Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus.

BACKGROUND AND OBJECTIVES: Alpha-1 antitrypsin (AAT) has been shown to reduce pro-inflammatory markers and protect pancreatic islets from autoimmune responses in recent studies. Our aim was to evaluate its safety and tolerability in three different doses, in a pediatric population with recent onset type 1 diabetes mellitus (T1DM). METHODS: A 37-wk prospective, open-label, phase I/II interventional trial, comprised of 24 recently diagnosed subjects (12 males; age 12.9 ± 2.4 yr), who received 18 infusions of 40, 60, or 80 mg/kg/dose high-purity, liquid, ready to use AAT over 28 wk (Glassia(®) ; Kamada Ltd., Ness Ziona, Israel). PRIMARY OUTCOMES: safety and tolerability; secondary outcomes: glycemic control, C-peptide reserve, and autoantibody levels. Possible responders were defined as individuals with peak C-peptide that declined less than 7.5% below baseline. RESULTS: No serious adverse events, diabetic ketoacidosis (DKA), or severe hypoglycemic episodes were reported. Adverse events were dose-independent and transient. Glycemic control parameters improved during the study in all groups, independent of dosage. Hemoglobin A1c (HbA1c) decreased from 8.43 to 7.09% (mean, p < 0.001). At the end of the study, 18 subjects (75%) had a peak C-peptide ≥0.2 pmol/mL. Eight subjects (33.3%) were considered possible responders and were characterized by shorter duration of T1DM at screening (54.5 ± 34.3 vs. 95.9 ± 45.7 d, p = 0.036) and greater decrease in their HbA1c during the study period (-2.94 ± 1.55 vs.-0.95 ± 1.83%, p = 0.016). CONCLUSIONS: AAT treatment was safe and well tolerated in pediatric subjects with recently diagnosed autoimmune diabetes. Placebo-controlled studies with larger cohorts and dose range are warranted in order to assess efficacy in maintaining pancreatic beta cell reserve and glycemic control.

Dissociation of electromyogram and mechanical response in sleep apnoea during propofol anaesthesia.

Pharyngeal collapsibility during sleep is believed to increase due to a decline in dilator muscle activity. However, genioglossus electromyogram (EMG) often increases during apnoeas and hypopnoeas, often without mechanical effect. 17 patients with obstructive sleep apnoea were anaesthetised and evaluated from termination of propofol administration to awakening. Genioglossus EMG, flow and pharyngeal area (pharyngoscopy) were monitored. Prolonged hypopnoeas enabled evaluation of the relationships between genioglossus EMG and mechanical events, before and after awakening. Additional dilator muscle EMGs were recorded and compared to the genioglossus. Electrical stimulation of the genioglossus was used to evaluate possible mechanical dysfunction. Prolonged hypopnoeas during inspiration before arousal triggered an increase in genioglossus EMG, reaching mean ± SD 62.2 ± 32.7% of maximum. This augmented activity failed to increase flow and pharyngeal area. Awakening resulted in fast pharyngeal enlargement and restoration of unobstructed flow, with marked reduction in genioglossus EMG. Electrical stimulation of the genioglossus under propofol anaesthesia increased the inspiratory pharyngeal area (from 25.1 ± 28 to 66.3 ± 75.5 mm(2); p<0.01) and flow (from 11.5 ± 6.5 to 18.6 ± 9.2 L · min(-1); p<0.001), indicating adequate mechanical response. All additional dilators increased their inspiratory activity during hypopnoeas. During propofol anaesthesia, pharyngeal occlusion persists despite large increases in genioglossus EMG, in the presence of a preserved mechanical response to electrical stimulation.

Respiratory functions in adolescents hospitalized for anorexia nervosa: a prospective study.

