Predictors of surface disruption with MR imaging in asymptomatic carotid artery stenosis.

BACKGROUND AND PURPOSE: Surface disruption, either ulceration or fibrous cap rupture, has been identified as a key feature of the unstable atherosclerotic plaque. In this prospective observational study, we sought to determine the characteristics of the carotid lesion that predict the development of new surface disruption. MATERIALS AND METHODS: One hundred eight asymptomatic individuals with 50%-79% carotid stenosis underwent carotid MR imaging at baseline and at 3 years. Multicontrast imaging criteria were used to determine the presence or absence of calcification, LRNC, intraplaque hemorrhage, and surface disruption. Volume measurements of plaque morphology and the LRNC and calcification, when present, were collected. RESULTS: At baseline, 21.3% (23/108) of participants were identified with a surface disruption. After 3 years, 9 (10.6%) of the remaining 85 individuals without disruption at baseline developed a new surface disruption during follow-up. Among all baseline variables associated with new surface disruption during regression analysis, the proportion of wall volume occupied by the LRNC (percentage LRNC volume; OR per 5% increase, 2.6; 95% CI, 1.5-4.6) was the strongest classifier (AUC = 0.95) during ROC analysis. New surface disruption was associated with a significant increase in percentage LRNC volume (1.7 +/- 2.0% per year, P = .035). CONCLUSIONS: This prospective investigation of asymptomatic individuals with 50%-79% stenosis provides compelling evidence that LRNC size may govern the risk of future surface disruption. Identification of carotid plaques in danger of developing new surface disruption may prove clinically valuable for preventing the transition from stable to unstable atherosclerotic disease.

Pathways to neuronal injury and apoptosis in HIV-associated dementia.

Human immunodeficiency virus-1 (HIV-1) can induce dementia with alarming occurrence worldwide. The mechanism remains poorly understood, but discovery in brain of HIV-1-binding sites (chemokine receptors) provides new insights. HIV-1 infects macrophages and microglia, but not neurons, although neurons are injured and die by apoptosis. The predominant pathway to neuronal injury is indirect through release of macrophage, microglial and astrocyte toxins, although direct injury by viral proteins might also contribute. These toxins overstimulate neurons, resulting in the formation of free radicals and excitotoxicity, similar to other neurodegenerative diseases. Recent advances in understanding the signalling pathways mediating these events offer hope for therapeutic intervention.

Psychological morbidity and coping skills in patients with brittle and non-brittle asthma: a case-control study.

BACKGROUND: An association between psychological morbidity and asthma is well recognized and an increase in negative psychosocial factors in brittle asthma has been previously reported. Such factors, apart from affecting patient perceptions, may alter patients' self-management of their condition. METHODS: We have undertaken a case-control study on 29 well characterized brittle and non-brittle asthmatics in the West Midlands Region to assess their level of psychological morbidity, using the General Health Questionnaire (GHQ) and the living with asthma questionnaire, and their responses to changes in asthma symptoms, using the Asthma Symptom Checklist and a taped interview. RESULTS: Significant differences in GHQ (mean score brittle 19.5 vs non-brittle 7.2, P = 0.0002) and living with asthma (mean score brittle 1.30 vs non-brittle 1.00, P = 0.002) reinforced the presence of psychological factors in this group of patients with severe asthma. Interviews regarding responses to hypothetical asthma attacks showed that patients with brittle asthma delayed seeking medical attention more often than those with non-brittle asthma and instead preferred to self-administer beta-agonist medication. Sixteen (55.2%) of the 29 patients with brittle asthma would have delayed 7 days before seeking medical attention in a slow onset attack compared with 6/29 (20.7%) in the non-brittle group. In a fast onset attack 14 (48.3%) patients with brittle asthma would not have summoned help, despite finding it difficult to walk to the kitchen for a drink whereas in the non-brittle group 24 out of 29 (82.8%) would have summoned help. Levels of family support tended to be lower in patients with brittle asthma (mean family APGAR 7.3 vs 8.65 P = 0.09). CONCLUSIONS: Brittle asthma is associated with greater psychological morbidity and altered strategies for coping with deteriorating asthma symptoms. Attention should be paid to the presence of such factors in the management of patients with brittle asthma.

Afferent influences on brainstem auditory nuclei of the chicken: regulation of transcriptional activity following cochlea removal.

