[Efficacy of biologics for severe asthma on allergic comorbidities]. / Efficacité des biothérapies de l'asthme sévère sur les comorbidités allergiques.

Identification of therapeutic targets other than asthma can guide the choice of biologics in cases of severe asthma. Some of the allergic diseases (atopic dermatitis, food allergies, allergic rhinoconjunctivitis) that may be associated with asthma can be treated with biologics. In this review, we aim to assess the effectiveness of these biologic therapies on the allergic comorbidities of asthma. In the treatment of atopic dermatitis, only Dupilumab, an anti-IL4Rα, has proven its effectiveness and has received reimbursement authorization for this indication. In patients presenting with allergic rhinoconjunctivitis, Omalizumab has shown effectiveness, but has not been approved for this indication. Data from post-hoc analyses of studies on severe asthma likewise suggest the effectiveness of Dupilumab regarding allergic rhinitis. While these two biologic therapies have shown positive signals, inducing oral food tolerance, the relevant data are not robust. Biologic therapies targeting IL-5 or its receptor (Mepolizumab, Benralizumab) have seldom been evaluated in allergic comorbidities, excepting atopic dermatitis, for which their effectiveness has not been proven. Lastly, there are interesting data on the combination of biologic therapy and allergen immunotherapy in cases of allergic rhinitis and food allergies, but they need to be confirmed by randomized studies.

Comparing clinical outcomes in HIV-infected and uninfected older men hospitalized with community-acquired pneumonia.

OBJECTIVES: Outcomes of community-acquired pneumonia (CAP) among HIV-infected older adults are unclear. METHODS: Associations between HIV infection and three CAP outcomes (30-day mortality, readmission within 30 days post-discharge, and hospital length of stay [LOS]) were examined in the Veterans Aging Cohort Study (VACS) of male Veterans, age ≥ 50 years, hospitalized for CAP from 10/1/2002 through 08/31/2010. Associations between the VACS Index and CAP outcomes were assessed in multivariable models. RESULTS: Among 117 557 Veterans (36 922 HIV-infected and 80 635 uninfected), 1203 met our eligibility criteria. The 30-day mortality rate was 5.3%, the mean LOS was 7.3 days, and 13.2% were readmitted within 30 days of discharge. In unadjusted analyses, there were no significant differences between HIV-infected and uninfected participants regarding the three CAP outcomes (P > 0.2). A higher VACS Index was associated with increased 30-day mortality, readmission, and LOS in both HIV-infected and uninfected groups. Generic organ system components of the VACS Index were associated with adverse CAP outcomes; HIV-specific components were not. Among HIV-infected participants, those not on antiretroviral therapy (ART) had a higher 30-day mortality (HR 2.94 [95% CI 1.51, 5.72]; P = 0.002) and a longer LOS (slope 2.69 days [95% CI 0.65, 4.73]; P = 0.008), after accounting for VACS Index. Readmission was not associated with ART use (OR 1.12 [95% CI 0.62, 2.00] P = 0.714). CONCLUSION: Among HIV-infected and uninfected older adults hospitalized for CAP, organ system components of the VACS Index were associated with adverse CAP outcomes. Among HIV-infected individuals, ART was associated with decreased 30-day mortality and LOS.

Antiretroviral therapy-induced mitochondrial toxicity: potential mechanisms beyond polymerase-γ inhibition.

We hypothesized that competition between nucleotide reverse-transcriptase inhibitor triphosphate and endogenous deoxyribonucleotide triphosphate (dNTP) may lead to depletion of dNTP pools and mitochondrial dysfunction independent of polymerase-γ (pol-γ) inhibition. We collected peripheral blood mononuclear cells from 75 adults (25 cases: HIV-infected patients with mitochondrial toxicity, 25 HIV-infected positive controls, and 25 HIV-negative controls). We observed statistically significant individual and group differences in ribonucleotide (RN) and deoxyribonucleotide (dRN) pools. The median values for the RN pools were 10,062 (interquartile range (IQR): 7,090-12,590), 4,360 (IQR: 3,058-6,838), and 2,968 (IQR: 2,538-4,436) pmol/10(6) cells for negative controls, positive controls, and cases, respectively. Cases had significantly higher absolute mitochondrial DNA copy number as compared with negative controls (P < 0.05). Moreover, cases had significantly higher expression levels of pol-γ, nucleotide transporters, cellular kinases, and adenosine triphosphate (ATP)-binding cassette (ABC) proteins as compared with controls. Antiretroviral therapy (ART) perturbs RN and dRN pools. Depletion of RN and dRN pools may be associated with ART-induced mitochondrial toxicity independent of pol-γ inhibition.

