Conventional CD4+ T cells regulate IL-22-producing intestinal innate lymphoid cells.

The innate and adaptive immune systems in the intestine cooperate to maintain the integrity of the intestinal barrier and to regulate the composition of the resident microbiota. However, little is known about the crosstalk between the innate and adaptive immune systems that contribute to this homeostasis. We find that CD4+ T cells regulate the number and function of barrier-protective innate lymphoid cells (ILCs), as well as production of antimicrobial peptides (AMPs), Reg3γ and Reg3ß. RAG1-/- mice lacking T and B cells had elevated ILC numbers, interleukin-22 (IL-22) production, and AMP expression, which were corrected by replacement of CD4+ T cells. Major histocompatibility class II-/- (MHCII-/-) mice lacking CD4+ T cells also had increased ILCs, IL-22, and AMPs, suggesting that negative regulation by CD4+ T cells occurs at steady state. We utilized transfers and genetically modified mice to show that reduction of IL-22 is mediated by conventional CD4+ T cells and is T-cell receptor dependent. The IL-22-AMP axis responds to commensal bacteria; however, neither the bacterial repertoire nor the gross localization of commensal bacteria differed between MHCII+/- and MHCII-/- littermates. These data define a novel ability of CD4+ T cells to regulate intestinal IL-22-producing ILCs and AMPs.

Using epidemiological studies to check the consistency of the cancer risks predicted by high-dose animal experiments: a methodological review.

Epidemiological studies have been cited in the literature as evidence both for and against the human cancer risks predicted by high-exposure rodent studies. However, there has been little overall consistency in the ways that these animal-to-human comparisons have been made. This review examines some examples of these types of comparisons and describes the methods and techniques used by different investigators. Eleven "key decision areas" that need to be addressed are identified and recommendations for consistent, logical, and statistically appropriate approaches that might be taken to standardize the process are provided. In general, it is suggested that investigators provide the most useful information when they use logical, transparent, and statistically valid comparisons to pursue limited and focused objectives, such as directly testing the validity of an existing regulatory guidance value. Other recommendations include selecting biologically plausible extrapolative models that fit the data and drawing conclusions that are consistent with the study results and objectives.

How useful is linear regression analysis in detecting the existence of dose-response relationships in large-scale epidemiologic studies when only a fraction of the population is sensitive? The case of methylmercury.

The existence of a dose response in epidemiologic studies is generally determined from the linear regression slope after controlling for covariates. This approach assumes the entire population is equally sensitive to the toxicant and that response is a function only of dose and a random error function. However, sensitive subpopulations have been identified for a variety of toxicants possibly including methylmercury (MeHg). The study of MeHg exposure in the Seychelles Islands has failed to find significant effects (dose-response slope not significantly different from zero) while other studies have found such effects. Using data on the error function in developmental test scores and MeHg exposure distributions from that study, and assuming plausible dose-response relationships for sensitive subpopulations, we conducted Monte-Carlo simulations of the power of linear regression analysis to detect a dose-response relationship from the total sample (n=700), and to compare dose-response slopes in the total and sensitive populations. Linear regression did not reliably detect a dose-response relationship for most scenarios when sensitives were 5% of the total and for some scenarios when sensitives were 10% of the total. We also found that the dose-response slope for the total population underestimated the sensitive dose-response slope in all cases by about an order of magnitude. These findings may have important implications for detection and quantification of dose-response relationships from epidemiologic studies.

An unusual manifestation of acquired syphilis.

Bone involvement is an unusual manifestation of acquired syphilis. We report a case of clinically apparent osteitis of the skull, secondary to acquired syphilis, which was the patient's presentation of human immunodeficiency virus infection.

Stressors, personality traits, and coping of Gulf War veterans with chronic fatigue.

OBJECTIVES: preliminary surveys of Persian Gulf veterans revealed a significant prevalence of self-reported symptoms consistent with chronic fatigue syndrome (CFS). The purpose of this study was to compare self-reported life stressors, combat, and chemical exposures, personality and coping between Gulf War veterans with CFS and healthy veterans. METHODS: following a complete physical, psychiatric, and neuropsychological evaluation, 45 healthy veterans, 35 veterans with CFS and co-morbid psychiatric disorder, and 23 veterans with CFS and no co-morbid psychiatric disorder completed questionnaires assessing war and non-war-related life stressors, self-reports of environmental exposure (e.g. oil well fires, pesticides), personality, and coping. RESULTS: measures of personality, self-reported combat and chemical exposures, and negative coping strategies significantly differentiated healthy veterans from those with CFS. CONCLUSION: a biopsychosocial model of veterans' illness was supported by the fact that personality, negative coping strategies, life stress after the war, and environmental exposures during the war were significant predictors of veterans' current physical function.

