Showing papers by "Veterans Health Administration published in 1991"

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD): Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

Abstract: The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as "definite Alzheimer's disease" (AD), "probable AD," "possible AD," and "normal brain" to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

The medial temporal lobe memory system

Abstract: Studies of human amnesia and studies of an animal model of human amnesia in the monkey have identified the anatomical components of the brain system for memory in the medial temporal lobe and have illuminated its function. This neural system consists of the hippocampus and adjacent, anatomically related cortex, including entorhinal, perirhinal, and parahippocampal cortices. These structures, presumably by virtue of their widespread and reciprocal connections with neocortex, are essential for establishing long-term memory for facts and events (declarative memory). The medial temporal lobe memory system is needed to bind together the distributed storage sites in neocortex that represent a whole memory. However, the role of this system is only temporary. As time passes after learning, memory stored in neocortex gradually becomes independent of medial temporal lobe structures.

Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer

Abstract: Background We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation. Methods Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy. Results After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease. Conclusions These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.

Age and Relative Adiposity Are Specific Negative Determinants of the Frequency and Amplitude of Growth Hormone (GH) Secretory Bursts and the Half-Life of Endogenous GH in Healthy Men*

Abstract: Mean plasma GH concentrations are controlled by the frequency, amplitude, and duration of underlying GH secretory bursts as well as by the half-life of endogenous GH. We investigated the specific mechanisms that subserve the clinically recognized negative effects of age and adiposity on mean serum GH concentrations. To this end, 21 healthy men, aged 21-71 yr, who were of nearly normal body weight underwent blood sampling at 10-min intervals for 24 h. Deconvolution analysis was used to estimate specific features of GH secretion and clearance. Compared to younger men, the older tertile of men had significant reductions in 1) GH secretory burst frequency, 2) the half-life of endogenous GH, and 3) the daily GH secretory rate, but not 4) GH secretory burst half-duration, amplitude, or mass. Linear regression analysis disclosed that age was a major negative statistical determinant of GH secretory burst frequency (r = -0.80; P = 0.005) and endogenous GH half-life (r = -0.70; P = 0.024). Body mass index, an indicator of relative obesity, was a significant negative correlate of GH half-life (P = 0.045) and GH secretory burst amplitude (P = 0.031). Age and body mass index each correlated negatively with the daily GH secretion rate (P = 0.0031 and P = 0.027, respectively), and together accounted for more than 60% of the variability in 24-h GH production rates (r = -0.78; P = 0.00056). On the average, for a normal body mass index, each decade of increasing age attenuated the GH production rate by 14% and the GH half-life by 6%. Conversely, each unit increase in body mass index, at a given age, reduced the daily GH secretion rate by 6%. We conclude that age and relative adiposity are distinct and specific correlates of individual attributes of GH secretion and clearance in men.

A Controlled Clinical Trial of E5 Murine Monoclonal IgM Antibody to Endotoxin in the Treatment of Gram-Negative Sepsis

Abstract: Objective. —To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with gram-negative sepsis. Design. —Double-blind, randomized, placebo-controlled trial. Setting. —Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. Patients. —Hospitalized adults with signs of gram-negative infection and a systemic septic response. Intervention. —Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against gram-negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. Main Outcome Measures. —Mortality over the 30-day study period, resolution of organ failures, and safety. Results. —Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed gram-negative sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with gram-negative sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P =.01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group ( P =.05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. Conclusions. —Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with gram-negative sepsis who are not in shock when treated. ( JAMA . 1991;266:1097-1102)

Infectious diseases associated with complement deficiencies.

Abstract: The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

Helicobacter pylori and Peptic Ulcer Disease

Abstract: A GRAM-NEGATIVE, microaerophilic curved bacillus found in gastric-biopsy specimens from patients with histologie gastritis was successfully cultured in Perth, Australia, in 1982 and was soon named Campylobacter pylori 1 (a name later changed to Helicobacterpylori). Little attention had been paid to previous descriptions of spiral organisms in biopsy specimens of human gastric mucosa,2 , 3 but it now appears that at the least the organism is responsible for most cases of gastritis not associated with another known primary cause (e.g., autoimmune gastritis or eosinophilic gastritis) and that it may also be a major factor in the pathogenesis of peptic ulcer disease. The . . .

