Showing papers by "Veterans Health Administration published in 1988"

Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells.

Abstract: Previous studies show that cytotoxic activated macrophages cause a reproducible pattern of metabolic inhibition in viable tumor target cells. This includes inhibition of DNA synthesis, two oxidoreductases of the mitochondrial electron transport chain (NADH: ubiquinone oxidoreductase and succinate: ubiquinone oxidoreductase), and the citric acid cycle enzyme aconitase. This pattern of metabolic inhibition is induced by a cytotoxic activated macrophage associated biochemical pathway with L-arginine deimination activity that synthesizes L-citrulline from L-arginine and oxygenated nitrogen derivatives from the imino nitrogen removed from the guanido group of L-arginine. Here we report that macrophages activated in vivo by infection with bacillus Calmette-Guerin or in vitro by murine rIFN-gamma or murine IFN-alpha/beta (in the presence of the second signal LPS in all cases) develop inhibition of aconitase and the same two oxidoreductases of the mitochondrial electron transport chain as was documented earlier in target cells of cytotoxic activated macrophages. In addition, this pattern of metabolic inhibition which develops in cytotoxic activated macrophages is caused by the L-arginine-dependent effector mechanism. Inhibition of mitochondrial respiration by effectors of the L-arginine-dependent cytotoxicity system results in a compensatory increase in activity of the glycolytic pathway. We speculate that the pattern of metabolic inhibition induced in cytotoxic activated macrophages by the L-arginine-dependent effector system causes changes in the macrophage intracellular environment that increases resistance to certain facultative and obligate intracellular pathogens.

Campylobacter pylori antibodies in humans

Abstract: Study Objective:To determine the diagnostic value of assays to measure serum antibodies toCampylobacter pylori, and to use these assays to determine the prevalence ofC. pyloriinfection in ...

Biochemical and Molecular Basis of Alcohol-Induced Injury to Liver and Other Tissues

Abstract: CIRRHOSIS of the liver, usually as a complication of alcoholism, is the third most frequent cause of death among those 25 to 64 years of age in urban areas such as New York City.1 This alcohol-indu...

Alzheimer's disease and Parkinson's disease: Comparison of speech and language alterations

Abstract: Speech and language alterations were assessed in 51 patients with Parkinson9s disease (PD) and 10 patients with dementia of the Alzheimer type (DAT). Thirty-five of the PD patients had no evidence of intellectual impairment on a conventional mental status questionnaire and 16 of the PD patients had dementia syndromes of comparable severity to the DAT patients. DAT produced significantly greater language disturbances, including anomia, decreased information content of spontaneous speech, and diminished word list generation. PD patients had significantly decreased phrase length, impaired speech melody, dysarthria, and agraphia. The results suggest that the dementia of PD is distinguishable from that of DAT: PD patients have prominent motor speech abnormalities, whereas DAT patients exhibit more profound language alterations.

Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta-thromboglobulin.

Abstract: Melanoma growth stimulatory activity (MGSA) is a mitogenic polypeptide secreted by Hs294T human melanoma cells. Comparison of the N-terminal sequences of the 13 and 16 kd MGSA species with the cDNA sequence revealed that the mature form of human MGSA is maximally 73 amino acids long. Expression of the cDNA in mammalian cells results in the secretion of this peptide with mitogenic activity. MGSA is structurally related to the platelet-derived beta-thromboglobulin and to several other polypeptides. These factors may constitute a family of growth factors. MGSA mRNA was detected in a variety of cell types. The level of MGSA mRNA in melanoma cells is strongly elevated by treatment with MGSA. MGSA is the gene product of a recently detected gene gro. The gene was mapped to chromosome 4 (region q13----q21). This same region also contains genes for two of the structurally related factors, for c-kit, a receptor for an as yet unidentified ligand, and for 'piebald trait', an inherited skin pigmentation disorder.

Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol.

Abstract: Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.

Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease.

