Rate of tuberculosis infection in children and adolescents with household contact with adults with active pulmonary tuberculosis as assessed by tuberculin skin test and interferon-gamma release assays.

Tuberculosis (TB) infection was evaluated in Brazilian immunocompetent children and adolescents exposed and unexposed (control group) to adults with active pulmonary TB. Both groups were analysed by clinical and radiological assessment, TST, QFT-IT and T-SPOT.TB. The three tests were repeated after 8 weeks in the TB-exposed group if results were initially negative. Individuals with latent tuberculosis infection (LTBI) were treated and tests were repeated after treatment. Fifty-nine TB-exposed and 42 controls were evaluated. Rate of infection was 69·5% and 9·5% for the exposed and control groups, respectively. The exposed group infection rate was 61% assessed by TST, 57·6% by T-SPOT.TB, and 59·3%, by QFT-IT. No active TB was diagnosed. Agreement between the three tests was 83·1% and 92·8% in the exposed and control groups, respectively. In the exposed group, T-SPOT.TB added four TB diagnoses [16%, 95% confidence interval (CI) 1·6-30·4] and QFT-IT added three TB diagnoses (12%, 95% CI 0-24·7) in 25 individuals with negative tuberculin skin test (TST). Risk factors associated to TB infection were contact with an adult with active TB [0-60 days: odds ratio (OR) 6·9; >60 days: OR 27·0] and sleeping in the same room as an adult with active TB (OR 5·2). In Brazilian immunocompetent children and adolescents, TST had a similar performance to interferon-gamma release assays and detected a high rate of LTBI.

Whole-body magnetic resonance imaging in the assessment of muscular involvement in juvenile dermatomyositis/polymyositis patients.

OBJECTIVES: Our aim was to demonstrate the benefit of whole-body magnetic resonance imaging (WBMRI) as a diagnostic modality in the detection of muscle activity in juvenile dermatomyositis (JDM)/polymyositis (JPM) patients and to correlate these findings with clinical evaluation, laboratory examinations, nailfold capillaroscopy (NFC), and muscle biopsy. METHOD: Thirty-four patients aged 5.5 to 18.9 years with a diagnosis of JDM/JPM were prospectively evaluated using clinical examination, muscle enzyme determination, the Childhood Myositis Assessment Scale (CMAS), Disease Activity Score (DAS), Manual Muscle Testing (MMT), NFC, and WBMRI. An open muscle biopsy was performed if muscle disease activity was detected on WBMRI. RESULTS: Disease activity was detected in WBMRI in four (11.7%) patients and confirmed by muscle biopsy. All four patients had elevation of at least one muscle enzyme and NFC showed scleroderma patterns in these patients. CONCLUSIONS: WBMRI allows us to evaluate the extent and symmetry of muscle disease and inflammatory activity. NFC is an important additional examination to assess disease activity.

Longitudinal relationship of early life immunomodulatory T cell phenotype and function to development of allergic sensitization in an urban cohort.

