Genetic influences on hormonal markers of chronic hypothalamic-pituitary-adrenal function in human hair.

BACKGROUND: Cortisol is the primary output of the hypothalamic-pituitary-adrenal (HPA) axis and is central to the biological stress response, with wide-ranging effects on psychiatric health. Despite well-studied biological pathways of glucocorticoid function, little attention has been paid to the role of genetic variation. Conventional salivary, urinary and serum measures are strongly influenced by diurnal variation and transient reactivity. Recently developed technology can be used to measure cortisol accumulation over several months in hair, thus indexing chronic HPA function. METHOD: In a socio-economically diverse sample of 1070 twins/multiples (ages 7.80-19.47 years) from the Texas Twin Project, we estimated effects of sex, age and socio-economic status (SES) on hair concentrations of cortisol and its inactive metabolite, cortisone, along with their interactions with genetic and environmental factors. This is the first genetic study of hair neuroendocrine concentrations and the largest twin study of neuroendocrine concentrations in any tissue type. RESULTS: Glucocorticoid concentrations increased with age for females, but not males. Genetic factors accounted for approximately half of the variation in cortisol and cortisone. Shared environmental effects dissipated over adolescence. Higher SES was related to shallower increases in cortisol with age. SES was unrelated to cortisone, and did not significantly moderate genetic effects on either cortisol or cortisone. CONCLUSIONS: Genetic factors account for sizable proportions of glucocorticoid variation across the entire age range examined, whereas shared environmental influences are modest, and only apparent at earlier ages. Chronic glucocorticoid output appears to be more consistently related to biological sex, age and genotype than to experiential factors that cluster within nuclear families.

Thin shell, high velocity inertial confinement fusion implosions on the national ignition facility.

Experiments have recently been conducted at the National Ignition Facility utilizing inertial confinement fusion capsule ablators that are 175 and 165 µm in thickness, 10% and 15% thinner, respectively, than the nominal thickness capsule used throughout the high foot and most of the National Ignition Campaign. These three-shock, high-adiabat, high-foot implosions have demonstrated good performance, with higher velocity and better symmetry control at lower laser powers and energies than their nominal thickness ablator counterparts. Little to no hydrodynamic mix into the DT hot spot has been observed despite the higher velocities and reduced depth for possible instability feedthrough. Early results have shown good repeatability, with up to 1/2 the neutron yield coming from α-particle self-heating.

A High-End Estimate of Sea Level Rise for Practitioners.

Sea level rise (SLR) is a long-lasting consequence of climate change because global anthropogenic warming takes centuries to millennia to equilibrate for the deep ocean and ice sheets. SLR projections based on climate models support policy analysis, risk assessment and adaptation planning today, despite their large uncertainties. The central range of the SLR distribution is estimated by process-based models. However, risk-averse practitioners often require information about plausible future conditions that lie in the tails of the SLR distribution, which are poorly defined by existing models. Here, a community effort combining scientists and practitioners builds on a framework of discussing physical evidence to quantify high-end global SLR for practitioners. The approach is complementary to the IPCC AR6 report and provides further physically plausible high-end scenarios. High-end estimates for the different SLR components are developed for two climate scenarios at two timescales. For global warming of +2°C in 2100 (RCP2.6/SSP1-2.6) relative to pre-industrial values our high-end global SLR estimates are up to 0.9 m in 2100 and 2.5 m in 2300. Similarly, for a (RCP8.5/SSP5-8.5), we estimate up to 1.6 m in 2100 and up to 10.4 m in 2300. The large and growing differences between the scenarios beyond 2100 emphasize the long-term benefits of mitigation. However, even a modest 2°C warming may cause multi-meter SLR on centennial time scales with profound consequences for coastal areas. Earlier high-end assessments focused on instability mechanisms in Antarctica, while here we emphasize the importance of the timing of ice shelf collapse around Antarctica. This is highly uncertain due to low understanding of the driving processes. Hence both process understanding and emission scenario control high-end SLR.

Late-onset of IgE sensitization to microbial allergens in young children with atopic dermatitis.