Dyslipidemia and lipid peroxidation of Saudi type 2 diabetics with proliferative retinopathy.

OBJECTIVES: To assess lipid profile and lipid peroxidation in type 2 diabetics with proliferative retinopathy (PDR), and investigate the association between these biochemical parameters and PDR. METHODS: This study was conducted between June 2011 and February 2012 in the Research Laboratory, College of Applied Medical Sciences, Qassim University, Qasssim, Kingdom of Saudi Arabia. The study included 54 patients with type 2 diabetes (21 with PDR and 33 controls) and 30 healthy subjects. The biochemical parameters were measured using standard laboratory procedures. RESULTS: Patients with PDR characterized by significantly (p<0.05) increased levels of serum cholesterol, triglyceride, low density lipoprotein (LDL-C), plasma malondialdehyde; decreased levels of serum high density lipoprotein (HDL-C) and apolipoprotein A1 (Apo A1); positive correlation of malondialdehyde with triglyceride, but negative with HDL-C, Apo A1. In logistic regression, malondialdehyde, LDL-C, and Apo A1 were not associated with PDR. However, triglyceride (OR = 1.745; p=0.000), total cholesterol (OR = 0.079; p=0.000), and HDL-C (OR = 10.676; p=0.000) were independent risk factors for developing PDR. CONCLUSION: Dyslipidemia and lipid peroxidation may play a role in pathogenesis of diabetic retinopathy. Patients with PDR displayed marked lipid abnormalities and increased lipid peroxidation. The control of lipid alterations through glycemic control and/or lipid lowering medication is required for type 2 diabetics at least to postpone or prevent loss of vision from retinopathy.

Vasopressin-containing neurons of the hypothalamic parvocellular paraventricular nucleus of the jerboa: plasticity related to immobilization stress.

The corticotropin-releasing hormone (CRH) neurons of the hypothalamic parvocellular paraventricular nucleus (PVN) have a high potential for phenotypical plasticity, allowing them to rapidly modify their neuroendocrine output, depending upon the type of stressors. Indeed, these neurons coexpress other neuropeptides, such as cholecystokinin (CCK), vasopressin (VP), and neurotensin, subserving an eventual complementary function to CRH in the regulation of the pituitary. Unlike in rats, our previous data showed that in jerboas, CCK is not coexpressed within CRH neurons in control as well as stressed animals. The present study explored an eventual VP participation in the phenotypic plasticity of CRH neurons in the jerboa. We analyzed the VP expression within the PVN by immunocytochemistry in male jerboas submitted to acute stress. Our results showed that, contrary to CRH and CCK, no significant change concerned the number of VP-immunoreactive neurons following a 30-min immobilization. The VP/CRH coexpression within PVN and median eminence was investigated by double immunocytochemistry. In control as well as stressed animals, the CRH-immunopositive neurons coexpressed VP within cell bodies and terminals. No significant difference in the number of VP/CRH double-labeled cells was found between both groups. However, such coexpression was quantitatively more important into the posterior PVN as compared with the anterior PVN. This suggests an eventual autocrine/paracrine or endocrine role for jerboa parvocellular VP which is not correlated with acute immobilization stress. VP-immunoreactive neurons also coexpressed CCK within PVN and median eminence of control and stressed jerboas. Such coexpression was more important into the anterior PVN as compared with the posterior PVN. These results showed the occurrence of at least two VP neuronal populations within the jerboa PVN. In addition, the VP expression did not depend upon acute immobilization stress. These data highlight differences in the neuroendocrine regulatory mechanisms of the stress response involving CRH/CCK or VP. They also underline that adaptative physiological mechanisms to stress might vary from one mammal species to another.

