Faculty Bibliography

Longitudinal modelling of lung function in Duchenne's muscular dystrophy is complicated by a mixture of both growth and decline in lung function within each subject, an unknown point of separation between these phases and significant heterogeneity between individual trajectories. Linear mixed effects models can be used, assuming a single changepoint for all cases; however, this assumption may be incorrect. The paper describes an extension of linear mixed effects modelling in which random changepoints are integrated into the model as parameters and estimated by using a stochastic EM algorithm. We find that use of this 'mixture modelling' approach improves the fit significantly

STUDY OBJECTIVES: To examine the hypothesis that respiratory events in obstructive sleep apnea syndrome (OSAS) end in arousal not detected by conventional electroencephalographic (EEG) leads. DESIGN: Observational. SETTING: The study was conducted at a major metropolitan sleep disorders center. SUBJECTS: 10 patients with untreated OSAS and 5 patients undergoing continuous positive airway pressure (CPAP) titration for OSAS. MEASUREMENTS AND RESULTS: Standard clinical nocturnal polysomnography recordings were supplemented to include frontal EEG leads and airflow measured by nasal cannula pressure. In 10 untreated subjects, 1465 obstructive events (apneas, hypopneas, and flow limitation events), and in 5 subtherapeutic CPAP-titrated subjects, 459 total events were identified during non-rapid eye movement (REM) sleep only. American Academy of Sleep Medicine arousal criteria applied to central leads and to frontal leads allowed detection of an additional 24% respiratory event-related arousals by frontal leads than by conventional leads. Frontal arousal detection differed by event type: 16% of apneas, 21% of hypopneas, and 35% of flow limitation events. Autonomic correlate (increased heart rate) of both conventional and frontal arousals was similar (in a subgroup of 8 untreated patients, analyzing only flow limitation events). Tabulating frontal arousals separately for each frontal lead indicated that Fz as the sole frontal lead (added to conventional leads) increased detection of arousals by 19% over using only conventional leads (total of 92% of all obstructive respiratory events). CONCLUSIONS: The addition of a single frontal lead (Fz) yields additional respiratory-related arousal information that appears physiologically relevant. Future studies are needed to assess clinical relevance to the evaluation and treatment of sleep-disordered breathing.

STUDY OBJECTIVES: To test the hypothesis that the presence of sensitization to indoor allergens is associated with increased severity of airway obstruction in elderly subjects with asthma. DESIGN: Cohort study of subjects enrolled in a public hospital asthma clinic. SETTING: Asthma clinic in a municipal public hospital serving an indigent population in New York City. PATIENTS: Subjects aged > or = 60 years with asthma who were enrolled in the Bellevue Hospital Asthma Clinic. Total serum IgE and allergen-specific IgE measurements were performed in a cohort of elderly never-smokers who had asthma (45 patients) who had undergone spirometry before and after bronchodilator (BD) therapy. MEASUREMENTS AND RESULTS: The results of radioallergosorbent tests demonstrated that most subjects (ie, 60%) were sensitized to at least one allergen, with many sensitized to at least one indoor allergen. Cockroach (CR) was the most common allergen to which subjects were sensitized, with 47% displaying an elevated serum-specific IgE level. Fewer subjects were sensitized to dust mite, cat, dog, or ragweed. Subjects sensitized to CR (CR+) had greater reductions in airflow compared to subjects not sensitized to CR (CR-) [64 +/- 4.4% predicted vs 77.1 +/- 4.1% predicted FEV(1), respectively; p < 0.05]. Following BD administration, only 29% of CR+ subjects achieved a normal post-BD FEV(1) compared to 58% of CR- subjects. Lung volume measurements differed between CR+ and CR- subjects, with a greater elevation of functional residual capacity in CR+ subjects. CONCLUSION: In a population of elderly urban patients with asthma, the presence of CR-specific serum IgE is associated with more severe asthma, as reflected by an increase in airway obstruction and hyperinflation.

