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PubMed2026

New approaches to uncover COPD pathobiology and develop therapies.

Chronic obstructive pulmonary disease (COPD) was the third leading cause of global mortality in 2011 but receives limited attention and research funding. This Review describes the current knowledge on COPD risk factors, including genetic and epigenetic determinants and their interactions with the microbiome and environmental exposures. Preclinical models are being refined and single-cell transcriptomic, metabolomic, and proteomic technologies are being implemented to investigate the molecular mechanisms of disease progression. Patient cohorts to define biomarkers of early disease and the latest approaches to diagnose pre-COPD are essential to accelerate the development of novel and effective therapeutic interventions and translate new findings into clinical trials. This Review is a summary of topics covered by a symposium organized by the COPD-iNET consortium, an international network of researchers who have established a platform that facilitates collaboration of this multidisciplinary group of preclinical, translational, and clinical researchers.

Humans↗
PubMed1992

Clinical pathology testing recommendations for nonclinical toxicity and safety studies. AACC-DACC/ASVCP Joint Task Force.

Clinical pathology testing in nonclinical toxicity and safety studies is an important part of safety assessment. In recent years, clinical laboratory testing has rapidly expanded and improved. Some government regulatory agencies provide guidelines for clinical pathology testing in nonclinical toxicity and safety studies. To improve these testing guidelines and the resultant safety assessments, the American Association for Clinical Chemistry's Division of Animal Clinical Chemistry and the American Society for Veterinary Clinical Pathology formed a joint committee to provide expert recommendations for clinical pathology testing of laboratory species involved in subchronic and chronic nonclinical toxicity and safety studies. These recommendations include technical recommendations on blood collection techniques and hematology, serum chemistry, and urinalysis tests.

Animals↗
PubMed2005

Coordination of hemiparetic locomotion after stroke rehabilitation.

OBJECTIVES: Determine whether a rehabilitation program targeting functional motor recovery of persons with poststroke hemiparesis improved motor coordination. METHODS: A subgroup of 20 persons with poststroke hemiparesis (n = 11 in intervention and n =9 in control group) was investigated from within a larger randomized controlled single-blind clinical trial of 100 patients. Motor coordination was measured using a pedaling task, and subjects in the intervention group pedaled during an intensive broad-based home exercise program that targeted flexibility, strength, balance, and endurance. Coordination variables based on paretic leg pedal forces and EMG of 4 thigh muscles were measured while pedaling pre- and postintervention. RESULTS: Despite extensive pedaling practice, up to 30 half-hour sessions that were progressively more intense, there was no effect (P > 0.05) of the intervention on percent of total work done by the paretic leg, quantitative measures of EMG, or pedaling speed. However, walking speed was improved and pedaling and walking faster were associated after the intervention. CONCLUSIONS: There is no evidence of improved locomotor coordination postintervention. The increased walking and pedaling speed was likely achieved by a more proficient use of the same impaired pattern without EMG timing changes, likely because of increased strength and endurance postintervention. A more task-specific intervention may be required to improve coordination, consistent with principles of use-dependent plasticity.

Aged↗
PubMed2005

Ankle plantar flexor force production is an important determinant of the preferred walk-to-run transition speed.

The mechanisms that govern the voluntary transition from walking to running as walking speed increases in human gait are not well understood. The objective of this study was to examine the hypothesis that plantar flexor muscle force production is greatly impaired at the preferred transition speed (PTS) due to intrinsic muscle properties and, thus, serves as a determinant for the walk-to-run transition. The plantar flexors have been shown to be important contributors to satisfying the mechanical energetic demands of walking and are the primary contributors to the observed ground reaction forces (GRFs) during the propulsion phase. Thus, if the plantar flexor force production begins to diminish near the PTS despite an increase in muscle activation, then a corresponding decrease in the GRFs during the propulsion phase would be expected. This expectation was supported. Both the peak anterior/posterior and vertical GRFs decreased during the propulsion phase at walking speeds near the PTS. A similar decrease was not observed during the braking phase. Further analysis using forward dynamics simulations of walking at increasing speeds and running at the PTS revealed that all lower extremity muscle forces increased with walking speed, except the ankle plantar flexors. Despite an increase in muscle activation with walking speed, the gastrocnemius muscle force decreased with increasing speed, and the soleus force decreased for walking speeds exceeding 80% PTS. These decreases in force production were attributed to the intrinsic force-length-velocity properties of muscle. In addition, the running simulation analysis revealed that the plantar flexor forces nearly doubled for similar activation levels when the gait switched to a run at the PTS due to improved contractile conditions. These results suggest the plantar flexors may serve as an important determinant for the walk-to-run transition and highlight the important role intrinsic muscle properties play in determining the specific neuromotor strategies used in human locomotion.