GAT-1 and reversible GABA transport in Bergmann glia in slices.

Although glial GABA uptake and release have been studied in vitro, GABA transporters (GATs) have not been characterized in glia in slices. Whole cell patch-clamp recordings were obtained from Bergmann glia in rat cerebellar slices to characterize carrier-mediated GABA influx and efflux. GABA induced inward currents at -70 mV that could be pharmacologically separated into GABA(A) receptor and GAT currents. In the presence of GABA(A/B/C) receptor blockers, mean GABA-induced currents measured -48 pA at -70 mV, were inwardly rectifying between -70 and +50 mV, were inhibited by external Na(+) removal, and were diminished by reduction of external Cl(-). Nontransportable blockers of GAT-1 (SKF89976-A and NNC-711) and a transportable blocker of all the GAT subtypes (nipecotic acid) reversibly reduced GABA-induced transport currents by 68 and 100%, respectively. A blocker of BGT-1 (betaine) had no effect. SKF89976-A and NNC-711 also suppressed baseline inward currents that likely result from tonic GAT activation by background GABA. The substrate agonists, nipecotic acid and beta-alanine but not betaine, induced voltage- and Na(+)-dependent currents. With Na(+) and GABA inside the patch pipette or intracellular GABA perfusion during the recording, SKF89976-A blocked baseline outward currents that activated at -60 mV and increased with more depolarized potentials. This carrier-mediated GABA efflux induced a local accumulation of extracellular GABA detected by GABA(A) receptor activation on the recorded cell. Overall, these results indicate that Bergmann glia express GAT-1 that are activated by ambient GABA. In addition, GAT-1 in glia can work in reverse and release sufficient GABA to activate nearby GABA receptors.

Carrier-mediated uptake and release of taurine from Bergmann glia in rat cerebellar slices.

Taurine uptake is essential for the maintenance of millimolar intracellular concentrations of taurine, which is released during ischaemia and is thought to be neuroprotective. To determine whether Bergmann glia express functional transporters that can mediate both taurine uptake and efflux, whole-cell patch-clamp recordings were obtained from these cells in rat cerebellar slices. Taurine-induced inward currents can be pharmacologically separated into GABA(A) receptor and taurine transporter currents. In the presence of GABA receptor blockers, residual taurine currents averaged -28 pA at -70 mV and were strictly inwardly rectifying between -70 and +50 mV. These residual currents were also abolished by external Na+ removal and diminished by reduction of external Cl-, consistent with transport currents. Taurine transport currents were reduced by a taurine transporter inhibitor, guanidinoethyl sulphonate (GES). Other classical inhibitors reduced taurine transport currents with an order of potency (hypotaurine > beta-alanine > GES > GABA) similar to that reported for cloned rat taurine transporters. Following intracellular taurine perfusion during the recording, a progressively developing outward current could be observed at -50 mV but not at -70 mV. Intracellular perfusion of taurine also decreased taurine-induced inward currents at both holding potentials. Outward currents induced by intracellular taurine increased in amplitude with depolarization, activated near -50 mV, and were affected by GES. For the first time, these results demonstrate that taurine activates both GABA(A) receptors and Na+/Cl--dependent taurine transporters in Bergmann glia in slices. In addition, our data show that taurine transporters can work in reverse and can probably mediate taurine efflux under ischaemic conditions.

Nocturnal enuresis in pediatric sickle cell disease.

To assess the prevalence of nocturnal enuresis in children and adolescents with sickle cell disease (SCD) and associated factors, structured telephone interviews were conducted with primary caregivers of 217 children and adolescents with SCD aged 5 years or older. Prevalence, perceived causes, interventions undertaken, and emotional impact were assessed. Nocturnal enuresis was significantly higher for males (28.2% of males) than for females (11% of females), p = .002, and compared with cited population prevalence rates, nocturnal enuresis was significantly higher for children with SCD, p < .01. SCD was the most common reason given by primary caregivers for enuresis. Primary caregivers used a wide range of interventions for nocturnal enuresis, but few used empirically supported treatments for enuresis or spoke with their health care team about the enuresis. These data suggest that systematic assessment and intervention for nocturnal enuresis must be implemented in the follow-up care of children and adolescents with SCD.

