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1.
N Engl J Med ; 357(1): 18-27, 2007 Jul 05.
Article in English | MEDLINE | ID: mdl-17611205

ABSTRACT

BACKGROUND: Acute mountain sickness occurs in some unacclimatized persons who travel to terrestrial altitudes at which barometric pressures are the same as those in commercial aircraft during flight. Whether the effects are similar in air travelers is unknown. METHODS: We conducted a prospective, single-blind, controlled hypobaric-chamber study of adult volunteers to determine the effect of barometric pressures equivalent to terrestrial altitudes of 650, 4000, 6000, 7000, and 8000 ft (198, 1219, 1829, 2134, and 2438 m, respectively) above sea level on arterial oxygen saturation and the occurrence of acute mountain sickness and discomfort as measured by responses to the Environmental Symptoms Questionnaire IV during a 20-hour simulated flight. RESULTS: Among the 502 study participants, the mean oxygen saturation decreased with increasing altitude, with a maximum decrease of 4.4 percentage points (95% confidence interval, 3.9 to 4.9) at 8000 ft. Overall, acute mountain sickness occurred in 7.4% of the participants, but its frequency did not vary significantly among the altitudes studied. The frequency of reported discomfort increased with increasing altitude and decreasing oxygen saturation and was greater at 7000 to 8000 ft than at all the lower altitudes combined. Differences became apparent after 3 to 9 hours of exposure. Persons older than 60 years of age were less likely than younger persons and men were less likely than women to report discomfort. Four serious adverse events, 1 of which may have been related to the study exposures, and 15 adverse events, 9 of which were related to study exposures, were reported. CONCLUSIONS: Ascent from ground level to the conditions of 7000 to 8000 ft lowered oxygen saturation by approximately 4 percentage points. This level of hypoxemia was insufficient to affect the occurrence of acute mountain sickness but did contribute to the increased frequency of reports of discomfort in unacclimatized participants after 3 to 9 hours. (ClinicalTrials.gov number, NCT00326703 [ClinicalTrials.gov].).


Subject(s)
Aircraft , Altitude Sickness/etiology , Altitude , Atmospheric Pressure , Hypoxia/complications , Adult , Aged , Altitude Sickness/blood , Altitude Sickness/physiopathology , Atmosphere Exposure Chambers , Exercise/physiology , Female , Humans , Male , Middle Aged , Oxygen/blood , Prospective Studies , Single-Blind Method , Surveys and Questionnaires , Travel
2.
Gene Ther ; 10(22): 1910-6, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14502220

ABSTRACT

Deficiency in acid alpha-D-glucosidase results in Pompe's disease. Modified single-stranded oligonucleotide (ODN) was designed to correct the acid alpha-D-glucosidase gene with a C1935 --> A (Asp --> Glu) point mutation which causes a complete loss of enzymatic activity for glycogen digestion in the lysosome. The ODN vectors contained a stretch of normal oligonucleotide flanked by phosphorothioated sequences. The 25mer and 35mer ODNs were homologous to the target sequence, except for a mismatched base in the middle. The ODNs caused permanent and inheritable restoration of acid alpha-D-glucosidase activity in skin fibroblast cells carrying this mutation derived from a Pompe's disease patient. Gene correction was confirmed by amplification refractory mutation system-PCR (ARMS-PCR), restriction fragment length polymorphism (RFLP) and direct DNA cloning and sequencing. The increased acid alpha-D-glucosidase activity was detected using 4-MUG as the artificial substrate. The correction efficiency, ranging from 0.5 to 4%, was dependent on the length and polarity of the MSSOV used, the optimal design being a sense-strand 35mer ODNs. Repeated treatment of the mutant fibroblast cells with the ODNs substantially increased correction. We also constructed ODN vectors to trigger specific and in vivo nonsense mutation in the mouse acid alpha-D-glucosidase gene. The ODNs were in complex with YEEE-K(18), an asialoglycoprotein-receptor ligand tagged with polylysine and targeted to hepatocytes and renal cells in vivo through intravenous injection. The mutated genotype was detected in the liver and the kidney by ARMS-PCR and glycogen accumulation in the lysosome of the liver cells. The studies demonstrate the utility of single-stranded ODN to direct targeted gene correction or mutation in a human hereditary disease and in an animal model. Our data open the possibility of developing ODN vector as a therapeutic approach for treatment of human hereditary diseases caused by point mutation.


