Search

Background: Insomnia, a known cardiovascular risk factor, is common in end-stage renal disease (ESRD) patients. There is growing acknowledgment of a potential bidirectional relationship between cardiovascular diseases and sleep disorders. We previously assessed the risk factors for common sleep disorders in ESRD patients. This follow-up study assesses the demographic and clinical cardiovascular-related risk factors for insomnia diagnosis in ESRD patients, given their increased cardiovascular burden., Methods: This study is a retrospective analysis of the United States Renal Data System to evaluate risk factors for insomnia diagnosis. All patients in the USRDS who started dialysis between 2005 and 2019 were eligible for inclusion. Demographic risk factors analyzed were age, race, sex, ethnicity, dialysis modality, and access type. Cardiovascular risk factors, including obstructive sleep apnea (OSA) and central sleep apnea (CSA), were also evaluated., Results: Female sex, OSA, CSA, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, diabetes, chronic obstructive pulmonary disease, obesity, and hypertension were associated with an increased risk of insomnia. Increasing age, non-white race, Hispanic ethnicity, and catheter or other/peritoneal dialysis access type were associated with a decreased risk of an insomnia diagnosis., Conclusion: Various cardiovascular diseases were independent risk factors for an insomnia diagnosis in this retrospective cohort. Further study is indicated to investigate potential mechanisms underlying this connection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Southern Society for Clinical Investigation. All rights reserved.)

Obstructive sleep apnea (OSA) is a prevalent pathology with current modalities of treatment including continuous positive airway pressure (CPAP), surgery, weight loss, hypoglossal nerve stimulation, and pharmacotherapy. While CPAP is the current standard treatment for OSA, lack of tolerance and side effects necessitate alternative modalities of treatment. Various pharmacologic agents exist with mechanisms that may target OSA. Early trials have demonstrated efficacy of noradrenergic-antimuscarinic combinations to stimulate the airway, promote pharyngeal muscle tone, and prevent airway collapse. These agents, which we discuss in detail, have demonstrated significant reductions in apnea-hypopnea index (AHI) and lowest oxygen saturations based on preliminary studies. Glucagon-like peptide 1 receptor agonists (GLP-1RA), which stimulate endogenous insulin, reducing glucagon release, and decreasing gastric emptying, have shown positive results for OSA patients through weight loss with reductions in AHI. In this narrative review article, we highlight the mechanisms, current data, and future potential for multiple drug classes, including respiratory stimulants and GLP-1RAs., Competing Interests: Conflicts of Interest: The authors declare no conflicts of interest.

In the general population, abdominal aortic aneurysm (AAA) is synonymous with vascular disease and associated with increased mortality. Vascular disease is common in end-stage renal disease (ESRD) patients on dialysis, but there is limited information on AAA in this population. To address this issue, we queried the United States Renal Data System for risk factors associated with a diagnosis of AAA as well as the impact of AAA on ESRD patient survival. Incident dialysis patients from 2005 to 2014 with AAA and other clinical comorbidities were identified using ICD-9 and ICD-10 codes. Time to death was defined using the time from the start of dialysis to the date of death or to December 31, 2015. Cox proportional hazards (CPH) modeling was used to determine the adjusted hazard ratio (aHR) and 95% confidence intervals (CI) for death. From a total cohort of 820,826, we identified 21,631 subjects with a diagnosis of AAA. When compared to patients without AAA, AAA patients were older and more likely to be of white race and male gender, have a higher mean Charlson comorbidity index (CCI), have hypertension as the ESRD etiology, and use tobacco. Although a bivariate CPH model showed that AAA patients had an increased mortality risk compared to patients without the diagnosis, in the final CPH model, AAA patients had a decreased risk of mortality (aHR = 0.83, 95% CI 0.81-0.84) due to confounding with age. These results suggest that AAA is not associated with increased risk of death in ESRD patients after controlling for various demographic and clinical risk factors., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Vitiligo is an autoimmune condition that causes patchy skin depigmentation. Although the mechanism by which vitiligo induces immunocompromise is unclear, other related autoimmune diseases are known to predispose those affected to infection. Individuals with vitiligo exhibit epidermal barrier disruption, which could potentially increase their susceptibility to systemic infections; patients with renal disease also show a predisposition to infection. Nevertheless, there is little research addressing the risk of infection in dialysis patients with vitiligo in comparison to those without it. A retrospective analysis was performed on patients with end-stage renal disease (ESRD) in the United States Renal Data System who started dialysis between 2004 and 2019 to determine if ESRD patients with vitiligo are at an increased risk of bacteremia, cellulitis, conjunctivitis, herpes zoster, or septicemia. Multivariable logistic regression modeling indicated that female sex, black compared to white race, Hispanic ethnicity, hepatitis C infection, and tobacco use were associated with an enhanced risk of vitiligo, whereas increasing age and catheter, versus arteriovenous fistula, and access type were associated with a decreased risk. After controlling for demographics and clinical covariates, vitiligo was found to be significantly associated with an increased risk of bacteremia, cellulitis, and herpes zoster but not with conjunctivitis and septicemia.

