Steady-state migrating intestinal dendritic cells induce potent inflammatory responses in naive CD4+ T cells.

Steady-state dendritic cells (DCs) migrating in the lymph from the intestine induce tolerance to harmless intestinal antigens, preventing inflammatory responses. To determine if such DCs are inherently tolerogenic we collected intestinal lymph DCs (L-DCs) by cannulation of the thoracic duct of rats after mesenteric lymphadenectomy, and examined their capacity to activate naive CD4+ lymphocytes in an allogeneic mixed leucocyte reaction. L-DCs stimulated strong proliferative responses, induced secretion of inflammatory cytokines including interferon-gamma, and induced FoxP3-positive lymphocytes to divide. To determine if the activated CD4+ T cells had been tolerized, they were rested and restimulated with irradiated splenocytes. The restimulated CD4+ T cells again proliferated and secreted inflammatory cytokines. These data demonstrate that the DCs, which migrate from the intestine in the steady state, are paradoxically able to induce strong inflammatory responses from naive T cells, despite their role in the maintenance of oral tolerance.

Norwalk-like viral gastroenteritis outbreak in U.S. Army trainees.

An outbreak of acute gastroenteritis hospitalized 99 (12%) of 835 U. S. Army trainees at Fort Bliss, El Paso, Texas, from August 27 to September 1, 1998. Reverse transcriptase polymerase chain reaction tests for Norwalk-like virus were positive for genogroup 2. Gastroenteritis was associated with one post dining facility and with soft drinks.

A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes.

This study identifies a dendritic cell (DC) subset that constitutively transports apoptotic intestinal epithelial cell remnants to T cell areas of mesenteric lymph nodes in vivo. Rat intestinal lymph contains two DC populations. Both populations have typical DC morphology, are major histocompatibility complex class II(hi), and express OX62, CD11c, and B7. CD4(+)/OX41(+) DCs are strong antigen-presenting cells (APCs). CD4(-)/OX41(-) DCs are weak APCs and contain cytoplasmic apoptotic DNA, epithelial cell-restricted cytokeratins, and nonspecific esterase (NSE)(+) inclusions, not seen in OX41(+) DCs. Identical patterns of NSE electrophoretic variants exist in CD4(-)/OX41(-) DCs, intestinal epithelial cells, and mesenteric node DCs but not in other DC populations, macrophages, or tissues. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL)-positive DCs and strongly NSE(+) DCs are present in intestinal lamina propria. Peyer's patches and mesenteric but not other lymph nodes contain many strongly NSE(+) DCs in interfollicular and T cell areas. Similar DCs are seen in the ileum and in T cell areas of mesenteric nodes in gnotobiotic rats. These results show that a distinct DC subset constitutively endocytoses and transports apoptotic cells to T cell areas and suggest a role for these DCs in inducing and maintaining peripheral self-tolerance.

A 3-dimensional analysis of modes of cardiovascular adaptation: concepts, methods and preliminary findings.

OBJECTIVE: To present a 3-dimensional approach to displaying and interpreting processes of cardiovascular adaptation. DESIGN: Laboratory study of blood pressure changes in response to a protocol set in advance. The authors plotted the coordinates of 3711 cardiovascular change events (CVCEs) in 3-dimensional space defined by changes in systolic blood pressure, diastolic blood pressure and heart rate. This was followed by cluster analyses and preliminary estimates of reliability and construct validity. SETTING: The teaching hospitals of a large southwestern US medical centre. PARTICIPANTS: Approximately 100 female nursing personnel aged 25 to 50 years. INTERVENTIONS: Medical history, self-administered questionnaires, laboratory protocol of pressor challenges, rest periods. RESULTS: Nine distinct clusters ("species of response") were identified and replicated in randomly chosen halves of the sample. Postural, isomorphic and psychologic challenges generated several distinctive profiles of "rising" responses, and were also followed by distinctive "declining" responses. The frequencies of various cardiovascular reactions ("clusters") to the same protocol were correlated with psychosocial characteristics and hypertension risk indicators. CONCLUSIONS: The 3-dimensional approach reveals many features of cardiovascular adaptation not discernible from traditional univariate displays and analyses. This paradigm might prove useful for matching patients with hypertension by their cluster patterns to their most suitable medication, but it requires further validation by direct hemodynamic measurements.

