Showing papers by "Veterans Health Administration published in 1993"

Efficacy of Carotid Endarterectomy for Asymptomatic Carotid Stenosis

Abstract: Background The efficacy of carotid endarterectomy in patients with asymptomatic carotid stenosis has not been confirmed in randomized clinical trials, despite the widespread use of operative intervention in such patients. Methods We conducted a multicenter clinical trial at 11 Veterans Affairs medical centers to determine the effect of carotid endarterectomy on the combined incidence of transient ischemic attack, transient monocular blindness, and stroke. We studied 444 men with asymptomatic carotid stenosis shown arteriographically to reduce the diameter of the arterial lumen by 50 percent or more. The patients were randomly assigned to optimal medical treatment including antiplatelet medication (aspirin) plus carotid endarterectomy (the surgical group; 211 patients) or optimal medical treatment alone (the medical group; 233 patients). All the patients at each center were followed independently by a vascular surgeon and a neurologist for a mean of 47.9 months. Results The combined incidence of ipsilatera...

Single-Drug Therapy for Hypertension in Men -- A Comparison of Six Antihypertensive Agents with Placebo

Abstract: Background Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents, but this clinically important issue has not been examined in sufficiently large trials, involving all standard treatments, to determine the effect of such factors. Methods In a randomized, double-blind study at 15 clinics, we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg, after a placebo washout period, to receive placebo or one of six drugs: hydrochlorothiazide (12.5 to 50 mg per day), atenolol (25 to 100 mg per day), captopril (25 to 100 mg per day), clonidine (0.2 to 0.6 mg per day), a sustained-release preparation of diltiazem (120 to 360 mg per day), or prazosin (4 to 20 mg per day). The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure, and the patients continued to receive therapy for at least one year. Results The mean (±SD) age of the randomized patients was 59 ±10 years, and 48 percent we...

The "bystander effect": tumor regression when a fraction of the tumor mass is genetically modified.

Abstract: Tumor cells expressing the herpes simplex virus thymidine kinase (HSV-TK) gene are sensitive to the drug ganciclovir (GCV). We demonstrate here that HSV-TK-positive cells exposed to GCV were lethal to HSV-TK-negative cells as a result of a "bystander effect." HSV-TK-negative cells were killed in vitro when the population of cultured cells contained only 10% HSV-TK-positive cells. The mechanism of this "bystander effect" on HSV-TK-negative cells appeared to be related to the process of apoptotic cell death when HSV-TK-positive cells were exposed to GCV. Flow cytometric and electron microscopic analyses suggested that apoptotic vesicles generated from the dying gene-modified cells were phagocytized by nearby, unmodified tumor cells. Prevention of apoptotic vesicle transfer prevented the bystander effect. The toxic effect of HSV-TK-positive cells on HSV-TK-negative cells was reproduced in an in vivo model. A mixed population of tumor cells consisting of HSV-TK-positive and HSV-TK-negative cells was inoculated s.c. into mice. Regression of the tumor mass occurred when the inoculum consisted of as few as 10% HSV-TK-expressing tumor cells. The bystander effect was also demonstrated in i.p. tumor studies. Initial experiments demonstrated that prolonged survival (> 70 days) occurred when a mixture containing 50% HSV-TK-positive and 50% HSV-TK-negative cells was injected i.p. followed by GCV treatment. Further, survival was prolonged for mice with a preexisting HSV-TK-negative i.p. tumor burden by injecting HSV-TK-positive cells and GCV. These results suggest that genetic modification of tumor cells may be useful for developing cancer therapies.

The Structure and Organization of Memory

Abstract: ly, so that it is sometimes difficult to appreciate what would count for or against it. A difficulty with the systems view is that the definition of the term \"system" is uncertain, and it is not always clear from studies of normal subjects when behavioral findings justify postulating a separate memory sys­ tem. The concept of brain systems, while not entirely free of problems itself, provides a more concrete and in the end a more satisfying basis for thinking about memory systems. This is because a long tradition of anatomical and physiological work on the structure and organization of the brain has con­ cerned itself with the identification and study of separable neural systems, sometimes independently of or in advance of any understanding of their func­ tional significance.

Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD Investigators

Abstract: Objective. —To study the potential usefulness of the 6-minute walk test, a self-paced submaximal exercise test, as a prognostic indicator in patients with left ventricular dysfunction. Design. —Data were collected during a prospective cohort study, the Studies of Left Ventricular Dysfunction (SOLVD) Registry Substudy. Setting. —Twenty tertiary care hospitals in the United States, Canada, and Belgium. Participants. —A stratified random sample of 898 patients from the SOLVD Registry who had either radiological evidence of congestive heart failure and/or an ejection fraction of 0.45 or less were enrolled in the substudy and underwent a detailed clinical evaluation including a 6-minute walk test. Patients were followed up for a mean of 242 days. Outcome Measures. —Mortality and hospitalization. Results. —During follow-up, 52 walk-test participants (6.2%) died and 252 (30.3%) were hospitalized. Hospitalization for congestive heart failure occurred in 78 participants (9.4%), and the combined endpoint of death or hospitalization for congestive heart failure occurred in 114 walk-test participants (13.7%). Compared with the highest performance level, patients in the lowest performance level had a significantly greater chance of dying (10.23% vs 2.99%;P=.01), of being hospitalized (40.91% vs 19.90%;P=.002), and of being hospitalized for heart failure (22.16% vs 1.99%;P Conclusion. —The 6-minute walk test is a safe and simple clinical tool that strongly and independently predicts morbidity and mortality in patients with left ventricular dysfunction. (JAMA. 1993;270:1702-1707)

Topographic organization of corticospinal projections from the frontal lobe: motor areas on the lateral surface of the hemisphere.

Abstract: We examined the topographic organization of corticospinal neurons in the primary motor cortex and in the two premotor areas on the lateral surface of the hemisphere [i.e., the dorsal premotor area (PMd) and the ventral premotor area (PMv)]. In two macaques, we labeled corticospinal neurons that project beyond T7 or S2 by placing crystals of HRP into the dorsolateral funiculus at these segmental levels. In another seven macaques, we labeled corticospinal neurons that project to specific segmental levels of the spinal cord by injecting the fluorescent tracers fast blue and diamidino yellow into the gray matter of the cervical and lumbosacral segments. In one set of experiments (n = 2), we defined the representations of the arm and leg in each cortical motor area by injecting one of the two fluorescent tracers into lower cervical segments (C7-T1) and the other fluorescent tracer into lower lumbosacral segments (L6-S1) of the same animal. In another set of experiments (n = 5), we defined the representations of distal and proximal parts of the forelimb in each cortical motor area by injecting one of the two fluorescent tracers into lower cervical segments (C7-T1) and the other tracer into upper cervical segments (C2-C4) of the same animal. In the primary motor cortex and the PMd, cortical regions that project to lower cervical segments were largely separate from those that project to lower lumbosacral segments. In the PMv, few neurons were labeled after tracer injections into lower cervical segments or lower lumbosacral segments. However, corticospinal neurons were labeled in the PMv after tracer injections into upper cervical segments and after HRP placement in the dorsolateral funiculus at T7. The region of the PMv that projects to upper cervical segments was separate from that which projects below T7. Cortical regions that project to upper and lower cervical segments of the spinal cord overlapped considerably in the primary motor cortex and in the PMd. Despite this overlap, we found that the regions of the primary motor cortex and PMd that project most densely to upper cervical segments were largely separate from those that project most densely to lower cervical segments. Furthermore, we found two separate regions within area 4 that send corticospinal projections primarily to the lower cervical segments. One of these regions was located within the classical "hand" area of the primary motor cortex. The other was located at the medial edge of arm representation in the primary motor cortex.(ABSTRACT TRUNCATED AT 400 WORDS)

Parasite Lactate Dehydrogenase as an Assay for Plasmodium falciparum Drug Sensitivity

Abstract: This report compares the use of the lactate dehydrogenase (pLDH) assay with 3H-hypoxanthine incorporation and Giemsa microscopy for the evaluation of anti-malaria drug inhibition of the growth of P. falciparum in vitro. The inhibition profiles and IC50 determinations of the pLDH assay were directly comparable to those determined by the radioactive uptake and microscopic methods. Furthermore, the pLDH culture sensitivity assay is reproducible, easily interpreted, rapid and inexpensive to perform, suggesting field applicability.

Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart.

