Biomedical subjects
K Steinberg
Publications and source records attributed to K Steinberg.
Diclofenac sodium (Voltaren) reduced exercise-induced injury in human skeletal muscle.
PURPOSE: To examine the effects of prolonged systemic administration of diclofenac sodium (Voltaren), a nonsteroidal anti-inflammatory drug, on objective indices of exercise-induced muscle damage in humans. METHODS: Fifty-four volunteers (mean age, 26.4 yr; range, 18-35) participated in this randomized double-blind, placebo-controlled trial. To achieve steady-state tissue levels, either placebo or diclofenac was orally administered two times a day for 27 consecutive days. A strenuous 20-min stepping exercise program, about which the subjects were unfamiliar, was conducted on day 15. Creatine kinase (CK) activities were measured immediately before the exercise session and on days 16, 18, and 27. Vastus lateralis muscle samples were obtained immediately before exercise and on day 27 for subsequent histological characterization of muscle inflammation. RESULTS: The preexercise muscle samples revealed no difference in muscle damage between the two groups. However, the postexercise muscle samples showed that the diclofenac-treated group demonstrated less muscle tissue damage than placebo-treated subjects (P = 0.002). The administration of diclofenac also resulted in a significant lowering of post-/pre-exercise CK ratios on days 18 (P = 0.03) and 27 (P = 0.02) compared with the placebo group, an indirect finding that supports the possibility of diclofenac reducing exercise-induced muscle damage. CONCLUSION: These findings demonstrate preadministration of diclofenac (in accordance with tissue half-life pharmacokinetics) significantly reduces quantitative indices of exercise-induced skeletal muscle damage in human muscle.
Talk is cheap: measuring drinking outcomes in clinical trials.
OBJECTIVE: To evaluate the correspondence among measures of self-reported drinking, standard biological indicators and the reports of collateral informants, and to identify patient characteristics associated with observed discrepancies among these three sources of research data. METHOD: Using data collected from a large-scale clinical trial of treatment matching with alcoholics (N = 1,726), these three alternative outcome measures were compared at the time of admission to treatment and at 12 months after the end of treatment. RESULTS: Patient self-reports and collateral reports agreed most (97.1%) at treatment admission when heavy drinking was unlikely to be denied. In contrast, liver function tests were relatively insensitive, with positive serum gamma-glutamyl transpeptidase (GGTP) values obtained from only 39.7% of those who admitted to heavy drinking. At 15-month follow-up the correspondence between client self-report and collateral report decreased to 84.7%, but agreement with blood chemistry values increased to 51.6%. When discrepancies occurred, they still indicated that the client' s self-report is more sensitive to the amount of drinking than the biochemical measures. Patients who presented discrepant results tended to have more severe drinking problems, more previous treatments, higher levels of pretreatment drinking and significantly greater levels of cognitive impairment, all of which could potentially interfere with accurate recall. CONCLUSIONS: In clinical trials using self-selected research volunteers, biochemical tests and collateral informant reports do not add sufficiently to self-report measurement accuracy to warrant their routine use. Resources devoted to collecting these alternative sources of outcome data might be better invested in interview procedures designed to increase the validity of self-report information.
Current activities at the Centers for Disease Control and Prevention's National Diabetes Laboratory.
In 1997, the Centers for Disease Control and Prevention established the National Diabetes Laboratory in order to help prevent and treat type 1 diabetes. This state-of-the-art laboratory collaborates with research scientists and key national and international organizations throughout the world to identify and study risk factors for type 1 diabetes by developing measurements for glycosylated proteins, developing and evaluating technology for measuring genetic risk factors for the disease, and working to standardize autoantibody measurements. Developing improved technologies for diagnosing and managing diabetes and developing reference materials for properly calibrating and standardizing blood glucose meters are also critical aspects of the laboratory's work. In addition, the laboratory provides quality storage for valuable collections of biologics and other materials and facilitates sharing of specimens, associated epidemiologic data, and test results. Working with our partners in diabetes research, we are improving the diagnosis, treatment, and prevention of type 1 diabetes.
Efficacy of computerized decision support for mechanical ventilation: results of a prospective multi-center randomized trial.
200 adult respiratory distress syndrome patients were included in a prospective multicenter randomized trial to determine the efficacy of computerized decision support. The study was done in 10 medical centers across the United States. There was no significant difference in survival between the two treatment groups (mean 2 = 0.49 p = 0.49) or in ICU length of stay between the two treatment groups when controlling for survival (F(1df) = 0.88, p = 0.37.) There was a significant reduction in morbidity as measured by multi-organ dysfunction score in the protocol group (F(1df) = 4.1, p = 0.04) as well as significantly lower incidence and severity of overdistension lung injury (F(1df) = 45.2, p < 0.001). We rejected the null hypothesis. Efficacy was best for the protocol group. Protocols were used for 32,055 hours (15 staff person years, 3.7 patient years or 1335 patient days). Protocols were active 96% of the time. 38,546 instructions were generated. 94% were followed. This study indicates that care using a computerized decision support system for ventilator management can be effectively transferred to many different clinical settings and significantly improve patient morbidity.
