Lisa Wolfe

Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker

Purpose : This report summarizes our experiences on the protective effect of angiotensin-converting enzyme (ACE) inhibitors, especially captopril and an angiotensin II type 1 receptor blocker on radiation-induced pulmonary injury. Method : In the first series of experiments, adult male Sprague Dawley rats were given a single dose of either 20 or 30 Gy of gamma rays to a 35 cm 2 right hemithorax port, whilst shielding the left, contralateral, lung. Perfusion scans and autopsies were performed at intervals up to 12 months post-radiation. Three different ACE inhibitors, penicillamine and pentoxifylline were given as radiation protectors and their activity compared. A model of irradiation for total bone marrow transplant (BMT) was used for the second group of experiments. Male WAC/Rij/MCW rats received total-body irradiation and a regimen of cyclophosphamide (CTX) in preparation for bone marrow transplant. The modifiers were two ACE inhibitors, captopril and enalapril, and L-158,809, an angiotensin II (A II) type 1 receptor blocker. All drugs were administered in the rats‚ drinking water and all were well-tolerated. Results : In the irradiated rats, pulmonary damage progressed from the presence of blebs and detachment from basement membranes of endothelial cells a few days after injury, to severe arteritis and interstitial collagen deposition at 3 months, and then on to severe pneumonitis and extensive pulmonary fibrosis at 6 months. Marked increase of hydroxyproline was also found in the lungs at 6 months. These morphological changes were associated with significant decrease of ACE and plasminogen activator activity (PLA) and a marked increase of prostaglandins (PG12) and thromboxane (Txa2), substances considered as indicators of endothelial pulmonary damage. ACE inhibitors captopril, CL 24817, enalapril and CGS 13945 prevented the markers of endothelial dysfunction. Captopril and CL 24817, which contain a sulphydryl (-SH) radical in their moiety and the AII type 1 receptor blocker, L-158,809, were the most efficient in protecting the lung parenchyma from the inflammatory response and subsequent fibrosis. Penicillamine, an SH-containing compound with weak ACE inhibitory activity was also a strong antifibrotic agent but showed only modest anti-inflammatory properties. Additionally, in the irradiated rats, captopril also reduced the incidence of squamous cell skin carcinomas and subcutaneous sarcomas consequent to the highest doses of radiation. Conclusion : ACE inhibitors and one AII type 1 receptor blocker were effective in protecting lungs from radiation-induced pneumonitis and the development of lung fibrosis in two models of rat radiation injury. In the first series of experiments (unilateral irradiation), those ACE inhibitors containing a sulphydryl radical were more effective than those without it. This observation led to the question of whether this protective effect is related to inhibition of AII synthesis or rather to some of the collateral pharmacologic properties of these drugs, such as anti-oxidation or protease inhibition. The AII receptor blocker, however, was shown to be equally effective, if not better, in its antifibrotic capacity than any ACE inhibitor with or without an SH radical, reaffirming the role of AII in modulation of collagen synthesis.

Stability of melatonin and temperature as circadian phase markers and their relation to sleep times in humans

Circadian rhythms of core body temperature and melatonin are commonly used as phase markers of the circadian clock. Melatonin is a more stable marker of circadian phase when measured under constant routine conditions. However, little is known about the variability of these phase markers under less controlled conditions. Moreover, there is little consensus about the preferred method of analysis. The objective of this study was to assess various methods of calculating melatonin and temperature phase in subjects with regular sleep schedules living in their natural environment. Baseline data were analyzed from 42 healthy young subjects who were studied on at least two occasions. Each hospital admission was separated by at least 3 weeks. Subjects were instructedto maintain a regular sleep schedule, which was monitored for 1 week before admission by sleep logs and actigraphy. Subjects spent one habituation night under controlled conditions prior to collecting baseline temperature and melatonin measurements. The phase of the melatonin rhythm was assessed by 9 different methods. The temperature nadir (Tmin) was estimated using both Cleveland and Cosine curve fitting procedures, with and without demasking. Variability between admissions was assessed by correlation analysis and by the mean absolute difference in timing of the phase estimates. The relationship to sleep times was assessed by correlation of sleep onset or sleep offset with the various phase markers. Melatonin phase markers were more stable and more highly correlated with the timing of sleep than estimates of Tmin. Of the methods for estimating Tmin, simple cosine analysis was the least variable. In addition, sleep offset was more strongly correlated with the various phase markers than sleep onset. The relative measures of melatonin offset had the highest correlation coefficients, the lowest study-to-study variability, and were more strongly associated with sleep timing than melatonin onsets. Concordance of the methods of analysis suggests a tendency for the declining phase of the melatonin profile to be more stable and reliable than either markers of melatonin onset or measures of the termination of melatonin synthesis.