Cardiovascular stress responses and their relation to symptoms in Gulf War veterans with fatiguing illness.

OBJECTIVE: The objective of this study was to examine whether inappropriate cardiovascular responses to stressors may underlie symptoms in Gulf War veterans with chronic fatigue. METHODS: Psychophysiological stress testing was performed on 51 Gulf War veterans with chronic fatigue (using the 1994 case definition of the Centers for Disease Control and Prevention) and 42 healthy veterans. Hemodynamic responses to cold pressor, speech, and arithmetic stressors were evaluated using impedance cardiography. RESULTS: Veterans with chronic fatigue had diminished blood pressure responses during cognitive (speech and arithmetic) stress tests due to unusually small increases in total peripheral resistance. The cold pressor test, however, evoked similar blood pressure responses in the chronic fatigue and control groups. Low reactivity to cognitive stressors was associated with greater fatigue ratings among ill veterans, whereas an opposite relation was observed among healthy veterans. Self-reported neurocognitive decline was associated with low reactivity to the arithmetic task. CONCLUSIONS: These results suggest a physiological basis for some Gulf War veterans' reports of severe chronic fatigue. A greater deficit with responses processed through cerebral centers, as compared with a sensory stimulus (cold pressor), suggests a defect in cortical control of cardiovascular function. More research is needed to determine the specific mechanisms through which the dissociation between behavioral and cardiovascular activities identified in this study may be contributing to symptoms in Gulf War veterans.

Medical evaluation of Persian Gulf veterans with fatigue and/or chemical sensitivity.

The purpose of this study was to determine if Gulf War veterans with complaints of severe fatigue and/or chemical sensitivity (n = 72) fulfill case definitions for chronic fatigue syndrome (CFS) and/or multiple chemical sensitivity (MCS) and to compare the characteristics of those veterans who received a diagnosis of CFS (n = 24) to a group of non-veterans diagnosed with CFS (n = 95). Thirty-three veterans received a diagnosis of CFS with 14 having MCS concurrently; an additional six had MCS but did not fulfill a case definition for CFS. The group of fatigued veterans receiving a diagnosis of CFS was comprised of significantly fewer women and fewer Caucasians than the civilian group, and significantly fewer veterans reported a sudden onset to their illness. Veterans with CFS had a milder form of the illness than their civilian counterparts based on medical examiner assessment of the severity of the symptoms, reported days of reduced activity, and ability to work. Since CFS in veterans seems less severe than that seen in civilians, the prognosis for recovery of veterans with this disorder may be better.

Physical activity before and after exercise in women with chronic fatigue syndrome.

We measured physical activity after strenuous exercise in 20 women with chronic fatigue syndrome (CFS), compared to 20 sedentary healthy volunteers who exercised no more than once per week. Activity was measured for 2 weeks using a portable waist-worn vertical accelerometer. After the first week of activity monitoring, all participants returned for a maximal treadmill test, followed by continued activity monitoring for the second week. Five activity measures were derived from the data: (i) average activity; (ii) total activity; (iii) duration of waking day; (iv) duration; and (v) number of daily rests. A repeated measures ANCOVA was used to determine post-treadmill group differences accounting for pre-treadmill differences. There was a significant reduction in overall average activity after the treadmill test, with the greatest decrease on days 12 through 14. This reduction was accompanied by a significant increase in the duration of the waking day and number of daily rests. Thus, marked exertion does produce changes in activity, but later than self-report would suggest, and are apparently not so severe that CFS patients cannot compensate.

Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis.