Abstract: Several lines of evidence indicate that tachykinin neuropeptides [substance P (SP), substance K (SK), and neuromedin K (NK)] play a role in regulating the inflammatory and immune responses. To test this hypothesis in a human inflammatory disease, quantitative receptor autoradiography was used to examine possible abnormalities in tachykinin binding sites in surgical specimens from patients with inflammatory bowel disease. Surgical specimens of colon were obtained from patients with ulcerative colitis (n = 4) and Crohn disease (n = 4). Normal tissue was obtained from uninvolved areas of extensive resections for carcinoma (n = 6). In all cases, specimens were obtained less than 5 min after removal to minimize influences associated with degradation artifacts and were processed for quantitative receptor autoradiography by using 125I-labeled Bolton-Hunter conjugates of NK, SK, and SP. In the normal colon a low concentration of SP receptor binding sites is expressed by submucosal arterioles and venules and a moderate concentration is expressed by the external circular muscle, whereas SK receptor binding sites are expressed in low concentrations by the external circular and longitudinal muscle. In contrast, specific NK binding sites were not observed in any area of the human colon. In colon tissue obtained from ulcerative colitis and Crohn disease patients, however, very high concentrations of SP receptor binding sites are expressed by arterioles and venules located in the submucosa, muscularis mucosa, external circular muscle, external longitudinal muscle, and serosa. In addition, very high concentrations of SP receptor binding sites are expressed within the germinal center of lymph nodules, whereas the concentrations of SP and SK binding sites expressed by the external muscle layers are not altered significantly. These results demonstrate that receptor binding sites for SP, but not SK or NK, are ectopically expressed in high concentrations (1000-2000 times normal) by cells involved in mediating inflammatory and immune responses. These data suggest that SP may be involved in the pathophysiology of inflammatory bowel disease and might provide some insight into the interaction between the nervous system and the regulation of inflammation and the immune response in human inflammatory disease.

The natural history of forced expiratory volumes. Effect of cigarette smoking and respiratory symptoms.

Abstract: Epidemiologic investigations into the natural history of airway obstructive disease have focused on both the growth and decline of lung function measurements. Although a general picture has emerged as to overall patterns of growth/decline, uncertainty remains with regard to important details of these patterns. Pulmonary function data from subjects aged 5 yr and and older who participated in any or all of the first 10 annual surveys of the East Boston population-based study have been used to investigate patterns of growth and decline of lung function derived from maximal forced expiratory maneuvers. At each annual survey, subjects completed a standardized respiratory illness and smoking questionnaire and provided forced expiratory volume-time curves from which forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were derived. A nonparametric curve smoothing method was used to provide an overall summary of growth and decline of each measure of function. Asymptomatic, nonsmoking males demonstrated a pattern of growth of FEV1 that included a prolonged plateau phase or period of slow, continued growth from ages 23 to 35 yr. Decline in lung function began after this period and occurred in two phases that averaged about -20 and -30 ml/yr. In contrast, no plateau phase was observed for male current smokers. In these smokers, decline in FEV1 began in the early part of the third decade at a rate only slightly greater than that observed for nonsmokers (-25 to -30 ml/yr). Similar patterns and rates of decline were observed for females, although the presence of a plateau phase was less clearly discernible. These data suggest that a major effect of cigarette smoking on lung function decline involves the premature onset of a "normal" rate of decline in function and, to a lesser extent, more rapid rates of decline later in life and that the pattern and magnitude of decline is similar in males and females.

Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6.

Abstract: Although certain forms of epilepsy have long been suspected to be inherited, heterogeneity has made it difficult to find the genes responsible for any subtypes. We found that families ascertained through patients with juvenile myoclonic epilepsy show linkage with the BF and HLA loci on human chromosome 6. There is some evidence that the locus may be outside the HLA complex and no evidence as yet of an association with any allele of the HLA complex.

Falls and Instability in the Elderly

Abstract: D r Rubenstein Falls and gait instability are among the most serious problems facing the aging population a major cause of mortality, morbidity, immobility, and premature nursing home placement. Many etiologies and risk factors predispose to falls, each requiring an individualized diagnostic and therapeutic approach to minimize likelihood of fall recurrence. In this discussion, two elderly individuals with complex, but fairly typical, fall problems are presented. These are followed by discussions of the epidemiology and common etiologies of falls, recommended diagnostic evaluations for patients following a fall, and more detailed discussion of three of the most important and least well-studied causes of falls: gait instability, muscle weakness, and environmental hazards.

Impaired learning of a motor skill in patients with Huntington's disease.

Abstract: The ability of patients with Huntington's disease (HD), patients with dementia of the Alzheimer's type (DAT), and amnesic patients (AMN) to acquire the motor skills underlying a pursuit rotor task was assessed. Differences between groups in initial levels of performance were minimized by adjusting the rotation speed of the disk. The HD and DAT groups were also administered a verbal recognition span test. The results showed that the DAT, AMN, and intact control groups all significantly improved their time on target over six test blocks whereas the HD group was severely impaired in the acquisition of this motor skill. On the verbal recognition span test, the DAT and HD groups were significantly and equally impaired, but the HD group evidenced better immediate and delayed recall than did the DAT group. These results provide further evidence that the basal ganglia are critically involved in the acquisition of motor skills.

Classically conditioned responses in opioid and cocaine dependence: a role in relapse?

Abstract: We have shown that conditioned phenomena occur in a number of drug-related settings and that they can be reliably elicited and studied. Our recent work suggests that conditioned craving is an extremely prevalent, if poorly understood, response to drug-related stimuli and that it can occur independent of conditioned withdrawal responses. Our current extinction protocols are effective in reducing the conditioned responses to both opioid and cocaine-related test stimuli. How well this extinction training generalizes to the "real world," is, of course, the crucial clinical question. We are trying to maximize the generalization of extinction through use of realistic, individualized drug "reminders." The final clinical impact of these extinction procedures awaits completion of our ongoing treatment/outcome studies in abstinent opioid and cocaine abusers.

