Biomedical subjects

V M Chinchilli

Publications and source records attributed to V M Chinchilli.

107 records · Page 6Linked to original sources

PubMed1987

Evaluation of the interaction of three genotoxic agents in eliciting sister-chromatid exchanges using response surface methodology.

Chinese hamster cells (V79) were treated with ethylnitrosourea (ENU), bischloroethylnitrosourea (BCNU), and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantitated as measures of genotoxicity of the three agents. The combination experiment employed a factorial design in which cells were treated, in various concentration combinations, with all agents simultaneously. Response surface methodology using a polynomial model in treatment variables to approximate the mean the distribution of SCE events was employed for analysis of the interactions of the three genotoxic agents. Due to unequal variances of the number of SCEs in the various treatment groups, a weighted least-squares analysis was used to estimate the parameters of the dose-response relationship. The single-agent results suggest that the DDP concentration-response curve has a much steeper slope than the ENU and BCNU curves, and is concave downward as compared to the relatively linear concentration-response curves of ENU and BCNU. The combination results suggest that ENU and DDP are involved in a negative interaction. The BCNU/DDP interaction, the ENU/BCNU interaction, and the three-factor interaction are not statistically significant. The analysis of these data demonstrates the usefulness of a statistical procedure for evaluating the biological effects resulting from exposure to multiple cytotoxic agents. The methodology can be used with many other types of endpoints and is not limited by the number of treatment agents.

Animals↗

PubMed1986

Estimation and analysis of the concentration-response surfaces associated with multiple-agent combinations.

Chinese hamster cells (V79) were treated with ethylnitrosourea (ENU) and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantified as measures of genotoxicity of the two agents. The combination experiment employed a factorial design in which cells were treated, in various concentration combinations, with both agents simultaneously. Response surface methodology, using a polynomial model based on a negative binomial distribution of SCE events, was employed for analysis of the interactions of the two genotoxic agents. The negative binomial distribution, a generalization of the Poisson distribution, is required since SCEs are discrete variables which, under the conditions of these experiments, have a distribution which exhibits extra-Poisson variability. The model of the ENU/DDP combinations indicated an increasingly less-than-additive effect resulting from increasing concentrations of each agent in the combination. The analysis of these experiments demonstrates the usefulness of a powerful statistical procedure for evaluating the biological effects resulting from exposure to multiple cytotoxic agents. The methodology can be used with many other types of endpoints and is not limited by the number of treatment agents.

Cells, Cultured↗

PubMed1986

Genetic predisposition to diabetes mellitus is associated with impaired humoral immunity to coxsackievirus B4.

Experiments were performed to determine whether genetic predisposition to diabetes mellitus (DM) or clinical DM or both exert an influence on the production of neutralization antibodies to coxsackievirus B4 (CB4). The homozygous diabetic mutant mouse db+/db+, on the inbred C57BL/KsJ genetic background, develops a diabetes-like disease when maintained on ad libitum diet but restriction of excess food intake prevents overt disease. The doubly heterozygote db+/+m or the homozygote +m/+m misty coat color mutant, on the C57BL/KsJ genetic background, do not develop DM and served as controls. Animals infected with one-half a previously determined LD50 of CB4 were bled prior to infection and at 3, 5, 7, 14, 21 days and at 1, 2, 3, 4 and 5 months after infection. Serum neutralization antibody (NA) levels were determined from the percent CB4 plaque reduction. Until 2 months following infection, NA levels were not significant in either of the homozygous diabetic mutant groups, db+/db+. In the diabetic mutant group db+/db+, without overt disease, neutralization of CB4 when observed, was low, short-lived, and apparently not specific. However, in the homozygous diabetic mutants with spontaneous diabetes, CB4 NA became evident at 2 months after infection. By 3 months post-infection, serum NA levels were sufficient to cause 90% virus plaque reduction. These observations demonstrate that hereditary DM as characterized by the mutation diabetes, db, in the C57BL/KsJ mouse, is associated with a marked impaired humoral immune response to a diabetogenic human CB4. Specifically, there is an inability to develop an adequate level of anti-CB4 antibodies. The type and degree of immunological impairment are apparently different prior to and after onset of diabetes mellitus.

Animals↗

PubMed1985

Calcium and phosphate metabolism in children with idiopathic hypoparathyroidism or pseudohypoparathyroidism: effects of 1,25-dihydroxyvitamin D3.