Adult↗
PubMed1976

Cardiac tamponade complicating closure of a median sternotomy.

A case of intraoperative cardiac tamponade manifested during closure of a median sternotomy is presented. We postulate that cardiac tamponade was caused by acute dilatation of the cardiac chambers as a result of intraoartic balloon pumping in a patient with aortic and mitral regurgitation. It has been shown experimentally that acute rises in ventricular end-diastolic pressure result in increased intrapericardial pressure and that if a certain point on the pericardial pressure-volume curve is reached, cardiac tamponade will occur. Sternotomy closure was accomplished easily as soon as the need for intra-aortic balloon pumping diminished.

Aortic Valve Insufficiency↗
PubMed2006

Cadmium and mercury levels in Saudi women and its possible relationship with hypertension.

The association between elevated blood pressure and blood cadmium and mercury levels was examined (2001-2002) in 185 Saudi women previously selected for a case-control study of lead and hypertension risk. Blood pressure was measured twice according to the World Health Organization recommendations. Cadmium and mercury were determined with graphite furnace and hydride system-atomic absorption spectrometry, respectively. Mean blood cadmium concentrations were 0.874 +/- 0.995 microg/L in hypertensive and 0.785 +/- 0.665 microg/L in controls. While blood mercury concentrations for hypertensives and controls were 3.506 +/- 3.617 microg/L and 3.687 +/- 3.186 microg/L, respectively. Participants were classified according to the median of blood cadmium and mercury levels. After adjustment for potentially confounding variables, the final logistic regression analyses revealed that women with blood cadmium > or = 0.627 microg/L were 3.934 times were more likely to be hypertensive than those with blood cadmium levels < 0.627 microg/L, although this was marginally significant (p = 0.098). This was likely the result of the small number of subjects, resulting in the weak power to detect a strong significant difference between hypertensives and control cases. On the other hand, the final regression model showed no association between hypertension and mercury. However, this finding should not be conclusive because of the inappropriate choice of the biomarker indicator. Nevertheless, our study supports the hypothesis that exposure to cadmium might increase the risk of hypertension.

Aged↗
PubMed2003

Heavy metal concentrations in the breast milk of Saudi women.

Lead, cadmium, and mercury concentrations were determined in breast milk of Saudi lactating mothers from Riyadh and Al-Ehssa regions in Saudi Arabia who were not occupationally exposed. The mean levels for cadmium, lead, and mercury were 1.732 microg/L, 31.671 microg/L, and 3.100 microg/L, respectively. In contrast to mercury, mothers living in the Al-Ehssa region had significantly higher cadmium and lead concentrations in their breast milk than those in the Riyadh region. The estimated weekly intakes of cadmium, lead, and mercury of breast-fed infants in this study were in some cases higher than the Provisional Tolerance Weekly Intake (PTWI) recommended by FAO/WHO, which pose a threat to their health. This necessitates the urgent need to undertake a comprehensive study to determine the sources of exposure to these heavy metals. Breast-feeding is of great beneficial value for the infant's development; therefore, efforts should be made to prevent its contamination with environmental pollutants.

Adolescent↗
PubMed2003

Histopathological effects of mercury in skin-lightening cream.

Rose skin-lightening cream with a mercury content of 77,513 +/- 71,063 ppm was selected and applied on mice for a period of 1 month at different intervals. Mercury levels were measured in a total of 58 liver, kidney, and brain tissue samples by atomic absorption spectrophotometer coupled to vapor generator accessory. The mean mercury concentration in the tissues of treated mice was 67,472 +/- 70,181 microg/g in the range of 0.391-288.759 microg/g. Looking at the mercury concentration in the tissue samples with respect to the application of skin lightening creams at different intervals, the highest mercury concentrations were found in the tissues of mice treated 3 times a day (116.806 +/- 83.182 microg/g, ranges 5.989-288.759 microg/g). On the other hand, the lowest mercury concentrations were found in the tissues of mice treated once a week (16.450 +/- 26.168 microg/g, ranges 0.391-95.642 microg/g). Histopathological changes were clearly seen in the brain, kidney, and liver sections of all treated mice. The severity of pathological changes observed in tissues increased with increasing the number of applications. It is evident that repeated application of Rose skin-lightening creams could induce permanent damage to the kidneys, brain, and liver. This study emphasizes the potential toxicity of mercury skin-lighting creams and the importance of discontinuing their manufacture and use.

Administration, Cutaneous↗
PubMed2006

Inhibition of glycogen synthesis by increased lipid availability is associated with subcellular redistribution of glycogen synthase.