Neuropsychological functioning and social functioning of survivors of pediatric brain tumors: evidence of nonverbal learning disability.

The purpose of the study was to examine if survivors of pediatric brain tumors exhibit a pattern of performance consistent with nonverbal learning disability (NVLD) and to explore the relationship between neuropsychological and social functioning in these children. A comprehensive neuropsychological battery and objective measures of psychosocial function designed to assess NVLD were administered to 15 survivors of brain tumors, ages 8-12 years. Despite the small sample size, a trend for better verbal skills compared to nonverbal skills was found using composite scores. Parents reported significant social deficits and a tendency for greater internalizing behavior problems as expected in NVLD. Additionally, there was a trend for a positive association between nonverbal scores and social function. Further research is needed to determine if the NVLD pattern observed is attributable to white matter damage of the right hemisphere. Routine neuropsychological and psychosocial assessment and intervention are indicated.

Surviving cancer competently intervention program (SCCIP): a cognitive-behavioral and family therapy intervention for adolescent survivors of childhood cancer and their families.

Psychological reactions to having had childhood cancer often continue after treatment ends, for survivors and their parents. Based on our previous research, we developed an intervention program for adolescent survivors of childhood cancer, their parents, and siblings. Surviving Cancer Competently: An Intervention Program--SCCIP--is a one-day family group intervention that combines cognitive-behavioral and family therapy approaches. The goals of SCCIP are to reduce symptoms of distress and to improve family functioning and development. SCCIP is described and data from a pilot study of 19 families are presented. Program evaluation data indicated that all family members found SCCIP helpful. Standardized measures administered before the intervention and again at 6 months after SCCIP showed that symptoms of posttraumatic stress and anxiety decreased. Changes in family functioning were more difficult to discern. Overall, the results were promising with regard to the feasibility of the program and its potential for reducing symptoms of distress for all family members.

Vitamin D3 deficiency and alterations of glucose metabolism in rat endocrine pancreas.

After 5 weeks of vitamin D3 deficiency, rats exhibited signs of rachitism, hypocalcaemia and hypoinsulinaemia. As the glucose-induced insulin release process requires calcium and energy production from glucose metabolism within beta cells of Langerhans islets, several steps in the glycolytic pathway and the tricarboxylic acid cycle within beta cells were investigated in vitro. The sensitivity of islets to glucose was studied during incubations in the presence of crescent concentrations of glucose (4.2 to 16.7 mM). Comparison of 50% maximal insulin response showed no modifications induced by vitamin D3 deficiency despite a large fall in the secretory capacity of beta cells. The use of two secretagogues (D-glucose and D-glyceraldehyde) to stimulate insulin release at two different glycolysis steps gave similar responses during perifusions performed in the presence of crescent concentrations of these nutrients, indicating that vitamin D3 deficiency was not a major influence on the first steps in glycolysis. Glucose utilisation by islets, as determined by 3HOH production from D-[5-3H]glucose, was slightly decreased during glucose stimulation of islets from vitamin D3-deficient rats, whereas glucose oxidation inside the tricarboxylic acid cycle, as measured by 14CO2 production from D-[6-14C]glucose, was severely affected. These data, which suggest that vitamin D3 deficiency affects the glycolytic pathway after the D-glyceraldehyde step and mainly alters oxidative events within the tricarboxylic acid cycle, support the hypothesis of an alteration of mitochondrial metabolism.

Predicting posttraumatic stress symptoms in mothers and fathers of survivors of childhood cancers.

OBJECTIVE: To predict posttraumatic stress symptoms in parents of survivors of childhood cancer, using as predictors the following: personality (trait anxiety); current family and individual variables (perceived life threat, perceived treatment intensity, life events, family functioning, and social support); posttreatment variables (time since treatment ended, child anxiety, medical sequelae); and treatment events (age at diagnosis, radiation therapy, intensity of treatment). METHOD: Mothers and fathers of 6- to 20-year-old survivors of childhood cancer (n = 331 families) completed a questionnaire battery in this two-site study. The outcome variable was the Posttraumatic Stress Disorder Reaction Index. Multiple regressions and path analyses were used to test the model. RESULTS: For both mothers and fathers, anxiety was the strongest predictor of posttraumatic stress symptoms. The current family and individual variables also contributed significantly, particularly with respect to the individual contributions of perceived life threat, perceived treatment intensity, and social support. Objective medical data did not contribute to posttraumatic stress symptoms. CONCLUSIONS: Parental anxiety warrants attention throughout the course of treatment for childhood cancer and after treatment ends. Beliefs about past and present life threats associated with cancer treatment and family and social support are other important targets for intervention.