Abstract: To define the mechanism(s) responsible for the negative inotropic effects of tumor necrosis factor-alpha (TNF alpha) in the adult heart, we examined the functional effects of TNF alpha in the intact left ventricle and the isolated adult cardiac myocyte. Studies in both the ventricle and the isolated adult cardiac myocyte showed that TNF alpha exerted a concentration- and time-dependent negative inotropic effect that was fully reversible upon removal of this cytokine. Further, treatment with a neutralizing anti-TNF alpha antibody prevented the negative inotropic effects of TNF alpha in isolated myocytes. A cellular basis for the above findings was provided by studies which showed that treatment with TNF alpha resulted in decreased levels of peak intracellular calcium during the systolic contraction sequence; moreover, these findings did not appear to be secondary to alterations in the electrophysiological properties of the cardiac myocyte. Further studies showed that increased levels of nitric oxide, de novo protein synthesis, and metabolites of the arachidonic acid pathway were unlikely to be responsible for the TNF alpha-induced abnormalities in contractile function. Thus, these studies constitute the initial demonstration that the negative inotropic effects of TNF alpha are the direct result of alterations in intracellular calcium homeostasis in the adult cardiac myocyte.

Normalization of Auditory Physiology by Cigarette Smoking in Schizophrenic Patients

Abstract: Objective: Because many schizophrenic patients are heavy smokers, it has been suggested that nicotine normalizes some neuronal deficit involved in their illness. Schizophrenic subjects have various difficulties with maintenance of attention and selective processing of sensory information. One defect in sensorygating in schizophrenia has been characterized by recording auditory evoked potentials. Most normal subjects have a decrease in the evoked response to the second oftwo closely paired stimuli, whereas most schizophrenic subjects do not. The aim of this study was to determine whether smoking normalizes this deficit in auditory sensory gating in schizophrenia. Method: Changes in auditory sensory gating in response to smoking cigarettes were studied in 1 0 smokers without psychiatric illness and 10 schizophrenic smokers. Both groups were asked to abstain from smoking from 1 1 :00 p.m. until 8:00 a.m. the next morning, when their auditory evoked responses to pairs of clicks were recorded. The ability to gate sensory information is reflected in a decrease in the P50 wave amplitude in response to the second of the two stimuli. After baseline recordings, the subjects smoked as much as they wished, and then two postsmoking recordings were performed. Results: The schizophrenic patients had a marked but briefimprovement in P50 auditory gating immediately after smoking, whereas P50 gating for the normalsmokers was slightly impaired. Conclusions: This study suggests that cigarette smoking can transiently normalize the impairment of auditory sensory gating in schizophrenic patients. (AmJ Psychiatry 1993; 150:1856-1861)

Risk Factors for Complications of Chronic Anticoagulation: A Multicenter Study

Abstract: Objective: To define risk factors for complications that occur during warfarin therapy. Design: Retrospective cohort study. Setting: Five anticoagulation clinics. Patients: Nine hundred twenty-eigh...

Heterogeneity of Mucin Gene Expression in Normal and Neoplastic Tissues

Abstract: To determine the relative expression of distinct mucin genes in normal and neoplastic tissue, antibodies and cDNA probes that recognize the core tandem repeat sequences of membrane-bound (MUC1) and secreted (MUC2 and MUC3) mucins were used for immunohistochemical and RNA Northern and slot-blot analysis. MUC1 mRNA was detected in all epithelial tissues tested. MUC1 core peptide, recognized by monoclonal antibodies 139H2 and DF3, was highly expressed on apical membranes of bronchus, breast, salivary gland, pancreas, prostate, and uterus, and was sparsely expressed in gastric surface cells, gallbladder, small intestine, and colonic epithelium. In contrast, MUC2 and MUC3 gene expression was primarily restricted to the intestinal tract. MUC2 mRNA was highly expressed in normal jejunum, ileum, and colon, compared with very low levels in normal bronchus and gallbladder. MUC3 mRNA was highly expressed in normal jejunum, ileum, colon, and gallbladder. Immunohistochemical studies using antibodies against synthetic MUC2 (anti-MRP) and MUC3 (anti-M3P) peptides indicate that MUC2- and MUC3-producing cells in the gastrointestinal tract are distinct. Goblet cells of the small intestine and colon reacted strongly with anti-MRP, whereas M3P reactivity was restricted to columnar cells of small intestinal villi, surface colonic epithelium, and gallbladder. Mucin protein epitopes and mRNA levels were frequently altered in adenocarcinomas compared to corresponding normal tissues. Alterations included increased expression, aberrant expression, and, less frequently, loss of expression. Increased MUC1 immunoreactivity was observed in most adenocarcinomas of the breast, lung, stomach, pancreas, prostate, and ovary. In addition, with the exception of prostate cancer, focal aberrant expression of MUC2 and MUC3 epitopes was frequently observed. Increased MUC1, MUC2, and MUC3 epitopes were present in colon adenocarcinomas of all histological subtypes, with the greatest increase of MUC2 epitopes observed in colloid (mucinous) colon cancers. MUC2 or MUC3 mRNA levels were increased in colloid colon cancer compared with normal colon, however in well- and moderately well-differentiated colon cancers MUC1, 2 and 3 mRNA levels were decreased. Compared with corresponding normal tissue, MUC1 mRNA levels were increased in breast cancer and well-differentiated lung cancers, and MUC3 mRNA was increased in gastric adenocarcinomas. Normal stomach lacked both MUC2 and MUC3 immunoreactivity and mRNA, however, MUC2 and MUC3 proteins and mRNA were highly expressed in gastric intestinal metaplasia. In conclusion, mucin genes are independently regulated and their expression is organ- and cell type-specific. Furthermore, neoplastic transformation is associated with dys-regulated expression of both membrane-bound and secreted mucin core protein epitopes and may be due to altered mucin mRNA levels and/or altered mucin glycosylation.