Banting lecture 1990. Beta-cells in type II diabetes mellitus.

Abstract: In 1960, immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a beta-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet beta-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently, it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals, including other substrates, hormones, and neural factors. When both obesity and glucose are taken into account, it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose beta-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release. Before the development of fasting hyperglycemia, only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear, so that there is a 75% loss of beta-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose. The etiology of the islet beta-cell lesion is not known, but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin, which is the major constituent of islet amyloid deposits, is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing, secondary to or in conjunction with defects in hormone secretion, lead to progressive accumulation of intracellular IAPP and pro-IAPP, which in cats, monkeys, and humans form intracellular fibrils and amyloid deposits with a loss of beta-cell mass.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone growth factors.

Abstract: Bone volume is determined by the relative rates of bone formation and bone resorption. Recent research in several laboratories suggests that growth factors may act locally to modulate bone formation by stimulating osteoblast proliferation and activity. A number of bone-derived growth factors have been isolated and characterized from bone matrix extracts and from media conditioned by bone cells and bone organs in culture. The growth factors found in bone matrix include insulinlike growth factors I and II, transforming growth factor-beta, acidic and basic fibroblast growth factor, platelet-derived growth factor, and bone morphogenetic proteins. Conditioned medium from bone cells contains several of these growth factors and also hematopoietic factors. These bone matrix-derived growth factors have different biologic activities, including mitogenic, differentiating, chemotactic, and osteolytic activities. Evidence suggests that bone cells produce substantial quantities of growth factors for extracellular storage in bone matrix. Apart from being produced for extracellular storage, it is possible that growth factors secreted by bone cells have acute effects on their neighboring osteoblastic cells, i.e., paracrine action, or on themselves, i.e., autocrine action. The release of matrix-stored growth factors by bone resorption may mean that growth factors act as delayed paracrine agents, e.g., osteoblasts deposit growth factors in bone and later when these growth factors are released from bone via bone resorption, the growth factors stimulate osteoblast precursors to proliferate. The findings that bone is a storehouse for growth factors and that bone cells in culture produce and respond to bone growth factors suggest bone growth factors may act as potential determinants of local bone formation. This review is focused on the structure, regulation, and biologic actions of the known bone growth factors.

Head Trauma as a Risk Factor for Alzheimer's Disease: A Collaborative Re-Analysis of Case-Control Studies

Abstract: A re-analysis of the data from 11 case-control studies was performed to investigate the association between head trauma and Alzheimer's disease (AD). To increase comparability of studies, exposures were limited to head trauma with loss of consciousness (hereafter referred to as 'head trauma') and comparisons were restricted to community (versus hospital) controls. Test for heterogeneity across studies was negative; consequently, data were pooled in subsequent analyses. The pooled relative risk for head trauma was 1.82 (95% confidence interval: 1.26-2.67). Stratified analyses showed stronger associations in cases without a positive family history of dementia and in males (versus females). Adjustment of the pooled relative risk for family history of dementia, education and alcohol consumption did not alter significantly the association between head trauma and AD. There was no interaction effect between head trauma and family history of dementia, suggesting that these risk factors operate independently. Mean age of onset was not significantly different in cases with a history of head trauma compared to cases without such a history. The findings of the pooled analysis support an association between reported head trauma and AD.

Impacts of Geriatric Evaluation and Management Programs on Defined Outcomes: Overview of the Evidence