BACKGROUND: Immunomodulatory T cells are thought to influence development of allergy and asthma, but early life longitudinal data on their phenotype and function are lacking. OBJECTIVES: As part of the Urban Environment and Childhood Asthma (URECA) study, we investigated the development of immunomodulatory T cell phenotype and function, and characterized their relation to allergic disease progression from birth through to 2 years of age. METHODS: Immunomodulatory T cell phenotype and function in cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) at 1 and 2 years of age were characterized by analysing CD25(bright) and FoxP3(+) expression, proliferative responses and cytokine production. The relation of immunomodulatory T cell characteristics to allergic sensitization and disease at 1- and 2-years of age was investigated. RESULTS: The proportion of CD4(+)CD25(bright) and CD4(+)CD25(+)FoxP3(+)T cells (n = 114, 83, 82 at birth, 1- and 2-years respectively) increased significantly, whereas there were no significant changes in the suppressive function of CD25(+)T cells (n = 78, 71, 81 at birth, 1- and 2-years respectively). Birth immunomodulatory T cell characteristics were not related to subsequent allergic sensitization or disease. However, increases in the numbers of CD4(+)CD25(bright) cells and their ability to suppress lymphoproliferative responses at 1 year of age were associated with reduced allergic sensitization at 1 (P = 0.03) and 2 (P = 0.02) years of age. Production of the anti-inflammatory cytokine IL-10 by CD25(+)T cells appeared to mediate this protective suppressive function. In contrast, by 2 years of age, we observed the emergence of a positive association of CD4(+)CD25(+) FoxP3(+) T cell numbers with allergic sensitization (P = 0.05) and eczema (P = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that the relationship between immunomodulatory T cell subsets, allergic sensitization and eczema is developmentally regulated. In the first year of life, CD4(+)CD25(+) IL-10 producing T cells are associated with a reduced incidence of allergic sensitization. Once allergic sensitization or eczema is established, CD4(+)CD25(+)FoxP3(+)T-reg cells expand to potentially counteract the allergic inflammatory response. Understanding the relationship between development of immunoregulatory T cells and early onset atopy could lead to new preventive strategies for allergic diseases.

The role of orexigenic and anorexigenic factors in an interdisciplinary weight loss therapy for obese adolescents with symptoms of eating disorders.

AIM: The aim of this study was to evaluate the role of orexigenic and anorexigenic factors in an interdisciplinary weight loss therapy for obese adolescents with symptoms of eating disorders. METHODS: Thirty-seven post-pubertal, obese adolescents (14 to 19 years old) with symptoms of eating disorders were submitted to long-term interdisciplinary therapy (1 year). Bulimic and binge eating symptoms were measured using the Bulimic Investigatory Test, Edinburgh, and the Binge Eating Scale respectively. Neuropeptide Y, melanin-concentrating hormone, total ghrelin, alpha-melanocyte stimulating hormone and leptin were measured using radioimmunoassay. RESULTS: After long-term interdisciplinary therapy, the adolescents showed significantly improved body composition, visceral and subcutaneous fat and reduced symptoms of bulimia and binge eating. Intriguingly, orexigenic peptides were up-regulated after short-term therapy and down-regulated at the end of therapy, whereas the anorexigenic pathway was improved with therapy. Furthermore, after long-term therapy, a negative correlation was observed between leptin concentration and melanin-concentrating hormone. DISCUSSION: We suggest that long-term therapy promotes an intrinsic association between weight loss, improvement of eating disorder symptoms and a decrease in orexigenic factors. Together, these results represent a more effective course by which patients can normalise behaviours related to eating disorders as well the actions of hormones involved in energy balance, and thus advance obesity control. CONCLUSION: Long-term interdisciplinary therapy was effective to improve anorexigenic and orexigenic factors that influence energy balance and avoid the development of eating disorders in obese adolescents. However, the associations between eating disorders and neuroendocrine factors need to be confirmed in future studies.

Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1.

The purified human immunodeficiency virus type-l (HIV-l) Tat protein inhibited lymphocyte proliferation induced by tetanus toxoid or Candida antigens by 66 to 97% at nanomolar concentrations of Tat. In contrast, Tat did not cause a significant reduction of lymphocyte proliferation in response to mitogens such as phytohemagglutinin or pokeweed mitogen. Inhibition was blocked by oxidation of the cysteine-rich region of Tat or by incubation with an antibody to Tat before the assay. A synthetic Tat peptide (residues 1 to 58) also inhibited antigen-stimulated proliferation. Experiments with H9 and U937 cell lines showed that Tat can easily enter both lymphocytes and monocytes. The specific inhibition of antigen-induced lymphocyte proliferation by Tat mimics the effect seen with lymphocytes from HIV-infected individuals and suggests that Tat might directly contribute to the immunosuppression associated with HIV infection.

An essential role for BLNK in human B cell development.