Reflectivity and Learning From Aversive Events: Toward a Psychological Mechanism for the Syndromes of Disinhibition

Abstract: Gorenstein and Newman (1980) proposed that poorly modulated responding for reward is the common diathesis underlying disinhibited behavior in several traditionally distinct person categories: psychopathy, hysteria, early onset alcoholism, childhood hyperactivity, and nonpathological impulsivity (e.g., extraversion). The authors extend this proposal by theorizing a psychological mechanism that highlights relations among disinhibition, reflection, and failures to learn from aversive feedback. The hypothesized mechanism is presented as 4 generic stages of response modulation: the dominant response set, the reaction to an aversive event, the subsequent behavioral adaptation, and the immediate and long-term consequences of reflection, or the lack thereof. The mechanism has implications for disinhibited individuals' impulsivity and provides a point of departure to study factors responsible for similarities and differences among these syndromes.

A Twin Study of Genetic and Environmental Contributions to Liability for Posttraumatic Stress Symptoms

Abstract: • We studied 4042 Vietnam era veteran monozygotic and dizygotic male twin pairs to determine the effects of heredity, shared environment, and unique environment on the liability for 15 self-reported posttraumatic stress disorder symptoms included in the symptom categories of reexperiencing the trauma, avoidance of stimuli related to the trauma, and increased arousal. Quantitative genetic analysis reveals that inheritance has a substantial influence on liability for all symptoms. Symptoms in the reexperiencing cluster and one symptom in the avoidance and numbing cluster are strongly associated with combat exposure, and monozygotic pairs are more highly concordant for combat exposure than dizygotic pairs. By fitting a bivariate genetic model, we show that there are significant genetic influences on symptom liability, even after adjusting for differences in combat exposure; genetic factors account for 13% to 30% of the variance in liability for symptoms in the reexperiencing cluster, 30% to 34% for symptoms in the avoidance cluster, and 28% to 32% for symptoms in the arousal cluster. There is no evidence that shared environment contributes to the development of posttraumatic stress disorder symptoms.

Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons

Abstract: Voltage-gated potassium (K+) channels display a wide variety of conductances and gating properties in vivo This diversity can be attributed not only to the presence of many K(+)-channel gene products, but also to the possibility that different K(+)-channel subunits co-assemble to form heteromultimeric channels in vivo When expressed in Xenopus oocytes or transfected cells, K(+)-channel polypeptides assemble to form tetramers Certain combinations of Shaker-like subunits have been shown to co-assemble, forming heteromultimeric channels with distinct properties It is not known, however, whether K(+)-channel polypeptides form heteromultimeric channels in vivo Here we describe the co-localization of two Shaker-like voltage-gated K(+)-channel proteins, mKv11 and mKv12, in the juxtaparanodal regions of nodes of Ranvier in myelinated axons, and in terminal fields of basket cells in mouse cerebellum We also show that mKv11 and mKv12 can be coimmunoprecipitated with specific antibodies that recognize only one of them These data indicate that the two polypeptides occur in subcellular regions where rapid membrane repolarization may be important and that they form heteromultimeric channels in vivo

