Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations.

Immune deficiency disorders are a heterogeneous group of diseases of variable genetic aetiology. While the hallmark of immunodeficiency is susceptibility to infection, it is increasingly clear that autoimmunity is prevalent, suggestive of a more general immune dysregulation in some cases. With the increasing use of genetic technologies, the underlying causes of immune dysregulation are beginning to emerge. Here we provide a review of the heterozygous mutations found in the immune checkpoint protein CTLA-4, identified in cases of common variable immunodeficiency disorders (CVID) with accompanying autoimmunity. Study of these mutations provides insights into the biology of CTLA-4 as well as suggesting approaches for rational treatment of these patients.

CD4 T cell differentiation in type 1 diabetes.

Susceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.

Clinical impact of DVH uncertainties.

Dose-volume histograms (DVH), along with dose and volume metrics, are central to radiotherapy planning. As such, errors have the potential to significantly impact the selection of appropriate treatment plans. Dose distributions that pass tests in one TPS may fail the same tests when transferred to another, even if using identical structures and dose grid information. This work shows the design and implementation of methods for assessing the accuracy of dose and volume computations performed by treatment planning systems (TPS), and other analytical tools. We demonstrate examples where differences in calculations between systems can change the assessment of a plan's clinical acceptability. Our work also provides a more detailed DVH analysis of single targets than earlier published studies. This is relevant for SRS plans and small structure dose assessments. Very small structures are a particular problem because of their coarse digital representation, and the impact of this is thoroughly examined. Reference DVH curves were derived mathematically, based on Gaussian dose distributions centered on spherical structures. The structures and dose distributions were generated synthetically, and imported into RayStation, MasterPlan, and ProKnow. Corresponding DVHs were analytically derived and taken as ground truth references, for comparison with the commercial DVH calculations. Two commonly used dose metrics PCI and MGI were used to determine the limit of calculation accuracy for small structures. In addition, to measure the DVH differences between a larger range of commercial DVH calculators, the D95 metric from a set of real clinical plans was compared across both the 3 DVH calculators under test, and across a further six TPSs from other hospitals. We show that even slight deviations between the results of DVH calculators can lead to plan check failures, and we illustrate this with the commonly used D95 planning metric. We present clinical data across eight planning systems that highlight instances where plan checks would pass in one software and fail in another due to DVH calculation differences. For the smallest volumes tested, errors of up to 20% were observed in the DVHs. RayStation was tested down to a 3 mm radius sphere (≈0.1 cc) and this showed close to 10% error, reducing to 1% for 10 mm radius (≈4.0 cc) and 0.1% for 20 mm radius (≈33 cc). In clinical plans, the variation in D95 was up to 9% for the smallest volumes, and typically around 2% in the range 0.5 cc-20 cc, and 1% in 20 cc-70 cc, falling to <0.1% for large volumes. Paddick Conformity Index (PCI) and Modified Gradient Index (MGI) are commonly used plan quality indicators for very small volumes. For volumes ≈0.1 cc we observed errors of up to 40% in PCI, and up to 75% in MGI. Our study extends the range of tested DVH calculators in published work, and shows their performance over a wider range of volume sizes. We provide quantitative evidence of the critical need to test the accuracy of DVH calculators in the TPS before clinical use. This work is particularly relevant for both stereotactic plan evaluation and for assessment of small volume doses in published dose constraint recommendations. We demonstrate that significant errors can occur in DVHs for volumes less than 1 cc, even if the volumes themselves are calculated accurately. Even for large structures, deviations between the outputs of DVH calculators can lead to indicated or reported plan check failures if they do not include appropriate tolerances. We urge caution in the use of DVH metrics for these very small volumes and recommend that appropriate DVH uncertainty tolerances are set in organ dose constraints when using them to evaluate clinical plans.

Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers.