Two children with congenital hypoparathyroidism and two children with pseudohypoparathyroidism were given maintenance doses of 15 to 45 ng/kg/day 1,25-dihydroxyvitamin D3 for a total of 255 months. The urinary calcium excretion showed an upward elevation after the first 2 years of treatment but was not significantly higher than that in 10 normal control subjects. The renal threshold for phosphate excretion stayed within the normal ranges compared with control values. Two hypercalcemic and two hypocalcemic episodes occurred during this period of treatment. Hypercalcemia was reversed within 1 week after withdrawal of 1,25-dihydroxyvitamin D3. Hypocalcemia was countered by increasing the dose of 1,25-dihydroxyvitamin D3. Renal functions were not adversely affected, as estimated by creatinine clearance and reciprocals of serum creatinine concentrations. The mean serum calcium concentration during 1,25-dihydroxyvitamin D3 treatment was significantly higher (P = 0.001) compared with that obtained during vitamin D2 treatment at a dose of 500 to 3000 IU/kg/day. These data provide additional support for the long-term use of 1,25-dihydroxyvitamin D3 in idiopathic hypoparathyroidism and pseudohypoparathyroidism.

Calcitriol↗

PubMed1985

Prediction of carrier status in Duchenne dystrophy by creatine kinase measurement.

Serum creatine kinase (CK) was measured in 515 healthy white women and 28 obligate carriers for Duchenne muscular dystrophy. There was substantial overlap between the control and carrier populations. To analyze the impact of the degree of overlap, the predictive value of a CK result was determined by (1) using sensitivity and specificity analysis, which assumes dichotomization into a positive or negative result based on a particular cut-off value; and (2) using likelihood ratio analysis, which evaluates an individual result based on the continuum observed for control and carrier populations. There was no clinically important difference whether an observed 57% or a hypothetical 33% overlap between control and carrier results was used. Because of the substantial overlap, the CK test utility is limited to those suspected carriers whose results fall above the healthy population interval. A low CK result does not provide sufficient assurance of noncarrier status.

Adult↗

PubMed1984

Influence of diabetes mellitus heredity on susceptibility to coxsackievirus B4.

Using the criteria of virus susceptibility as defined by the 50 percent lethal dose response and the percent cumulative mortality response it was shown that the diabetic mutation db, located on chromosome 4, exerted a particular influence on the host response to CB4 challenge. Neither the yellow obese mutation Ay on chromosome 2 nor the misty coat color mutation located one centimorgan from the db mutation had the same effect on CB4 response. The obese diabetic mutation ob located on chromosome 6 appeared to enhance susceptibility to CB4. However, the high susceptibility of the inbred C57BL/6J line on which the ob mutation is found was apparently a significant contributing factor to the ob mutant high virus susceptibility. The response to CB4 was also a useful criteria to discern differences in the genetic background of closely related inbred lines. Based on the CB4 LD50 values the C57BL/6J inbred line was the most susceptible while the C57BL/Ks inbred line was the most resistant. However, using the percent cumulative mortality response as an index of host resistance, the C57BL/KsJ was the most susceptible and the C57BL/Ks the least. These findings further support the thesis that genetic predisposition to diabetes mellitus, as characterized by the mutation db on chromosome 4 is associated with a particular susceptibility and host response to coxsackie-virus B4. It also illustrates that under specific conditions, comparison of the response to virus challenge can be used as an indicator of genetic differences between closely related inbred lines.

Animals↗

PubMed1984

High-density lipoproteins decrease the biliary concentration of chlordecone in isolated perfused pig liver.

Chlordecone (CD) is an organochlorine pesticide associated with albumin and high-density lipoproteins (HDL) in the plasma. It is found in higher concentrations in the liver than in other tissues and is excreted in the bile. The influence of plasma HDL on the biliary excretion of CD was studied using isolated pig liver perfused with a Krebs-Ringer bicarbonate solution containing albumin, dextrose, and pig red blood cells. Within 5 min after administration into the perfusion medium of [14C]CD bound to albumin or to HDL, only 13% of the [14C]CD dose remained in the perfusate, showing that CD is rapidly taken up by the liver. After 60 min the plasma concentration was constant at 0.008% dose/ml when [14C]CD was administered bound to albumin in the absence of HDL and at 0.004% dose/ml when administered bound to HDL. The mean concentration of CD in the bile was higher when CD was administered bound to albumin in the absence of HDL (0.039% dose/ml) than when it was administered bound to HDL (0.010% dose/ml). The elimination rate constant of CD from the liver into the bile was 0.007/min whether CD was administered bound to albumin or to HDL. The addition of HDL to the perfusion system after the administration of albumin-bound CD resulted in lower biliary CD concentrations. The results suggest that HDL affects the distribution of CD between the perfusate and liver and between liver and bile. In both cases, distribution toward the liver is favored.

Animals↗

PubMed1984

Confidence interval about the response at the stationary point of a response surface, with an application to preclinical cancer therapy.

A method of calculating a confidence interval about the response at the stationary point of a response surface is presented. We show that the technique can also be used to calculate a confidence region about the location of the stationary point. The procedure is applied, via Cox's proportional-hazards model, to the analysis of survival data from a preclinical cancer chemotherapy experiment involving the combination of two drugs. It is seen that the results can be useful in determining the existence of a therapeutic synergism.