Increased lipid availability is associated with diminished insulin-stimulated glucose uptake and glycogen synthesis in muscle, but it is not clear whether alterations in glycogen synthase activity itself play a direct role. Because intracellular localization of this enzyme is involved in its regulation, we investigated whether fat oversupply causes an inhibitory redistribution. We examined the recovery of glycogen synthase in subcellular fractions from muscle of insulin-resistant, fat-fed rats and chow-fed controls, either maintained in the basal state or after a euglycaemic-hyperinsulinaemic clamp. Although glycogen synthase protein and activity were mostly recovered in an insoluble fraction, insulin caused translocation of activity from the smaller soluble pool to the insoluble fraction. Fat-feeding, which led to a reduction in glycogen synthesis during the clamp, was associated with a depletion in the soluble pool, consistent with an important role for this component. A similar depletion was also observed in cytosolic fractions of muscles from obese db/db mice, another model of lipid-induced insulin resistance. To investigate this in more detail, we employed lipid-pretreated L6 myotubes, which exhibited a reduction in insulin-stimulated glycogen synthesis independently of alterations in glucose flux or insulin signalling through protein kinase B. In control cells, insulin caused redistribution of a minor cytosolic pool of glycogen synthase to an insoluble fraction, which was again forestalled by lipid pretreatment. Glycogen synthase recovered in the insoluble fraction from pre-treated cells exhibited a low fractional velocity that was not increased in response to insulin. Our results suggest that the initial localization of glycogen synthase in a soluble pool plays an important role in glycogen synthesis, and that its sequestration in an insulin-resistant insoluble pool may explain in part the reduced glycogen synthesis caused by lipid oversupply.

Animals↗
PubMed2005

Comparison of (+)- and (-)-hemipalmitoylcarnitinium as inhibitors of hepatic mitochondrial carnitine palmitoyltransferases in diabetic rats.

The syntheses of (R)- and (S)-norcarnitine ethyl esters are described starting with an optimized, chiral chemical reduction of ethyl 4-chloroacetoacetate followed by azide substitution, reduction, and dimethylation. The reaction of (R)- and (S)-norcarnitine ethyl esters with 1-bromoheptadecan-2-one gives (+)- and (-)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, respectively, which hydrolyzes to (+)- and (-)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, (+)- and (-)-HPC), respectively, upon treatment with a hydroxide resin. (+)- and (-)-HPC are reversible active-site directed inhibitors of hepatic mitochondrial CPTs. Both stereoisomers inhibit CPT I and CPT II in control and streptozotocin diabetic rat to the same extent (Imax=100%). Using intact mitochondria (CPT I), I50values for (-)-HPC and (+)-HPC were 15.5 microM and 47.5 microM, respectively. The I50 values for CPT II were 6.7 microM and 38.5 microM for (-)-HPC and (+)-HPC, respectively. The mode of inhibition was uncompetitive for CPT I with respect to acyl-CoA. The apparent K(i) for (-)-HPC is about 5 microM. These data suggest that (-)-HPC may be useful for further evaluation as an antidiabetic agent.

Animals↗
PubMed1994

Risks associated with the use of IV contrast material: analysis of patients' awareness.

OBJECTIVE: Opinions differ on the need to obtain informed consent for IV administration of contrast material. If the potential risks are common knowledge among most patients, the need for informed consent is reduced. The purpose of this study was to assess patients' baseline knowledge of the risks associated with use of IV contrast material. SUBJECTS AND METHODS: This study included 150 consecutive outpatients who had radiographic studies (CT or excretory urography) requiring use of IV contrast material. Before the procedure, patients were asked to complete a 10-question questionnaire assessing their understanding of the risks associated with the use of contrast material. Questions concerned the nature of their test and the reasons for and risks of contrast material. Analysis was done with Fisher's exact chi 2-test of association and Wilcoxon's two-sample test. RESULTS: On average, the patients performed significantly better on this questionnaire than if they had randomly picked each answer, indicating that the average patient has acquired some information about IV contrast material. However, the mean score was 51%, demonstrating that the average patient is not knowledgeable about all risks associated with the use of IV contrast material. We found no differences associated with sex or age. Patients with more than a high school level of education and who had previously received contrast material scored better, although they still correctly answered only 56% and 54% of the questions, respectively. CONCLUSION: Information about the risks associated with use of IV contrast material cannot be considered common knowledge among the general population of patients.

Aged↗
PubMed2000

Computer modeling and simulation of human movement. Applications in sport and rehabilitation.

Computer modeling and simulation of human movement plays an increasingly important role in sport and rehabilitation, with applications ranging from sport equipment design to understanding pathologic gait. The complex dynamic interactions within the musculoskeletal and neuromuscular systems make analyzing human movement with existing experimental techniques difficult but computer modeling and simulation allows for the identification of these complex interactions and causal relationships between input and output variables. This article provides an overview of computer modeling and simulation and presents an example application in the field of rehabilitation.

Algorithms↗