Human parathyroid hormone-(1-34) increases bone mass in ovariectomized and orchidectomized rats.

Abstract: In intact growing rats, intermittent administration of low doses of PTH increases bone mass. As gonadal hormones are considered to be essential for normal bone growth, the anabolic effect of PTH may be mediated or modified by these hormones. The objective of this research was to determine if the anabolic effect of PTH would be altered in female ovariectomized (OVX) and male orchidectomized (ORCHX) rats. Two weeks after ovariectomy, orchidectomy, or sham operations, 5-week-old rats (eight per group) were given daily sc injections of human PTH (1–34) (8 μg/100 g) or vehicle. After 12 days of treatment, all rats were killed; castration was confirmed, and sera, femurs, tibias, and kidneys were collected. Calcium (Ca) and dry weight (DW) of trabecular and cortical bone of distal half-femurs were measured. Female OVX rats were osteopenic compared to their shamoperateJ controls, as the bone mass of distal femurs decreased while body weight increased. In PTH-treated females, total bone Ca and DW per 100 g BW incr...

Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease

Abstract: Alzheimer's disease is the most common form of dementia among the elderly population. Although the etiology is unknown, inheritance plays a role in the pathogenesis of the disease. Recent work indicates that an autosomal dominant gene for Alzheimer's disease is located on chromosome 21 at band q21. In the present study of a group of autopsy-documented kindreds, no evidence for linkage was found between familial Alzheimer's disease (FAD) and chromosome 21q21 markers (D21S1/D21S72 and the amyloid beta gene). Linkage to the D21S1/D21S72 locus was excluded at recombination fractions (theta) up to 0.17. Linkage to the amyloid gene was excluded at theta = 0.10. Apparent recombinants were noted in two families for the amyloid gene and in five families for the D21S1/D21S72 locus. These data indicate that FAD is genetically heterogeneous.

Cancer as a cause of back pain: frequency, clinical presentation, and diagnostic strategies.

Abstract: Back pain is very common. Rarely, it may be the first manifestation of cancer. Although many advocate selective use of laboratory and x-ray tests for back pain patients, the early detection of cancer may be an important reason to obtain such tests. To develop a diagnostic approach that would identify malignancies while remaining parsimonious, the authors evaluated 1,975 walk-in patients with α chief complaint of back pain. Thirteen patients (0.66%) proved to have underlying cancer. Findings significantly associated with underlying cancer (p 1 month, failure to improve with conservative therapy, elevated erythrocyte sedimentation rate (ESR), and anemia. Combining historical features and ESR results led to an algorithm that would have limited x-ray utilization to just 22% of subjects while recommending an x-ray for every cancer patient. It would further suggest which patients with negative x-ray findings require further work-up.

Self-Rated Depression Scales and Screening for Major Depression in the Older Hospitalized Patient with Medical Illness

Abstract: Until now, no self-rated depression scale had been validated as a screening measure for major depression in the older patient hospitalized with medical illness. The present report establishes the validity of two brief, easily administered depression screening tests, the Geriatric Depression Scale (GDS) and the Brief Carroll Depression Rating Scale (BCDRS), in this population. Structured psychiatric interviews were performed and self-rated depression measures administered to 128 men, aged 70 and over, consecutively admitted to medical and neurological services of a VA hospital. The GDS and BCDRS were both shown to have high sensitivity and specificity for detecting major depression in this setting. Optimal cut-off scores determined by the receiver operating curve characteristics of these tests were 11 for the GDS and 6 for the BCDRS. At a cutoff score of 11, the GDS had a sensitivity of 92%, a specificity of 89%, and a negative predictive value of 99%; lowering the break point to 8 did not increase sensitivity. At a cutoff score of 6, the BCDRS achieved a 100% sensitivity, 93% specificity, and 100% negative predictive value. Whether clinicians decide to implement either of these depression screens in their practice will depend to a large degree on the importance ascribed to the detection of these disorders and on attitudes toward the benefits of treatment.

Lexical and semantic priming deficits in patients with Alzheimer's disease.

Abstract: Two experiments utilizing priming procedures examined the status of semantic memory in demented and amnesic patients. In the first investigation, lexical priming was assessed in patients with dementia of the Alzheimer type (DAT), Huntington's Disease (HD), alcoholic Korsakoff's syndrome (KS), and in intact control subjects. Subjects were first exposed to a list of words in a rating task and then required to complete three-letter stems with the “first word that comes to mind”. Half of the stems could be completed with the previously presented words and the other half were used to assess baseline guessing rates. Recall and recognition of incidentally exposed words was also assessed. Although all three patient groups were impaired on tests of recall and recognition, only the DAT patients exhibited a priming deficit on the stem-completion task. In the second experiment, DAT, HD, and intact control subjects were administered a semantic priming test which required the subject to “free associate” to the...