The purpose of this study was to evaluate the immune dysfunction hypothesis of chronic fatigue syndrome (CFS) by comparing immunologic data from patients with CFS with data from patients with other fatiguing illnesses--major depression and multiple sclerosis (MS)--and with data from healthy sedentary controls. The subjects were 65 healthy sedentary controls, 71 CFS patients (41 with no axis-I diagnosis), 23 patients with mild MS, and 21 patients with major depression. Blood was sampled and assayed for the following: (1) immunologic serologic variables--circulating immune complexes (i.e., Raji cell and C1q binding), immunoglobulins A, E, G, and M, and IgG subclasses; (2) cell surface activation markers--the proportion of CD4+ cells expressing CD45RA+ and CD45RO+ and the proportion of CD8+ cells expressing CD38+, CD11b-, HLA-DR+ and CD28+; and (3) natural killer (NK) total cell count as well as the proportion of lymphocytes expressing NK cell surface markers (i.e., CD3-/CD16+ and CD56+. Of the 18 variables studied, differences between CFS patients and controls were found only for IgG1 and IgG3. When CFS patients were stratified by the presence or absence of concurrent axis-I disease, it was the group with axis-I disorder that had the lowest IgG1 values-contrary to expectation. When data from patients with MS and major depression were also evaluated, the subclass deficiency was no longer significant. The one group to show evidence for immune activation (i.e., an elevated proportion of CD4+ cells expressing the CD45RA+ activation marker) was the group with mild MS. These data support neither immune dysfunction nor immune activation in CFS or in major depression, for the variables studied. The reductions in IgG subclasses may be an epiphenomenon of patient or control subject composition. In contrast, MS, even in the mild and early stages, as in the patients studied here, is associated with immune activation.

Relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome.

OBJECTIVES: To examine the relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome, and determine whether the relation is independent of psychiatric factors. METHODS: The subjects were 53 patients with chronic fatigue syndrome and 32 healthy controls who did not exercise regularly. Subjects were administered a structured psychiatric interview and completed questionnaires focusing on depression and functional disability. They also completed a battery of standardised neuropsychological tasks focusing on the cognitive domains that patients with chronic fatigue syndrome experience as particularly difficult: memory (verbal and visual), and attention/concentration. A test score was defined as failing when it was > or =2 SD below the mean of the healthy controls after controlling for demographic factors. RESULTS: Those patients with chronic fatigue syndrome with higher numbers of failing neuropsychological test scores reported significantly more days of general inactivity in the past month than those with fewer failing scores. This result remained significant even after partialling out the contribution of the presence of a comorbid axis I psychiatric episode and the overall level of depressive symptomology. Patients with failing verbal memory scores were particularly functionally disabled compared with those with passing scores. CONCLUSION: A relation was found between cognitive impairment and functional disability which could not be explained entirely on the basis of psychiatric factors.

Single-blind, placebo phase-in trial of two escalating doses of selegiline in the chronic fatigue syndrome.

AIM: To perform a clinical trial of selegiline in 25 patients with chronic fatigue syndrome (CFS) where patients were told they would receive placebo or active agent at different times during the 6-week trial. We chose selegiline, a specific monoamine oxidase (MAO) B receptor inhibitor, because a prior trial of lowdose phenelzine, a nonspecific MAO inhibitor, showed a small but significant therapeutic effect. METHODS: Questionnaires comprised of 19 tests of mood, fatigue, functional status and symptom severity were collected at the start and end of the trial as well as 2 weeks after its start. The trial was done in three 2-week blocks: in the first, 2 placebo pills were given per day; in the next, one 5-mg tablet of agent and one placebo were given per day, and in the last, a 5-mg tablet of agent was given twice a day. The plan was to compare the changes in the 19 tests during the placebo phase to those found in the active treatment phase in 19 patients completing the trial. FINDINGS: Significant improvement in 3 variables-tension/anxiety, vigor and sexual relations-was found. A significant pattern of improvement compared to worsening was found for the 19 self-report vehicles during active treatment as compared with placebo treatment. Evidence for an antidepressant effect of the drug was not found. CONCLUSIONS: Selegiline has a small but significant therapeutic effect in CFS which appears independent of an antidepressant effect.

The effects of fatigue on neuropsychological performance in patients with chronic fatigue syndrome, multiple sclerosis, and depression.