Mice rendered deficient in CD28 signaling by the soluble competitor, cytotoxic T lymphocyte-associated molecule 4-immunoglobulin G1 fusion protein (CTLA4-Ig), fail to upregulate OX40 expression in vivo or form germinal centers after immunization. This is associated with impaired interleukin 4 production and a lack of CXC chemokine receptor (CXCR)5 on CD4 T cells, a chemokine receptor linked with migration into B follicles. Germinal center formation is restored in CTLA4-Ig transgenic mice by coinjection of an agonistic monoclonal antibody to CD28, but this is substantially inhibited if OX40 interactions are interrupted by simultaneous injection of an OX40-Ig fusion protein. These data suggest that CD28-dependent OX40 ligation of CD4 T cells at the time of priming is linked with upregulation of CXCR5 expression, and migration of T cells into B cell areas to support germinal center formation.

Stressful life events and somatic complaints in adolescents.

Although life stress has often been associated with recurrent pain in children and adolescents, level of stress has not previously been found useful in differentiating patients with functional pain from those in whom other conditions are diagnosed. In this study, a standard measure of stressful life events was systematically administered to 172 adolescents seen for the first time at an outpatient adolescent clinic. Patients with recurrent pain for which no organic etiology could be identified reported significantly higher life stress than patients being seen for routine checkup, acute minor illness, stable chronic illness, or pain with clinically diagnosed organic cause. Furthermore, patients referred for behavior problems indicated significantly higher life stress than all other patient groups. It is suggested that a measure of stressful life events may be a useful adjunct to the clinical interview and is of particular value in identifying specific stressors and planning treatment to address them.

Cystic fibrosis and family stress: effects of age and severity of illness.

Stress and adjustment in mothers of children with cystic fibrosis was compared with that in a control group of mothers of healthy children. Mothers of children in four age groups were included: preschool, middle childhood, early adolescence, and late adolescence. Mothers of children with cystic fibrosis did not report significantly higher levels of stress than did the control group mothers; nor did they report greater feelings of inadequacy as parents. However, mothers of children with cystic fibrosis in two age groups, preschool and early adolescence, scored higher on a measure of depression than did mothers of healthy children in the same age groups. The relationship of illness severity to maternal stress and adjustment was examined in the cystic fibrosis group. The mother's subjective rating of the child's illness severity was a better indicator of her reported stress than was the Schwachman clinical rating. It appears that many mothers are able to adapt to the presence of cystic fibrosis in the family, although certain periods in the child's life and perceived increases in illness severity are associated with increased maternal distress.

Clozapine's functional mesolimbic selectivity is not duplicated by the addition of anticholinergic action to haloperidol: a brain stimulation study in the rat.

This study examined whether the anticholinergic potency of the clinically superior antipsychotic drug clozapine contributes to clozapine's anatomically-selective functional inhibition of the mesolimbic dopamine (DA) system, using an electrical brain-stimulation reward (BSR) paradigm in rats that has been previously shown to be highly sensitive to clozapine's mesolimbic functional selectivity. Rats were chronically administered saline, clozapine, haloperidol, or haloperidol plus the anticholinergic compound trihexyphenidyl, and threshold sensitivity of the mesolimbic and nigrostriatal DA systems was assessed using the BSR paradigm, to infer degree of functional DA blockade produced by the chronic drug regimens. Chronic saline produced no change in either DA system. Congruent with previous findings, chronic clozapine powerfully inhibited the mesolimbic DA system but spared the nigrostriatal DA system. Also congruent with previous findings, chronic haloperidol powerfully inhibited both DA systems. Compared to chronic haloperidol alone, chronic haloperidol plus chronic trihexyphenidyl exerted diminished anti-DA action in both the mesolimbic and nigrostriatal DA systems. These results suggest that clozapine's anticholinergic potency is not an adequate explanation for its functional mesolimbic selectivity.

Relation of alcohol expectancies to changes in problem drinking among college students.