Abstract: Comprehensive geriatric assessment is a technique for multidimensional diagnosis of frail elderly people with the purpose of planning and/or delivering medical, psychosocial, and rehabilitative care. When comprehensive geriatric assessment is coupled with some therapy, then the term geriatric evaluation and management (GEM) will be used. Following a brief history of comprehensive geriatric assessment, we describe the varied patterns of GEM program organization and review the literature of studies examining GEM effectiveness. Program diversity complicates drawing firm conclusions about GEM effects; however, the vast majority of studies report positive, if not uniformly significant, results. Our analysis suggests that much of the variability in findings is due to sample size limitations. In order to reach conclusions of program effects across studies and to avoid problems of small sample sizes, we undertook a formal meta-analysis. In this initial meta-analysis, we sought to evaluate the effect of GEM programs on a single outcome: mortality. We pooled all published GEM controlled trials into four major groups: inpatient consultation services, inpatient GEM units, home assessment services, and outpatient GEM programs. Meta-analysis of 6-month mortality demonstrates a 39% reduction of mortality for inpatient consultation services (odds ratio 0.61, 95% confidence interval 0.46-0.81, P = 0.0008) and a 37% reduction of mortality for inpatient GEM units (odds ratio 0.63, 95% CI 0.42-0.93, P = 0.02). Home assessment services reduced mortality by 29% (odds ratio 0.71, 95% CI 0.55-0.90, P = 0.005). On the other hand, no significant survival effect was found for outpatient GEM programs (odds ratio 0.96, 95% confidence interval 0.61-1.49).(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant Granulocyte-Macrophage Colony-Stimulating Factor after Autologous Bone Marrow Transplantation for Lymphoid Cancer

Abstract: Background. The period of neutropenia after autologous bone marrow transplantation results in substantial morbidity and mortality. The results of previous phase I-II clinical trials suggest that recombinant human granulocytemacrophage colony-stimulating factor (rhGM-CSF) may accelerate neutrophil recovery and thereby reduce complications in patients after autologous bone marrow transplantation. Methods. We conducted a randomized, double-blind, placebo-controlled trial at three institutions. The study design and treatment schedules were identical, and the results were pooled for analysis. One hundred twenty-eight patients were enrolled. Sixty-five patients received rhGM-CSF in a two-hour intravenous infusion daily for 21 days, starting within four hours of the marrow infusion, and 63 patients received placebo. Results. No toxic effects specifically ascribed to rhGM-CSF were observed. The patients given rhGM-CSF had a recovery of the neutrophil count to 500×106 per liter 7 days earlier than the patients who...

Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man.

Abstract: We have examined the mechanisms underlying reduced circulating GH concentrations in the obese human. Computer-assisted (deconvolution) analysis was used to determine endogenous GH secretory and clearance rates quantitatively from entire 24-h plasma GH concentration profiles. These analyses revealed that the half-life (t 1/2) of endogenous GH was significantly shorter in obese (11.7 +/- 1.6 min) than in normal weight subjects (15.5 +/- 0.81 min; P less than 0.01). The accelerated blood disposal rate of GH was not due to decreased circulating concentrations of GH-binding protein, since the latter were similar in obese (25 +/- 1.0%) and normal weight (24 +/- 2.3%) men. However, obese men had significantly fewer GH secretory bursts (3.2 +/- 0.53 vs. 9.7 +/- 0.67/day; P less than 0.01). Among the rare GH secretory bursts that occurred in obese subjects, there were significantly prolonged mean intersecretory burst intervals (282 +/- 65 vs. 131 +/- 11 min; P less than 0.05). The resultant daily GH production rate in obese men was reduced to one fourth that in normal weight individuals. Both GH secretion rate and burst frequency were negatively correlated with the degree of obesity (ponderal index). The decreases in GH burst frequency and half-life were specific, since GH secretory pulse amplitude (maximal rate of GH release), the mass of GH released per burst, and the duration of computer-resolved GH secretory bursts were not different in obese and normal weight men. We conclude that obese men harbor a double defect in GH dynamics involving both GH secretion and clearance, and that the severity of the GH secretory deficiency is proportionate to the degree of obesity.

Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism.

