IgG4-subclass of glutamic acid decarboxylase antibody is more frequent in latent autoimmune diabetes in adults than in type 1 diabetes

Aims/hypothesis Glutamic acid decarboxylase autoantibodies (GADA) are the most frequent beta-cell-specific autoantibodies in type 1 diabetes and in latent autoimmune diabetes in adults (LADA). The autoimmune attack on pancreatic islet cells is associated with a T helper 1 cell (T_h1) response, mainly represented by IgG₁-subclass in humans. It has been proposed that the presence of IgG₄ may be associated with a T_h2 response. The aim of our study was to compare the GADA IgG-subclass distribution between adult patients with type 1 diabetes and LADA.Methods Patients with type 1 diabetes (n=45) and patients with LADA (n=60) were included. Radioimmunoprecipitation assay with IgG-subclass specific Sepharose (IgG₁, IgG₂, IgG₃ and IgG₄) was used to precipitate the antibody/antigen-complex.Results We only detected IgG₄-subclass of GADA in subjects with LADA (26.7%; p<0.001). IgG₁ was the most common GADA-subclass in both groups, however IgG₁ as the solely expressed subclass was more common among type 1 diabetic patients (77.8%; p<0.05). The rank order of the frequencies of IgG-subclasses in type 1 diabetes was IgG₁>IgG₃>IgG₂>IgG₄ and in LADA patients IgG₁>IgG₄>IgG₂>IgG₃.Conclusions/interpretation The difference in GADA IgG-subclasses could indicate a different immune response, possibly an altered balance between T_h1 and T_h2 cytokine profile in pancreatic islets. This difference could contribute to the slower rate of beta cell destruction in LADA patients, as reflected by a higher C-peptide level at clinical onset.     

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.     

Relationships between ventilatory impairment,sleep hypoventilation and type 2 respiratory failure

Conditions that increase load on respiratory muscles and/or reduce their capacity to cope with this load predispose to type 2 (hypercapnic) respiratory failure. In its milder forms, this imbalance between load and capacity may primarily manifest as sleep hypoventilation which, if untreated, can increase the likelihood of wakeful respiratory failure. Such problems are commonly seen in progressive respiratory neuromuscular disorders, morbid obesity and chronic obstructive pulmonary disease, either separately or together. Identifying patients at risk can be important in determining whether and when to intervene with treatments such as non‐invasive ventilatory assistance. Measurements of wakeful respiratory function are fundamental to this risk assessment. These issues are reviewed in this paper.     

Inspiratory muscle performance in endurance athletes and sedentary subjects

OBJECTIVE: The aim of this study was to determine whether whole-body endurance training is associated with increased respiratory muscle strength and endurance. METHODOLOGY: Respiratory muscle strength (maximum inspiratory pressure (PImax)) and endurance (progressive threshold loading of the inspiratory muscles) were measured in six marathon runners and six sedentary subjects. RESULTS: PImax was similar between the two groups of subjects but the maximum threshold pressure achieved was greater in marathon runners (90 +/- 8 vs 78 +/- 10% of PImax, respectively, mean +/- SD, P < 0.05). During progressive threshold loading, marathon runners breathed with lower frequency, higher tidal volume, and longer inspiratory and expiratory time. At maximum threshold pressure, marathon runners had lower arterial O2 saturation, but perceived effort (Borg scale) was maximal in both groups. Efficiency of the respiratory muscles was similar in both groups being 2.0 +/- 1.7% and 2.3 +/- 1.8% for marathon runners and sedentary subjects, respectively. CONCLUSIONS: The apparent increase in respiratory muscle endurance of athletes was a consequence of a difference in the breathing pattern adopted during loaded breathing rather than respiratory muscle strength or efficiency. This implies that sensory rather than respiratory muscle conditioning may be an important mechanism by which whole-body endurance is increased.     

Use of in vivo-induced antigen technology for identification of Escherichia coli O157:H7 proteins expressed during human infection

Using in vivo-induced antigen technology (IVIAT), a modified immunoscreening technique that circumvents the need for animal models, we directly identified immunogenic Escherichia coli O157:H7 (O157) proteins expressed either specifically during human infection but not during growth under standard laboratory conditions or at significantly higher levels in vivo than in vitro. IVIAT identified 223 O157 proteins expressed during human infection, several of which were unique to this study. These in vivo-induced (ivi) proteins, encoded by ivi genes, mapped to the backbone, O islands (OIs), and pO157. Lack of in vitro expression of O157-specific ivi proteins was confirmed by proteomic analysis of a mid-exponential-phase culture of E. coli O157 grown in LB broth. Because ivi proteins are expressed in response to specific cues during infection and might help pathogens adapt to and counter hostile in vivo environments, those identified in this study are potential targets for drug and vaccine development. Also, such proteins may be exploited as markers of O157 infection in stool specimens.     

Effects on upper airway collapsibility of presence of a pharyngeal catheter

Catheters that traverse the pharynx are often in place during clinical or research evaluations of upper airway function. The purpose of this study was to determine whether the presence of such catheters affects measures of upper airway collapsibility itself. To do so, pharyngeal critical closing pressure (Pcrit) and resistance upstream of the site of collapse Rus) were assessed in 24 propofol‐anaesthetized subjects (14 men) with and without a multi‐sensor oesophageal catheter (external diameter 2.7 mm) in place. Anaesthetic depth and posture were maintained constant throughout each study. Six subjects had polysomnography(PSG)‐defined obstructive sleep apnea (OSA) and 18 either did not have or were at low risk of OSA. Airway patency was maintained with positive airway pressure. At intervals, pressure was reduced by varying amounts to induce varying degrees of inspiratory flow limitation. The slope of the pressure flow relationship for flow‐limited breaths defined Rus. Pcrit was similar with the catheter in and out (?1.5 ± 5.4 cmH₂O and ?2.1 ± 5.6 cmH₂O, respectively, P = 0.14, n = 24). This remained the case both for those with PSG‐defined OSA (3.9 ± 2.2 cmH₂O and 2.6 ± 1.4 cmH₂O, n = 6) and those at low risk/without OSA (?3.3 ± 4.9 cmH₂O and ‐3.7 ± 5.6 cmH₂O, respectively, n = 18). Rus was similar with the catheter in and out (20.0 ± 12.3 cmH₂O mL^?1 s^?1 and 16.8 ± 10.1 cmH₂O mL^?1 s^?1, P = 0.22, n = 24). In conclusion, the presence of a small catheter traversing the pharynx had no significant effect on upper airway collapsibility in these anaesthestized subjects, providing reassurance that such measures can be made reliably in their presence.