision for certain digital osteochondral injuries. Successful use of fibrin sealant fixation for a patient with an osteochondral fracture involving the proximal interphalangeal joint is documented, and the literature on fibrin sealant for osseous fixation is reviewed.

Accidental Falls↗

PubMed1997

Preliminary risk-benefit analysis of ropivacaine in labour and following surgery.

Ropivacaine is a new, long-acting local anaesthetic, prepared as a single enantiomer (the S form). Ropivacaine has a pKa of 8.07, a protein binding of approximately 94%, but a lower lipid solubility than bupivacaine. Extensive animal toxicological studies have shown a lower propensity for cardiotoxicity with ropivacaine than with bupivacaine. Studies in sheep have shown that the systemic toxicity of ropivacaine is not enhanced by gestation. Studies in human male volunteers have shown that ropivacaine is associated with at least 25% less CNS and cardiovascular adverse effects than bupivacaine following use of intravenous infusions of either drug at a rate of 10 mg/min, to a maximum dose of 150 to 250 mg. With its lower toxicity, especially cardiovascular toxicity, and less intense motor blockade, ropivacaine may have advantages over bupivacaine in epidural pain relief during labour. In general, comparative studies have shown ropivacaine and bupivacaine to have similar efficacy, but ropivacaine has a greater degree of separation between motor and sensory blockade than bupivacaine when it given epidurally for epidural pain relief during labour (as intermittent doses or continuous infusion) or for caesarean section. A significantly lower rate of instrumental deliveries and significantly higher neurological and adaptive capacity scores in neonates at 24 hours were noted for following epidural relief during labour with ropivacaine in a meta-analysis of 6 studies comparing this agent with bupivacaine. Ropivacaine is also of great interest when used as an epidural infusion for postoperative analgesia. There are a few studies evaluating epidural infusions of ropivacaine 0.1%, 0.2% or 0.3% (10 ml/h for 21 hours) after upper or lower abdominal or orthopaedic surgery, and epidural infusion of ropivacaine 0.2% (6 to 14 ml/h) after orthopaedic surgery. The studies show that ropivacaine provides postoperative pain relief in a dose-related manner with minimal or a low degree of dose-related motor blockade. Recommended doses of ropivacaine given epidurally to control postsurgical pain or labour pain are 20 to 40 mg as a bolus with 20 to 30 mg as a top-up with an interval > or = 30 minutes. Alternatively, ropivacaine 2 mg/ml (0.2%) can be given as a continuous epidural infusion at a rate of 6 to 14 ml/h (lumbar) or 4 to 8 ml/h (thoracic). Epidural ropivacaine 0.2% provides a good level of analgesia with minimal motor block, but the effects of a combination of ropivacaine and an opioid administered epidurally could have potential and need to be investigated. Preoperative or postoperative subcutaneous wound infiltration, during cholecystectomy or hernia repair, with ropivacaine 100 to 175 mg has been shown to be more effective than placebo and as effective as bupivacaine in reducing wound pain. The adverse effects associated with epidural administration of ropivacaine include hypotension, nausea, bradycardia, transient paraesthesia, back pain, urinary retention and fever. In comparative studies of ropivacaine and bupivacaine, the 2 drugs appear to be associated with a similar incidence of similar types of adverse effects excluding cardiovascular and CNS toxicities which are lower with ropivacaine. In conclusion, ropivacaine is effective for pain relief during labour and in the postoperative period. Ropivacaine is associated with less cardiovascular and CNS toxicity than bupivacaine and provides a greater degree of dissociation between sensory and motor effects producing less intense motor blockade and more rapid recovery to full patient mobilisation.

Amides↗

PubMed1993

Heterogeneity in the development of apoptosis in irradiated murine tumours of different histologies.

Fifteen different murine tumours were evaluated with respect to the degree of apoptosis development that occurs in the tumour tissue in the first few hours following irradiation in vivo. Animals were killed at 3 or 6 h following irradiation with 0, 2.5, 10 or 25 Gy. Apoptosis was scored as percent aberrant nuclei by microscopic examination of histological sections made from the tumour specimens. Results showed that three of four mammary adenocarcinomas, one ovarian adenocarcinoma, and one lymphoma displayed at least 10% apoptotic cells after 25 Gy, whereas five sarcomas, three squamous cell carcinomas, and a hepatocarcinoma did not. The time courses and dose responses were similar in those tumours that responded. These data were compared with the known response of these same tumours when analysed using conventional assays. The tumours that did respond by significant apoptosis had longer specific growth delays and lower TCD50 (dose to cure 50% of animals) doses, thus suggesting that an acute apoptotic response following irradiation may be a feature of certain tumours that respond well to irradiation. Additionally, this analysis revealed heterogeneity in the apoptotic response both within an individual tumour specimen and among different tumour types. These observations of intra and intertumour heterogeneity are consistent with the idea that the propensity for apoptosis in tumours is genetically regulated.

Adenocarcinoma↗

PubMed1998

Shyness and boldness in pumpkinseed sunfish: individual differences are context-specific.