OBJECTIVE: To examine the effects of malnourishment on the respiratory system of adolescents with anorexia nervosa (AN) hospitalized for medical stabilization. METHOD: Prospective study. STUDY GROUP: hospitalized adolescents with recent onset (<1 year) AN. CONTROL GROUP: adolescents hospitalized for other diagnoses. Excluded: participants with lung disease. RESULTS: Patients' characteristics (mean ± SD) for the AN (n = 16) and the control group (n = 13) on admission were: age: 15.0 ± 1.7 vs. 15.2 ± 1.4 years, p = 0.7; body mass index (BMI): 15.5 ± 2.3 vs. 19.8 ± 2.9 kg/m², p < 0.001; venous pH 7.34 ± 0.02 vs. 7.38 ± 0.03, p < 0.001; PCO2 53.3 ± 4.1 vs. 42.5 ± 3.1 mm Hg, p < 0.001; and HCO3 28.7 ± 2.0 vs. 25.3 ± 2.4 meq/L, p < 0.001, respectively. There were no significant differences in nocturnal respiratory rates, pulse-oximetry oxygen saturations, or end-tidal CO2. Pulmonary function tests (PFTs) in adolescents with AN revealed no obstructive, restrictive, or significant pulmonary vascular disease except for lower peak expiratory flow rates (PEFRs). During hospitalization (12.3 ± 3.8 days), their weight, BMI, mean nocturnal heart rate, and respiratory rate increased significantly, while their venous PCO2 and HCO3 decreased significantly without significant changes in PFTs. DISCUSSION: Adolescents with recent onset AN, admitted for medical stabilization, demonstrate hypercapnia despite normal PFTs, except for decreased PEFRs. These could result from decreased respiratory muscle strength and/or abnormal control of breathing.

Effect of coactivation of tongue protrusor and retractor muscles on pharyngeal lumen and airflow in sleep apnea patients.

The present study evaluated the effect of coactivation of tongue protrusors and retractors on pharyngeal patency in patients with obstructive sleep apnea. The effect of genioglossus (GG), hyoglossus (HG), and coactivation of both on nasal pressure (Pn):flow relationships was evaluated in a sleep study (SlS, n = 7) and during a propofol anesthesia study (AnS, n = 7). GG was stimulated with sublingual surface electrodes in SlS and with intramuscular electrodes in AnS, while HG was stimulated with surface electrodes in both groups. In the AnS, the cross-sectional area (CSA):Pn relationships was measured with a pharyngoscope to estimate velopharyngeal compliance . In the SlS, surface stimulation of GG had no effect on the critical pressure (Pcrit), HG increased Pcrit from 2.8 +/- 1.7 to 3.7 +/- 1.6 cmH(2)O, but coactivation lowered Pcrit to 0.2 +/- 1.9 cmH(2)O (P < 0.01 for both). In the AnS, intramuscular stimulation of GG lowered Pcrit from 2.6 +/- 1.3 to 1.0 +/- 2.8 cmH(2)O, HG increased Pcrit to 6.2 +/- 2.5 cmH(2)O (P < 0.01), and coactivation had a similar effect to that of GG (Pcrit = 1.2 +/- 2.4 cmH(2)O, P < 0.05). None of the interventions affected significantly velopharyngeal compliance. We conclude that the beneficial effect of coactivation depends on the pattern of GG fiber recruitment: although surface stimulation of GG failed to protrude the tongue, it prevented the occlusive effect of the retractor, thereby improving pharyngeal patency during coactivation. Stimulation of deeper GG fibers with intramuscular electrodes enlarged the pharynx, and coactivation had no additive effect.

Mechanical parameters determining pharyngeal collapsibility in patients with sleep apnea.

The relative impact of mechanical factors on pharyngeal patency in patients with obstructive sleep apnea is poorly understood. The present study was designed to evaluate parameters of the "tube law" on pharyngeal pressure-flow relationships and collapsibility in patients with obstructive sleep apnea. We developed a mathematical model that considered the collapsible segment of the pharynx to represent an orifice of varying diameter. The model enabled us to assess the effects of pharyngeal compliance (C), neutral cross-sectional area (A(o)), external peripharyngeal pressure (P(ex)), and the resistance proximal to the site of collapse on flow mechanics and pharyngeal collapsibility [critical pressure (P(crit))]. All parameters were measured in 15 patients with obstructive sleep apnea under propofol anesthesia, both at rest and during mandibular advancement and electrical stimulation of the genioglossus. The data was used both to confirm the validity of the model and to compare expected and actual relationships between the tube-law parameters and the pharyngeal pressure-flow relationship and collapsibility. We found a close correlation between predicted and measured P(crit) (R = 0.98), including changes observed during pharyngeal manipulations. C and A(o) were closely and directly interrelated (R = 0.93) and did not correlate with P(crit). A significant correlation was found between P(ex) and P(crit) (R = 0.77; P < 0.01). We conclude that the pharynx of patients with obstructive sleep apnea can be modeled as an orifice with varying diameter. Pharyngeal compliance and A(o) are closely interrelated. Pharyngeal collapsibility depends primarily on the surrounding pressure.