Background and Objectives : Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin condition affecting 16.5 million adults in the United States. AD is characterized by an impaired epidermal barrier that can predispose individuals to infection. End-stage renal disease (ESRD) is also commonly complicated by infections due to chronic vascular access and immune-system dysfunction, possibly related to uremia. Multiple studies have reported that renal disease is a common comorbidity in adults with atopic dermatitis. The aim of this study was to determine whether AD is a risk factor for certain infections in patients with ESRD. Materials and Methods : Using the United States Renal Data System, a retrospective cohort analysis was conducted on adult ESRD patients initiating dialysis between 2004 and 2019 to investigate associations between infections and AD in this population. Results : Of 1,526,266 patients, 2290 were identified with AD (0.2%). Infectious outcomes of interest were bacteremia, septicemia, cellulitis, herpes zoster, and conjunctivitis. In all infectious outcomes except for conjunctivitis, patients with the infectious outcomes were more likely to carry a diagnosis of AD. After controlling for demographic and clinical covariates, AD was associated with an increased risk of cellulitis (adjusted relative risk (aRR) = 1.39, 95% confidence interval (CI) = 1.31-1.47) and herpes zoster (aRR = 1.67, CI = 1.44-1.94), but not with bacteremia (aRR = 0.96, CI = 0.89-1.05), septicemia (aRR = 1.02, CI = 0.98-1.08), or conjunctivitis (aRR = 0.97, CI = 0.740-1.34). Conclusions : Overall, after controlling for demographic and clinical covariates and adjusting for person-years-at-risk, AD was associated with an increased risk for some, but not all, infections within the population of patients with ESRD.

Background: Sleep disturbances in patients with end-stage renal disease (ESRD) are common and more prevalent than in the general population. This study aims to assess the demographic and clinical risk factors for the diagnosis of sleep disorders in ESRD patients., Methods: This study is a retrospective analysis of the United States Renal Data System (USRDS) to evaluate risk factors for the diagnosis of sleep disorders, including hypersomnolence, insomnia, restless leg syndrome (RLS), or obstructive or central sleep apnea (OSA/CSA). All ESRD subjects enrolled in the USRDS between 2004-2015 were eligible for inclusion. The risk factors analyzed were age, race, sex, ethnicity, access type, dialysis modality, and the Charlson Comorbidity Index (CCI). All statistical analysis was performed using SAS 9.4, and statistical significance was assessed using an alpha level of 0.05. Descriptive statistics on all variables overall and by each sleep diagnosis were determined., Results: Increasing age, black race, other race, and Hispanic ethnicity were associated with decreased risk of each sleep diagnosis while CCI was associated with increased risk. Females were at increased risk of RLS and insomnia while males were at increased risk of OSA/CSA. Catheter and graft access decreased risk of RLS but increased risk of insomnia compared to AVF access. Catheter access increased risk of OSA/CSA compared to graft access. Hemodialysis increased risk of OSA/CSA compared to peritoneal dialysis., Conclusions: Some ESRD patients are at an increased risk for diagnosis of sleep disorders based on age, race, sex, comorbid health conditions, and dialysis modality., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Southern Society for Clinical Investigation. All rights reserved.)

Sleep apnea (SA) is highly prevalent in the end-stage renal disease (ESRD) population. However, the impact of SA on mortality in ESRD is unclear. This study investigates the relationship between SA and mortality in ESRD. The United States Renal Data System was queried in a retrospective cohort study to identify ESRD patients aged 18-100 years who initiated hemodialysis between 2005 and 2013. Diagnoses of SA and comorbidities were determined from International Classification of Disease-9 codes and demographic variables from Centers for Medicare and Medicaid Services Form-2728. Cox proportional hazards models were used to examine the association of SA with mortality controlling for multiple variables. Of 858,131 subjects meeting inclusion criteria, 587 were found to have central SA (CSA) and 22,724 obstructive SA (OSA). The SA cohort was younger and more likely to be male and Caucasian compared to the non-SA cohort, with more diagnoses of tobacco and alcohol use, hypertension, heart failure, and diabetes. Both CSA (adjusted hazard ratio (aHR) = 1.42, 95% confidence interval (CI): 1.29-1.56) and OSA (aHR = 1.35, 95% CI: 1.32-1.37) were associated with increased mortality. Other variables associated with increased mortality included age, dialysis initiation with a catheter or graft, alcohol use, hypertension, and cardiovascular disease. Factors associated with decreased mortality included female sex, black race, Hispanic ethnicity, diagnosis of heart failure or diabetes, and an ESRD etiology of glomerulonephritis or polycystic kidney disease. Since a diagnosis of either OSA or CSA increases mortality risk, early identification of SA and therapy in this ESRD population may improve survival.

