Impaired antibody responses in the hyperimmunoglobulin E syndrome

Patients with the hyper-IgE (HIE) syndrome have recurrent bacterial infections with Staphylococcus aureus and other polysaccharide encapsulated organisms. To determine whether an impairment of the antibody response to polysaccharide antigens contributes to infections in this syndrome, we measured serum antibody to the teichoic acid of S. aureus and to the capsular polysaccharide of Haemophilus influenzae type b. Compared to control subjects who had no history of S. aureus infections (N = 14), sera from patients with HIE (N = 9) lacked the expected elevation of serum antibody to teichoic acid (p greater than 0.05) and had significantly lower levels of this antibody than sera from 14 patients with atopic dermatitis, complicated by recurrent cutaneous S. aureus infections (p less than 0.01). After immunization with the capsular polysaccharide of Haemophilus influenzae type of vaccine, the antibody response of patients with HIE was significantly impaired compared to that of age-matched control subjects (p = 0.01). Although patients with HIE syndrome had normal total IgG levels, most patients with HIE but not patients with atopic dermatitis had IgG2 subclass deficiency. Defective antibody responses in patients with HIE were not restricted to polysaccharide antigens because the serum levels of antitetanus toxoid antibody in these patients were significantly lower than that of control subjects (p less than 0.001). Impaired antigen-specific antibody responses in patients with HIE syndrome may contribute to their increased susceptibility to infection.     

The lack of effect of histamine on spontaneous activity in the isolated human myometrium

The effects of histamine on the spontaneous activity of the isolated human myometrium were studied. Both the frequency and force of contractions of the muscle strips were not significantly altered by histamine. The presence of either a histamine H₁-or H₂-receptor antagonist in the organ bath did not significantly change the responses of the uterine muscle to histamine. These findings suggest that histamine has negligible effects on the human myometrium, possibly due to the absence, or paucity, of histamine receptors.     

Chronic intracranial pressure monitoring by telemetry: Clinical experience

Intracranial pressure (ICP) monitoring is a critical measure for avoiding severe brain dysfunction or brain death by directing supportive therapy so as to prevent ICP increase severe enough to reduce cerebral blood perfusion. Such situations occur with brain swelling, increased cerebral vascular volume, and increase in cerebrospinal fluid (CSF) volume. Causes include ischemic stroke, subarachnoid bleeding, brain contusion, encephalitis (as in Reye's syndrome), and hydrocephalus from meningitis or neoplasm. When several days of ICP monitoring can direct resolution of the pressure crisis, the invasive direct connection of an intracranial sensor with external recording device carries only minimal infection risk. Prolonged ICP monitoring for weeks or months demands telemetry and becomes desirable in a number of chronic disease problems including both congenital and acquired hydrocephalus where enlarged and pressurized cerebral ventricles develop with reduced absorption of continuously secreted CSF. Although the primary disturbance in CSF circulation can remain incurable, its palliation by valve-regulated CSF diversions or shunting can restore normal brain function and in infants permit normal brain development. Missing this goal can result from failure to maintain a sufficiently normal pattern of CSF dynamics and ICP. Monitoring of the CSF pressure fluctuations transmitted through an intraventricular catheter provides the most accurate record of ICP pulsations. Therefore, a pressure sensing module can be “T'd” into an existing shunt system in continuity with the already placed ventricular tube. The capacity to monitor ICP accurately by telemetry was first established in dogs made hydrocephalic to assure free CSF pulse through a ventricular catheter (1,2,3, 4,5). The subsequent use of ICP monitoring by telemetry in three patients will be described.     