Animals↗

PubMed1984

Sampling from a skewed population distribution as exemplified by estimation of the creatine kinase upper reference limit.

Creatine kinase (EC 2.7.3.2) was measured in sera from 580 females, ages 1-77 years, and 550 males, ages 1-63 years. The distribution of results for male and female groups shows pronounced skewing toward higher values. The observed distribution of results could not be described by any of six mathematical formulas for skewed distributions, an indication of the unsuitability of such formulas to transform these data for parametric analysis. The range of 97.5 percentile estimates produced by six independent samples of 100, 200, and 400 observations randomly selected from a mathematical model defined by the adult female distribution showed progressive narrowing from the 150-380 U/L interval for the samples of 100 observations to 200-265 U/L for the samples of 400 observations; no further improvement was seen when 800 observations were used. The samples of 100 and 200 observations contained extreme value points that might appear as "outliers" but were shown to be valid members of the population distribution when larger sample sizes were collected.

Adolescent↗

PubMed1984

Are reference limits for serum creatine kinase valid in detection of the carrier state for Duchenne muscular dystrophy?

We evaluated serum creatine kinase (CK) as an index to heterozygosity in Duchenne muscular dystrophy. When the 97.5th percentile of the CK normal reference interval was selected as the cutoff point, only 31% of 28 obligate carrier mothers and 24% of 43 mothers of simplex cases (those with only one occurrence of dystrophy in the kindred) exceeded this cutoff value. The outcome depended to some degree on the method used for establishing the reference limit for 379 presumably non-carrier, ambulatory women. The considerable overlap of CK activities between the control and carrier population as well as the non-gaussian distribution of the data permitted no satisfactory approach for differentiating these two populations. Neither the application of likelihood ratios, which evaluates a continuum of results without the dichotomy of a cutoff point, nor the application of predictive value based on sensitivity and specificity, which involves use of a cutoff value for decision making, provided a reliable estimate of carrier status. There was no significant difference (2 alpha = .19) between the median CK activity of obligate carrier mothers and mothers of simplex cases. The serum CK test does not provide data that either support or reject the Haldane hypothesis.

Adolescent↗

PubMed1984

A likelihood ratio test for a patterned covariance matrix in a multivariate growth-curve model.

In a multivariate growth-curve model, the estimator of the parameter matrix is a function of the matrix of the sums of squares and of the cross-products due to error. However, if the assumption of a patterned covariance matrix is valid, then the parameter estimator does not depend on the error matrix. A likelihood ratio test of this patterned covariance matrix is constructed and its distribution is discussed. A numerical example is provided in which the design consists of two treatment groups, with three repeated measures being taken of the three response variables.

Growth↗

PubMedDate not supplied

Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial.

CONTEXT: Long-acting beta(2)-agonists are prescribed for patients with persistent asthma and are sometimes used without inhaled corticosteroids (ICSs). No evidence exists, however, to support their use as monotherapy in adults with persistent asthma. OBJECTIVE: To examine the effectiveness of salmeterol xinafoate, a long-acting beta(2)-agonist, as replacement therapy in patients whose asthma is well controlled by low-dose triamcinolone acetonide, an ICS. DESIGN AND SETTING: A 28-week, randomized, blinded, placebo-controlled, parallel group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 to January 1999. PARTICIPANTS: One hundred sixty-four patients aged 12 through 65 years with persistent asthma that was well controlled during a 6-week run-in period of treatment with inhaled triamcinolone (400 microg twice per day). INTERVENTIONS: Patients were randomly assigned to continue triamcinolone therapy (400 microg twice per day; n = 54) or switch to salmeterol (42 microg twice per day; n = 54) or to placebo (n = 56) for 16 weeks, after which all patients received placebo for an additional 6-week run-out period. MAIN OUTCOME MEASURES: Change in morning and evening peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), self-assessed asthma symptom scores, rescue albuterol use, asthma-specific quality-of-life scores, treatment failure, asthma exacerbation, bronchial reactivity, and markers of airway inflammation, compared among the 3 treatment groups. RESULTS: During the 16-week randomized treatment period, no significant differences between the salmeterol and triamcinolone groups were observed for conventional outcomes of clinical studies of asthma therapy-morning PEF, evening PEF, asthma symptom scores, rescue albuterol sulfate use, or quality of life. Both active treatments were superior to placebo. However, the salmeterol group had more treatment failures than the triamcinolone group (13/54 [24%] vs 3/54 [6%]; P =.004), as well as more asthma exacerbations (11/54 [20%] vs 4/54 [7%]; P =.04), greater increases in median (interquartile range) sputum eosinophils (2.4% [0.0% to 10.6%] vs -0.1% [-0.7% to 0.3%]; P<.001), eosinophil cationic protein (71 [-2 to 430] U/L vs -4 [-31 to 56] U/L; P =.005), and tryptase (3.1 [2.1 to 7.6] ng/mL vs 0.0 [0.0 to 0.7] ng/mL; P<.001). The duration of benefit when patients were switched from active treatment to placebo after 22 weeks of randomized treatment was not significantly longer in the triamcinolone group than in the salmeterol group. CONCLUSIONS: Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.