Background A significant proportion of young children with atopic dermatitis (AD) is sensitized to microbial allergens, which play a potential role in the pathogenesis of AD inflammation. Objective To study the timing of IgE sensitization to microbial allergens including staphylococcal superantigens, Malassezia species and Candida albicans in young children with AD. Method Specific IgE antibodies to staphylococcal superantigens, Malassezia species, C. albicans and control inhalant/food allergens were measured in 53 young children with mild to moderate AD. The presence of IgE sensitization relative to age (> or = 3 years vs. < 3 years) was analysed by logistic regressions. Results IgE sensitization to the staphylococcal superantigen group, Malassezia species and C. albicans was significantly associated with older age in children with AD [P = 0.02, odds ratio (OR) 4.9; P = 0.02, OR 4.7; and P = 0.05, OR 4.0, respectively]. Conclusion IgE sensitization to microbial allergens is associated with an older age group in young children with mild to moderate AD.

Climate change. How fast are sea levels rising?

Sea levels are rising as a result of global warming, but assessing the rate of the rise is proving difficult. In his Perspective, Church highlights the report by Cabanes et al., who have reassessed observational data and find that it is closer to model estimates than previously found. However, observational data are still limited and models disagree in their regional projections. With present data and models, regional sea-level changes cannot be predicted with confidence.

A modified technique for the radioallergosorbent test.

A modification of the radioallergosorbent test (RAST) is described utilizing a multiple automated sample harvester. The technique increases the efficiency of the procedure by shortening the time required for its performance. A study is reported in which this method is compared to that recommended by the manufacturer.

A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection.

OBJECTIVES: To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. DESIGN: Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses). PATIENTS: Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/microL (range 2 to 2290 cells/microL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy. RESULTS: As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity. CONCLUSIONS: Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.

Circulating immune complexes in patients with cystic fibrosis.

Circulating immune complexes (CICs) were measured in the sera of clinically stable and acutely infected patients with cystic fibrosis (CF). Twenty CF patients were studied when clinically stable; and additional 18 patients were studied during an acute exacerbation of pulmonary infection as evidenced by fever, tachypnea, increased white blood cell count, increased sputum production, and acute chest x-ray film changes. Three methods for determining CICs were employed: polyethyelene glycol precipitation, a C1q phase assay, and the Raji cell radioimmune assay. Ten of 20 clinically stable CF patients had one or two positive assays for CICs; two of 20 had two positive assays. In contrast, 16 of 18 acutely infected CF patients had a positive CIC test, and 12 of these were positive with two or three of the assays employed. Serum C3 and C4 concentrations and total hemolytic complement activity did not correlate with the presence of CICs in either patient group. These findings suggest that immune complex formation may mediate some of the tissue damage characteristic of CF, although this usually does not involve intravascular complement activation.

Immunologic and virologic effects of glucocorticoids on human immunodeficiency virus infection in children: a preliminary study.

The immune dysfunction in human immunodeficiency virus (HIV) infection is complex and cannot be explained solely on the basis of numerical depletion of T lymphocytes. Inappropriate, uncontrolled activation of the immune system may be involved. In a test of this hypothesis, five HIV-infected children were prospectively treated with prednisone and selected immunologic and virologic indices were analyzed. Subjects had marked T lymphopenia (CD4+ T lymphocytes < 500 cells/ml) and antigenemia (serum p24 antigen > 30 pg/ml) and were free of opportunistic infections. There was a significant drop in serum p24 antigen concentrations from baseline (60.2 +/- 10.1% SEM; P < 0.005) 4 weeks after initiation of prednisone, which returned to baseline concentrations as the prednisone was tapered. Concomitant with this decrease, there was decreased expression of cell surface activation markers (HLA-DR, CD25 (interleukin 2 receptor) and CD26 (Ta-1)) in peripheral T lymphocytes. There was no significant change in either T lymphocyte subset numbers or mitogen and antigen-specific lymphoproliferation. A regulatory dysfunction of the immune system, allowing inappropriate activation of T lymphocytes, may be involved in the pathogenesis of HIV disease, and further studies involving selective immunosuppression in HIV disease are warranted.