Neuronal survival in the cochlear nucleus of young animals is regulated by afferent activity. Removal or blockade of nerve VIII input results in the death of 20-40% of neurons in the cochlear nucleus, nucleus magnocellularis (NM), of the 10-14 days posthatch chick. Neuronal death in NM is preceded by complete failure of protein synthesis and degradation of ribosomes. In addition, there is a biphasic change in the immunoreactivity of ribosomes for a monoclonal antiribosomal RNA antibody, Y10B. Initially, the entire population of afferent-deprived NM neurons loses Y10B immunoreactivity, but, after 6 or 12 hours of afferent deprivation, lack of Y10B immunoreactivity specifically marks dying NM neurons. Whether RNA synthesis is also altered in afferent-deprived NM neurons has not previously been studied. To determine whether RNA synthesis in NM neurons is regulated by loss of afferent activity, we injected chicks with 3H-uridine following unilateral cochlea removal and measured the incorporation of RNA precursor with tissue autoradiography. As early as 1 hour after cochlea removal, there was a significant decrease in 3H-uridine incorporation by afferent-deprived NM neurons. After longer periods of afferent deprivation (6 or 12 hours), the majority of dying NM neurons (marked by loss of Y10B immunoreactivity) fail to incorporate RNA precursor. Six or 12 hours following cochlea removal, the subpopulation of surviving NM neurons incorporates 3H-uridine at increased levels over those observed 1 or 3 hours after cochlea removal. These findings suggest that nuclear function is regulated by afferent synaptic activity and that failure of RNA synthesis occurs early in the cell death process.

Protein masking of a ribosomal RNA epitope is an early event in afferent deprivation-induced neuronal death.

Cell death in the developing nervous system is regulated by both afferent synaptic activity and target-derived neurotrophic factors. Loss of afferent innervation via unilateral cochlea removal results in the death of 20-40% of neurons in the neonatal chick cochlear nucleus, nucleus magnocellularis (NM). The process of NM neuronal death involves structural and functional alterations in ribosomes, including decreased protein synthesis, loss of immunoreactivity for a monoclonal anti-ribosomal RNA (rRNA) antibody, Y10B, and eventual ribosome degradation. In the present report we confirm that the Y10B antibody binds specifically to ribosomes in chick NM neurons by electron microscopy. We then performed experiments designed to determine whether loss of rRNA immunoreactivity observed in NM neurons following cochlea removal involves induction of a protein-rRNA interaction. Brain stem tissue from animals subjected to unilateral cochlea removal was treated with protease prior to immunolabeling. Protease treatment restored rRNA immunoreactivity after 3 h of afferent deprivation, confirming that afferent deprivation induces protein-rRNA interactions which mask the Y10B epitope. Immunoprecipitation experiments confirmed that the Y10B antibody recognizes a specific rRNA sequence without posttranscriptional modification.

A biphasic change in ribosomal conformation during transneuronal degeneration is altered by inhibition of mitochondrial, but not cytoplasmic protein synthesis.

Following loss of eighth nerve input, 20-40% of neurons in the neonatal chick cochlear nucleus, nucleus magnocellularis (NM), undergo cell death. Intracellular changes that precede the death of NM neurons include increased oxidative metabolism and mitochondrial volume, decreased cytoplasmic protein synthesis, and destruction of ribosomes. Six hours following afferent deprivation, dying NM neurons demonstrate complete loss of ribosomes and cessation of protein synthesis, suggesting that the rapid destruction of ribosomes leads to neuronal death. Increased NM neuron death occurs when mitochondrial upregulation is prevented by chloramphenicol, a mitochondrial protein synthesis inhibitor. This finding suggests that increased oxidative capacity is required for neuronal survival following loss of afferent input. To study changes in the ribosomes of afferent-deprived NM neurons, we obtained a monoclonal antibody to ribosomal RNA. This monoclonal antibody, Y10B, labels ribosomes of all NM neurons receiving normal synaptic activity. Following removal of afferent input, NM neurons demonstrate a biphasic change in their pattern of Y10B label. During the initial phase, there is a uniform decrease in the density of Y10B label. In the second phase, some NM neurons recover the capacity to bind the Y10B antibody while others remain unlabeled. During this second phase, NM neurons putatively destined to die, based on their failure to synthesize protein, are unlabeled by the Y10B antibody. New gene expression is not necessary to initiate the change in ribosomal immunoreactivity that leads deafferented NM neurons toward cell death. Blocking cytoplasmic protein synthesis with cycloheximide had no effect on the biphasic change in Y10B labeling of afferent-deprived NM neurons. Treating chicks with chloramphenicol, however, prevented the recovery of Y10B immunoreactivity in NM neurons during the second phase of the response to afferent deprivation.