The effects of fatigue on neuropsychological performance were examined in patients with fatiguing illnesses. Repeated testing with the Paced Auditory Serial Addition Test (PASAT; Gronwall, 1977) was employed over the course of a demanding neuropsychological testing session. It was hypothesized that if fatigue affects performance, one would expect to observe "blunting" of the PASAT practice effect. Fifteen of the study participants live with chronic fatigue syndrome (CFS), 15 with multiple sclerosis (MS), 14 with depression (DEP), and 15 are healthy, sedentary controls. Overall PASAT performance was significantly reduced for CFS and DEP participants compared to controls, whereas mean performance did not differ across the three fatiguing illness groups. Degree of improvement across trials (i.e., practice effect) for the groups did not differ from controls'. Neither subjective fatigue or DEP were significantly related to PASAT performance. These findings suggest that fatigue does not universally impair performance during neuropsychological assessment even in groups in which fatigue is a prominent symptom.

Estimation of fish consumption and methylmercury intake in the New Jersey population.

Despite scientific attention to the toxicology of methylmercury (MeHg), little is known about population-based exposure to this compound. In this study, fish consumption and MeHg intake were estimated based on a seven-day recall survey of fish consumption among 1000 randomly selected New Jersey residents. Survey data were reported on a per-meal basis, and the fish species/dishes consumed at each meal were identified. Portion sizes for each meal were reported or estimated. To correct a possible bias due to underrepresentation of infrequent consumers, several schemes for weighting fish consumption data were investigated. MeHg concentration for most fish species was estimated from the National Marine Fisheries Service database or from recent United States Food and Drug Administration data. Commercial fish accounted for about 95% of all consumption. Mean fish consumption is estimated for all New Jersey adult consumers at 50.2 g/day (90th percentile = 107.4 g/day) and for women 18-40 years old (childbearing age) at 41.0 g/day (90th percentile = 88.1 g/day). Mean MeHg intake is estimated for all New Jersey adult consumers at 7.5 micrograms/day (90th percentile = 1.79 micrograms/day) and for women 18-40 at 6.3 micrograms/day (90th percentile = 14.8 micrograms/day). When MeHg concentrations are adjusted to account for the possible overestimation of current concentrations by the 20-year-old National Marine Fisheries Service database, it is estimated that MeHg intakes may be about 70-80% of unadjusted estimates. Based on these analyses, it is estimated that 21-30% of New Jersey women 18-40 and 5-8% of all New Jersey adults exceed their respective U.S. Environmental Protection Agency Reference Doses for MeHg. Because of uncertainty associated with the Reference Doses, exceeding the U.S. Environmental Protection Agency guidelines does not necessarily correspond to adverse effects on consumers or their fetuses.

Prevalence of and potential risk factors for symptoms associated with insecticide use among animal groomers.

Pet groomers make numerous insecticide applications during the flea season, but few studies have examined their health complaints. The Pesticide Control Program of the New Jersey Department of Environmental Protection conducted a health and safety survey of this population. All licensed pet applicators in New Jersey were contacted, as were New Jersey veterinarians listed as pet-animal practitioners by the American Veterinary Medical Association. Approximately 36% of the respondents indicated that during the 1994 flea season, they had experience at least one of the 17 symptoms associated with insecticide application. Central nervous system symptoms (headache, dizziness, or confusion) and skin symptoms (skin rash or numbness/tingling) were reported most frequently. Logistic regression results suggest that applications per season, years as an applicator, certain hygiene variables, certain classes of products, and status of applicator (veterinary vs veterinary) are potentially important risk factors.

Chromium exposure assessment of outdoor workers in Hudson County, NJ.

A large quantity of chromate chemical production waste, containing hexavalent chromium, has been used as fill at over 150 sites in Hudson County, New Jersey. One site is in a state park, and several other sites are adjacent to the park. Blood and urinary chromium levels were compared between 17 employees at the Hudson County park and 35 employees from two other state parks. A limited number of soil and personal air samples were also taken. Urinary and RBC chromium levels between the two groups were similar, even after adjusting for potentially confounding variables. The air sampling results demonstrated slightly higher chromium levels at Hudson County, but these were still very low level in nature (mean = 0.18 micrograms/m3). These results call into question the utility of chromium biomonitoring under environmental exposure conditions.

Comparative plaque removal efficacy of three toothbrushes in two independent clinical studies.