Childhood physical abuse and combat-related posttraumatic stress disorder in Vietnam veterans

Abstract: OBJECTIVE: Early trauma in the form of childhood physical or sexual abuse has been associated with adult psychopathology. The purpose of this study was to compare rates of childhood abuse in Vietnam veterans with and without combat-related posttraumatic stress disorder (PTSD). METHOD: Premilitary stressful and traumatic events including childhood abuse and other potential predisposing factors were assessed in Vietnam combat veterans who sought treatment for PTSD (N = 38) and Vietnam combat veterans without PTSD who sought treatment for medical disorders (N = 28). Stressful and traumatic events including childhood physical abuse were assessed with the Checklist of Stressful and Traumatic Events and a clinician-administered interview for the assessment of childhood abuse. Level of combat exposure was measured with the Combat Exposure Scale. RESULTS: Vietnam veterans with PTSD had higher rates of childhood physical abuse than Vietnam veterans without PTSD (26% versus 7%). The association between childhood abuse and PTSD persisted after controlling for the difference in level of combat exposure between the two groups. Patients with PTSD also had a significantly higher rate of total traumatic events before joining the military than patients without PTSD (mean = 4.6, SD = 4.5, versus mean = 2.8, SD = 2.9). CONCLUSIONS: These findings suggest that patients seeking treatment for combat-related PTSD have higher rates of childhood physical abuse than combat veterans without PTSD. Childhood physical abuse may be an antecedent to the development of combat-related PTSD in Vietnam combat veterans. Language: en

A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180.

Abstract: Subepidermal blistering associated with the human skin diseases bullous pemphigoid and herpes gestationis has been thought to be an IgG autoantibody-mediated process; however, previous attempts to demonstrate the pathogenicity of patient autoantibodies have been unsuccessful. An immunodominant and potentially pathogenic epitope associated with these blistering diseases has recently been mapped to the extracellular domain of a human epidermal antigen, BP180. Patient autoantibodies that react with this well-defined antigenic site failed to crossreact with the murine form of this autoantigen and thus could not be assayed for pathogenicity in a conventional passive transfer mouse model. As an alternative, rabbit polyclonal antibodies were generated against a segment of the murine BP180 protein homologous with the human BP180 autoantibody-reactive site and were passively transferred into neonatal BALB/c mice. The injected animals developed a subepidermal blistering disease that closely mimicked bullous pemphigoid and herpes gestationis at the clinical, histological, and immunological levels. Autoantibodies that recognize the human BP180 ectodomain are therefore likely to play an initiatory role in the pathogenesis of bullous pemphigoid and herpes gestationis.

Abnormal Noradrenergic Function in Posttraumatic Stress Disorder

Abstract: • To evaluate possible abnormal noradrenergic neuronal regulation in patients with posttraumatic stress disorder (PTSD), the behavioral, biochemical, and cardiovascular effects of intravenous yohimbine hydrochloride (0.4 mg/kg) were determined in 18 healthy male subjects and 20 male patients with PTSD. A subgroup of patients with PTSD were observed to experience yohimbine-induced panic attacks (70% [14/20]) and flashbacks (40% [8/20]), and they had larger yohimbine-induced increases in plasma 3-methoxy-4-hydroxyphenylglycol levels, sitting systolic blood pressure, and heart rate than those in healthy subjects. In addition, in the patients with PTSD, yohimbine induced significant increases in core PTSD symptoms, such as intrusive traumatic thoughts, emotional numbing, and grief. These data were consistent with a large body of preclinical data that indicated that uncontrollable stress produces substantial increases in noradrenergic neuronal function. We discuss the implications of these abnormalities in noradrenergic functional regulation in relation to the long-term neurobiological sequelae of severe uncontrollable stress and the pathophysiological relationship between PTSD and other anxiety disorders, such as panic disorder.