A controlled trial of fluoxetine in nondepressed patients with Huntington's disease.
To examine the antidepressant specificity of fluoxetine in Huntington's disease (HD), we carried out a randomized, double-blind, placebo-controlled trial of this medication in nondepressed HD patients. Thirty patients with early HD who were depressed (Hamilton Depression Inventory < 16) were randomized to placebo (N = 13) or fluoxetine 20 mg/day (N = 17) and were followed up for 4 months. Outcome measures included changes in total functional capacity (TFC) and in standardized neurological, cognitive, and behavioral ratings. After adjustment for the higher education level found in the placebo group at baseline, no differences between the treatment groups were found in TFC, neurological, or cognitive ratings. Fluoxetine-treated patients did show a slight reduction in agitation and in the need for routine. Although fluoxetine may be a useful antidepressant in depressed HD patients, it failed to exert substantial clinical benefits in nondepressed HD patients.
Assessment of coenzyme Q10 tolerability in Huntington's disease.
We performed a 6-month open-label trial to evaluate the tolerability and efficacy of coenzyme Q10 (CoQ) in 10 patients with Huntington's disease (HD). Subjects were evaluated at baseline, 3 months, and 6 months using the HD Rating Scale (HDRS), the HD Functional Capacity Scale (HDFCS), and standardized neuropsychological measures. Adverse events (AEs) were assessed by telephone interview every month. CoQ doses ranged from 600 to 1,200 mg per day. All subjects completed the study, although four subjects reported mild AEs, including headache, heartburn, fatigue, and increased involuntary movements. There was no significant effect of the treatment on the clinical ratings. The good tolerability of CoQ suggests that it is a good candidate for evaluation in long-term clinical trials designed to slow the progression of HD.
Coexistence of Huntington's disease and familial amyotrophic lateral sclerosis: case presentation.
We present the clinical, molecular genetic and neuropathological findings of an 81-year-old man with concurrent Huntington's disease (HD) and familial amyotrophic lateral sclerosis (FALS). His mother had been diagnosed clinically as having ALS. There was no known family history of HD, but a maternal uncle had died in a chronic care psychiatric hospital. The diagnosis of HD in the patient was suspected at age 66, after 8 years of personality change, hallucinations, agitation, cognitive decline and choreoathetosis. No symptoms of motor neuron disease were noticed at that time, but progressive weakness developed later. Postmortem examination revealed cerebral atrophy, marked atrophy of basal ganglia (grade 3), and atrophy of brain stem and spinal cord. The neostriatum displayed massive neuronal loss and gliosis. The neocortex showed changes characteristic of Alzheimer's disease. Pathological lesions also included loss of neurons and gliosis in the anterior horns, Clarke's columns and the hypoglossal nuclei; degeneration of the lateral corticospinal tracts, dorsal spinocerebellar tracts and fasciculus gracilis; and rare Bunina bodies and ubiquitin-positive filamentous skeins in motor-neuron perikarya. Molecular analysis demonstrated chromosome 4p16.3 expansion of trinucleotide repeats characteristic of HD. Analysis of Cu,Zn superoxide dismutase gene and heavy neurofilament subunit gene failed to demonstrate mutations. The concurrence of HD and FALS in our patient and three previously reported cases did not appear to be associated with cosegregation in other family members.
Evaluation of in vivo interactions in mice between flurazepam and two neuroactive steroids.
The development of neuroactive steroids as anticonvulsant medications may be useful both as a primary treatment and as an adjuvant to other anticonvulsants. They may be limited, however, by sedative and ataxic side effects. In the current study, 3 alpha-hydroxy-5 beta-pregnan-20-one and alfaxalone, two prototypic neuroactive steroids, were shown to potentiate the ability of flurazepam to antagonize electrically precipitated tonic hindlimb extension in mice at doses that by themselves had little antiseizure efficacy. While alfaxalone alone lacked motor incoordinating effects at a dose (18.0 mg/kg) that potentiated the antiseizure efficacy of flurazepam, the same dose of 3 alpha-hydroxy-5 beta-pregnan-20-one possessed both the ability to potentiate flurazepam's anticonvulsant effect and disrupt mouse rotorod performance. The data suggest that allosteric interactions that have been described in vitro between neuroactive steroids and other modulators of the GABAA receptor complex may have relevance for the intact animal. Finally, the data also suggest that neuroactive steroids could be developed as short-lived adjuvant antiseizure medications in certain critical situations (e.g., medication-refractory status epilepticus). However, the motor incoordinating effects resulting from the combination of neuroactive steroids and flurazepam suggest that their usefulness as adjuvant medications in the chronic therapy of seizure disorders may be limited.