Abstract: Interleukins (ILs) 1 alpha and 1 beta are important components of the neuroimmune axis. Recent work has shown that human 125I-IL-1 alpha can enter the brain from the blood by a saturable system, suggesting a mechanism that may directly link the immune and nervous systems. Here, it is shown that radioiodinated murine IL-1 beta and especially murine IL-1 alpha are even more rapidly transported into the brain of the mouse than is radioiodinated human IL-1 alpha after i.v. injection. All three cytokines exhibited self-inhibition, thus demonstrating saturable transport. Also, they all cross-inhibited the transport of each other. This shows that there are not three separate transport systems, but that they either share transport systems with overlapping affinities or share a single system. It was calculated that 0.06% to 0.08% of the dose of human 125I-IL-1 alpha injected i.v. was present in the brain during the first 60 min. By contrast, no saturable component could be detected in the brain to blood passage of the three ILs. No disruption of the blood-brain barrier to radioactively labeled albumin was found with i.v. doses of up to 50 micrograms/kg of human IL-1 alpha. Additional studies on the blood to brain transport of human 125I-IL-1 alpha showed no modification by dexamethasone, morphine, indomethacin or alpha-melanocyte stimulating hormone. Studies with antibodies directed toward the binding or nonbinding sites of IL or its receptor on the murine T lymphocyte suggest similar, but not identical, structural requirements for transport and for receptor binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Group A streptococcal infections and acute rheumatic fever.

Abstract: STREPTOCOCCUS PYOGENES (group A streptococcus) is one of the most common and ubiquitous of human pathogens. It causes a wide array of infections, the most frequent of which are acute pharyngitis ("...

The reliability of peer review for manuscript and grant submissions: A cross-disciplinary investigation

Abstract: The reliability of peer review of scientific documents and the evaluative criteria scientists use to judge the work of their peers are critically reexamined with special attention to the consistently low levels of reliability that have been reported. Referees of grant proposals agree much more about what is unworthy of support than about what does have scientific value. In the case of manuscript submissions this seems to depend on whether a discipline (or subfield) is general and diffuse (e.g., cross-disciplinary physics, general fields of medicine, cultural anthropology, social psychology) or specific and focused (e.g., nuclear physics, medical specialty areas, physical anthropology, and behavioral neuroscience). In the former there is also much more agreement on rejection than acceptance, but in the latter both the wide differential in manuscript rejection rates and the high correlation between referee recommendations and editorial decisions suggests that reviewers and editors agree more on acceptance than on rejection. Several suggestions are made for improving the reliability and quality of peer review. Further research is needed, especially in the physical sciences.

Psychiatric complications during flooding therapy for posttraumatic stress disorder.

Abstract: The authors use six case vignettes to illustrate underrecognized complications occurring during flooding therapy for posttraumatic stress disorder (PTSD), including exacerbation of depression, relapse of alcoholism, and precipitation of panic disorder. A common denominator to the majority of these cases appears to be the mobilization of negative posttrauma appraisal, accompanied by shame, guilt, and anger. The authors suggest that flooding may not be helpful for these negative emotions in the manner that it is for anxiety. Suggestions for preventing and treating complications of flooding therapy for PTSD include employing more cognitive forms of therapy in cases at risk; supporting abstinence from alcohol and other substances; providing adjunctive pharmacologic treatment as indicated, e.g., tricyclics for depression or panic; and providing long-term follow-up.

Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction.