Subject(s)
Genetic Therapy/methods , Genetic Vectors/administration & dosage , Glycogen Storage Disease Type II/therapy , Liver/enzymology , Oligonucleotides/genetics , alpha-Glucosidases/deficiency , alpha-Glucosidases/genetics , Animals , Base Sequence , Codon, Nonsense , Fibroblasts/enzymology , Genetic Vectors/genetics , Humans , Kidney/enzymology , Mice , Microscopy, Fluorescence , Molecular Sequence Data , Polymerase Chain Reaction/methods
3.
Am J Physiol ; 274(6 Pt 2): H2177-87, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9841543

ABSTRACT

We studied interactions between CO2 chemoreflexes and arterial baroreflexes in 10 supine healthy young men and women. We measured vagal carotid baroreceptor-cardiac reflexes and steady-state fast Fourier transform R-R interval and photoplethysmographic arterial pressure power spectra at three arterial pressure levels (nitroprusside, saline, and phenylephrine infusions) and three end-tidal CO2 levels (3, 4, and 5%, fixed-frequency, large-tidal-volume breathing, CO2 plus O2). Our study supports three principal conclusions. First, although low levels of CO2 chemoreceptor stimulation reduce R-R intervals and R-R interval variability, statistical modeling suggests that this effect is indirect rather than direct and is mediated by reductions of arterial pressure. Second, reductions of R-R intervals during hypocapnia reflect simple shifting of vagally mediated carotid baroreflex responses on the R-R interval axis rather than changes of baroreflex gain, range, or operational point. Third, the influence of CO2 chemoreceptor stimulation on arterial pressure (and, derivatively, on R-R intervals and R-R interval variability) depends critically on baseline arterial pressure levels: chemoreceptor effects are smaller when pressure is low and larger when arterial pressure is high.


Subject(s)
Baroreflex/physiology , Blood Pressure/physiology , Carbon Dioxide/blood , Chemoreceptor Cells/physiology , Models, Cardiovascular , Adult , Analysis of Variance , Arteries/physiology , Female , Fourier Analysis , Humans , Male , Models, Statistical , Nitroprusside/administration & dosage , Phenylephrine/administration & dosage , Photoplethysmography , Sodium Chloride/administration & dosage , Supine Position , Vasoconstrictor Agents/administration & dosage , Vasodilator Agents/administration & dosage
4.
Stat Med ; 14(24): 2675-84, 1995 Dec 30.
Article in English | MEDLINE | ID: mdl-8619107

ABSTRACT

A simple form of non-ignorable missing data mechanisms based on two parameters is used to characterize the amount of missing data and the severity of non-randomness in clinical trials. Based on the formulation, the effect of non-randomly missing data on simple analyses which ignore the missing data is studied for binary and normally distributed response variables. In general, the effect of the non-randomly missing data on the bias and the power increases with the severity of non-randomness. The bias can be positive or negative and the power can be less than or greater than when the data are missing at random. The results of the analysis, ignoring the missing data, can be seriously flawed if the non-randomness is severe, even when only a small proportion of the sample is missing. The problem is more pronounced in the case of normally distributed response variables with unequal variances.


Subject(s)
Bias , Clinical Trials as Topic , Data Interpretation, Statistical , Patient Dropouts , Stochastic Processes , Binomial Distribution , Humans , Normal Distribution , Reproducibility of Results , Treatment Outcome
5.
J Psychoactive Drugs ; 27(4): 375-87, 1995.
Article in English | MEDLINE | ID: mdl-8788693

ABSTRACT

This prospective study investigated in-treatment relapse in a sample of perinatal substance abusers in intensive outpatient treatment. Sixty-four female first-time admissions to a perinatal treatment program completed comprehensive psychological and psychosocial assessment before beginning treatment. Relapse was detected by urine toxicology screening and self-report. A regression analysis resulted in variable reduction, then survival analysis identified the impact of in-treatment relapse and other predictors on treatment length. Fifty-five percent of the subjects were classified as relapsers. Two risk factors for and six protective factors from in-treatment relapse were identified. The survival curves for relapsers and nonrelapsers did not differ until covariates were considered. Subjects with more severe consequences of drug use and less social exposure to drug use during treatment tended not to relapse during treatment, perhaps in order to prevent deterioration such as loss of children or incarceration. Relapse alone did not result in fewer treatment days. Few addiction characteristics were related to either in-treatment relapse or length of treatment. Rather, personality and demographic variables were more salient in both the regression and survival models. Treatment staff may need to reconsider their views of the meaning of relapse and should develop enhanced engagement and retention strategies for women at greater risk of relapse.


Subject(s)
Perinatal Care , Substance-Related Disorders/rehabilitation , Adolescent , Adult , Female , Humans , Patient Compliance , Personality , Pregnancy , Prospective Studies , Recurrence , Risk Factors , Smoking/psychology , Socioeconomic Factors , Substance-Related Disorders/psychology
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