Psychiatric and social aspects of brittle asthma.

BACKGROUND: Many studies have shown that emotional factors play a part in asthma, but few have compared patients with differing severities of asthma. It was our impression that patients with "brittle" asthma (BA; more than 40% diurnal variation in peak flow on 15 or more days a month over a period of at least six months, and persistent symptoms despite multiple drug treatment) had greater psychosocial morbidity than asthmatic patients with less variable asthma. METHODS: Twenty patients with BA and a control group of less severe asthmatic subjects matched for age, sex, and duration of illness were asked to complete the General Health Questionnaire (GHQ), a screening test for psychiatric disorders, the Eysenck Personality Inventory which measures extraversion and neuroticism, and to participate in a life events interview and a structured clinical interview (SCID) to diagnose psychiatric disorder. RESULTS: The mean (SD) age was 45.6 (12.3) years for the BA group, and 45.7 (13.1) years for the control group. All patients were receiving inhaled steroids and regular beta 2 agonists; nine patients with BA but no control patients were taking oral steroids, and 12 of the patients with BA but no controls were receiving beta 2 agonists by subcutaneous infusion or injection. Eight of the patients with BA scored more than 11 on the GHQ compared with five of the control group (NS). Significantly more subjects with BA (12/20) than controls (5/20) had intercurrent or past psychiatric disorder, and 7/20 subjects with BA had a lifetime history of anxiety disorder compared with 3/20 controls. Life events analysis showed no overall difference in the total number, but the patients with BA had significantly more life events related to asthma. There was no difference in personality profiles between the two groups. CONCLUSIONS: The results suggest that patients with "brittle" asthma have greater psychiatric morbidity than those with less severe asthma, but that their personality profiles and overall life event experiences are similar.

Beta-2 microglobulin as a marker of HIV disease status in Nairobi, Kenya.

Serum beta-2 microglobulin (beta 2-M) has prognostic value similar to lymphocyte profiles for predicting disease progression in those infected with the human immunodeficiency virus (HIV). However, the relationship between beta 2-M and HIV disease progression among inhabitants of countries with endemic tropical diseases has not been evaluated. To determine the relationship between serum beta 2-M levels and HIV infection and disease status in an African population, serum beta 2-M levels were measured in 369 patients attending a sexually transmitted disease (STD) clinic in Nairobi, Kenya. Mean serum beta 2-M was significantly higher in HIV seropositive than in HIV seronegative individuals. Among HIV infected patients, higher mean beta 2-M levels were observed in those with HIV associated symptoms or laboratory markers of advanced HIV disease. Significant inverse correlations between beta 2-M and the percentage of CD4 lymphocytes or CD4/CD8 ratio were found. These findings suggest that beta 2-M measurements may have prognostic value for HIV infected populations in developing countries.

A female monozygotic twin pair discordant for transsexualism. Some theoretical implications.

A 13-year-old girl was referred because of sexual identity problems. There was no mental illness or neurological abnormalities. As her twin sister had no sexual identity problems, it appears that transsexualism is not transmitted by a simple genetic mechanism.

Lack of correspondence between mRNA expression for a putative cell death molecule (SGP-2) and neuronal cell death in the central nervous system.

Neuronal death during nervous system development, a widely observed phenomenon, occurs through unknown mechanisms. Recent evidence suggests an active, destructive process requiring new gene expression. Sulfated glycoprotein-2 (SGP-2), a secretory product of testicular Sertoli cells has been shown to up-regulate in several nonneural tissues undergoing programmed cell death and in several types of neuronal degeneration. In order to determine if this message up-regulates in neurons undergoing developmentally determined cell death, we have studied the expression of SGP-2 mRNA in the developing and adult rat central nervous system (CNS) with in situ hybridization. We also report on the expression of this message in nonneural tissues from several regions of the developing embryo. The developing and adult rat central nervous system as well as widely varied tissues in the rat embryo express SGP-2 mRNA in a pattern that does not correlate with regions undergoing developmental cell death. In the nervous system, SGP-2 mRNA is expressed in neuronal populations including motor neurons, cortical neurons, and hypothalamic neurons at ages when the period of developmental cell death has passed. In a nonneural tissue (palatal shelve epithelium) for which a developmental cell death period has been described, SGP-2 mRNA was not present in the region where cell death occurs. We conclude that SGP-2 mRNA expression cannot be correlated with programmed cell death in neural or nonneural tissues. The results of this study as well as recently reported SGP-2 homologies indicate a possible role for this protein in secretion and lipid transport.