OBJECTIVE: To evaluate the relation between alcohol expectancies and problem drinking during 3 years of college. DESIGN: Cohort with 3-year follow-up. SETTING: Private university campus. PARTICIPANTS: A random sample of 260 students entered a longitudinal study of alcohol use at the beginning of their freshman year. One hundred eighty-four students completed follow-up measures at the end of their junior year. Respondents were 90% white, with a mean (+/-SD) age of 17.9 +/- 0.5 years. INTERVENTIONS: None. MAIN OUTCOME MEASURES: A standardized measure of expectations and subjective evaluations of outcomes associated with drinking, quantity and frequency of alcohol use, and a composite measure of alcohol-related problems. RESULTS: Students were divided into nondrinking, low-risk, and high-risk groups for problem drinking. A repeated-measures multivariate analysis of variance indicated significant interaction effects for risk group by expectancy scale (P < .009) and for expectancy scale by time (P < .001). The three risk groups differed significantly from each other on positive outcome expectations at entry into college and positive expectations and negative outcome evaluations at the end of the junior year. Students who became problem drinkers during college had significantly higher positive outcome expectation scores at both times and developed less concern for negative outcomes by the end of their junior year. The few initial problem drinkers who moderated their drinking during college demonstrated an increased concern for negative outcomes by their junior year. CONCLUSIONS: Alcohol expectancies are associated with differing patterns of alcohol use and are longitudinally related to subsequent changes in alcohol use and problem drinking.

Longitudinal evaluation of a screening measure for problem drinking among female college freshmen.

OBJECTIVE: A previous study suggested that combining the CAGE (cutting down of drinking, feeling annoyed by criticisms of drinking, feeling guilty about something that happened because of drinking, having an eye-opener) questionnaire with the Perceived-Benefit-of-Drinking Scale, an adolescent's use of tobacco, the age at which an adolescent first started drinking, and an adolescent's best friend's drinking pattern is a useful composite screening measure for problem drinking among adolescents. The present study was undertaken to evaluate prospectively this composite screening measure as a predictor of subsequent problem drinking among college women during their freshman year. DESIGN: Cross-sectional. SETTING: Private university student health service. PARTICIPANTS: A random sample of 248 college freshman women entered a longitudinal study of alcohol use at the beginning of their freshman year. One hundred twenty (48%) completed follow-up measures of alcohol use at the end of the year. Respondents were 90% white, with a mean age of 17.9 years (SD = 0.5 years). MAIN OUTCOME MEASURES: An index of the quantity and frequency of alcohol use and a composite measure of specific alcohol-related problems. RESULTS: The CAGE questionnaire score, the Perceived-Benefit-of-Drinking Scale score, the student's tobacco use, the student's best friend's drinking pattern, and the age at which the student first started drinking as reported at the beginning of the year together explained 38% of the variance in subsequent drinking habits and 26% of the variance in alcohol-related problems reported during the freshman year. Use of the composite screening measure significantly increased sensitivity and specificity beyond that obtained with the CAGE questionnaire or the Perceived-Benefit-of-Drinking Scale alone for problem drinking. CONCLUSIONS: The CAGE questions, the Perceived-Benefit-of-Drinking Scale, the student's tobacco use, the student's best friend's drinking pattern, and the age at which the student first started drinking may together constitute a clinically useful screening measure for subsequent problem drinking among female college freshmen.

Recurrent abdominal pain in children: psychiatric diagnoses and parental psychopathology.

Approximately 12% of children report recurrent episodes of abdominal pain. In only about 10% of these cases, however, can an organic etiology be identified, and therefore it often is assumed that these children have emotional problems. To test this hypothesis, children with recurrent abdominal pain (RAP) with no identifiable organic cause were compared to children with an organic diagnosis for their abdominal pain, children with psychiatric disorders, and healthy controls. Both groups of children with abdominal pain had significantly more psychiatric disorders (predominantly anxiety and depression) than did the healthy group. Both RAP and psychiatric children had significantly higher Child Behavior Checklist internalizing scores; psychiatric children were rated as significantly more maladjusted on the Children's Global Assessment Scale. Mothers of RAP children were significantly more anxious than mothers of organic pain and healthy children. Psychiatric children were significantly more likely than the other three groups to underreport their psychiatric symptoms relative to their mothers.