Study Objectives: To determine if obstructive sleep apnea syndrome (OSAS) predisposes patients to glaucoma and macular disease due to vascular compromise by evaluating retinal and optic nerve vasculature and function using optical coherence tomography angiography and Humphrey visual field testing, respectively., Methods: In this prospective, observational, cross-sectional study 45 patients undergoing polysomnography ordered per standard of care were selected and stratified based on apnea-hypopnea index (AHI). Medical history, visual acuity testing, 24-2 Humphrey visual field, intraocular pressure measurement, and optical coherence tomography angiography studies of the macular and peripapillary retina were obtained. Correlations between polysomnography parameters and imaging data were analyzed., Results: The radial peripapillary capillary vascular density demonstrated no relationship to AHI (95% confidence interval [CI] [-0.026,0.038]) or severity of OSAS (95% CI: [-0.772, 3.648]) for moderate OSAS compared to mild/normal and (-1.295, 3.1421) for severe compared to mild/normal. Optical coherence tomography angiography superficial parafoveal vascular density (95% CI: [-0.068,0.011], deep parafoveal vascular density (95% CI: [-0.080,0.009]), and foveal avascular zone (95% CI: [-0.001, 0.001]) showed no statistically significant relationship to AHI or OSAS severity after controlling for confounders. Optical coherence tomography retinal nerve fiber layer thickness increased with AHI ( P = .014), but there was no statistically significant correlation with OSAS severity with retinal nerve fiber layer thickness (95% CI: [-12.543, 6.792] for moderate comparing to normal and [-2.883, 16.551] for severe comparing to normal). Visual field parameters were unaffected by OSAS (95% CI: mean deviation [-0.21,0.29], pattern standard deviation: [-0.351, 0.121], visual field index: [-0.166, 0.329]). Optical coherence tomography choroidal thickness showed a statistically significant decrease when OSAS was grouped by severity ( P = .0092) but did not correlate with AHI ( P = .129, 95% CI: [-1.210, 0.095])., Conclusions: The severity of OSAS did not show a statistically significant effect on parameters associated with glaucoma or macular vascular disease. Larger cohorts may be required to determine the physiologic consequences of OSAS on the macular and optic nerve vasculature, structure, and function., Citation: Davanian A, Williamson L, Taylor C, et al. Optical coherence tomography angiography and Humphrey visual field in patients with obstructive sleep apnea. J Clin Sleep Med 2022;18(9):2133-2142., (© 2022 American Academy of Sleep Medicine.)

Background: Renal transplant patients are at increased risk for mucormycosis. Diabetes, neutropenia, deferoxamine therapy, and immunosuppressive medications have been associated with increased risk of mucormycosis in studies of solid organ transplant recipients. To focus on renal transplant patients, the US Renal Data System (USRDS) was queried to determine the incidence and risk factors for mucormycosis., Methods: All renal transplant patients in the USRDS from 1988 to 2015 were queried for a diagnosis of mucormycosis after the first transplant date using ICD-9 and ICD-10 codes. The International Classification of Diseases (ICD) codes, which currently exist in the ninth and tenth revisions, are a global system of classification used to code diagnoses, procedures, and symptoms. We defined proven mucormycosis by a histopathologic or fungal stain procedure code within 7 days of the diagnosis code. Logistic regression controlling for person-years at risk was used to examine demographic and clinical diagnosis risk factors for mucormycosis., Results: Of the 306,482 renal transplant patients, 222 (0.07%) had codes consistent with proven mucormycosis. The incidence of mucormycosis increased from 1990 to 2000 (peak 17.6 per 100,000 person-years) and subsequently demonstrated more variability. Hispanic ethnicity (OR=1.45), age 65 years or greater (OR=1.64), other or black race compared with white race (OR=1.96 and 1.74), cadaver or other donor type (OR=2.41), and receiving tacrolimus (OR=2.09) were associated with increased risk. Comorbidities associated with decreased risk of mucormycosis included female sex (OR=0.68), iron overload (OR=0.56), and receiving mycophenolate mofetil (OR=0.67) or azathioprine (OR=0.53)., Conclusions: In renal transplant patients, age, deceased donor graft transplant, tacrolimus administration, race other than white, and Hispanic ethnicity were associated with increased risk of mucormycosis. Unexpectedly, iron overload was protective. Mucormycosis is a rare infection in renal transplant patients which should be considered in patients with the above risk factors after more common infections have been ruled out., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