Abstract: Todetermine theclinical consequences ofreocclusion ofaninfarct-related artery after reperfusion therapy, weevaluated 810patients with acute myocardial infarction. Patients were admitted intofoursequential studies with similar entry criteria inwhich patency ofthe infarct-related artery wasassessed bycoronary arteriography 90minutes after onsetof thrombolytic therapy. Successful reperfusion wasestablished acutely in733patients. Thrombolytic therapy included tissue-type plasminogen activator (t-PA) in517, urokinase in87,and acombination oft-PAandurokinase in129patients. Allpatients received aspirin, intravenous heparin andnitroglycerin, anddiltiazem during therecovery phase. A repeat coronary arteriogram wasperformed in88%ofpatients atamedian of7daysafter theonsetof symptoms. Reocclusion oftheinfarct-related artery occurred in91patients (12.4%), and58% ofthese weresymptomatic. Angiographic characteristics at90minutes after thrombolytic therapy that wereassociated with reocclusion compared with sustained coronary artery patency were right coronary infarct-related artery (65% versus 44%, respectively) andThrombolysis in Myocardial Infarction (TIMI) flow0or1(21% versus 10%,respectively) before further intervention. Median(interquartile value) degree ofstenosis intheinfarct-related artery at90 minutes wassimilar between groups: 99%forreoccluded (value, 90/100%6) compared with 95% forpatent (value, 80/99%). Patients withreocclusion hadsimilar left ventricular ejection fractions compared withpatients withsustained patency atfollow-up. However, patients with reocclusion atfollow-up hadworse infarct-zone function at-2.7(value, -3.2/-1.8) versus -2.4(SD/chord) (value, -3.11-1.3) (p=0.016). Therecovery ofbothglobal andinfarct-zone function wasimpaired byreocclusion oftheinfarct-related artery compared withmaintained patency; medianA ejection fraction was-2compared with1(p=0.006) andmedianA infarct-zone wall motion was-0.10compared with 0.34 SD/chord (p=0.011), respectively. In addition, patients withreocclusion hadmorecomplicated hospital courses andhigher in-hospital mortality rates (11.0%7 versus 4.5%, respectively; p=0.01). We conclude that reocclusion oftheinfarct-related artery after successful reperfusion isassociated with substantial morbidity andmortality rates. Reocclusion isalso detrimental tothefunctional recovery ofbothglobal andinfarct-zone regional left ventricular function. Thus, newstrategies inthepostinfarction period need tobedeveloped toprevent reocclusion oftheinfarct-related artery. (Circulation 1990;82:781-791)

Nonsteroidal anti-inflammatory drugs and peptic ulcer disease

Abstract: Evidence has accumulated that nonsteroidal anti-inflammatory drugs (NSAIDs) cause clinically important gastroduodenal ulcers. The pathogenesis, which involves the impairment of mucosal resistance to injury in an acid-peptic environment, is multifactorial and controversial. Ulcers caused by NSAIDs can occur either in mucosa inflamed because of infection with Helicobacter pylori or in histologically normal mucosa. The use of these drugs has been linked to an unexpectedly high incidence of ulcer complications, and a history of peptic ulcer disease is common in such cases. Nonsteroidal anti-inflammatory drugs thus appear both to exacerbate an underlying peptic diathesis and to cause de novo ulcers. The association between the use of these drugs and ulcer complications is supported by ulcer prevalence data from cross-sectional studies, and by data from case-controlled and cohort studies, and from randomized, experimental trials. Drug-induced gastric ulcers have been prevented by misoprostol, but not by H2 blocker therapy. Several therapies have been reported to promote ulcer healing despite continued use of NSAIDs, but adequate controlled trials have not been done. Small gastric and duodenal ulcers readily heal, whereas larger gastric ulcers require vigorous and prolonged therapy. The relative efficacies of various therapies in preventing ulcers, healing ulcers, or preventing complications remain to be established.

Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes.

Abstract: Human immunodeficiency virus type 1 (HIV-1) infection of T lymphocytes requires cellular proliferation and DNA synthesis. Human monocytes were shown to have low DNA synthesis rates, yet the monocytotropic BaL isolate of HIV-1 was able to infect these cells efficiently. Monocytes that were irradiated to assure no DNA synthesis could also be readily infected with HIV-1BaL. Such infections were associated with the integration of HIV-1BaL DNA into the high molecular weight, chromosomal DNA of monocytes. Thus, normal, nonproliferating monocytes differ from T lymphocytes in that a productive HIV-1 infection can occur independently of cellular DNA synthesis. These results suggest that normal nonproliferating mononuclear phagocytes, which are relatively resistant to the destructive effects of this virus, may serve as persistent and productive reservoirs for HIV-1 in vivo.

Methicillin-resistant staphylococcal colonization and infection in a long-term care facility.

Abstract: Objective: To determine the natural history of colonization by methicillin-resistant Staphylococcus aureus (MRSA) among patients in a long-term care facility. We specifically sought to determine if...

Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558.