Responsiveness of the aging circadian clock to light.

The present study assessed whether advances in sleep times and circadian phase in older adults might be due to decreased responsiveness of the aging circadian clock to light. Sixteen young (29.3+/-5.6 years) and 14 older adults (67.1+/-7.4 years) were exposed to 4h of control dim (10lux) or bright light (3500lux) during the night. Phase shifts of the melatonin rhythm were assessed from the nights before and after the light exposure. Bright light delayed the melatonin midpoint in both young and older adults (p<0.001). Phase delays for the older subjects were not significantly different from those of the young subjects for either the bright or dim light conditions. The magnitude of phase delays was correlated with both sleep offset and phase angle in the older, but not the younger subjects. The present results indicate that at light intensities commonly used in research as well as clinical practice older adults are able to phase delay to the same extent as younger subjects.

Prevention of radiation-induced nephropathy and fibrosis in a model of bone marrow transplant by an angiotensin II receptor blocker.

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.

The complex sleep apnea resolution study: A prospective randomized controlled trial of continuous positive airway pressure versus adaptive servoventilation therapy

INTRODUCTION Prior studies show that adaptive servoventilation (ASV) is initially more effective than continuous positive airway pressure (CPAP) for patients with complex sleep apnea syndrome (CompSAS), but choosing therapies has been controversial because residual central breathing events may resolve over time in many patients receiving chronic CPAP therapy. We conducted a multicenter, randomized, prospective trial comparing clinical and polysomnographic outcomes over prolonged treatment of patients with CompSAS, with CPAP versus ASV. METHODS Qualifying participants meeting criteria for CompSAS were randomized to optimized CPAP or ASV treatment. Clinical and polysomnographic data were obtained at baseline and after 90 days of therapy. RESULTS We randomized 66 participants (33 to each treatment). At baseline, the diagnostic apnea-hypopnea index (AHI) was 37.7 ± 27.8 (central apnea index [CAI] = 3.2 ± 5.8) and best CPAP AHI was 37.0 ± 24.9 (CAI 29.7 ± 25.0). After second-night treatment titration, the AHI was 4.7 ± 8.1 (CAI = 1.1 ± 3.7) on ASV and 14.1 ± 20.7 (CAI = 8.8 ± 16.3) on CPAP (P ≤ 0.0003). At 90 days, the ASV versus CPAP AHI was 4.4 ± 9.6 versus 9.9 ± 11.1 (P = 0.0024) and CAI was 0.7 ± 3.4 versus 4.8 ± 6.4 (P < 0.0001), respectively. In the intention-to-treat analysis, success (AHI < 10) at 90 days of therapy was achieved in 89.7% versus 64.5% of participants treated with ASV and CPAP, respectively (P = 0.0214). Compliance and changes in Epworth Sleepiness Scale and Sleep Apnea Quality of Life Index were not significantly different between treatment groups. CONCLUSION Adaptive servoventilation (ASV) was more reliably effective than CPAP in relieving complex sleep apnea syndrome. While two thirds of participants experienced success with CPAP, approximately 90% experienced success with ASV. Because both methods produced similar symptomatic changes, it is unclear if this polysomnographic effectiveness may translate into other desired outcomes. CLINICAL TRIALS Clinicaltrials.Gov NCT00915499.

Management of pulmonary complications in neuromuscular disease.

Restrictive lung disease occurs commonly in patients with neuromuscular disease. The earliest sign of respiratory compromise in the patient with neuromuscular disease is nocturnal hypoventilation, which progresses over time to include daytime hypoventilation and eventually the need for full-time mechanical ventilation. Pulmonary function testing should be done during regular follow-up visits to identify the need for assistive respiratory equipment and initiate early noninvasive ventilation. Initiation of noninvasive ventilation can improve quality of life and prolong survival in patients with neuromuscular disease.