Two independent studies were conducted to evaluate and compare the clinical performance of three toothbrushes on plaque removal. Both studies were carried out under the same protocol. A total of 73 adult male and female subjects who met the inclusion/exclusion criteria completed Study I and 78 different subjects completed Study II. Subjects were initially screened for dental plaque eligibility. After plaque was scored on the facial and lingual surfaces of all natural teeth using the Rustogi, et al. index, qualifying subjects were randomly assigned to one of three groups on the basis of initial plaque scores and number of teeth. Subjects were then dismissed and scheduled to return for Visit 1 a week later, having abstained from all oral hygiene procedures for a prior 24-hour period. At Visit 1, each group was evaluated for plaque before brushing with their assigned toothbrush for sixty seconds. They were again scored for plaque after brushing. Subjects were dismissed and instructed to resume their normal routine and return to the clinical site for two more weekly visits. At each visit, a different test toothbrush was assigned to each group in a cross-over design. Plaque evaluations and brushing procedures were performed as in Visit 1 of the study. In both studies, the Colgate Precision toothbrush was significantly more effective (p < 0.01) than both the Oral-B 40 and Reach Full-Head soft toothbrushes in reducing the whole mouth plaque scores, as well as plaque at the gumline and at interproximal areas. The Oral-B 40 and Reach toothbrushes were not significantly different from each other with regard to plaque removal.

Clinical studies regarding the plaque removal efficacy of manual toothbrushes.

Two independent cross-over design studies were performed to compare two toothbrushes for their ability to remove plaque. In Study I, the Colgate Precision toothbrush was compared to the Oral-B 40 toothbrush; in Study II, the Colgate Precision toothbrush was compared to the Reach Full-Head soft toothbrush. A total of 54 and 72 adult male and female subjects who met the inclusion/exclusion criteria completed Study I and Study II, respectively. In each study, subjects refrained from brushing for 24 hours, and were screened for dental plaque on the facial and lingual surfaces of all natural teeth, using the Rustogi, et al. index. Based on mean scores and number of teeth, qualifying subjects were randomly assigned to one of two groups. Subjects were then scheduled to return one week later, having again abstained from all oral hygiene procedures for a 24-hour period. At this visit, each subject was evaluated for plaque, then brushed with his/her assigned toothbrush for sixty seconds, and was again scored for plaque after brushing. Subjects were instructed to resume their normal routine and return to the clinical site one week later. At this visit, a different test toothbrush was assigned to each group in a cross-over design. Plaque evaluations and toothbrushing procedures were again performed. In both studies, the Colgate Precision toothbrush was significantly more effective (p < 0.01) than either the Oral-B 40 toothbrush or the Reach Full-Head soft toothbrush in reducing whole mouth plaque scores, plaque scores at the gumline, and plaque scores at interproximal areas.

Refinement of the Modified Navy Plaque Index to increase plaque scoring efficiency in gumline and interproximal tooth areas.

To improve the assessment of plaque present on teeth, a new index, based on the original Modified Navy Plaque Index, has been developed. The primary modifications to the original Modified Navy Plaque Index were: (1) extending areas F (distal) and D (mesial) into the region just below the interproximal contact point, and (2) extending areas C and A so as to increase the gumline (or marginal gingiva) region. The new index assesses the amount of plaque in the tooth area bounded by the tooth contact, the free gingival margin, and mesial or distal line angles. The use of this new index enables the examiner to evaluate and record both the gumline (or marginal areas) and interproximal areas of the tooth, thus giving these an anatomical areas an increased importance. A pilot clinical assessment study was conducted to utilize this new index in evaluating the plaque removal efficacy of five manual toothbrushes. The results from this pilot study indicated that, when the new plaque scoring index was used, significant differences between pre-toothbrushing and post-toothbrushing plaque scores (as well as among toothbrush groups) could be demonstrated. Further, these differences (plaque removal efficacy) were demonstrated on an interproximal (mesial and distal) basis and a gumline (or gingival margin) basis, as well as on a whole mouth basis.

Upstream sequences required for transcription of the TFIIIA gene in Xenopus oocytes.

The DNA sequences required for efficient initiation of transcription of the Xenopus transcription factor IIIA (TFIIIA) gene were determined by microinjecting a series of deletion and linker substitution mutants into Xenopus oocyte nuclei. An upstream activating sequence, which resides between residues -283 and -238, and perhaps a second sequence between -167 and -122 preceding the transcription start site, together stimulate transcription about 30-fold. The distance between the two sequences and the distance from them to the initiation site can vary by at least 13 base pairs without loss of activity. The TFIIIA upstream sequences can stimulate transcription of other genes, for example, they stimulate transcription from the herpes thymidine kinase promoter about 30-fold.