Functional decline in Huntington's disease.
We prospectively evaluated 129 patients with manifest Huntington's disease (HD) to determine the rate of illness progression and the clinical features that correlate with functional decline. A single examiner evaluated each patient using the HD Functional Capacity Scale. Standardized motor performance was also assessed in 94 of the patients (73%) using the HD Rating Scale. Total Functional Capacity declined at a rate of 0.63 +/- 0.75 U per year. As functional capacity worsened, chorea lessened, and dystonia intensified. There was no correlation between rate of functional decline and age at onset of HD, body weight, gender of affected parent, or history of neuroleptic use.
Trinucleotide repeat length and progression of illness in Huntington's disease.
The genetic defect causing Huntington's disease (HD) has been identified as an unstable expansion of a trinucleotide (CAG) repeat sequence within the coding region of the IT15 gene on chromosome 4. In 50 patients with manifest HD who were evaluated prospectively and uniformly, we examined the relationship between the extent of the DNA expansion and the rate of illness progression. Although the length of CAG repeats showed a strong inverse correlation with the age at onset of HD, there was no such relationship between the number of CAG repeats and the rate of clinical decline. These findings suggest that the CAG repeat length may influence or trigger the onset of HD, but other genetic, neurobiological, or environmental factors contribute to the progression of illness and the underlying pace of neuronal degeneration.
Automated subpicomole protein sequencing using an alternative postcleavage conversion chemistry.
An automated subpicomole sequencing method is described. It is based on a chemistry that generates easily detectable amino acid derivatives from the postcleavage products of the classical Edman degradation. These products, which include the amino acid anilinothiazolinone (ATZ), phenylthiocarbamyl (PTC), and phenylthiohydantoin (PTH), are converted to a homogeneous preparation of ATZ that can react with sensitivity-enhancing compounds such as fluorescent amines. The method is demonstrated with a protein of known sequence (alpha-lactalbumin) and appears to offer a significant improvement over current high-sensitivity protein sequencing strategies. Modifications to the sequencer hardware or to the Edman degradation chemistry are not required.
The generation of phenylthiocarbamyl or anilinothiazolinone amino acids from the postcleavage products of the Edman degradation.
A method is described for the generation of phenylthiocarbamyl (PTC) amino acids from phenylthiohydrantoin (PTH) or anilinothiazolinone (ATZ) amino acids. An aqueous base containing a reducing agent promotes the opening of the PTH or ATZ ring to form a stable PTC amino acid. The new reaction is essentially quantitative for all of the amino acids and may be used instead of the established Edman conversion with an aqueous acid. The PTC amino acids may be analyzed directly or used for generating other analytes. A further method is described for the generation of ATZ amino acids from either the PTH or PTC derivatives. This chemistry involves a Lewis acid-catalyzed dehydration of the PTC. The resulting ATZ may be combined with labels that permit high-sensitivity detection. This reaction is also essentially quantitative for all of the amino acids except aspartic acid, which exhibits a strong preference for the PTH form under these conditions. Taken together, these chemistries allow the preparation of homogeneous PTC or ATZ amino acids from any mixture of amino acid derivatives resulting from the Edman degradation and promise to greatly facilitate the high-sensitivity analysis of protein.
[Traumatic paraplegia with injury of the upper extremity--effects on the success of rehabilitation].
The evaluation of a greater number of patients with traumatic paraplegia and tetraplegia showed more than 20% of associated injuries of the upper limbs. In view of the fact that arms and shoulders of the paraplegic person take over a decisive weight-bearing function, we were interested in the effects of these special injuries on rehabilitation outcome. Injuries of the distal arm were found to have more serious repercussions for achievement of the rehabilitation aim than the relatively more impressing injuries of the shoulder girdle and the upper arm. Serious limitations were found in the range of motion of the affected joints. Compensation was due only to the skill of the paraplegics in dealing with these deficits in motion and in using the uninjured extremity. This is the main reason why the functional deficits in independence were relatively minor.
Prevalence and prediction of osteopenia in chronic liver disease.