A 53-year-old African American male smoker presented with epigastric pain, tarry stools, and laboratory results indicative of acute pancreatitis. Chest X-ray showed a right perihilar mass with pleural effusion. Computed tomography scan showed multiple large right paratracheal and hilar nodes with internal calcification. The patient underwent a fiberoptic bronchoscopy with biopsies which were negative for malignancy. Mediastinoscopy was performed and revealed amyloidosis. Evaluation for multiple myeloma showed elevated kappa and lambda light chains and diffuse polyclonal gammopathy, but there was no monoclonal spike on serum protein electrophoresis. Bone marrow and abdominal fat pad were negative for amyloid, and the patient continues to lack chronic underlying systemic disease with no symptoms on cardiac or pulmonary examination., Competing Interests: None

Bronchiectasis Nontuberculous mycobacterium (NTMnb) infection is an emerging health problem in breast cancer (BCa) patients. We measured sera exosome proteome in BCa-NTMnb subjects and controls by Mass Spectroscopy. Extracellular matrix protein 1 (ECM1) was detected exclusively in the circulating exosomes of 82% of the BCa-NTMnb cases. Co-culture of ECM1+ exosomes with normal human mammary epithelial cells induced epithelial to mesenchymal transition accompanied by increased Vimentin/CDH1 expression ratio and Glutamate production. Co-culture of the ECM1+ exosomes with normal human T cells modulated their cytokine production. The ECM1+ exosomes were markedly higher in sera obtained from BCa-NTMnb subjects. Exclusive expression of APN, APOC4 and AZGP1 was evident in the circulating exosomes of these BCa-NTMnb cases, which predicts disease prevalence independent of the body max index in concert with ECM1. Monitoring ECM1, APN, APOC4 and AZGP1 in the circulating exosomes could be beneficial for risk assessment, monitoring and surveillance of BCa-NTMnb.

Background: Bedaquiline is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent minimal inhibitory concentrations for Mycobacterium tuberculosis and nontuberculous mycobacterial (NTM) lung disease, especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab). Bedaquiline appears to be effective for the treatment of multidrug-resistant TB but has not been tested clinically for NTM disease., Methods: We describe a case series of off-label use of bedaquiline for treatment failure lung disease caused by MAC or Mab. Only patients whose insurance would pay for the drug were included. Fifteen adult patients were selected, but only 10 (six MAC, four Mab) could obtain bedaquiline. The 10 patients had been treated for 1 to 8 years, and all were on treatment at the start of bedaquiline therapy. Eighty percent had macrolide-resistant isolates (eight of 10). The patients were treated with the same bedaquiline dosage as that used in TB trials and received the best available companion drugs (mean, 5.0 drugs). All patients completed 6 months of therapy and remain on bedaquiline., Results: Common side effects included nausea (60%), arthralgias (40%), and anorexia and subjective fever (30%). No abnormal ECG findings were observed with a mean corrected QT interval lengthening of 2.4 milliseconds at 6 months. After 6 months of therapy, 60% of patients (six of 10) had a microbiologic response, with 50% (five of 10) having one or more negative cultures., Conclusions: This small preliminary report demonstrates potential clinical and microbiologic activity of bedaquiline in patients with advanced MAC or Mab lung disease but the findings require confirmation with larger studies.