Comparative intraocular penetration of topical and injected cefuroxime.

AIMS: The choice of a prophylactic antibiotic for cataract surgery is dependent on its antibacterial activity and tissue penetration. The influence of the route and timing of administration of cefuroxime on its intraocular concentrations was examined. METHODS: 120 patients were recruited before cataract surgery into a prospective trial to compare the anterior chamber concentration of cefuroxime at a fixed time after administration by three routes. In a further 110 patients, the interval before sampling was varied in order to permit an examination of the kinetics of penetration. In another 10 patients, cefuroxime was given topically at the completion of surgery to assess the effect of a corneal wound on aqueous penetration. Cefuroxime concentrations were measured by high performance liquid chromatography on 0.2 ml samples of aqueous aspirated from the anterior chamber. Mean aqueous concentrations of cefuroxime for each group were compared using Student's t test. RESULTS: After 25 mg cefuroxime, mean aqueous concentrations increased in the order forniceal (< 0.1 microgram/ml) < topical (0.18 microgram/ml) < subconjunctival (2.31 microgram/ml) when sampled 12-24 minutes after administration. Aqueous concentrations of cefuroxime reached a peak between 80 and 110 minutes after both forniceal and peribulbar injection but were still rising at this time after subconjunctival injection. Topical application of 12.5 mg cefuroxime to eyes with a 10 mm corneal wound resulted in a mean aqueous concentration of 9.34 micrograms/ml. CONCLUSION: In the intact eye, only sub-conjunctival injection resulted in clinically significant aqueous concentrations of cefuroxime (> 1 microgram/ml) between 12 and 24 minutes after administration. For all routes, maximal aqueous concentrations were delayed by at least 80 minutes from administration. In the presence of a corneal wound, high aqueous levels of cefuroxime were rapidly attained after topical application.

Predicting completeness of symptom relief after major heart surgery.

The authors hypothesized that the same biopsychosocial factors that raise the risk of illness incidence would influence the speed and completeness of relief from physical symptoms during recovery following cardiac surgery. This multicenter prospective study involved 463 patients aged 35 to 69 years who underwent coronary artery bypass graft or cardiac valve surgery. Predictor data were gathered 1 to 3 days before surgery, and outcome measures were collected 6 months postoperatively. The following predictors were associated with postoperative freedom from cardiac symptoms: fewer preoperative cardiac hospitalizations; low levels of angina, dyspnea, fatigue, and sleep problems; low levels of anxiety, depression, hostility, and life-change events; and high levels of psychosocial well-being, hopefulness, overall satisfaction, and social support. The predictors of not requiring daytime bed rest because of cardiac symptoms during the 6th postoperative month were male gender, higher education, less cardiac disability preoperatively, low levels of angina, dyspnea, sleep problems, depression and fatigue, and absence of Type A behavior and of intraoperative hypotension. By using separate multiple logistic regression equations, the authors identified the variables printed in bold face as independent significant contributors to prediction. Many of the predictors are strong enough and simple enough to be used in clinical practice. Many of them may also predict recovery after acute illnesses and injuries involving other organ systems.

Endotoxin-mediated dendritic cell release from the intestine. Characterization of released dendritic cells and TNF dependence.

