Prevalence and prediction of exercise-induced oxygen desaturation in patients with chronic obstructive pulmonary disease

Background: Previous studies with small sample sizes reported contradicting findings as to whether pulmonary function tests can predict exercise-induced oxygen desaturation (EID). Objective: To evaluate whether forced expiratory volume in one second (FEV(1)), resting oxygen saturation (SpO(2)) and diffusion capacity for carbon monoxide (DLCO) are predictors of EID in chronic obstructive pulmonary disease (COPD). Methods: We measured FEV(1), DLCO, SpO(2) at rest and during a 6-min walking test as well as physical activity by an accelerometer. A drop in SpO(2) of >4 to <90% was defined as EID. To evaluate associations between measures of lung function and EID univariate and multivariate analyses were used and positive/negative predictive values were calculated. Receiver operating characteristic curve analysis was performed to determine the most useful threshold in order to predict/exclude EID. Results: We included 154 patients with COPD (87 females). The mean FEV(1) was 43.0% (19.2) predicted and the prevalence of EID was 61.7%. The only independent predictor of EID was FEV(1) and the optimal cutoff value of FEV(1) was at 50% predicted (area under ROC curve, 0.85; p < 0.001). The positive predictive value of a threshold of FEV(1) <50% was 0.83 with a likelihood ratio of 3.03 and the negative predicting value of a threshold of FEV(1) ≥80% was 1.0. The severity of EID was correlated with daily physical activity (r = -0.31, p = 0.008). Conclusions: EID is highly prevalent among patients with COPD and can be predicted by FEV(1). EID seems to be associated with impaired daily physical activity which supports its clinical importance.     

Metabolic labeling enables selective photocrosslinking of O-GlcNAc-modified proteins to their binding partners

O-linked β-N-acetylglucosamine (O-GlcNAc) is a reversible posttranslational modification found on hundreds of nuclear and cytoplasmic proteins in higher eukaryotes. Despite its ubiquity and essentiality in mammals, functional roles for the O-GlcNAc modification remain poorly defined. Here we develop a combined genetic and chemical approach that enables introduction of the diazirine photocrosslinker onto the O-GlcNAc modification in cells. We engineered mammalian cells to produce diazirine-modified O-GlcNAc by expressing a mutant form of UDP-GlcNAc pyrophosphorylase and subsequently culturing these cells with a cell-permeable, diazirine-modified form of GlcNAc-1-phosphate. Irradiation of cells with UV light activated the crosslinker, resulting in formation of covalent bonds between O-GlcNAc-modified proteins and neighboring molecules, which could be identified by mass spectrometry. We used this method to identify interaction partners for the O-GlcNAc-modified FG-repeat nucleoporins. We observed crosslinking between FG-repeat nucleoporins and nuclear transport factors, suggesting that O-GlcNAc residues are intimately associated with essential recognition events in nuclear transport. Further, we propose that the method reported here could find widespread use in investigating the functional consequences of O-GlcNAcylation.     

North American Birds as Potential Amplifying Hosts of Japanese Encephalitis Virus

Japanese encephalitis virus (JEV) is an emerging arbovirus, and inter-continental spread is an impending threat. The virus is maintained in a transmission cycle between mosquito vectors and vertebrate hosts, including birds. We detected variation in interspecies responses among North American birds to infection with strains of two different JEV genotypes (I and III). Several native North American passerine species and ring-billed gulls had the highest average peak viremia titers after inoculation with a Vietnamese (genotype I) JEV strain. Oral JEV shedding was minimal and cloacal shedding was rarely detected. The majority of birds, both viremic (72 of 74; 97.3%) and non-viremic (31 of 37; 83.8%), seroconverted by 14 days post-inoculation and West Nile virus-immune individuals had cross-protection against JEV viremia. Reservoir competence and serologic data for a variety of avian taxa are important for development of JEV surveillance and control strategies and will aid in understanding transmission ecology in the event of JEV expansion to North America.     

Severity of Peripheral Arterial Disease is Associated With Aortic Pressure Augmentation and Subendocardial Viability Ratio

J Clin Hypertens (Greenwich). 2012; 14:855–860. ©2012 Wiley Periodicals, Inc.Peripheral arterial disease (PAD) is associated with increased cardiovascular mortality that correlates with peripheral perfusion impairment as assessed by the ankle‐brachial arterial pressure index (ABI). Furthermore, PAD is associated with arterial stiffness and elevated aortic augmentation index (AIx). The purpose of this study was to investigate whether ABI impairment correlates with AIx and subendocardial viability ratio (SEVR), a measure of cardiac perfusion during diastole. AIx and SEVR were assessed by radial applanation tonometry in 65 patients with stable PAD (Rutherford stage I–III) at a tertiary referral center. AIx corrected for heart rate and SEVR were tested in a multivariate linear and logistic regression model to determine the association with ABI. Mean ABI was 0.8±0.2, AIx 31%±7%, and SEVR 141%±26%. Multiple linear regression with AIx as a dependent variable revealed that AIx was significantly negatively associated with ABI (β=−11.5; 95% confidence interval [CI], −18.6 to −4.5; P=.002). Other variables that were associated with AIx were diastolic blood pressure (β=0.2; 95% CI, 0.1–0.4; P<.001), height (β=−46.2; 95% CI, −62.9 to −29.4; P<.001), body mass index (β=−0.4; 95% CI, −0.8 to −0.1; P=.023), and smoking (β=3.6; 95% CI, 0.6–6.6; P=.019). Multiple regression with SEVR as a dependent variable showed a significant correlation with ABI (β=33.2; 95% CI, 2.3–64.1; P=.036). Severity of lower limb perfusion impairment is related to central aortic pressure augmentation and to subendocardial viability ratio. This may be a potential pathophysiologic link that impacts cardiac prognosis in patients with PAD.