Cloning and characterisation of malE in Burkholderia pseudomallei

No recombinant protein is available for serodiagnosis or skin test in the diagnosis of melioidosis. This report describes the cloning of the malE gene, which encodes an immunogenic protein of Burkholderia pseudomallei. Bi-directional DNA sequencing of malE revealed that the gene contained a single open reading frame encoding 416 amino acid residues with a predicted molecular mass of 44.4 kDa. BLAST analysis showed that the putative protein encoded by malE is homologous to the maltose-binding protein (MBP) of other bacteria. It has 48% and 63% amino acid identity and similarity with the MBP of Brucella abortus, and malE complementation assay showed that it partially complemented the function of the MBP of Escherichia coli. Several highly conserved regions among the MBP of B. pseudomallei, Br. abortus, Salmonella enterica serotype Typhimurium, E. coli and Enterobacter aerogenes were observed. These regions represent signatures A, B, C, D and F identified in the MBP of E. coli. Further sequence analysis revealed that the first 24 amino acid residues of the MBP of B. pseudomallei probably represent the N-terminal signal peptide of the protein. Similar to the signal peptide of the MBP of E. coli, Ent. aerogenes and S. Typhimurium, the MBP of B. pseudomallei contains two basic residues in the first eight amino acids, followed by a hydrophobic core, with the last three amino acids in the signal peptide being Ala-Gln-Ala, conforming to the consensus sequence Ala-X-Ala at positions -3 to -1 relative to the site of proteolytic cleavage for recognition by signal peptidase I. Further studies on serodiagnosis of melioidosis with recombinant MBP should be performed.     

Additive immunosuppressive effects of 1,25-dihydroxyvitamin D3 and corticosteroids on TH1, but not TH2, responses

BACKGROUND: The biologic role of the vitamin D analogue 1, 25-dihydroxyvitamin D(3), such as antiinflammatory functions, reduction of cytokine production by T cells, and immunoglobulin production by B cells, has been reported. Such immunomodulatory effects may be potentially useful in dealing with autoimmunity and transplantation. However, whether this hormone has an additive immunosuppressive effect when it is used with corticosteroids has not been investigated, although these agents are commonly used together. OBJECTIVE: Our purpose was to investigate the additive immunomodulatory effects of 1,25-dihydroxyvitamin D(3) on lymphocyte proliferation and cytokine production when used with corticosteroids. METHODS: To investigate the additive effects of 1, 25-dihydroxyvitamin D(3) and dexamethasone on suppression of lymphocyte proliferation, normal PBMCs were cultured in anti-CD3 with or without different concentrations of dexamethasone (0-10(-7) mol/L) plus or minus different concentrations of 1, 25-dihydroxyvitamin D(3) (0-10(-6) mol/L). After 3 days, lymphocyte proliferation was assessed by [(3)H]-thymidine incorporation. To investigate the additive effects of 1,25-dihydroxyvitamin D(3) and dexamethasone on cytokine production, PBMCs were cultured for 3 days in the presence of anti-CD3 with or without 10(-6) mol/L dexamethasone plus or minus 10(-6) mol/L 1,25-dihydroxyvitamin D(3). IFN-gamma, IL-5, and IL-13 production in supernatants were measured by ELISA. RESULTS: Our study demonstrated that, at concentrations of 10(-8), 10(-7), and 10(-6) mol/L, 1,25-dihydroxyvitamin D(3) significantly decreased lymphocyte proliferation compared with an ethanol control (P <.05). The IC(50) for dexamethasone was 4 x 10(-9) mol/L in culture without 1,25-dihydroxyvitamin D(3.) When 10(-9) mol/L of 1,25-dihydroxyvitamin D(3) was added to cultures with dexamethasone, IC(50) became 2 x 10(-9) mol/L. Moreover, when 10(-6), 10(-7), and 10(-8) mol/L of 1,25-dihydroxyvitamin D(3) were added in culture with dexamethasone, IC(50) became less than 1 x 10(-9) mol/L. IFN-gamma production in culture with either dexamethasone or 1,25-dihydroxyvitamin D(3) was significantly decreased compared with media or ethanol control (P <.0001). Moreover, when both agents were added in the same culture, IFN-gamma production was further decreased compared with either agent alone (P <.05). In contrast, 1,25-dihydroxyvitamin D(3) significantly (P <. 0001) increased IL-5 and IL-13, whereas dexamethasone significantly decreased these 2 cytokines (P <.0005). When 1,25-dihydroxyvitamin D(3) was combined with dexamethasone, IL-5 and IL-13 production was increased compared with dexamethasone alone (P <.001). CONCLUSIONS: Our results demonstrate that 1,25-dihydroxyvitamin D(3) has significant additive effects on dexamethasone-mediated inhibition of lymphocyte proliferation. This hormone also has additive effects on inhibition of T(H)1 cytokine production when combined with dexamethasone. However, this hormone upregulates T(H)2 cytokines and inhibits steroid-mediated suppression of cytokines. These findings demonstrate the potential use of 1,25-dihydroxyvitamin D(3) as an immunosuppressive agent when combined with corticosteroids in T(H)1, but not T(H)2, immune responses.     