Dendritic cells (DC) acquire Ag in peripheral tissues and transport it to lymph nodes where they efficiently activate resting T cells. We have shown that i.v. endotoxin causes increased release of intestinal DC into lymph. In this paper we further characterize the release of DC and the properties of the released cells. A total of 50 micrograms of endotoxin injected i.v. causes an increase in DC output within 6 h that peaks between 12 and 24 h, with a maximum output of 8 to 15 times normal. At the same time lymphocyte output is markedly decreased. The increased output of DC is followed by a decrease to subnormal levels. The stimulated release of DC is almost totally blocked by a monoclonal anti-TNF-alpha Ab. A second injection of TNF-alpha does not result in further DC release. DC are not released from lymph nodes into efferent lymph by endotoxin. DC collected from lymph after endotoxin treatment show increased expression of the p55 IL-2 receptor and the OX48 Ag but otherwise resemble normal lymph DC. In functional assays they show no significant differences from normal in their ability to stimulate a MLR or to present Ags to sensitized T cells. Immunocytochemistry with the use of MRC OX62 suggests that the DC are released into lymph from the lamina propria of the small intestine. The stimulated release of DC mediated by TNF-alpha may be important in regulating Ag presentation in lymph nodes draining inflammatory sites.

An integrated behavioral medicine approach to improving care of patients with diabetes mellitus.

A detailed approach to integrating behavioral techniques into patient education, case management, and treatment evaluation of persons with diabetes mellitus is offered. The author asks a series of "what if" questions to stimulate new thinking about ways to improve patient-physician relations in overcoming problems in managing the condition, citing recent research findings in the field. Adherence to regimens, self-management, goals of an integrated diabetes program and steps along the way to achieving it, psychophysiologic mechanisms in glucose metabolism, and the function of social support are among the topics covered.

Quantifying and predicting recovery after heart surgery.

The validity of the biopsychosocial approach to the study of health and illness is reaffirmed by the prospective findings of the Recovery Study. This is a multidisciplinary examination, conducted in four teaching hospitals, of the predictors of symptoms of cardiac illness in 463 patients 6 months after coronary artery bypass or cardiac valve surgery. We found that the following preoperative measures predict freedom from cardiac symptoms 6 months after surgery: low levels of all of the following: angina pain, shortness of breath, fatigue and sleep problems, lifetime cigarette usage, and preoperative hospitalization for cardiac treatment; low levels of anxiety, depression, and hostility, and few life change events; high levels of all of the following: self-esteem, well-being, vigor; prevalence of activities and hobbies, social participation, and social support. The six variables in bold print contributed independently in a multiple regression equation that accounted for 21% of the variance of the symptoms score and was associated with an estimated 45% difference in success of recovery. The statistical strength and general nature of many of the predictors indicate that the predictors may also be important in recovery from other health crises. Psychosocial and biomedical factors correlate across time (predictively), as well as cross-sectionally, indicating that psychological, social, and biological mechanisms may be parts of a single general multifaceted process influencing recovery of health. A clinical trial could determine if psychological, social, or behavioral interventions will hasten and improve recovery from physical illness or trauma.

Effects of antihypertensive medications on quality of life in elderly hypertensive women.

The impact of antihypertensive medications on the quality of life of elderly hypertensive women has rarely been systematically evaluated in large clinical trials using drugs from the new generations of pharmaceutic preparations. We carried out a multicenter, randomized double-blind clinical trial with 309 hypertensive women aged 60 to 80 years to assess effects of atenolol, enalapril, and isradipine on measures of quality of life over a 22-week period. The patients had mild to moderate hypertension. Hydrochlorothiazide was added to treatment if monotherapy was inadequate in lowering blood pressure. At the conclusion of the trial the three drug groups did not differ in degree of reduction of diastolic blood pressure or in supplementation with hydrochlorothiazide. Over the 22-week trial, linear trend analysis showed no differences between the treatment groups in change from baseline on quality of life measures of well-being, physical status, emotional status, cognitive functioning, and social role participation. Regarding each of 33 physical side effects over the 22 weeks, we found no general difference between atenolol, enalapril, and isradipine groups on measures of change in distress over symptoms except for enalapril patients who worsened in distress over cough (P = .001) and atenolol patients who worsened in distress over dry mouth (P = .014). Centering on three medications that are relatively new additions to the armamentarium for blood pressure control, the findings underline the increasing opportunities for the physician to select drugs that can control blood pressure while maintaining the quality of life of elderly hypertensive women.