Soluble proteins from rat olfactory bulb promote the survival and differentiation of cultured basal forebrain neurons.

A previous study of cholinergic development indicated a possible trophic relationship between the olfactory bulb and its afferents from the basal forebrain (Large et al., J. Neurochem., 46 (1986) 671-680). To examine this possibility further, cultured embryonic basal forebrain neurons from rat were used as a test system for trophic factor activity hypothesized to be present in olfactory bulb. Basal forebrain neurons grown in defined medium typically died within 2-3 days. However, survival and differentiation were strikingly enhanced by soluble extracts of olfactory bulb tissue. This trophic effect was noticeable with 2 micrograms/ml olfactory bulb protein, and plateaued at 100 micrograms/ml. The activity was heat- and trypsin-sensitive, non-dialyzable, stable in the cold, resistant to NGF antiserum, and approximately 100-150 kDa in size. Nerve growth factor, bovine serum albumin, laminin and extracts from heart did not mimic the activity. Long-term growth (21 days) in the presence of olfactory bulb proteins resulted in extensive neurite production, formation of thick neurite fascicles, and aggregation of cells. Some glia were present, as evidenced by the presence of glial fibrillary acidic protein, and large numbers of cells were positive for neuron-specific enolase and true acetylcholinesterase. Trophic activity was also present in medium conditioned by olfactory bulb slices, implying secretion of active factors.

beta-Glucoside Activators of Mung Bean UDP-Glucose: beta-Glucan Synthase : I. Identification of an Endogenous beta-Linked Glucolipid Activator.

Heat-stable activators of membranous beta-glucan synthase have been isolated from the supernatant fraction of crude mung bean (Vigna radiata) extracts by DEAE-cellulose and silica-gel chromatography. One of the activators has been partially purified and characterized on the basis of susceptibility to various enzymes and by analysis of the products formed upon total acid hydrolysis, alkaline-methanolysis, and beta-glucosidase digestion. This activator has the characteristics of a 1,2-dioleoyl diglyceride containing beta-linked glucose residue(s) at the C-3 position. When expressed per mole of glucosyl residues, the maximal K(a) value of the activator is estimated to be 25 micromolar. Both the intact glucosyl and fatty acid moiety are essential to the stimulatory effect of the activator.

Metabolic and hormonal responses during squash.

The metabolic and hormonal response during squash was observed in eight normal men. Significant increases from resting were found for blood glucose, lactate, pyruvate, alanine and glycerol while total ketone bodies and plasma nonesterified fatty acids rose after play stopped. Insulin and C-peptide decreased significantly and catecholamines, ACTH, prolactin and growth hormone increased.

The pharmacokinetics and tissue penetration of teicoplanin.

The pharmacokinetics of teicoplanin were studied following a 440 mg intravenous dose in six male volunteers. The levels of the compound were measured in serum, blister fluid and urine. The mean serum level 0.5 h after injection was 44.6 mg/l falling to 3.6 mg/l at 49 h. The elimination half-life of teicoplanin from serum was 34.2 h and the apparent distribution half-life 1.5 h. Penetration into blister fluid was moderately fast, the mean maximum concentration (14.8 mg/l) occurring at 2.7 h, and the mean percentage penetration being 77.4%. Urinary recovery of the drug was 48.3% by 96 h.

Pharmacokinetics and tissue penetration of carumonam, a new synthetic monobactam.

The pharmacokinetics of the monobactam carumonam (Ro 17-2301) as derived from serial measurement of the concentrations of this agent in serum, blister fluid, and urine were studied in six male volunteers subsequent to intravenous infusion of a single 2-g dose. Drug levels in serum in excess of 75 micrograms/ml were achieved 0.5 h after the end of infusion, declining to 2.9 micrograms/ml at 8 h. The mean serum and blister fluid elimination half-lives were 1.68 and 1.7 h, respectively. The urinary recovery of the drug by 24 h was 80.6% (range, 68.3 to 91.1%). Carumonam penetrated blister fluid well, the mean percentage penetration (as measured by the ratio of areas under curves) being 101.6%.