Background: Low birth weight (LBW) is an important public health problem in undernourished populations., Objective: We tested whether improving women's dietary micronutrient quality before conception and throughout pregnancy increases birth weight in a high-risk Indian population., Design: The study was a nonblinded, individually randomized controlled trial. The intervention was a daily snack made from green leafy vegetables, fruit, and milk (treatment group) or low-micronutrient vegetables (potato and onion) (control group) from ≥ 90 d before pregnancy until delivery in addition to the usual diet. Treatment snacks contained 0.69 MJ of energy (controls: 0.37 MJ) and 10-23% of WHO Reference Nutrient Intakes of β-carotene, riboflavin, folate, vitamin B-12, calcium, and iron (controls: 0-7%). The primary outcome was birth weight., Results: Of 6513 women randomly assigned, 2291 women became pregnant, 1962 women delivered live singleton newborns, and 1360 newborns were measured. In an intention-to-treat analysis, there was no overall increase in birth weight in the treatment group (+26 g; 95% CI: -15, 68 g; P = 0.22). There was an interaction (P < 0.001) between the allocation group and maternal prepregnant body mass index (BMI; in kg/m(2)) [birth-weight effect: -23, +34, and +96 g in lowest (<18.6), middle (18.6-21.8), and highest (>21.8) thirds of BMI, respectively]. In 1094 newborns whose mothers started supplementation ≥ 90 d before pregnancy (per-protocol analysis), birth weight was higher in the treatment group (+48 g; 95% CI: 1, 96 g; P = 0.046). Again, the effect increased with maternal BMI (-8, +79, and +113 g; P-interaction = 0.001). There were similar results for LBW (intention-to-treat OR: 0.83; 95% CI: 0.66, 1.05; P = 0.10; per-protocol OR = 0.76; 95% CI: 0.59, 0.98; P = 0.03) but no effect on gestational age in either analysis., Conclusions: A daily snack providing additional green leafy vegetables, fruit, and milk before conception and throughout pregnancy had no overall effect on birth weight. Per-protocol and subgroup analyses indicated a possible increase in birth weight if the mother was supplemented ≥ 3 mo before conception and was not underweight. This trial was registered at www.controlled-trials.com/isrctn/ as ISRCTN62811278.

RESEARCH QUESTION: Intakes of micronutrient-rich foods are low among women of child-bearing age living in slums. We investigated relationships between consumption of these foods and socio-demographic variables. METHODOLOGY: A 91-item Food Frequency Questionnaire was administered to women (n=1651) aged 16-40 yrs living in a Mumbai slum. We identified associations between categorical demographic variables and consumption frequency of these foods using chi-square tests. Associations with age and body mass index were investigated using one-way ANOVAs. RESULTS: A quarter of women ate fruit and green leafy vegetables < 3 times per week, Apart from in tea, median consumption of milk and milk products was < twice a week, 16% never consumed non-vegetarian foods. Median consumption of non-vegetarian foods was 4.5 times per week. Women employed in unskilled jobs and those whose husbands had skilled occupations ate green leafy vegetables more frequently. Participants educated to tertiary level consumed fruit and milk most frequently (p<0.05).

Of the idiopathic lung diseases, idiopathic pulmonary fibrosis (IPF) and sarcoidosis have been the focus of a growing number of epidemiological investigations on the risk of environmental and occupational exposures. To date, the consistency of epidemiological evidence is suggestive of a causal relationship between several environmental exposures and IPF, with the strongest evidence for cigarette smoking and metal dust. Current knowledge about pathogenesis provides further support for a causal link. However, scant epidemiological evidence for dose-response and temporality weaken the case for making causal inferences. In contrast to IPF, the quantity of epidemiological evidence for environmental exposures and sarcoidosis is smaller. Two studies provide consistent evidence for exposures to agricultural dust and musty odor/mold/mildew, and studies among military personnel and firefighters suggest mixed dust and fume exposures as risk factors for sarcoidosis. Although studies of the pathogenesis of sarcoidosis also provide evidence supporting environmental causation, more epidemiological studies are needed to establish consistency of associations, dose-response, and temporality. Future investigations, of gene-environment interaction offer the potential for strengthening the evidence of causation between several environmental and occupational exposures and idiopathic lung diseases.

Human inducible nitric oxide synthase (iNOS) is active as a dimer of two identical subunits. Each subunit has an amino-terminal oxygenase domain that binds the substrate l-Arg and the cofactors heme and tetrahydrobiopterin and a carboxyl-terminal reductase domain that binds FMN, FAD, and NADPH. We previously demonstrated that a subdomain in the oxygenase domain encoded by exons 8 and 9 is important for dimer formation and NO synthesis. Further, we identified Trp-260, Asn-261, Tyr-267, and Asp-280 as key residues in that subdomain. In this study, using an Escherichia coli expression system, we produced, purified, and characterized wild-type iNOS and iNOS-Ala mutants. Using H(2)O(2)-supported oxidation of N(omega)-hydroxy-l-Arg, we demonstrate that the iNOS mutants' inabilities to synthesize NO are due to selective defects in the oxygenase domain activity. Detailed characterization of the Asp-280-Ala mutant revealed that it retains a functional reductase domain, as measured by its ability to reduce cytochrome c. Gel permeation chromatography confirmed that the Asp-280-Ala mutant exists as a dimer, but, in contrast to wild-type iNOS, urea-generated monomers of the mutant fail to reassociate into dimers when incubated with l-Arg and tetrahydrobiopterin, suggesting inadequate subunit interaction. Spectral analysis reveals that the Asp-280-Ala mutant does not bind l-Arg. This indicates that, in addition to dimerization, proper subunit interaction is required for substrate binding. These data, by defining a critical role for Asp-280 in substrate binding and subunit interactions, give insights into the mechanisms of regulation of iNOS activity.