Somatic complaints in pediatric patients: a prospective study of the role of negative life events, child social and academic competence, and parental somatic symptoms.

This prospective study of 197 pediatric patients with chronic abdominal pain examined the role of negative family life events and several potential moderator variables (child social and academic competence, parental somatic symptoms, and child sex) in child somatic complaints 1 year after a clinic visit. Results indicated that (a) among children low in social competence at the time of the initial clinic visit, higher levels of subsequent negative life events predicted higher levels of somatic complaints at follow-up; (b) among boys in families with high levels of negative life events, those whose mothers were characterized by high levels of somatic symptoms had higher levels of somatic complaints at follow-up; and (c) children whose fathers were characterized by high levels of somatic symptoms showed higher levels of somatic complaints at follow-up, regardless of the level of life events. Possible mechanisms accounting for these findings are discussed.

The relation of daily stressors to somatic and emotional symptoms in children with and without recurrent abdominal pain.

Prior investigations of the relation between stressors and symptoms in children with recurrent abdominal pain (RAP) have focused on major negative life events. This study used consecutive daily telephone interviews to assess daily stressors and symptoms in 154 pediatric patients with RAP and 109 well children. Results showed that patients with RAP reported more frequent daily stressors than well children reported both at home and at school. Idiographic (within-subject) analyses indicated that the association between daily stressors and somatic symptoms was significantly stronger for patients with RAP than for well children. In contrast, the relation between daily stressors and negative affect did not differ between the groups. The relation between daily stressors and somatic symptoms was stronger for patients with RAP who had higher levels of trait negative affectivity.

Psychosocial correlates of recurrent childhood pain: a comparison of pediatric patients with recurrent abdominal pain, organic illness, and psychiatric disorders.

Pediatric patients with recurrent abdominal pain (RAP) were compared with patients with peptic disease, patients with emotional disorders, and well children with regard to (a) emotional and somatic symptoms and (b) theoretically derived variables, including negative life events, competence, family functioning, and the modeling and encouragement of illness behavior. RAP patients had levels of emotional distress and somatic complaints higher than those of well children and lower than those of psychiatric patients, but not different from those of patients with peptic disease. RAP patients had fewer negative life events, better family functioning, and higher competence than children with emotional disorders. In comparison with well children and psychiatric patients, both RAP and peptic disease patients had a higher incidence of illness in other family members and perceived greater parental encouragement of illness behavior for abdominal symptoms.

Chromium picolinate effects on body composition and muscular performance in wrestlers.

PURPOSE: The purpose of this study was to assess the effects of 14 wk of chromium picolinate supplementation during the final 16 wk of a preseason resistance and conditioning program on body composition and neuromuscular performance in NCAA Division I wrestlers. During this phase of training, wrestlers are primarily interested in trying to improve physical performance and wrestling technique and are not engaged in severe, acute weight loss practices commonly employed before competition. METHODS: This double-blinded, randomized placebo-controlled study involved 20 wrestlers from the University of Oklahoma assigned to either a treatment group (Cr+3; N = 7; 20.4 yr +/- 0.1) receiving 200 micrograms chromium picolinate daily, a placebo group (P; N = 7; 19.9 yr +/- 0.2), or a control group (C; N = 6; 20.2 yr +/- 0.1) using a stratified random sampling technique based on weight classification. Body composition, neuromuscular performance, metabolic performance, and serum insulin and glucose were measured before and immediately following the supplementation and training period. RESULTS: Repeated measures ANOVA indicated no significant changes in body composition for any of the groups. Aerobic power increased significantly (P < 0.002) in all groups, independent of supplementation. There were significant trial and group x trial interactions for upper body endurance (P = 0.038) and relative bench press power (P = 0.050). Post-hoc analyses revealed that the C group increased upper body endurance (P = 0.006), but none of the pre- to post-test changes in bench press power were significant. CONCLUSIONS: These results suggest that chromium picolinate supplementation coupled with a typical preseason training program does not enhance body composition or performance variables beyond improvements seen with training alone.