Selection and the evolution of genetic life cycles.

The evolution of haploid and diploid phases of the life cycle is investigated theoretically, using a model where the relative length of haploid and diploid phases is under genetic control. The model assumes that selection occurs in both phases and that fitness in each phase is a function of the time spent in that phase. The equilibrium and stability conditions that allow for all-haploid, all-diploid, or polyphasic life cycles are considered for general survivorship functions. Types of stable life cycles possible depend on the form of the viability selection. If mortality rates are constant, either haploidy or diploidy is the only stable life cycle possible. Departures from constant mortality can give qualitatively different results. For example, when survivorship in each phase is a linear, decreasing function of the time spent in the phase, stable haploid, diploid or polyphasic life cycles are possible. The addition of genetic variation at a coevolving viability locus does not qualitatively affect the outcome with respect to the maintenance of polyphasic cycles but can lead to situations where more than one life cycle is concurrently stable. These results show that trade-offs between the advantages of being diploid and of being haploid may help explain the patterns of life cycles found in nature and that the type of selection may be critical to determining the results.

Assessment of outcomes of health intervention.

This paper proposes that the most comprehensive current approach to the assessment of health interventions is exemplified in the expanding field of research into health-related quality of life. The paper initiates discussion of 11 conceptual and methodological issues which should be dealt with explicitly rather than by default in any such research study. Decisions about these 11 issues will shape the future directions of the field of health outcomes research. Health policy decisions will increasingly be based on outcome studies of health-related quality of life.

Relation of hostility to medication adherence, symptom complaints, and blood pressure reduction in a clinical field trial of antihypertensive medication.

The impact of hostility was examined in relation to the conduct and results of a clinical field trial. Data were derived from a multi-center randomized double-blind study of the comparative effects of antihypertensive therapy (captopril, methyldopa and propranolol) on the quality of life of 620 hypertensive men. Hostility levels were higher in subjects reporting skipping medication dosages compared to those reporting they always complied with the medication schedule. Reporting of symptoms often associated with antihypertensive drug regimens was positively related to hostility scores throughout the study, even during the blinded placebo period. Persons with high hostility scores showed the greatest decline in blood pressure independent of type of antihypertensive medication. However, there was some limited evidence that hostility levels were significantly reduced by one antihypertensive medication. Overall, the present findings suggest that double-blind pharmacologic clinical trials may benefit from using reliable measures of hostility as covariates in the evaluation of symptom reports and amount of blood pressure reduction.

A two-dimensional intervention plan to reduce risk factors for ischaemic heart disease.

Although most cardiologists and public health officials are convinced of the great value of reducing risk factors for cardiovascular diseases, efforts to reduce these factors have seldom reached effectively beyond those persons in direct touch with physicians. This paper describes nine channels which health officials can utilise to inform, motivate, and change health behaviours in the general public. The channels are: individuals, family and friends, health professionals and institutions, schools and teachers, business and labour, mass media, local organizations, community leaders, regional and national government. Using all these channels in an integrated programme to reduce multiple risk factors in the community results in a two-dimensional intervention plan in which the various components reinforce one another. Specific programmatic suggestions are made for each of the following cardiovascular risk factors: cigarette smoking, high blood pressure, lack of exercise, high serum cholesterol, and stress.

Randomised single blind trial to compare the toxicity of subconjunctival gentamicin and cefuroxime in cataract surgery.

Comparatively little attention has been paid to the conjunctival toxicity of antibiotics administered at the time of cataract surgery. We have observed the effect of subconjunctival gentamicin and cefuroxime injection, using colour photography in a randomised single blind trial of 121 patients undergoing routine cataract surgery. Our results suggest that a hyperaemic eye is likely to occur about twice as often in patients injected with gentamicin (p less than 0.001). Gentamicin is associated with more pain postoperatively (p less than 0.05). Significant manifestations of gentamicin toxicity are conjunctival oedema and capillary closure. Cefuroxime has some theoretical advantages over gentamicin in its antibacterial spectrum.