Abstract: Two of the cytosolic NADPH oxidase components, p47-phox and p67-phox, translocate to the plasma membrane in normal neutrophils stimulated with phorbol myristate acetate (PMA). We have now studied the translocation process in neutrophils of patients with chronic granulomatous disease (CGD), an inherited syndrome in which the oxidase system fails to produce superoxide due to lesions affecting any one of its four known components: the gp91-phox and p22-phox subunits of cytochrome b558 (the membrane-bound terminal electron transporter of the oxidase), p47-phox, and p67-phox. In contrast to normal cells, neither p47-phox nor p67-phox translocated to the membrane in PMA-stimulated CGD neutrophils which lack cytochrome b558. In one patient with a rare X-linked form of CGD caused by a Pro----His substitution in gp91-phox, but whose neutrophils have normal levels of this mutant cytochrome b558, translocation was normal. In two patients with p47-phox deficiency, p67-phox failed to translocate, whereas p47-phox was detected in the particulate fraction of PMA-stimulated neutrophils from two patients deficient in p67-phox. Our data suggest that cytochrome b558 or a closely linked factor provides an essential membrane docking site for the cytosolic oxidase components and that it is p47-phox that mediates the assembly of these components on the membrane.

I. Helicobacter pylori: Its epidemiology and its role in duodenal ulcer disease

Abstract: Helicobacter pylori is now accepted as the major cause of chronic gastritis in humans. The histologic pattern of H . pylori gastritis is typically one of patchy acute on chronic inflammation, most severe in the antrum. The association of chronic gastritis with the environmental or epidemic type of gastric carcinoma prompted a number of investigations of the epidemiology of gastritis, and the results of those studies could be reasonably transferred to H . pylori to provide H . pylori investigators with a head start in the study of the epidemiology of a new disease, H . pylori gastritis. This data transfer allowed early definition of important questions designed to confirm previous associations with gastritis and extend them to H . pylori. Factors known to be associated with gastritis include low socioeconomic class, large family size, crowding, and ethnic group.lV2 Factors found to be unimportant in the pathogenesis of chronic gastritis included use of drugs such as ethanol, nicotine, or nonsteroidal anti-inflammatory drugs (Table l).' The prevalence of gastritis increases with age. For many years it was thought that the gastric mucosa of geriatric patients was normally atrophic, a 'wear-and-tear' phenomenon. Although it is difficult to distinguish changes in the gastrointestinal tract due to ageing from those resulting from environmental effects acting over long periods of time, most now believe that chronic gastritis in the elderly is generally the end result of H . pylori infection.a-6 The acquisition of H . pylori infection continues throughout life but, once acquired, the duration of the infection appears to be very long, possibly for life.7 The rate of acquisition of H . pylori infection varies remarkably between and within populations. The age-specific prevalence of H. pylori infections (usually measured as presence of anti-Hi. pylori IgG) is higher in developing countries than developed countries (Fig. 1). Within a specific country there are further stratifications; the age-specific rate of acquisition of H . pylori infection is higher in those of lower socio-economic status whether assessed by income, housing, educational level, ethnic or religious group. One factor that appears to unify the disparate epidemiology results is differences in sanitation and hygiene practices.8 The mode(s) of transmission is unknown but the geographic and social patterns of H. pylori infection are consistent with faecal-oral transmission as one major pathway. This is also consistent with recent data Peru, demonstrating a direct association bet valence of H. pylori infection and source of drinking water (Fig. 2).9 One particularly striking recent finding is that motile spiral forms of H. pylori can survive for at least a week in river water.I0 Coccoid forms of H. pylori can also survive in river water for a year or more, but the clinical relevance of that observation remains unclear.tX\"rin my opinion, coccoid forms from nature are unlikely to be infectious for %mans. Coccoid forms have also been found in the stomach. Although coccoid forms are unlikely to survive long in the stomach becsuse the rapid turnover of the gastric epithelium probably precludc; prolonged residence, they may be responsible for some instances of relapse after antimicrobial therapy. H . pylon' has not yet been isolated from the environment but the technology now available (e.g. cDNA probes) can address this question. Iatrogenic transmission of H. pylori infection has been documented12*13 and the high prevalence of H. pylori infection in endoscopists who did not always use gloves suggests s p r e e o m instruments contaminated with gastric secretions (gastric secretion!oral spread).'j Finally, H. pylori has been recovered from dental plaque15 and, although this appears to be a rare phenomenon, it emphasizes that there may be many potential pathways for transmission. In developed countries, H . pylori infection is infrequent in children and increases at 1-270 per year (Fig. 3), approximately the same rate as previously described for gastritis or for the onset of new cases of dyspepsia.16-z1 The rate of acquisition of H . pylori infection appears to be similar in the United States, Australia and the United Kingdom. Even within developed countries, there are ethnic and racial differences in the prevalence of H . pylm' For example, in the United States, the rate of acquisition of H. pylori infection is higher in blacks than whites and preliminary studies have shown high ageadjusted rates in Chinese, East Indians and Mexicans studying in, or recently emigrating to, the United States.7.23.24 In most instances the difference in prevalence Between ethnic group or race represents a surrogate xrwb~ for differences in exposure(s), such as differences in standards of living or sanitation practices. Importantly, the differences in age-adjusted frequency of H. pylon' between whites and blacks in the United State8 remains when