Concurrent and prospective screening for problem drinking among college students.

PURPOSE: Previous studies suggest that combining the CAGE questionnaire with the Perceived Benefit of Drinking Scale (PBDS), information about an adolescent's use of tobacco, and best friend's drinking pattern is a useful composite screening measure for problem drinking. The present study was undertaken to evaluate this composite screening measure prospectively as a predictor of subsequent problem drinking among late adolescents across 3 years of college. METHODS: A random sample of 452 college freshmen entered a longitudinal study of alcohol use at the beginning of their freshman year. A total of 184 (58%) completed follow-up measures of alcohol use 32 months later. Outcome measures included the quantity and frequency of alcohol use and a composite measure of specific alcohol-related problems. RESULTS: CAGE scores, PBDS scores, tobacco use, and best friend's drinking patterns as reported at college entry together explained 33% of the variance in the quantity/frequency measure and 37% of the variance in the alcohol-related problems measure from the end of the junior year. These same variables as reported at the end of the junior year explained 50% of the variance in the quantity/frequency measure and 61% of the variance in the alcohol-related problems measure. The composite screening measure as reported at college entry had a sensitivity of 73%, specificity of 70%, positive predictive value (PPV) of 63%, and negative predictive value (NPV) of 78% for students at high risk for problem drinking at the end of the junior year. A similar concurrent composite screening measure consisting of the same variables reported at the end of the junior year had a sensitivity of 88%, specificity of 56%, PPV of 60%, and NPV of 83% for high-risk drinkers. A total of 70-73% of students could be correctly categorized by each composite screening measure. These composite screening tests had significantly better test characteristics than the CAGE or PBDS alone. CONCLUSIONS: College students' responses to the CAGE, PBDS, tobacco use, and their friends' drinking remain consistent over 3 years and correlate with concurrent and future risk for problem drinking. These variables explain significant variance in drinking and alcohol-related problems and may constitute a useful screening measure for current and future problem drinking.

Relationship of alcohol expectancies to problem drinking among college women.

PURPOSE: To evaluate the stability of expectancies about alcohol and their ability to prospectively explain drinking patterns and the occurrence of alcohol-related problems among college freshman women. METHODS: College women (n = 120) completed a standardized measure of expectations and subjective evaluations of positive and negative outcomes associated with drinking and a questionnaire assessing drinking patterns and common alcohol-related problems at both the beginning and end of the school year. Ninety percent of the students were Caucasian with a mean age of 17.9 years (SD = 0.5). RESULTS: Students' positive and negative outcome expectations and their subjective evaluations at the beginning of the year were significantly correlated with drinking patterns at the end of the year (p's < .05). During the year, students at low risk for problem drinking developed stronger positive attitudes toward the effects of alcohol upon courage, became less concerned about potential behavioral impairment, and perceived less negative effects upon self-perception. High risk students showed a significant decline in their positive attitudes toward the effects of alcohol upon their sociability. Expectancies about alcohol at the beginning of the school year explained 33% of variance in subsequent drinking (F = 6.17; p < .0004) and 20% of the variance in alcohol-related problems occurring during the year (F = 3.26; p < .02). Outcome evaluation scales at the beginning of the year explained more variance in subsequent drinking and alcohol-related problems than did outcome expectation scales. CONCLUSIONS: Alcohol outcome expectations and their subjective evaluations were relatively stable across the freshman year for these college women. Alcohol expectancies on entry into college explained significant amounts of variability in drinking behavior and the occurrence of alcohol-related problems during the subsequent freshman year. Students' attitudes toward perceived outcomes may be more important than the perceived likelihood of the outcomes themselves.