Association between atrial fibrillation and central sleep apnea

BACKGROUND: We previously described an association between atrial fibrillation and central sleep apnea in a group of patients with congestive heart failure. We hypothesized that the prevalence of atrial fibrillation might also be increased in patients with central sleep apnea in the absence of other cardiac disease. METHODS AND RESULTS: We compared the prevalence of atrial fibrillation in a series of 60 consecutive patients with idiopathic central sleep apnea (apnea-hypopnea index > 10 events per hour, > 50% central events) with that in 60 patients with obstructive sleep apnea (apnea-hypopnea index > 10, > 50% obstructive events) and 60 patients without sleep apnea (apnea-hypopnea index < 10), matched for age, sex, and body mass index. Subjects with a history of congestive heart failure, coronary artery disease, or stroke were excluded from the study. The prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was found to be significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively, P < .001). However, hypertension was most common and oxygen desaturation most extreme among patients with obstructive sleep apnea. CONCLUSIONS: We conclude that there is a markedly increased prevalence of atrial fibrillation among patients with idiopathic central sleep apnea in the absence of congestive heart failure. Moreover, the high prevalence of atrial fibrillation among patients with idiopathic central sleep apnea is not explainable by the presence of hypertension or nocturnal oxygen desaturation, since both of these were more strongly associated with obstructive sleep apnea.     

No association between VNTR polymorphisms of dopamine transporter gene and attention deficit hyperactivity disorder in Chinese children.

Dopamine transporter (DAT) gene is implicated in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Previously a meta-analysis concluded no association between the variable-number-of-tandem-repeats (VNTR) polymorphisms of the DAT gene and ADHD. However, significant heterogeneity was present among studies and no conclusion can be drawn about the association in any single ethnicity given the small number of studies. There were also conflicting results in Chinese populations. We therefore perform the present study to investigate the association in Chinese children in Hong Kong. In this prospective family-based and case-control study during January to June 2004, we recruited consecutive Chinese children diagnosed with ADHD by DSM-IV criteria, their family members, and sex-matched controls admitted for acute upper respiratory infection, excluding those with perinatal brain insults, mental retardation, or neurological deficits. VNTR polymorphisms of the DAT gene were determined by standard PCR followed by agarose gel electrophoresis. Sixty-four ADHD cases (52 boys, 12 girls), their family members and 64 normal controls were recruited. The 10-repeat allele (92.6%) and the 10/10 repeat genotype (85.2%) were the most prevalent. Both family-based and case-control analyses showed no association between the DAT gene polymorphisms and ADHD (transmission dysequilibrium test: P = 0.99; odds ratio of 10-repeat allele = 0.89 (95%CI 0.35-2.28), P = 0.81; odds ratio of 10/10 repeat genotype = 0.69 (95%CI 0.26-1.84), P = 0.46). We concluded that VNTR polymorphism of the DAT gene is not associated with ADHD in Chinese children, and further studies are needed to clarify the polygenic and environmental influences for pathogenesis of ADHD.