The signal transduction events that control the progenitor B cell (pro-B cell) to precursor B cell (pre-B cell) transition have not been well delineated. In evaluating patients with absent B cells, a male with a homozygous splice defect in the cytoplasmic adapter protein BLNK (B cell linker protein) was identified. Although this patient had normal numbers of pro-B cells, he had no pre-B cells or mature B cells, indicating that BLNK plays a critical role in orchestrating the pro-B cell to pre-B cell transition. The immune system and overall growth and development were otherwise normal in this patient, suggesting that BLNK function is highly specific.

Relationship between nonalcoholic fatty liver disease prevalence and visceral fat in obese adolescents.

BACKGROUND: Visceral adiposity is the major risk factor for paediatric nonalcoholic fatty liver disease. AIMS: Determine the prevalence of nonalcoholic fatty liver disease according to the visceral fat quartile. SUBJECTS: 181 obese adolescents including 113 girls (16.58+/-1.56 years) and 68 boys (16.87+/-1.62 years) were evaluated. METHODS: The inclusion criteria were obesity and post-pubertal stage of Tanner. Visceral fat of obese adolescents was distributed in quartiles after ultrasound nonalcoholic fatty liver disease diagnosis. RESULTS: Nonalcoholic fatty liver disease prevalence was 45.30%. It was observed that 62.07% and 76.47% of girls and boys with nonalcoholic fatty liver disease were found in the 4th quartile. In a multivariate logistic analysis it was observed that only visceral fat remained statistically significant, every 1cm increase in visceral fat was associated with a 1.97 fold (95% CI 1.06-3.66) in boys and 2.08 fold (95% CI 1.38-3.13) in girls increased risk to develop nonalcoholic fatty liver disease. Indeed it was verified a positive correlation between visceral fat, body mass index, insulin levels, homeostasis model assessment insulin resistance index and steatosis degree. CONCLUSIONS: Our findings suggested that the expansion of visceral fat was a determinant factor to increase nonalcoholic fatty liver disease prevalence and the visceral fat measured by ultrasound might be a good predictor to identify risk for nonalcoholic fatty liver disease in obese adolescents. It was confirmed by a stronger correlation between visceral fat and body mass index.

JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome.

X-linked autoimmunity-allergic disregulation syndrome (XLAAD) is an X-linked recessive immunological disorder characterized by multisystem autoimmunity, particularly early-onset type 1 diabetes mellitus, associated with manifestations of severe atopy including eczema, food allergy, and eosinophilic inflammation. Consistent with the allergic phenotype, analysis of two kindreds with XLAAD revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, we have identified in both kindreds mutations in JM2, a gene on Xp11.23 that encodes a fork head domain-containing protein. One point mutation at a splice junction site results in transcripts that encode a truncated protein lacking the fork head homology domain. The other mutation involves an in-frame, 3-bp deletion that is predicted to impair the function of a leucine zipper dimerization domain. Our results point to a critical role for JM2 in self tolerance and Th cell differentiation.

Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. ACTG 375 team. AIDS Clinical Trials Group.