Screening for problem drinking among college freshmen.

PURPOSE: This study identified predictors of older adolescents at risk for problem drinking. METHODS: College freshmen (n = 492) completed a questionnaire that addressed drinking patterns, risk factors for problem drinking, the CAGE questions, the Perceived-Benefit-of-Drinking Scale (PBDS), and the Children of Alcoholics Screening Test (CAST). They also responded to questions regarding alcohol-related problems including blackouts; alcohol-related injury, illness, violence, or legal problems; driving under the influence; and missing class. 50% of students were male with a mean age of 17.9 years (SD = 0.5). RESULTS: Higher scores on the CAGE and PBDS, use of tobacco, best friend's drinking pattern, and younger age at first drinking were associated with higher scores on a quantity/frequency drinking index and with reports of significantly more alcohol-related problems. Regression models using these variables explained 40% to 51% of the variance in drinking habits and alcohol-related problems. CONCLUSION: A composite screening measure had significantly better sensitivity and specificity than either the CAGE or PBDS alone in identifying older adolescents at high risk for problem drinking.

Alcohol expectancies, problem drinking, and adverse health consequences.

This study evaluated a measure of positive and negative expected effects of alcohol and their subjective evaluation in the identification of college freshmen at high risk for problem drinking and associated morbidities. It was hypothesized that greater expectations of positive outcomes and fewer negative evaluations of negative outcomes would be associated with reports of heavier drinking and more alcohol-related health problems. College freshmen (n = 328) completed a standardized measure of expectations and subjective evaluations of positive and negative outcomes associated with drinking, and a questionnaire assessing drinking patterns and common alcohol-related health problems. Fifty-two percent of students were male and the mean age was 17.9 years (SD = 0.5). Students' expectations of positive outcomes and their subjective evaluations of both positive and negative outcomes from drinking were significantly correlated with drinking and alcohol-related health problems indices (p < 0.001). Gender, expectation of positive outcomes, and evaluation of negative outcomes explained 29% of the variance in drinking and 15% of the variance in alcohol-related health problems indices. Heavier-drinking students and those reporting more health problems expected more positive effects on their sociability and sexuality (p < 0.03) and were less concerned about cognitive and behavioral impairment as a result of drinking (p < 0.001). Students with more health problems were less concerned that drinking would lead to risk-taking or aggressive behavior (p < 0.003). Positive and negative outcome expectancies and their subjective evaluations accounted for a significant portion of the variability in drinking and alcohol-related health problems.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychosomatic problems and stress in adolescence.

Psychosomatic problems are common in adolescents, and stress frequently plays a role in their development and maintenance. Armed with an understanding of the stressors experienced by adolescents, the individual's vulnerabilities and competencies and their level of social support, the physician can systematically assess each of these factors. Once the assessment is complete, a management plan can be formulated to address the particular psychosomatic problem. Symptom relief, stress reduction, and promotion of competence are important interventions that can be initiated by the primary care physician. When referrals are made for counseling and other stress management techniques, the primary care physician should maintain contact with the patient and family and remain an integral part of the management team. Incorporating brief discussions about the potential role of stress in health and illness into anticipatory guidance sessions may also help prevent the development of psychosomatic problems in adolescents.

Somatization symptoms in pediatric abdominal pain patients: relation to chronicity of abdominal pain and parent somatization.

Symptoms of somatization were investigated in pediatric patients with recurrent abdominal pain (RAP) and comparison groups of patients with organic etiology for abdominal pain and well patients. Somatization scores were higher in RAP patients than well patients at the clinic visit, and higher than in either well patients or organic patients at a 3-month followup. Higher somatization scores in mothers and fathers were associated with higher somatization scores in RAP patients, but not in organic or well patients. Contrary to the findings of Ernst, Routh, and Harper (1984), chronicity of abdominal pain in RAP patients was not significantly associated with their level of somatization symptoms. Psychometric information about the Children's Somatization Inventory is presented.