alpha1-Adrenergic agonists inhibit hyperventilation-induced bronchoconstriction (HIB) in dogs. We tested the hypothesis that alpha-agonists inhibit HIB by reducing bronchovascular leakage and edema that theoretically could cause airway obstruction. Peripheral airways were isolated by using a bronchoscope; pretreated with either methoxamine (Mx), norepinephrine (NE), or saline aerosol; and then exposed to a 2,000 ml/min dry-air challenge (DAC) for 2 min. Colloidal carbon was injected before DAC and used to quantify bronchovascular permeability. Mx-, NE-, and vehicle-treated airways were prepared for morphometric analysis within 1 h after DAC. Light microscopy revealed that the 2-min DAC produced minimal bronchovascular leakage and little epithelial damage. However, pretreatment with either Mx or NE significantly enhanced dry air-induced bronchovascular hyperpermeability and mucosal injury. The increased damage associated with these alpha1-agonists implicates a protective role for the bronchial circulation. The fact that alpha1-agonists inhibit HIB suggests that neither dry air-induced leakage nor injury directly contributes to the development of airway obstruction. In addition, our data suggest that alpha-agonists attenuate HIB in part by augmenting hyperventilation-induced bronchovascular leakage and by replacing airway water lost during a DAC.

Furosemide attenuates hyperpnea-induced airway obstruction (HIAO) in asthmatic subjects via unknown mechanism(s). We studied the effect of furosemide on dry air-induced bronchoconstriction, mucosal injury, and bronchovascular hyperpermeability in a canine model of exercise-induced asthma. Peripheral airway resistance (Rp) was recorded before and after a 2-min dry-air challenge (DAC) at 2,000 ml/min. After pretreatment with aerosolized saline containing 0.75% dimethyl sulfoxide, DAC increased Rp 72 +/- 11% (SE, n = 7) above baseline; aerosolized furosemide (10(-3) M) reduced this response by approximately 50 +/- 6% (P < 0.01). To assess bronchovascular permeability, colloidal carbon was injected (1 ml/kg i.v.) 1 min before DAC, and after 1 h, the vehicle- and furosemide-treated airways were prepared for morphometric analysis. Light microscopy confirmed previous studies showing that DAC damaged the airway epithelium and enhanced bronchovascular permeability. Furosemide did not inhibit dry air-induced mucosal injury or bronchovascular hyperpermeability and in fact tended to increase airway damage and vascular leakage. This positive trend toward enhanced bronchovascular permeability in DAC canine peripheral airways is consistent with the hypothesis that furosemide inhibits HIAO in part by enhancing microvascular leakage and thus counterbalancing the evaporative water loss that occurs during hyperpnea.

Cystic fibrosis is a lethal autosomal recessive disorder. In 1989, the cystic fibrosis gene was isolated on chromosome 7. Positional cloning, linkage analysis, saturation cloning, and chromosome jumping enabled the isolation and cloning of the gene that encodes the cystic fibrosis transmembrane conductance regulator. Current work focuses on the safe, efficient delivery of a functional cystic fibrosis transmembrane conductance gene to patients who are afflicted with cystic fibrosis and the expression of the gene in somatic cells to correct the genetic defect and restore chloride channel function. It is hoped that successful gene therapy will be a feasible and cost-efficient approach that will lead to a cure.

Background: Carbon dioxide elimination (VCO2) at steady state corresponds to the metabolic rate. A change in tidal ventilation will lead to a transient response in VCO2 if other determinants of VCO2 are constant. This principle may be applied in the critical care unit to reset ventilators., Objective: To define and characterize the transient response of VCO2 to a well-defined change in ventilation., Methods: Forty-four patients in stable condition receiving volume-controlled mechanical ventilation had trend recordings of ventilator pressures, flow, volumes, VCO2, and end-tidal CO2 (ETCO2) for 20 min. At time t0, the minute ventilation was either increased (n = 22) or decreased (n = 22) by 10% after which these parameters were monitored over 30 min. Blood gas values were measured 5 and 20 min after the change in ventilation and the dead space fractions were computed using the single breath-CO2 test., Data Analysis: The first ten breaths (till t1) after a change in ventilation were excluded. The time constant (tau) of the relative change in VCO2 (delta VCO2) was calculated by fitting exponential regressions to delta VCO2 for periods up to 20 min after t1., Results: The delta VCO2 at t1 was proportional to the relative change in tidal volume (delta VT). The proportionality decreased gradually during 20 min. The proportionality of the relative change in ETCO2 (delta ETCO2) or PaCO2 (delta PaCO2) with delta VT was minimal at t1 and increased during the 20 min. tau increased progressively when calculated over longer periods (p < 0.001). tau was similar in the groups with increased and decreased ventilation up to 5 min, after which it was longer in the group with decreased ventilation (p < 0.05). The delta PaCO2 after 20 min correlated best with delta VCO2 at t1 (r = -0.8) and with delta ETCO2 at the end of 20 min (r = 0.8)., Conclusions: Noninvasively monitored VCO2 provides an instantaneous indication of the change in alveolar ventilation in well-sedated, mechanically ventilated patients in stable condition without significant cardiopulmonary disease.