OBJECTIVES: To ascertain if immunization results in the restoration of responses to recall antigens, in the development of responses to presumed neoantigens, and to identify the virologic and immunologic correlates of these responses in persons with HIV-1 infection. DESIGN AND SETTING: Open-label study carried out at three university-affiliated AIDS Clinical Trials Units in the United States. SUBJECTS AND METHODS: Thirty-one subjects participating in AIDS Clinical Trials Group Protocol 375 who had received zidovudine, lamivudine, and ritonavir for at least 48 weeks. Subjects were immunized with tetanus toxoid (TT) at entry and with inactivated hepatitis A vaccine (hep A) and keyhole limpet hemocyanin (KLH) at entry and 6 weeks. The development of antibody, lymphocyte proliferative assay (LPA), and delayed-type hypersensitivity (DTH) responses after immunization were monitored. RESULTS: The LPA and DTH responses to TT improved in 57 and 68% of participants, respectively; 73 and 65% developed enhanced LPA and DTH responses to KLH. Forty-eight percent of patients developed a four-fold increase in antibody concentration to tetanus. Seventy-three percent of patients without detectable hepatitis A antibodies at baseline developed antibodies after immunization. Eighty-three percent of patients experienced at least a four-fold rise in KLH antibody concentration. Immune activation and viral load predicted poor recall responses and the number of memory CD4+ T-cells predicted good responses to recall antigens. Naïve CD4+ T-cell numbers, decrease in viral load, increases in CD4+ and CD28+ cells, and decreases in immune activation were associated with responses to presumed neoantigens. CONCLUSIONS: Most HIV-infected patients treated with potent combination antiretrovirals develop responses to recall and presumed neoantigens after immunization. Functional immune restoration in response to immunization is related to control of viral replication, decreased immune activation as well as to both quantitative and qualitative restoration of circulating T- lymphocyte subpopulations.

X-linked agammaglobulinemia: an analysis of 96 patients.

We have defined the clinical presentation and course of X-linked agammaglobulinemia (X-LA) by means of a multi-center retrospective survey of 96 patients. Infections were the most common presenting feature of patients with X-LA. The most frequent infections involved the upper respiratory tract (75%), lower respiratory tract (65%), gastrointestinal tract (35%), skin (28%), and central nervous system (16%). Clinical clues to the diagnosis of X-LA were the chronic or recurrent nature of infections, a family history of immunodeficiency, and infections at more than one anatomic location. Infections remained a significant problem after the diagnosis of X-LA was made and gamma-globulin prophylaxis had been instituted. One or more chronic infectious diseases occurred in 71% of patients. The respiratory tract was the most common site of disease, and the gastrointestinal tract was relatively spared. Patients died at a mean age of 17 years. The two major causes of death were chronic pulmonary disease with resultant cardiac failure, and disseminated viral infections which characteristically caused a dermatomyositis-like syndrome, hepatitis, pneumonitis, and meningoencephalitis.

Oligo-/monoclonal gammopathy and hypergammaglobulinemia in ataxia-telangiectasia. A study of 90 patients.

We investigated the presence of hypergammaglobulinemia and oligo-/monoclonal gammopathy in 90 patients (from 80 families) with ataxia-telangiectasia ranging in age from 2 to 29 years. Of the 90 patients, 38.8% displayed hypergammaglobulinemia. An isolated increase in IgM was the most common finding (23.3%) followed by a simultaneous increase in IgM and IgG (8.8%), an isolated increase in IgA (3.3%), an elevated level of IgG (2.2%) and a concomitant increase in IgM and IgA (1.1%), respectively. Seven of the patients (8.1%) had oligo-/monoclonal gammopathy. The gammopathies included all major immunoglobulin isotypes. Chemotherapeutic intervention in 2 cases precipitated the emergence of new clones within a matter of weeks. Further investigation of oligo-/monoclonal gammopathies in these patients may lead to a clearer understanding of the clinical course and provide further insight into the underlying mechanisms of B-cell abnormalities in ataxia-telangiectasia.

Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature.

The true incidence of sarcoidosis in common variable immunodeficiency (CVID) is unknown. We report here 8 cases of sarcoidosis among 80 patients with CVID followed in our clinics, along with 22 well-documented cases reported in the literature. Sarcoidosis, therefore, represents an important entity to consider among patients with CVID who exhibit clinical, radiographic, laboratory, and biopsy findings compatible with sarcoidosis. Conversely, the diagnosis of CVID should be considered in patients with sarcoidosis who do not exhibit the characteristic hypergammaglobulinemia and who have a history of recurrent infections. Although many features of sarcoidosis are similar in patients with CVID to those in patients with sarcoidosis alone, there are many important differences. Patients with CVID in whom sarcoidosis develops present with hypogammaglobulinemia rather than hypergammaglobulinemia and have a higher prevalence of recurrent infections, thrombocytopenia, and splenic involvement. Steroids, in most cases, appeared helpful in reducing adenopathy and splenomegaly, improving uveitis, lowering serum alkaline phosphatase, and reversing hematologic abnormalities. The underlying pathophysiology responsible for the association of these 2 disorders in the same patient remains obscure. However, as more patients are identified, it may be possible to gain a better understanding of the immunologic defect responsible for the dual presentation of these 2 relatively uncommon diseases.