Prevention of acute hypercapnia during obstructive events in obstructive sleep apnea requires a balance between carbon dioxide (CO(2)) loading during the event and CO(2) unloading in the interevent period. Earlier studies have demonstrated that acute CO(2) retention may occur despite high interevent ventilation when the interevent duration is short relative to the duration of the preceding event. The present study examines the relationship between apnea and interapnea durations and relates this assessment of ventilatory periodicity to the degree of chronic hypercapnia in subjects with severe sleep apnea. A total of 18 subjects with sleep apnea (> 40 apnea/hour; chronic awake Pa(CO2) 36-62 mm Hg) and without underlying lung disease underwent polysomnography. For each event, apnea duration, interapnea duration, and apnea/interapnea duration ratio were determined. No relationship was observed between chronic Pa(CO2) and mean apnea or interapnea duration (p > 0.1). However, Pa(CO2) was directly related to apnea/interapnea duration ratio (r = 0.48; p < 0.05) such that with increasing chronic hypercapnia the interapnea duration shortens relative to the apnea duration. The present study suggests that control of the interapnea ventilatory duration relative to the duration of the preceding apnea, is an important component of the integrated ventilatory response to CO(2) loading during apnea and may contribute toward the development and/or maintenance of chronic hypercapnia in obstructive sleep apnea/hypopnea syndrome.

Gene transfer of p53 induces cell death in most cancer cells, and replication-defective adenoviral vectors expressing p53 are being evaluated in clinical trials. However, low transduction efficiency limits the efficacy of replication-defective vector systems for cancer therapy. The use of replication-competent vectors for gene delivery may have several advantages, holding the potential to multiply and spread the therapeutic agent after infection of only a few cells. However, expression of a transgene may adversely affect viral replication. We have constructed a replicating adenoviral vector (Adp53rc) that expresses high levels of p53 at a late time point in the viral life cycle and also contains a deletion of the adenoviral death protein (ADP). Adp53rc-infected cancer cells demonstrated high levels of p53 expression in parallel with the late expression pattern of the adenoviral fiber protein. p53 expression late in the viral life cycle did not impair effective virus propagation. Survival of several lung cancer cell lines was significantly diminished after infection with Adp53rc, compared with an identical p53-negative control virus. p53 expression also improved virus release and spread. Interestingly, p53 was more cytotoxic than the ADP in cancer cells but less cytotoxic than the ADP in normal cells. In conclusion, late expression of p53 from a replicating virus improves tumor cell killing and viral spread without impairing viral replication. In addition, in combination with a deletion of the ADP, specificity of tumor cell killing is improved.

Maintenance of eucapnia during sleep in obstructive sleep apnea (OSA) requires a balance between CO(2) loading during apnea and CO(2) elimination. This study examines individual respiratory events and relates magnitude of postevent ventilation to CO(2) load during the preceding respiratory event in 14 patients with OSA (arterial PCO(2) 42-56 Torr). Ventilation and expiratory CO(2) and O(2) fractions were measured on a breath-by-breath basis during daytime sleep. Calculations included CO(2) load during each event (metabolic CO(2) production - exhaled CO(2)) and postevent ventilation in the 10 s after an event. In 12 of 14 patients, a direct relationship existed between postevent ventilation and CO(2) load during the preceding event (P < 0.05); the slope of this relationship varied across subjects. Thus the postevent ventilation is tightly linked to CO(2) loading during each respiratory event and may be an important mechanism that defends against development of acute hypercapnia in OSA. An inverse relationship was noted between this postevent ventilatory response slope and the chronic awake arterial PCO(2) (r = 0.90, P < 0.001), suggesting that this mechanism is impaired in patients with chronic hypercapnia. The link between development of acute hypercapnia during respiratory events asleep and maintenance of chronic awake hypercapnia in OSA remains to be further investigated.