Biological effects of electromagnetic fields

Abstract: Life on earth has evolved in a sea of natural electromagnetic (EM) fields. Over the past century, this natural environment has sharply changed with introduction of a vast and growing spectrum of man-made EM fields. From models based on equilibrium thermodynamics and thermal effects, these fields were initially considered too weak to interact with biomolecular systems, and thus incapable of influencing physiological functions. Laboratory studies have tested a spectrum of EM fields for bioeffects at cell and molecular levels, focusing on exposures at athermal levels. A clear emergent conclusion is that many observed interactions are not based on tissue heating. Modulation of cell surface chemical events by weak EM fields indicates a major amplification of initial weak triggers associated with binding of hormones, antibodies, and neurotransmitters to their specific binding sites. Calcium ions play a key role in this amplification. These studies support new concepts of communication between cells across the barriers of cell membranes; and point with increasing certainty to an essential physical organization in living matter, at a far finer level than the structural and functional image defined in the chemistry of molecules. New collaborations between physical and biological scientists define common goals, seeking solutions to the physical nature of matter through a strong focus on biological matter. The evidence indicates mediation by highly nonlinear, nonequilibrium processes at critical steps in signal coupling across cell membranes. There is increasing evidence that these events relate to quantum states and resonant responses in biomolecular systems, and not to equilibrium thermodynamics associated with thermal energy exchanges and tissue heating.

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain.

Abstract: By acting in the central nervous system, circulating insulin may regulate food intake and body weight We have previously shown that the kinetics of insulin uptake from plasma into cerebrospinal fluid (CSF) can best be explained by passage through an intermediate compartment To determine if transport kinetics into this compartment were consistent with an insulin receptor-mediated transport process, we subjected overnight fasted, anesthetized dogs to euglycemic intravenous insulin infusions for 90 min over a wide range of plasma insulin levels (69-5,064 microU/ml) (n = 10) Plasma and CSF samples were collected over 8 h for determination of immunoreactive insulin levels, and the kinetics of insulin uptake from plasma into CSF were analyzed using a compartmental model with three components (plasma-->intermediate compartment-->CSF) By sampling frequently during rapid changes of plasma and CSF insulin levels, we were able to precisely estimate three parameters (average standard deviation 14%) characterizing the uptake of insulin from plasma, through the intermediate compartment and into CSF (k1k2); insulin entry into CSF and insulin clearance from the intermediate compartment (k2 + k3); and insulin clearance from CSF (k4) At physiologic plasma insulin levels (80 +/- 74 microU/ml), k1k2 was determined to be 107 x 10(-6) +/- 13 x 10(-6) min-2 With increasing plasma levels, however, k1k2 decreased progressively, being reduced sevenfold at supraphysiologic levels (5,064 microU/ml) The apparent KM of this saturation curve was 742 microU/ml (approximately 5 nM) In contrast, the rate constants for insulin removal from the intermediate compartment and from CSF did not vary with plasma insulin (k2 + k3 = 0011 +/- 00019 min-1 and k4 = 0046 +/- 0021 min-1) We conclude that delivery of plasma insulin into the central nervous system is saturable, and is likely facilitated by an insulin-receptor mediated transport process

Epidemiologic evidence for multiple sclerosis as an infection.

Abstract: The worldwide distribution of multiple sclerosis (MS) can be described within three zones of frequency: high, medium, and low. The disease has a predilection for white races and for women. Migration studies show that changing residence changes MS risk. Studies of persons moving from high- to low-risk areas indicate that in the high-risk areas, MS is acquired by about age 15. Moves from low- to high-risk areas suggest that susceptibility is limited to persons between about ages 11 and 45. MS on the Faroe Islands has occurred as four successive epidemics beginning in 1943. The disease appears to have been introduced by British troops who occupied the islands for 5 years from 1940, and it has remained geographically localized within the Faroes for half a century. What was introduced must have been an infection, called the primary MS affection (PMSA), that was spread to and from successive cohorts of Faroese. In this concept, PMSA is a single widespread systemic infectious disease (perhaps asymptomatic) that only seldom leads to clinical neurologic MS. PMSA is also characterized by a need for prolonged exposure, limited age of susceptibility, and prolonged incubation. I believe that clinical MS is the rare late outcome of a specific, but unknown, infectious disease of adolescence and young adulthood and that this infection could well be caused by a thus-far-unidentified (retro)virus. Images

The learning of categories: parallel brain systems for item memory and category knowledge

Abstract: A fundamental question about cognition concerns how knowledge about a category is acquired through encounters with examples of the category. Amnesic patients and control subjects performed similarly at classifying novel patterns according to whether they belonged to the same category as a set of training patterns. In contrast, the amnesic patients were impaired at recognizing which dot patterns had been presented for training. Category learning appears to be independent of declarative (explicit) memory for training instances and independent of the brain structures essential for declarative memory that are damaged in amnesia. Knowledge about categories can be acquired implicitly by cumulating information from multiple examples.