A comparative study of transfusion-acquired human immunodeficiency virus-infected children with and without disseminated Mycobacterium avium complex.

For identification of the features of disseminated Mycobacterium avium complex (DMAC) in human immunodeficiency virus (HIV)-infected children, a retrospective medical record review of 31 long-term survivors with transfusion-acquired HIV was conducted. Nine patients developed DMAC defined as positive isolation of M. avium complex from peripheral blood. DMAC was diagnosed in patients 51 to 132 months of age (mean, 101). The time from HIV-infecting transfusion to DMAC diagnosis ranged from 37 to 132 months (mean, 92) and survival from the time of DMAC diagnosis ranged from 4 to 21 months (mean, 10). Selected laboratory and clinical measures in DMAC-positive and DMAC-negative subjects were compared. DMAC-positive patients had significantly lower CD4+ T cell counts and higher HIV p24 antigen concentrations than DMAC-negative patients at comparable times. Increased percentages of circulating leukocyte band forms and increased aspartate aminotransferase values were seen more often in DMAC-positive patients. Fever and abdominal pain were the only clinical features seen more often in DMAC-positive than in DMAC-negative patients. At the end of the study period overall survival of DMAC-positive patients was less than that of DMAC-negative children, at 33% vs. 73%. DMAC occurs in profoundly immunocompromised children with advanced HIV disease and significantly affects survival. The clinical and laboratory features of DMAC are relatively nonspecific and a high index of suspicion in patients with markedly reduced CD4+ T cells is essential.

Complications of central venous catheters in pediatric patients with acquired immunodeficiency syndrome.

Medical records of 18 pediatric acquired immunodeficiency syndrome patients with 24 central venous catheters (CVCs) were reviewed to determine the rates and types of CVC complications and to evaluate the influence of selected social factors, absolute granulocyte counts and CD4+ T cell counts on the rate of CVC infections. CVCs were in place for a total of 4233 days. CVCs were used for blood sampling, administration of blood products and infusions of intravenous immune globulin, parenteral nutrition and medications. Complications included catheter-related infections (8 episodes; with a rate of 1.9/1000 CVC days), occlusions (15 episodes) and unplanned catheter removals (9 episodes). Reduced CD4+ T cell counts were not predictive of CVC infection. The CVC infection rate in our pediatric acquired immunodeficiency syndrome patients was similar to rates reported in children with cancer and adults with cancer and acquired immunodeficiency syndrome.

Acquired protein S deficiency in children infected with human immunodeficiency virus.

OBJECTIVES: To determine the prevalence of an acquired deficiency of protein S, a coagulation inhibitor, in children infected with the human immunodeficiency virus (HIV) and to identify clinical and laboratory features associated with this coagulation abnormality. METHODS: A convenience sample of HIV-infected children, ages 2 to 18 years, was evaluated for total, free and functional protein S; total and functional protein C; prothrombin and activated partial thromboplastin times; fibrinogen; antithrombin III activity; dilute Russell viper venom time; IgG anticardiolipin antibodies; von Willebrand factor antigen; C4b-binding protein; CD4+ T lymphocyte counts; HIV p24 antigen concentration; and serum beta 2-microglobulin concentrations. RESULTS: Thirty-four subjects were evaluated. Twenty-four subjects were infected perinatally and 10 by transfusion. Nine of the subjects were CDC Class N (asymptomatic), 13 were Class A/B (symptomatic without AIDS-defining condition) and 12 were Class C (AIDS). None had previously documented thrombosis, nephrosis or significant hepatic dysfunction. Twenty-six subjects (76.5%) had decreased free protein S, and 19 (55.9%) had functional protein S < 2 SD below the mean of laboratory controls. Decreased functional protein S was seen in 33.3% of Class N, 53.8% of Class A/B and 75.0% of Class C subjects. The prevalence of decreased total and functional protein S was greater in those with absolute CD4+ T lymphocyte counts < 200/mm3 compared to those with CD4+ counts > or = 200/mm3 (75.0% vs. 38.9%; chi square, 4.48, P = 0.034). A trend toward negative correlation was observed between protein S and duration of HIV infection only for Class N subjects. No linear correlation was seen between protein S and CD4+ T lymphocyte counts; and no significant relationships were observed between protein S values and CMV status, HIV p24 antigen, C4b-binding protein, von Willebrand factor antigen, IgG anti-cardiolipin antibodies or serum beta 2-microglobulin values. CONCLUSIONS: Acquired protein S deficiency is common in HIV-infected children. The high prevalence of this anticoagulant abnormality suggests an increased risk for thrombotic complications in this population.