Background: The onset of irregular inspiratory muscle activity has been observed toward the breakpoint of the breath-holding maneuver. We wondered if this was similar to the increased respiratory effort with paradoxical breathing seen during the resolution of an apnea in obstructive sleep apnea syndrome (OSAS)., Study Objective: To compare the breakpoint of breath holding in normal subjects, OSAS patients, and snorers., Methods: Thirty normal subjects, 30 patients with OSAS, and 16 snorers performed serial breath-holding maneuvers at functional residual capacity (FRC) under standardized pretest conditions using the rebreathing method of Read., Results: Intergroup comparisons were carried out by analysis of variance with post hoc Tukey's Highest Significant Difference tests. Basal end-tidal carbon dioxide (EtCO2) was significantly higher in OSAS than in normal subjects and snorers. Basal breath-holding time (BHT) was shorter in OSAS as compared with that in normal subjects and snorers (p < 0.05). The maximal EtCO2 level attained was higher in OSAS as compared with normal subjects (p < 0.05) and snorers (p = 0.052). The maximal BHT in OSAS was shorter than in normal subjects (p < 0.05) but not in snorers. The slope of BHT/EtCO2 differed significantly in OSAS compared with normal subjects and snorers (p < 0.05). No significant correlation was found between slope BHT/EtCO2 and age or body mass index using multiple regression analysis. The FRC of OSAS patients and snorers were similar (p = 0.792)., Conclusion: We conclude that BHT and slope of BHT/EtCO2 are different in OSAS subjects as opposed to those in normal subjects and snorers.

Background: Acute increases in nasal resistance are known to induce upper airway occlusion in predisposed subjects. With the limited efficacy of nasal surgery alone in the treatment of obstructive sleep apnea (OSA), the relevance of chronically increased nasal resistance in the pathophysiologic features of OSA remains undetermined., Methods: Seventy-one patients with OSA (apnea+hypopnea index > 15 [AHI]) and 70 antisocial snorers (ASS [AHI < 15]) referred for routine assessment of sleep-disordered breathing had concomitant measurement of combined (CNR) and highest unilateral (HUNR) nasal resistance by anterior rhinomanometry., Results: Nine individuals (five of 71 in the OSA group and 4 of 70 in the ASS group, 0.5 < p < 0.75) had an abnormally elevated CNR. The HUNR was increased in 21 individuals (11 of 70 in the ASS group and 10 of 71 in the OSA group, 0.25 < p < 0.5). There was no significant difference between CNR in OSA (1.5[0.5]) (mean [SE]) and ASS (1.6 [0.2]) groups. No correlation was found between CNR and the AHI in OSA or in ASS. The Mean HUNR in the OSA group was 5.5 (0.9) (mean [SE]) and in ASS was 5.3(0.6), which were not significantly different (p = 0.89). The HUNR also did not correlate with the AHI in either OSA or ASS., Conclusion: Chronic changes in nasal resistance are not a significant risk factor for the development or severity of OSA.

With mucosal inflammation contributing to the pathogenesis of asthma, it is increasingly accepted that long term steroid inhalers may induce remission in chronic long standing asthmatics. The present study involved 44 stable asthmatics who were randomly given either beclomethasone dipropionate inhaler (50 ug) 2 puffs qds or salbutamol inhaler (100 mcg) 2 puffs tds in addition to their oral bronchodilators. Pulmonary function testing, bronchoalveolar lavage and complete blood count were done at basal and weekly intervals and at the end of the study. The absolute eosinophil count showed a significant drop in the beclomethasone group as compared to the salbutamol group. Serial lung functions showed a significant improvement in the pre-bronchodilator PEFR and the pre-bronchodilator FVC in the beclomethasone group as compared to the salbutamol group. There was no significant change in the lavage eosinophil count pre and post-bronchodilator in both groups. Steroid inhalers are thus useful in long term management of bronchial asthma especially with respect to reducing bronchodilator requirement.