Is posttraumatic stress a viable model for understanding responses to childhood cancer?

The application of a trauma model to understanding the impact of life-threatening illness has been informative. In the case of childhood cancer patients, it appears clear that a full PTSD syndrome is not the normative response either during or after treatment. Some aspects of cancer diagnosis and treatment, however, are experienced as traumatic by a subset of children, some of whom report symptoms of posttraumatic stress. There is some evidence that children may respond to cancer treatment as a repeated trauma, with the result of more subtle changes in affect modulation, world view, and interpersonal relationships. This area requires further investigation. The trauma model is also useful in understanding parental responses to childhood cancer. The epidemiologic data to date regarding posttraumatic stress symptoms in parents of childhood cancer survivors is consistent with the trauma literature regarding responses to moderate-magnitude traumatic exposure. These findings have important implications for clinical interventions for families of childhood cancer patients. More research is needed in the prediction and prevention of the long-term distress reported by so many parents of children who have undergone successful treatment for life-threatening illness.

Predictors of posttraumatic stress symptoms in childhood cancer survivors.

OBJECTIVE: The diagnosis and treatment of childhood cancer are extremely stressful experiences, with psychological sequelae which can persist many years after the end of treatment. This study investigated the relative contributions of general anxiety, treatment intensity, medical sequelae of treatment, and the subjective appraisal of life threat and treatment intensity to later posttraumatic stress symptoms, such as intrusive memories, avoidance, and hypervigilance. METHOD: One hundred eighty-six childhood cancer survivors ages 8 through 20 years, off of treatment for more than 1 year, and their parents completed questionnaires. Medical sequelae of treatment and intensity of treatment were rated by a pediatric oncologist. RESULTS: Significant, independent predictors of persistent posttraumatic stress symptoms included: 1) the survivor's retrospective subjective appraisal of life threat at the time of treatment, and the degree to which the survivor experienced the treatment as "hard" or "scary"; 2) the child's general level of anxiety; 3) history of other stressful experiences; 4) time since the termination of treatment (negative association); 5) female gender; and 6) family and social support. Mother's perception of treatment and life threat contributed to anxiety and subjective appraisal for the survivor, but did not independently contribute to posttraumatic stress symptoms. CONCLUSIONS: Symptoms of posttraumatic stress seem to decrease with time, but are persistent in a subset of childhood cancer survivors. Other than time and gender, the predictors of posttraumatic stress symptoms are primarily subjective factors (ie, anxiety and subjective appraisal) rather than objective stressors of treatment and medical sequelae.

Involvement of both calcium influx and calcium mobilization in growth hormone-induced [Ca2+]i increases in Chinese hamster ovary cells.

This study reports rapid effects of growth hormone (GH) on the intracellular free calcium concentration ([Ca2+]i) in Chinese hamster ovary (CHO) cells stably expressing rabbit GH receptor. [Ca2+]i was measured by spectrofluorimetric methods in single cells and membrane Ca2+ currents by patch clamp techniques in the whole-cell configuration. In individual CHO cells, bathed in a standard saline solution containing 2 mM Ca2+, basal [Ca2+]i was 191 +/- 27 nM (mean +/- S.D.; n=83). Short term administration of GH (100 ng/ml, 30 s) induced a [Ca2+]i increase in 54% of cells tested (n = 398 of 743). Responses were clearly heterogeneous. Maximum calcium increase varied from 16 to 853 nM and time to peak varied from 4 to 320 s. On examination of the [Ca2+]i increases, it was possible to define two different types of calcium responses to GH. Experimental manipulations of extracellular and intracellular calcium concentrations demonstrated that GH-induced calcium increases involved both calcium influx and calcium mobilization. Calcium influx, a long lasting, small amplitude (63 +/- 34 nM) response, was observed in 121 out of 398 cells (30%) whereas calcium mobilization, a transient, large amplitude (263 +/- 175 nM) response, was observed in 277 out of 398 cells (70%). Moreover, patch clamp data show that influx did not involve the dihydropyridine-sensitive calcium channels.