Impact of a medical journal club on house-staff reading habits, knowledge, and critical appraisal skills. A randomized control trial.

Abstract: The journal club is an established teaching modality in many house-staff training programs. To determine if a journal club improves house-staff reading habits, knowledge of epidemiology and biostatistics, and critical appraisal skills, we randomized 44 medical interns to receive either a journal club or a control seminar series. A test instrument developed by the Delphi method was administered before and after the interventions (mean, five journal club sessions). By self-report, 86% of the house staff in the journal club group improved their reading habits vs 0% in the control group. Knowledge scores increased more in the journal club group than in the control group, and a trend was found toward more knowledge gained as more sessions were attended. Ability to appraise critically a test article increased slightly in each group, but there was no significant difference between the groups. We conclude that a journal club is a powerful motivator of critical house-staff reading behavior and can help teach epidemiology and biostatistics to physicians-in-training. (JAMA1988;260:2537-2541)

The insulin and glucose responses to meals of glucose plus various proteins in type II diabetic subjects

Abstract: We previously have shown that ingested beef protein is just as potent as glucose in stimulating a rise in insulin concentration in type II diabetic patients. A synergistic effect was seen when given with glucose. Therefore, we considered it important to determine if other common dietary proteins also strongly stimulate an increase in insulin concentration when given with glucose. Seventeen type II (non-insulin-dependent) untreated diabetic subjects were given single breakfast meals consisting of 50 g glucose, or 50 g glucose plus 25 g protein in the form of lean beef, turkey, gelatin, egg white, cottage cheese, fish, or soy. The peripheral plasma concentrations of glucose, insulin, glucagon, alpha amino nitrogen, urea nitrogen, free fatty acids, and triglycerides were measured. Following ingestion of the meals containing protein, the plasma insulin concentration was increased further and remained elevated longer compared with the meal containing glucose alone. The relative area under the insulin response curve was greatest following ingestion of the meal containing cottage cheese (360%) and was least with egg white (190%) compared with that following glucose alone (100%). The glucose response was diminished following ingestion of the meals containing protein with the exception of the egg white meals. The peripheral glucagon concentration was decreased following ingestion of glucose alone and increased following all the meals containing protein. The alpha amino nitrogen concentration varied considerably. It was decreased after glucose alone, was unchanged after egg white ingestion, and was greatest after ingestion of gelatin. The free fatty acid concentration decrease was 4- to 8-fold greater after the ingestion of protein with glucose compared with ingestion of glucose alone.

Identification, cellular localization, isolation, and characterization of human Clara cell-specific 10 KD protein.:

Abstract: Human lung lavage proteins were fractionated by centrifugation and molecular sieving. An antiserum to the post-albumin fraction of the soluble proteins reacted with a 10 KD protein and this protein was isolated by conventional chromatography. The protein, which has a pI of 4.8, consists of two 5 KD polypeptides and is rich in glutamic acid, leucine, serine, and aspartic acid amino acids. The protein does not bind to concanavalin A, pancreatic elastase, leukocyte elastase, or trypsin, and lacks anti-protease activity. It constitutes about 0.15% of the soluble proteins in lung lavage. Antibodies to the 10 KD protein specifically and exclusively stain Clara cells in human, dog, and rat. Staining of granules of Clara cells was prominent in the distal bronchioles; however, the non-ciliated cells of respiratory bronchioles did not stain for the 10 KD protein. This 10 KD protein appears in fetal lungs at 21 weeks of gestation, and was present in about 10% of the primary pulmonary adenocarcinomas. As a specific m...

Familial aggregation in Alzheimer's disease: comparison of risk among relatives of early-and late-onset cases, and among male and female relatives in successive generations.

Abstract: Although the morbid risk of Alzheimer's disease (AD) is increased among relatives of AD index cases, it is not yet clear whether the extent of familial aggregation is similar for probands of all ages, or for male and female relatives. The present study investigated the incidence of AD-like illness among 379 first-degree relatives of 79 probands in a continuing longitudinal study of AD. Cumulative incidence among relatives increased strikingly with age to 49% by age 87, and the risks observed did not differ appreciably among relatives of presenile-onset versus senile-onset probands. Risks were also similar among parents and sibs. Female relatives appeared to develop the disease earlier than males, but the age-specific risk curves for the two sexes did not differ significantly. These results should not be viewed as direct evidence for dominant genetic transmission of late-onset AD, but they suggest a rationale for formal genetic studies in late-onset (often apparently "sporadic") disease as well as earlier-onset ("familial") cases.