Analysis of Interstrain Variation in Cytomegalovirus Glycoprotein B Sequences Encoding Neutralization-Related Epitopes

Abstract: Nucleotide sequences of a part of the envelope glycoprotein B (gB) gene of human cytomegalovirus (CMV), encoding epitopes recognized by virus-neutralizing monoclonal antibodies, were determined for 12 distinct clinical strains of CMV after amplification of suitable templates using the polymerase chain reaction. Sequence analysis of this region (codons 384-717) revealed that the clinical strains and previously sequenced laboratory strains Towne and AD169 belong to one of four variant groups, each with a characteristic nucleotide and peptide sequence. Peptide homology was greater than 99% for strains within a group, and varied from 91% to 98% for strains in different groups. Variation was most frequent between codons 448 and 480. The gB group of a CMV strain could be determined by restriction analysis of a small target sequence amplified from viral genomic DNA, and an additional 28 clinical strains were grouped in this manner. The existence of a limited number of variants of gB among clinical strains facilitates analysis of biologic function and cross-reactivity of immune responses.

The Assessment of Posttraumatic Stress Disorder in Battered Women

Abstract: This study examined battered women's psychological symptoms using instruments developed to assess posttraumatic stress disorder (PTSD) in other trauma victims. Women who had been in a physically violent relationship (n = 26) were assessed for PTSD using self-report measures and the Structured Clinical Interview for DSM-III-R (SCID). Results indicated that 45% of those subjects interviewed met full DSM-III-R criteria for PTSD on the SCID, and that exposure to violence was significantly associated with PTSD symptomatology. When divided into high and low exposure groups based on degree of life threat, 60% of those in the high exposure group met criteria for diagnosable PTSD in contrast to a 14% rate in the low exposure group. These data suggest that battered women do experience symptoms of psychological trauma, and future cross-trauma research that includes this population, along with other previously identified trauma groups, would be beneficial.

The use of the Karnofsky Performance Scale in determining outcomes and risk in geriatric outpatients.

Abstract: The Karnofsky Performance Scale (KPS) was evaluated in a geriatric outpatient population with regard to three issues: its strength of association with widely used and validated geriatric instruments; its ability to predict patient outcomes; and its ability to serve as an identifier of high-risk patients. The 134-patient sample was given a comprehensive geriatric assessment which included the KPS, the Activities of Daily Living (ADL) scale, the Instrumental Activities of Daily Living (IADL) scale, and other psychosocial and sensory tests. The KPS, ADL, and IADL were significantly correlated with each other, and the KPS showed the strongest associations with other functional measures. The KPS was also highly predictive of outcomes, performing better or equally well as the ADL and IADL. The KPS designation of high- and low-risk groups resulted in statistically significant score differences between groups in all but one assessment area, demonstrating better ability to discriminate than either the ADL or IADL. Thus, the KPS was shown to serve as an effective proxy score for a patient's health and functional status. It also was a significant predictor of hospitalizations, survival time, community residence, and institutionalization. Finally, the KPS was shown to adequately distinguish risk groups to aid in the targeting of services to ambulatory geriatric patients.