Administration, Inhalation↗

PubMedDate not supplied

Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.

CONTEXT: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy. OBJECTIVE: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen. DESIGN AND SETTING: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999. PARTICIPANTS: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day). INTERVENTION: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group). MAIN OUTCOME MEASURE: Time to asthma treatment failure in patients receiving salmeterol. RESULTS: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001). CONCLUSIONS: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.

Administration, Inhalation↗

PubMedDate not supplied

Smooth muscle cell proliferation in response to co-culture with venous and arterial endothelial cells.

PURPOSE: The critical role of endothelial cells (ECs) in arterial disease is well established, but little is known of their role in venous disease. Previous studies suggest inherent differences between arteries and veins: arterial stenoses demonstrate a large lipid component, whereas hemodialysis-related venous stenoses are characterized by marked smooth muscle cell (SMC) proliferation. This study compares effects of venous versus arterial ECs on SMC proliferation in co-culture. MATERIALS AND METHODS: Human saphenous vein ECs (HSV-ECs) or human aortic ECs (HA-ECs) were cultured on the underside of 10-micron, porous polycarbonate membranes and allowed to grow to confluence for 48 hours. After EC confluence, human aortic SMCs (HA-SMCs) were cultured on the membranes opposite the EC (day 0). On days 0, 1, 2, 4, 6, and 8, membranes were harvested (n = 3 per day), stained with Hoechst dye, and HA-SMCs were counted by fluorescence microscopy. Controls were HA-SMCs cultured alone. Comparisons were made by two-way multivariate analysis of variance. RESULTS: During the entire 8-day period, there was significant induction of HA-SMC proliferation by both HSV-ECs (P = .0003) and HA-ECs (P = .0012). Maximal inductions were 88% +/- 11% for HSV-ECs (P = .0015) and 24% +/- 6% for HA-ECs (P = .0015). HSV-ECs exhibited a three- to ninefold greater induction than HA-ECs (P = .0003). CONCLUSION: HSV-ECs induce adjacent HA-SMC proliferation, possibly in a paracrine manner to a significantly greater extent than HA-ECs.

Aorta↗

PubMedDate not supplied

The role of sex hormone replacement therapy on self-perceived competence in adolescents with delayed puberty.

The objective of the present study was to determine the role of sex steroids in the development of self-perceived competence during adolescence. The Harter Self-Perception Scale was administered to 56 adolescents with delayed puberty who were receiving depo-testosterone (males) or conjugated estrogens (females) administered in 3-month blocks alternating with placebo. Treatment was given at three dose levels approximating early, middle, and late pubertal replacement levels. Hormone treatments had a significant positive effect for both males and females in one subscale domain--perceived job competence. Significant positive hormone effects were also obtained for perceptions of romantic appeal and close friendship in females and perception of athletic abilities in males. It can be inferred from the results of this study that the hormonal changes associated with sexual maturation have targeted influences on specific domains of self-perceived competence and that there are clear gender differences.

Adolescent↗

PubMedDate not supplied

Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma.

BACKGROUND: Regular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent. METHODS: We examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use. RESULTS: During the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27. CONCLUSIONS: Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Adolescent↗

PubMedDate not supplied

Protein tyrosine kinase activity in breast cancer and its relation to prognostic indicators.

Tyrosine kinase dependent oncogenes and growth factor receptors are of prognostic importance in breast cancer, but the relation of cytosolic protein tyrosine kinase (PTK) activity to traditional prognostic indicators is poorly defined. We determined cytosolic PTK activity in tumor extracts of 61 women with invasive breast cancer, including 51 primary specimens and 12 nodal or metastatic specimens, 7 women with in situ breast cancer, and 8 control breast specimens. PTK activity (pmol/min/mg) was measured in a dot blot assay using phosphotyrosine antibodies to detect phosphorylated tyrosyl residues in the tissue extracts. Compared with control specimens (mean PTK = 20.5), tyrosine kinase activity was significantly greater in invasive primary cancers (mean PTK = 298.1; p = 0.0008), and nodal/metastatic specimens (mean PTK = 491.5; p = 0.0009). PTK levels of invasive cancers did not correlate with age (p = 0.36), tumor size (p = 0.83), nodal status (p = 0.37), estrogen receptor status (p = 0.66), or progesterone receptor status (p = 0.09). Thus, while tyrosine kinase activity is increased in breast cancer, correlations with traditional prognostic indicators were not found.

Breast↗