Racial Differences in the Use of Invasive Cardiovascular Procedures in the Department of Veterans Affairs Medical System

Abstract: Background Previous studies have found racial differences in the use of invasive cardiovascular procedures, which may be due in part to the greater financial incentives to perform such procedures in white patients. In Department of Veterans Affairs hospitals, direct financial incentives affecting use of the procedures are minimized for both patients and physicians. Methods We analyzed retrospectively the use of cardiovascular procedures among black and white male veterans discharged from Veterans Affairs hospitals with primary diagnoses of cardiovascular disease or chest pain during fiscal years 1987 through 1991. We used coded discharge data to determine whether cardiac catheterization, percutaneous transluminal coronary angioplasty, or coronary artery bypass grafting was performed during or immediately after such admissions. We used logistic-regression analysis to adjust for the primary discharge diagnosis, the presence of coexisting conditions, age, marital status, type of eligibility to receive care a...

Pathophysiological mechanisms of brain damage from status epilepticus.

Abstract: Human status epilepticus (SE) is consistently associated with cognitive problems, and with widespread neuronal necrosis in hippocampus and other brain regions. In animal models, convulsive SE causes extensive neuronal necrosis. Nonconvulsive SE in adult animals also leads to widespread neuronal necrosis in vulnerable regions, although lesions develop more slowly than they would in the presence of convulsions or anoxia. In very young rats, nonconvulsive normoxic SE spares hippocampal pyramidal cells, but other types of neurons may not show the same resistance, and inhibition of brain growth, DNA and protein synthesis, and of myelin formation and of synaptogenesis may lead to altered brain development. Lesions induced by SE may be epileptogenic by leading to misdirected regeneration. In SE, glutamate, aspartate, and acetylcholine play major roles as excitatory neurotransmitters, and GABA is the dominant inhibitory neurotransmitter. GABA metabolism in substantia nigra (SN) plays a key role in seizure arrest. When seizures stop, a major increase in GABA synthesis is seen in SN postictally. GABA synthesis in SN may fail in SE. Extrasynaptic factors may also play an important role in seizure spread and in maintaining SE. Glial immaturity, increased electronic coupling, and SN immaturity facilitate SE development in the immature brain. Major increases in cerebral blood flow (CBF) protect the brain in early SE, but CBF falls in late SE as blood pressure falters. At the same time, large increases in cerebral metabolic rate for glucose and oxygen continue throughout SE. Adenosine triphosphate (ATP) depletion and lactate accumulation are associated with hypermetabolic neuronal necrosis. Excitotoxic mechanisms mediated by both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors open ionic channels permeable to calcium and play a major role in neuronal injury from SE. Hypoxia, systemic lactic acidosis, CO2 narcosis, hyperkalemia, hypoglycemia, shock, cardiac arrhythmias, pulmonary edema, acute renal tubular necrosis, high output failure, aspiration pneumonia, hyperpyrexia, blood leukocytosis and CSF pleocytosis are common and potentially serious complications of SE. Our improved understanding of the pathophysiology of brain damage in SE should lead to further improvement in treatment and outcome.

Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists.

Abstract: There is demand on community pathologists to perform autopsies to confirm the clinical diagnosis of Alzheimer's disease, the most common cause of dementia in our increasingly aging society. Yet many pathologists are reluctant to examine autopsy brains because they have little experience with neuropathology and with the common histopathologic staining methods needed to evaluate dementia cases. This article provides interested pathologists with a simple, practical protocol to use in meeting this demand. While there is no absolute diagnostic gold standard for Alzheimer's disease and the histopathologic diagnosis remains imperfect, the guidelines presented are adapted from those used by many neuropathologists at Alzheimer's disease research centers participating in CERAD, the Consortium to Establish a Registry for Alzheimer's Disease. Recipes for appropriate stains and specific case examples are provided for convenience.

Molecular Epidemiology: Application of Contemporary Techniques to the Typing of Microorganisms

Abstract: Joel N. Maslow, Maury Ellis Mulligan, and Robert D. Arbeit From the Research Service, Veterans Affairs Medical Center, and the Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; the Infectious Diseases Service, Veterans Affairs Medical Center, Long Beach, California; and the Department of Medicine, University of California, Irvine, California