Posttraumatic stress, family functioning, and social support in survivors of childhood leukemia and their mothers and fathers.

Psychological sequelae are examined in 130 former childhood leukemia patients and 155 comparison participants and their parents. The major dependent variables are symptoms of anxiety and posttraumatic stress, family functioning, and social support. Multivariate analyses of covariance indicated significantly more posttraumatic stress symptoms in mothers and fathers of childhood leukemia survivors (p < .001) and no differences between survivors and peers. There were no significant group differences for family functioning or social support, although they were associated with anxiety and posttraumatic stress outcomes. Current child age, age at diagnosis, and months off treatment were not significantly correlated with outcome. These findings document the long-term impact of childhood cancer treatment on parents. The lack of significant differences for survivors argues for further attention to the relevance of posttraumatic stress disorder for childhood cancer survivors. The clinical implications are that psychological interventions are needed during and after cancer treatment.

Brief report: parenting stress and quality of life during treatment for childhood leukemia predicts child and parent adjustment after treatment ends.

Evaluated relationships between parenting stress and parent-rated child quality of life during treatment for childhood leukemia and later parental posttraumatic stress symptoms and parent and child anxiety after completion of cancer treatment in 29 families of patients with leukemia. Correlations among in-treatment and off-treatment variables showed strong patterns of association between parenting stress during treatment and later parental adjustment, for both mothers and fathers. Parent-rated child quality of life was also significantly associated with later adjustment for mothers and children. Despite the small sample, data point to the importance and consistency of parental reactions from diagnosis through the end of treatment and have clinical implications for psychosocial services during and after treatment.

Families surviving childhood cancer: a comparison of posttraumatic stress symptoms with families of healthy children.

Compared posttraumatic stress symptoms in 309 8- to 20-year-old survivors of childhood cancer and their parents with healthy children and their parents who responded to child-related stressors. The relationship of child demographic, cancer and treatment, and family and social support factors with posttraumatic stress symptoms was analyzed also. Results indicate that mothers and fathers of childhood cancer survivors showed significantly higher levels of posttraumatic stress symptoms than comparison parents. The survivors themselves did not differ from their healthy counterparts. Past perceived life threat and family and social support resources contributed to posttraumatic stress symptoms in survivors and their parents. Survivor mother and child and survivor father and child symptoms were associated. Implications for the long-term functioning of families of survivors and suggestions for preventive interventions are discussed.

Management of fatal illness and death in children or their parents.

Assisting families facing a death necessitates constant reevaluation of each family's adaptation to the illness. Protracted terminal illness is particularly difficult because the prolonged stress, suffering, and pain may be much more difficult to cope with than the death itself. Successful management requires acknowledging the families' emotions, assuring them that their responses are normal, and providing them a balanced perspective through supportive, honest, and open communication. In so doing, the pediatrician can help families predict reactions, manage problems, and avoid long-term psychological consequences.

Children with physical handicaps and their mothers: the interrelation of social support, maternal adjustment, and child adjustment.

Examined the interrelation of maternal adjustment, mother-child interaction, and child adjustment in 29 families of children with spina bifida and without mental retardation and in 28 families of children without handicaps. A multivariate, ecological model proposed that adjustment of mother and child depends on the adaptiveness of maternal response to the stress of the physical handicap and on the ability of mothers to create an optimal caregiving environment through mother-child interaction. Analyses examining the relationships among maternal social support, maternal psychological adjustment, and child adjustment are reported. Social support was found to be related to higher maternal psychological adjustment and to higher child adjustment, and maternal psychological adjustment was related positively to child adjustment in both groups. No significant differences were found between groups in the examined relationships or in the levels of resources and adjustment. Results underscore strengths of families of children with spina bifida in their adaptation to the stress of the handicap.