Natural selection often promotes a mix of behavioural phenotypes in a population. Adaptive variation in the propensity to take risks might explain individual differences in shyness and boldness in humans and other species. It is often implicitly assumed that shyness and boldness are general personality traits expressed across many situations. From the evolutionary standpoint, however, individual differences that are adaptive in one context (e.g. predator defence) may not be adaptive in other contexts (e.g. exploration of the physical environment or intraspecific social interactions). We measured the context specificity of shyness and boldness in a natural population of juvenile pumpkinseed sunfish, Lepomis gibbosus, by exposing the fish to a potentially threatening stimulus (a red-tipped metrestick extended towards the individual) and a nonthreatening stimulus (a novel food source). We also related these measures of shyness and boldness to behaviours observed during focal observations, both before and after the introduction of a predator (largemouth bass, Micropterus salmoides). Consistent individual differences were found within both contexts, but individual differences did not correlate across contexts. Furthermore, fish that were scored as intermediate in their response to the metrestick behaved most boldly as foragers and in response to the bass predators. These results suggest that shyness and boldness are context-specific and may not exist as a one-dimensional behavioural continuum even within a single context. Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed1993

Comparison of coronary angiographic findings in acute and chronic first presentation of ischemic heart disease.

BACKGROUND: It is generally assumed that the clinical manifestations of ischemic heart disease occur randomly on the same underlying pathological process. Therefore, coronary angiographic findings should be similar whether the first presentation of ischemic heart disease is acute myocardial infarction or uncomplicated chronic stable angina. METHODS AND RESULTS: We studied 102 patients (men < or = 60 years old, women < or = 65 years old) presenting with either acute myocardial infarction as first manifestation of coronary artery disease with a concomitant coronary angiogram (55 patients; mean age, 50.2 years) or stable angina for at least 2 years with no history, ECG, or left ventriculographic evidence of any acute event and with an angiogram performed at least 2 years after initial symptoms (47 patients; mean age at symptom onset, 51.7 years). These angiograms were evaluated blindly for severity (number of vessels diseased, stenoses > or = 50%, occlusions), extent of disease (with an index derived by assigning a score of 0-3 per segment, depending on the proportion of lumen length irregularity and dividing the sum by the number of visualized segments), and pattern (discrete: three or fewer loci of disease never involving more than 50% of the length of any segment or diffuse: anything exceeding this). Patients with unheralded myocardial infarction had fewer vessels diseased, fewer stenoses and occlusion, and a lower extent index than those with uncomplicated stable angina (mean +/- SD of 1.3 +/- 0.8 versus 2.1 +/- 0.8, p < 0.001; 2.1 +/- 1.8 versus 3.9 +/- 1.8, p < 0.001; 0.6 +/- 0.6 versus 1.0 +/- 0.9, p < 0.02; and 0.6 +/- 0.5 versus 1.2 +/- 0.5, p < 0.001, respectively). A discrete pattern was present in 54.5% of patients with unheralded infarction and in only 8.5% of those with uncomplicated angina (p < 0.001). CONCLUSIONS: These very different angiographic findings suggest that unheralded acute myocardial infarction and uncomplicated chronic stable angina do not occur randomly on a common atherosclerotic background but rather that additional factors, such as a varying propensity to thrombosis, may predispose to one or the other of these two clinical syndromes.

Angina Pectoris↗

PubMed2004

Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder.

UNLABELLED: Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia. PHARMACOLOGICAL PROPERTIES: Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased). THERAPEUTIC EFFICACY: The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomised trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neurocognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day. TOLERABILITY: Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.

Antipsychotic Agents↗

PubMed2000

Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10.

We studied a large kindred with nonsyndromic autosomal dominant thrombocytopenia to define the phenotype and used genomic linkage analysis to determine the locus of the abnormal gene. Affected family members are characterized by lifelong moderate thrombocytopenia (mean = 42.7 x 10(9)/L) with moderate propensity toward easy bruising and minor bleeding. Megakaryocytes are present in bone marrow with reduced frequency, and there are no apparent abnormalities of myeloid or erythroid cells. This type of inherited thrombocytopenia has no evident association with hematopoietic malignancy or progression to aplastic anemia. In the past, members of this family have failed therapeutic trials of immunosuppression and splenectomy. In our investigation, we found that affected individuals had normal platelet size compared with unaffected family members and modestly increased thrombopoietin levels. Hematopoietic colony assays from bone marrow and peripheral blood demonstrated that megakaryocyte precursors (CFU-Mk) were dramatically increased in both number and size in affected individuals. Bone marrow cells grown in liquid culture with thrombopoietin failed to develop polyploid cells greater than 8N. Also, electron microscopy demonstrated that megakaryocytes from an affected individual had markedly delayed nuclear and cytoplasmic differentiation. Genome-wide linkage analysis established a single locus for the disease gene on the short arm of chromosome 10 with a maximum 2-point lod score of 5.68 (at theta = 0). By recruiting additional family members, the genomic region was narrowed to 17 centimorgans. We conclude that a gene in this locus plays an important role in megakaryocyte endomitosis and terminal maturation.

Bone Marrow Cells↗