Quantitative neurologic assessment of ataxia-telangiectasia.

BACKGROUND: Ataxia telangiectasia (A-T) is a rare disorder with many distinctive neurologic features. Although there is substantial individual variation in the rate of progression of these features, their relationship to one another or to age has not been characterized. METHODS: We formulated and tested multiple elements that assess different neurologic functions known to be affected by A-T. The overall index was applied to 52 patients with A-T, 2 to 29 years of age. RESULTS: Seven elements items proved to be informative, and three elements were added based on face validity. In a linear regression model of individuals under 19 years of age, controlled for correlation within sibships, age accounted for 87% of the variation in the A-T Index. CONCLUSION: Despite substantial individual variability of the phenotypic elements of A-T, scores on this multidimensional index have a very high correlation with age, indicating that there is a characteristic rate of progression of the disease, although functional domains in the brain are differentially affected. The pattern of scores suggests that a severe and a mild form of A-T may be distinguished by this quantitative measure. With further development this index may become useful as an outcome measure for treatment studies and prognosis.

Corticosteroids for prevention of adverse reactions to intravenous immune serum globulin infusions in hypogammaglobulinemic patients.

Severe adverse reactions to intravenous immune serum globulin occurred repeatedly in four of 10 hypogammaglobulinemic patients. Treatment-limiting symptoms included fever, chills, headache, hypertension, and chest pain. Pretreatment of patients with hydrocortisone immediately prior to infusion prevented subsequent adverse reactions and permitted these patients to receive immune serum globulin intravenously.

Increased susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia.

The incidence and morbidity of Mycoplasma infections were examined in a group of 23 patients with hypogammaglobulinemia. Among this group of patients, 18 had one or more episodes of acute respiratory illness during which Ureaplasma urealyticum, Mycoplasma orale, or Mycoplasma pneumoniae were isolated from sputum. Resolution only followed institution of specific antibiotic therapy and elimination of the Mycoplasma. In addition to respiratory illness, U. urealyticum was isolated from the urine of two patients with urinary tract infection and from an area of cellulitis in another patient. M. pneumoniae was isolated from the joint of a patient with arthritis. In six patients with chronic lung disease, Mycoplasma was frequently isolated and clinical improvement, albeit transient, coincided with negative Mycoplasma culture results. These findings emphasize the unique susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia.

Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease.

Seven patients with hypogammaglobulinemia and chronic sinopulmonary infections were treated with a preparation of intravenous gammaglobulin. In order to maintain levels of serum IgG at greater than 500 to 750 mg/dl four weeks after infusion, 0.6 g/kg was administered every month. Stable serum levels were achieved after three to eight months. After six to 12 months of this regimen, there was significant reduction in acute infections requiring hospitalization, amelioration of clinical and radiographic evidence of chronic maxillary sinusitis, and improvement in pulmonary symptoms and pulmonary function test results. The administration of increased amounts of IgG intravenously is of benefit in patients with chronic sinopulmonary infections.

Consequences of the delayed diagnosis of ataxia-telangiectasia.