Development of an instrument to assess nutritional risk factors for children infected with human immunodeficiency virus.

OBJECTIVE: To produce a simple and effective instrument to evaluate and monitor the nutritional risk of children infected with the human immunodeficiency virus (HIV). DESIGN: The test instrument was developed in consultation with 5 physicians, 5 nutritionists, and 5 social workers with expertise in caring for HIV-infected children. Patient information was collected through medical record review for 19 sociodemographic, 10 anthropometric, 4 biochemical, 6 dietary intake, and 19 medical factors. As a part of routine nutrition care, anthropometric data were obtained and the caregiver was asked to complete a 3-day diet record. Also recorded were the most recent CD4+ T-cell numbers and serum HIV p24 antigen and plasma HIV RNA levels. SUBJECTS/SETTING: Thirty-nine HIV-infected children were selected using quota sampling; that is, subjects were stratified by clinical class as defined by the Centers for Disease Control and Prevention. STATISTICAL ANALYSIS: The severity or degree of potential nutritional risk in each section (anthropometric, biochemical, dietary intake, and medical data) was graded (0 to 4, 0 = low risk) and summed. Reliability of internal consistency was determined through covariance matrixes. Validity was determined through Pearson product moment correlation coefficients to measure convergent and divergent validity; predictive validity was determined using analysis of variance. Correlation for validity was compared to 6 selected dependent variables: weight for height, weight growth velocity, lean body mass, serum albumin level, CD4+ T-cell numbers, and quantitative plasma HIV RNA levels. RESULTS: Of the 38 factors that were analyzed for reliability, 11 fell in the strongly reliable range: height for age, weight for age, clinical class, somatic protein stores, mid-arm circumference, weight for height, serum albumin, immunologic status, body mass index, energy intake, and opportunistic infection. CONCLUSIONS: Anthropometric, dietary intake, and medical data were reliable indicators of nutritional risk. The entire instrument was reliable after 8 of the weakest items were removed. The instrument was found to be valid and a good predictor of nutritional risk in HIV-infected children.

Primary Candida meningitis and chronic granulomatous disease.

The occurrence of two rare entities in a single patient can be fortuitous or may signify some deeper relationship. A young boy was recently treated for primary Candida meningitis. Autopsy findings suggested to an experienced pathologist the presence of chronic granulomatous disease (CGD), unrecognized during his life. The patient's identical twin brother was tested and found to have the typical laboratory features of CGD. The literature on Candida meningitis was reviewed and 15 cases were discovered that apparently arose in the absence of recognized predisposing causes. All but one of these cases occurred in males, and most occurred during the first three decades of life. The case reports and literature review presented herein suggest that CGD should be suspected when a case of "primary" Candida meningitis is encountered.

The diagnostic challenge of the child born "at risk" for HIV infection.

Standard serologic tests for human immunodeficiency (HIV)-specific antibodies are difficult to interpret in young infants born "at risk" for HIV infection owing to transplacentally acquired maternal IgG. This article reviews the treatment advantages of early diagnosis of HIV infection, the indications for HIV testing in children, the general principles and use of individual HIV assays, and an idealized evaluation schedule for infants born "at risk" for HIV infection.

The use of revised habituation in the treatment of obsessive-compulsive disorders.

The effectiveness of the technique of revised habituation (Salkovskis & Westbrook, 1989) has received limited attention in the literature. This paper describes a clinical example which demonstrates both the utility and power of this intervention in complex cases of obsessive-compulsive disorder.

Plasma fibronectin levels after splenectomy and splenic autoimplantation in rats with and without dietary ascorbic acid supplementation.