Objective: To determine pulmonary functions in portal hypertension of different etiologies and with various grades of ascites., Setting: Gastrointestinal clinic in a large community based and secondary referral hospital., Patients and Methods: Forty five patients with portal hypertension, including 19 cirrhotics with tense ascites, 8 with moderate ascites, 6 with no ascites and 12 patients with non-cirrhotic portal hypertension. All patients underwent basal pulmonary function testing by spirometry and helium dilution technique, and arterial blood gas estimation and measurement of ascitic fluid pressure. Patients with tense ascites underwent paracentesis of up to 2 liters following which ascitic fluid pressure and pulmonary functions were estimated again., Main Results: In cirrhotic patients without ascites, FVC (forced vital capacity), RV (residual volume), TLC (total lung capacity) and FRC (functional residual capacity) were lower than predicted values. In patients with ascites, FVC, FEV1 (forced expired volume in one second) and FEF25-75 (forced expired volume in one second) and FEF25-75 (forced expiratory flow rate between 25% and 75% of forced vital capacity) were significantly lower as compared to predicted values. FVC, FEV1, FEF25-75, pO2, pCO2 and SaO2% decreased significantly with increasing ascites. Paracentesis in patients with tense ascites led to clinical improvement and significantly improved lung volumes., Conclusions: Pulmonary functions are impaired in patients with cirrhosis, and ascites causes further deterioration. Patients with non-cirrhotic portal hypertension have normal pulmonary functions.

Cardiopulmonary exercise testing has a definitive place in objective evaluation of the subjective sensation of breathlessness. In the present study 21 patients with COPD, 10 with ILD and 17 normals were subjected to stage 1 exercise testing and correlations were sought between Vo2 and work, FVC, FeV1, Ve, respiratory rate and tidal volume and between VCO2 and work. In COPD and ILD the Vo2 correlated with work, Fev1, Fvc and Ve whereas in normals it correlated with the VE but not with the FeV1 and FVC. In COPD VO2 correlated with TV though this was not the case in ILD. Thus stage 1 exercise testing can be a useful additional method to assess the disability in COPD and ILD although differentiation between these two respiratory diseases on basis of exercise testing alone may not be possible.

Bromhexeine has been widely used as an adjunct in the management of lower respiratory infections and is useful in altering the physical characteristics of sputum. Its effect on the sputum penetration of an antibiotic has been sparsely studied. The present study highlights the improvement in sputum amoxycillin (amoxy) levels when a combination tablet, amoxy 500 mg plus bromhexeine 8 mg, is administered as compared to plain amoxy 500 mg. Sputum amoxy levels were significantly higher in the combination group (0.674 +/- 0.588 micrograms ml-1) as compared to 0.272 +/- 0.19 micrograms ml-1 in the amoxy group (P = 0.028). The clinical responses assessed by the physician as well as the patient were significantly better in the amoxy plus bromhexeine group as compared to the amoxy group. The radiological and bacteriological responses were similar in both groups. There was no increase in the side-effects due to bromhexeine and, overall, its use can be recommended in the treatment of acute lower respiratory infections.

Sixteen patients with advanced chronic obstructive pulmonary disease (COPD) and stable chronic respiratory failure (pO2 less than 60 mm Hg, pCO2 greater than 45 mm Hg) were given 2-3 L/min oxygen 18 hours/day for 3 weeks. These were serially assessed for changes in pO2, pCO2, ECG, chest radiographs and haemodynamics. Initially all patients were in grade IV heart failure. There was no change in lung function after oxygen treatment but right descending pulmonary artery diameter and cardiothoracic ratio decreased significantly (P less than 0.01), as also the height of the P wave in ECG (P less than 0.05). There were significant changes in mean pO2 (51.8 to 61.9 mmHg; P less than 0.01), pCO2 (55.3 to 47.6 mmHg; P less than 0.001), mean pulmonary artery pressure (41.8 to 34.5 mmHg; P less than 0.01) and pulmonary vascular resistance (PVR) (346.4 to 163.3 dynes; P less than 0.05). The initial (P less than 0.05) and 3 week (P less than 0.01) pO2 levels correlated with the right descending pulmonary artery diameter. The height of the P wave also correlated with pO2 (P less than 0.01). The changes in pO2 levels correlated with those of the PVR and pulmonary blood flow (P less than 0.05). Three week oxygen therapy resulted in objective improvement in advanced COPD cases.