OBJECTIVES: Ataxia-telangiectasia (AT) is a rare, autosomal recessive neurodegenerative disorder in which the diagnosis is obvious when ataxia and telangiectasia are both present. However, the diagnosis can be made upon the onset of ataxia and before the appearance of telangiectasia if confirmed by laboratory tests. Early diagnosis is important for genetic counseling, appropriate care, and avoidance of unnecessary tests. The purpose of this study is to identify factors responsible for delays in the diagnosis of AT. DESIGN: The records of all patients seen at the Ataxia-Telangiectasia Clinical Center from July 1, 1995 to April 1, 1997 were reviewed to determine age of onset of gait abnormality, recognition of telangiectasia, and diagnosis. RESULTS: In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months). In the majority of cases (34/48), telangiectasia appeared before the diagnosis was established. The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis. CONCLUSIONS: The term AT, although a concise and memorable label for the disorder, is also a barrier to early diagnosis. We recommend the use of routine serum alpha-fetoprotein testing for all children with persistent ataxia.

The Tel Hashomer camptodactyly syndrome: report of a new case and review of the literature.

We report on a new case of Tel Hashomer camptodactyly syndrome and review the literature. This syndrome is characterized by skeletal dysplasia, muscle hypoplasia, camptodactyly, and abnormal dermatoglyphics. The inheritance is autosomal recessive with probable partial expression in the heterozygote.

Sperm quality of subfertile males before and after treatment with human follicle-stimulating hormone.

OBJECTIVE: To assess the potential of short-term systemic administration of FSH for improving sperm quality, including ultrastructure, in teratozoospermic patients having normal endocrine profiles. DESIGN: Semen parameters were assessed prospectively using light microscopy (LM), biochemical analysis, and quantitative ultramorphological analyses within 2 months before FSH administration and within 5 days after the end of treatment. SETTING: Samples were collected from patients who were referred to the male fertility clinic at Bar-Ilan University. PATIENTS: Thirty-one patients with teratozoospermia who exhibited normal hormonal profiles and who failed to fertilize their wives in at least two previous IVF attempts (n = 17) or who had wives with apparent normal fertility unable to conceive for > or = 5 years (n = 14) were classified as subfertile. One hundred one males with no previous history of infertility, whose wives conceived after < or = 12 months of pregnancy expectation, served as the control group. INTERVENTION: Treatment was 75 IU FSH administered daily for 30 days. MAIN OUTCOME MEASURES: Pretreatment and post-treatment sperm evaluation of basic and quantitative ultramorphological analyses parameters. The hypothesis was FSH treatment may improve spermatid morphogenesis by its multiple actions on the Sertoli-gamete cell compartment without interfering with the testicular hormonogenic function. RESULTS: A significant improvement in agenesis of the acrosome and in the amorphous heads was observed, reaching normal values after treatment with FSH. The axonema deteriorated. No significant changes were observed in basic semen analysis parameters. CONCLUSIONS: Because malformations of the fine structure of the sperm head subcellular organelles seem to be prerequisites for the success of FSH treatment, ultramorphological examination of the sperm may serve as an indication for the probability of success of this treatment.

Judgment of duration in individuals with ataxia-telangiectasia.

Several clinical investigations with adults suggest that the cerebellum may be critical for judgment of explicit time intervals; however, little work has been done in populations with lesions of the cerebellum acquired during development. We evaluated 17 individuals with ataxia-telangiectasia (AT), an autosomal recessive disorder with on-set in early childhood characterized by diffuse, almost selective, degeneration of the cerebellar cortex, and 21 normal controls, matched for age. Because patients with AT have motor impairment, verbal IQ (VIQ) was used to estimate intelligence; VIQ was significantly lower in the group with AT (p < .0001). Participants were tested using a test of judgment of duration that has been found to be impaired in adults with cerebellar lesions and a contrasting auditory control task (not impaired in adults with cerebellar lesions) involving judgment of pitch. After statistically controlling for VIQ, the 2 groups did not differ significantly on judgment of pitch, but those with AT performed significantly worse than controls on judgment of duration (p = .01). Children and adolescents with AT show deficits in judgment of duration but not of pitch, suggesting that the cerebellum may be critical for judgment of explicit time intervals at all ages.