Gastrostomy tube placement by endoscopy versus radiologic methods in patients with ALS: A retrospective study of complications and outcome

Abstract Gastrostomy tube placement for malnutrition and weight loss stabilization occurs in many patients with ALS. We sought to compare the outcome and complications of gastrostomy tube placement by endoscopic (PEG) and multiple radiologic (RIG) methods in ALS patients. A retrospective analysis was conducted on all ALS patients evaluated at Northwestern University who received gastrostomy tubes between January 2009 and March 2012. One hundred and eight gastrostomy tube attempts were made on a total of 100 different patients. Failed gastrostomy tube placement occurred in 15.7% of PEGs and 1.9% of RIGs. Post-procedure aspiration was recognized after 10.5% PEG and 0 RIG attempts. Multivariate analysis revealed a linear increase in risk of post-procedure aspiration for every increase in ALSFRS swallow score. No statistically significant differences in failure or complications were observed when comparing two different methods of RIG (push-type vs. pull-type). Our findings support gastrostomy tube placement by radiographic methods in ALS patients. Gastrostomy tube placement by RIG was more often successful and less often associated with aspiration. Our findings add to the growing body of literature that argues for early gastrostomy tube placement in young patients with prominent bulbar involvement.

Hyperinflation is associated with lower sleep efficiency in COPD with co-existent obstructive sleep apnea.

ABSTRACT Prior research has shown that individuals with obstructive lung disease are at risk for sleep fragmentation and poor sleep quality. We postulated that patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (known as overlap syndrome) who have more severe lung disease, as measured by lung hyperinflation (inspiratory capacity/total lung capacity), would have greater sleep disturbances independent of traditional measures of sleep apnea. We performed a retrospective chart review of consecutive patients evaluated and treated in an academic pulmonary clinic for overlap syndrome. Pulmonary function tests and polysomnogram data were collected. Thirty patients with overlap syndrome were included in the analysis. We found significant univariable associations between sleep efficiency and apnea/hypopnea index (β = −0.285, p = 0.01) and between sleep efficiency and lung hyperinflation (β = 0.654, p = 0.03). Using multivariable linear regression, the relationship between sleep efficiency and lung hyperinflation remained significant (β = 1.13, p = 0.02) after adjusting for age, sex, body mass index, apnea/hypopnea index, FEV1% predicted, oxygen saturation nadir, medications, and cardiac disease. We conclude that increased severity of hyperinflation is associated with worse sleep efficiency, independent of apnea and nocturnal hypoxemia. The mechanisms underlying this observation are uncertain. We speculate that therapies aimed at reducing lung hyperinflation may improve sleep quality in patients with overlap syndrome.

Ictal central apnea as a predictor for sudden unexpected death in epilepsy

Epidemiological evidence associating ictal hypoventilation during focal seizures with a heightened risk for subsequent sudden unexpected death in epilepsy (SUDEP) is lacking. We describe a patient with temporal lobe epilepsy with two focal seizures recorded in the epilepsy monitoring unit that were associated with central apnea lasting 57 and 58 seconds. During these events, she demonstrated oxygen desaturation down to 68 and 62%. The patient subsequently died at home from autopsy-confirmed SUDEP. The family was not alerted of any seizure activity by the auditory alarm system in her room nor by sleeping in the adjacent room with open doors. This case emphasizes the fact that ictal hypoxia and SUDEP may occur in seizures without noticeable convulsive activity. The report gives credibility to the growing body of literature suggesting that epilepsies affecting the autonomic nervous system may predispose to SUDEP independent of the effects of a secondary generalized convulsion.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: review and update.

Purpose of review The focus of this review is to compare and contrast two orphan disorders of late-onset hypoventilation. Specifically, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) and congenital central hypoventilation syndrome (CCHS) are distinct in presentation, pathophysiology, and etiology. Recent findings While limited new information is available, appreciation and understanding of rare disorders can be attained through case reports. Recent literature in ROHHAD has included case reports with new findings that may provide insight into pathophysiology involving possible aberrant immune process and dysregulation at the level of the orexinergic system. Summary The etiology of ROHHAD continues to be elusive. The hope is that, with growing recognition, discussion, and investigation into the overlap of ROHHAD with disorders outside congenital central hypoventilation syndrome, further advancement will be made.