To obtain information on the prevalence and clinical and laboratory correlates of osteopenia in patients with chronic liver disease, we measured bone densities and 30 selected laboratory variables in 133 subjects (70 men, 63 women) with liver disease. Thirty-two had alcoholic liver disease, 18 had primary biliary cirrhosis, 16 had primary sclerosing cholangitis, 48 had other forms of cirrhosis (cryptogenic, posthepatic) and 19 had chronic hepatitis or fibrosis without cirrhosis. Bone densities of the lumbar spine and three sites of the proximal femur (neck, Ward's triangle, greater trochanter) were estimated by dual-photon absorptiometry. Bone densities at all sites were significantly correlated to one another (r = 0.4 to 0.9; 95% confidence intervals = 0.24-0.54 to 0.81-0.90; p less than 0.0001 for all). Compared with an age- and gender-matched reference group, patients with liver disease had highly significant decreases in bone densities (greater than 2 standard deviations below control values; p less than 0.0008 at all sites). Decreases were particularly marked (24% to 42%) at Ward's triangle, the site of the femoral neck particularly prone to fracture. The prevalence of decreased bone densities ranged from 10% to 56%, depending on the site studied and the nature of the liver disease. Among 30 laboratory variables studied, there were significant (p less than 0.05) correlations with bone densities at more than one site for urinary creatinine (r = 0.21, 0.25), urinary calcium (r = -0.18, -0.23), serum total alkaline phosphatase (r = -0.18, -0.27) and the liver-1 isozyme of serum alkaline phosphatase (r = -0.19, -0.26).(ABSTRACT TRUNCATED AT 250 WORDS)
Psychosocial determinants of compliance in adolescents with iron deficiency.
The relationship between selected psychosocial variables and compliance was studied in 71 adolescents prescribed medication for iron deficiency. The mean compliance rate in the study group was 67%. Home pill counts were highly correlated with the other methods of measuring compliance, ie, change in serum ferritin level and urinary assay for tracer riboflavin. Statistically significant predictors of compliance included adverse side effects, initial estimate by the adolescent as to his probable level of compliance, and frequency of family reminders to take the medication. There was no significant correlation between self-esteem, locus of control, or most variables of the Health Belief Model and the level of patient compliance. Our findings suggest that home pill counts are an accurate method of assessing compliance and that instituting family reminders may be helpful in those adolescents who are potentially non-compliant.
Evaluation of potential health effects associated with serum polychlorinated biphenyl levels.
In late 1983, we conducted a cross-sectional epidemiologic study to evaluate persons at risk of exposure to three chemical waste sites by comparing clinical disease end points and clinical chemistry parameters with serum polychlorinated biphenyls (PCB) levels. A total of 106 individuals participated in the study. The only statistically significant finding in regard to self-reported, physician-diagnosed health problems was a dose-response relationship between serum PCB levels and the occurrence of high blood pressure; however, this association failed to achieve statistical significance (p = 0.08) when we controlled for possible confounding effects of both age and smoking. Serum triglyceride and cholesterol levels were also higher in the group with elevated serum PCBs; additionally, there were isolated statistically significant correlations of serum aspartate aminotransferase (SGOT) with serum lipid fraction-adjusted PCB level (r = -0.21) and serum albumin (r = -0.24) and total bilirubin (r = 0.30) with serum PCB level. Although the ranges of serum levels reported herein from exposures to PCBs in the general environment are lower than those that have been associated with acute symptoms or illness in other studies, whether these levels are associated with long-term health risks is not known. Associations of such chronic, low-dose exposures with observable health effects as suggested by this study must be evaluated further before any final conclusions can be drawn.
Influence of photoperiod and temperature on weight gain, food consumption, fat pads and thyroxine in male golden hamsters.
Weight gain in control and pinealectomized male golden hamsters is enhanced by exposure to short photoperiods (LD 8:16). Modest temperature reductions (10 degrees C) enhanced weight gain also, especially in the blinded animals. In the absence of both eyes and the pineal gland, neither temperature nor photoperiod had much or any effect on weight gain. Food consumption on the other hand increased only as a consequence of lowered temperature. Efficiency of food utilization was maximal at higher (22 degrees C) temperature and long photoperiods (LD 16:8). Epididymal fat pads in control animals were consistently increased by short photoperiods in either temperature. They were increased in pinealectomized and decreased in blinded animals as a consequence of lowered temperatures in either photoperiod. Total body weight gain in the several environments was not correlated directly with fat pad weights. Free thyroxine (T4) levels in control animals seemed to be negatively correlated with fat pad weights. Both T4 levels and fat pads were unchanged by temperature or photoperiod in blinded, pinealectomized animals. The data suggest a complex interaction of temperature, light and the pineal gland on body weight, fat deposition and serum T4.