The critical role of the spleen in protecting subjects from systemic bacterial infection is well known. Plasma fibronectin (PF), cold-insoluble globulin, and opsonic alpha2 surface binding glycoprotein, has regulatory influence on reticuloendothelial system clearance activity and it is important for maximal phagocytosis. Ascorbic acid (AA) also appears to play an important role in phagocytic cell function. The purposes of this study were to determine the effects of splenectomy and splenectomy with autoimplantation, with and without dietary AA supplementation, on PF levels. Six-week-old male Sprague-Dawley rats were divided into four experimental groups of 20 animals each: Nonoperated controls, sham-operated controls, totally splenectomized animals, and splenectomized animals with intraperitoneal autoimplantation. Each group was further randomly divided into two subgroups of 10 animals, those receiving dietary AA supplementation and those not receiving AA. PF levels were measured with a colorimetric assay immediately prior to and at 4 and 8 weeks after operation. Plasma AA determinations documented the effectiveness of dietary AA supplementation. PF levels in nonoperated and sham-operated controls increased significantly during the 8 weeks of experimentation. In contrast, PF levels decreased significantly following total splenectomy from 328 +/- 46 mcg/mL (mean +/- S.D.) to 285 +/- 46 at 4 weeks and rose to 303 +/- 77 at 8 weeks postoperatively in non-AA supplemented animals. Splenic autoimplantation eliminated this decrease in PF levels at 4 weeks. AA supplementation also protected against the decrease in PF levels in the splenectomized group. In the intragroup comparisons, AA supplementation did not produce a significant elevation of PF.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe combined immunodeficiency: otolaryngological presentation and management.

In order to increase the awareness of otolaryngologists of severe combined immunodeficiency syndrome (SCIDS) so they may contribute to an earlier diagnosis of this disorder, we performed a retrospective chart review of a multicenter series from 2 children's hospital medical centers. Eighteen cases were identified, and 14 had an otolaryngological presentation. The average age of presentation was 3.3 months, and 72% were males. Most cases were inherited in an X-linked fashion. Five patients had thrush; 4 had recurrent otitis media. Other otolaryngological presentations included cough, mouth ulcers, pharyngitis, mastoiditis, and bilateral neck abscess. The most severe form of immunodeficiency, SCIDS is a rare condition that involves a disorder in both T and B cell functions. The manifestations involving the head and neck include recurrent upper respiratory tract infections, otitis media, thrush, oral ulcers, and abscesses. It is important that SCIDS be considered in any infant with recurrences of these common infections.

Allergic rhinitis: diagnosis and management.

Allergic rhinitis affects up to 20 per cent of the pediatric population and occurs in children of all ages. Secondary infection, dental malocclusion and a variety of other sequelae may complicate the primary disorder. The diagnosis of allergic rhinitis is based on historic features, physical findings and selected laboratory investigations. Treatment may involve antigen avoidance programs and immunotherapy. However, pharmacotherapy with antihistamines, sympathomimetics and, in severe cases, corticosteroids, is most frequently used.

Underdiagnosis and undertreatment of chronic sinusitis in children.

A review of outpatients diagnosed with sinusitis during the previous year by the allergy services of Childrens Hospital of Los Angeles and Kaiser Permanente, Orange County, revealed 34 patients who had protracted discomforting and debilitating symptoms. The mean duration of symptoms was approximately six months (range 1-14 months). None had been previously diagnosed as having sinusitis or received appropriate treatment. Although all were referred for evaluation of allergic rhinitis and/or asthma, approximately 1/3 were found to have neither of these conditions. Among patients who had asthma, their asthmatic symptoms were aggravated by the sinusitis. All patients eventually responded favorably to appropriate antibiotic therapy. Earlier diagnosis and appropriate therapy would have foreshortened the course of this very discomforting condition. In recent years, we have observed a marked increase in the number of patients referred with the chief complaint of "worsening allergy" and who were subsequently found to have sinusitis. Most of the patients experienced significant incapacitation for protracted periods before a correct diagnosis was made and treatment instituted. In all but a few cases, prompt and sustained improvement followed appropriate therapy. The purpose of this report is to present a retrospective review of 34 illustrative cases.