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that affects more than 5% of the aged population. ¹ , ² PAD is associated with impairment in functional activity and with an increased risk of cardiovascular events. ³ , ⁴ For this reason, PAD is considered a marker for systemic atherosclerosis. ⁵ To date, the most powerful prognostic indicator in PAD patients is the ankle‐brachial arterial pressure index (ABI). ⁶ , ⁷ , ⁸ ABI is a measure to define impairment of lower limb perfusion that has been shown to predict survival rate in patients with PAD. ¹ , ⁹ , ¹⁰ The mechanisms through which the presence of PAD increases this risk are not understood in detail. PAD represents a vascular disease with extensive atherosclerotic involvement. Systemic inflammation and increased levels of oxidative stress parallel this. Both are known to destabilize atherosclerotic plaque and thus may be associated with vascular events. ¹¹ In addition, the extensive atherosclerotic alterations along the vascular tree conduit are thought to increase pulse wave velocity, and lower limb arterial obstructions may favor premature pulse wave reflections. ¹² , ¹³ Khaleghi and colleagues ¹² reported significant differences in augmentation index (AIx) between subjects with normal and abnormal ABI. Furthermore, an association between ABI and the degree of subendocardial viability ratio (SEVR) impairment in patients with type 1 diabetes has been reported. ¹⁴ A recent publication by Rabkin and colleagues ¹⁵ describes an association between ABI and AIx in patients without PAD. Given that, we assume that ABI impairment might be associated with AIx and SEVR.We therefore tested whether degree of ABI impairment is related to an increased AIx and decreased SVER as assessed noninvasively by radial pulse wave analysis in patients with stable PAD.     

A case–control study of visual,auditory and audio–visual sensory interactions in children with autism spectrum disorder

To assess the relative integrity of early visual and auditory processes in autism spectrum disorder (ASD), we used frequency-tagged visual and auditory stimulation and high-density electroencephalogram recordings of unimodal and dual-modality responses in a case–control design. To test for the specificity of effects on ASD, we recorded from a smaller group of children with attention-deficit hyperactivity disorder (ADHD). Horizontal 3 cycle per degree (cpd) gratings were presented at 5 Hz, and a random stream of /ba/, /da/, /ga/ syllables was presented at 6 Hz. Grating contrast response functions were measured unimodally and in the presence of a 64-dB auditory input. Auditory response functions were measured unimodally and in the presence of a 40% contrast grating. Children with ASD (n = 34) and ADHD (n = 13) showed a common lack of audio–visual interaction compared to typically developing children (n = 40) when measured at the first harmonic of the visual stimulus frequency. Both patient groups also showed depressed first harmonic responses at low contrast, but the ADHD group had consistently higher first-harmonic responses at high contrast. Children with ASD had a preferential loss of second-harmonic (transient) responses. The alteredtransient responses in ASD are likely to arise very early in the visual pathway and could thus have downstream consequences for many other visual mechanisms and processes. The alteration in audio–visual interaction could be a signature of a comorbid phenotype shared by ASD and ADHD, possibly due to alterations in attentional selection systems.     

Isolation of Stenotrophomonas maltophilia in asymptomatic lung transplant recipients: effects of treatment on eradication and outcome

In this retrospective, single‐center data analysis, we audited our clinical practice to treat Stenotrophomonas maltophilia in asymptomatic lung transplant recipients (LTRs). Eighteen LTRs with confirmed isolation of S. maltophilia were identified. Twelve of these LTRs have been treated with antibiotics, while 6 were managed without treatment. Treatment was based on antibiograms (trimethoprim/sulfamethoxazole [TMP/SMX] (8/12), levofloxacin (1/12), or both (3/12). Clearance (12/12 vs 6/6), eradication (10/12 vs 3/6, P=.27), and freedom from S. maltophilia recurrence (83%±11% vs 40%±22% after one year, log‐rank P=.09) were not found to differ significantly between treated and untreated patients. None of the patient groups showed significant changes in lung function or biochemical variables. Creatinine levels at the end of the study period were found to be higher in treated patients compared to the untreated group (P=.049). De novo acquired TMP/SMX resistance in S. maltophilia strains was not observed. These results indicate no evidence that antibiotic treatment for S. maltophilia in asymptomatic LTRs alters lung function or the clinical outcome.     

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma

POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild-type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance (real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8-OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.