Biomedical subjects

J Kerner

Publications and source records attributed to J Kerner.

At least 19 recordsLinked to original sources

PubMed2001

Rat liver mitochondrial contact sites and carnitine palmitoyltransferase-I.

In hepatic mitochondria, the outer membrane enzyme, carnitine palmitoyltransferase-I (CPT-I), appears to colocalize with contact sites. We have prepared contact sites that are essentially devoid of noncontact site membranes. The contact site fraction has a high specific activity for CPT-I and contains a protein at 88 kDa that is recognized by antibodies directed at two different peptide epitopes on CPT-I. Similarly long-chain acyl-CoA synthetase (LCAS) specific activity is high in this fraction; a protein at 79 kDa is recognized by an antibody against LCAS. Although activity of carnitine palmitoyltransferase-II (CPT-II) is present, it is not enriched in the contact site fraction, and a protein of 68 kDa weakly reacted with anti-CPT-II antibody. Likewise, carnitine-acylcarnitine translocase (CACT) protein is present, but at a somewhat reduced level. Using an analytical continuous sucrose gradient, we demonstrate that the activities of CPT-I and LCAS and their associated immunoreactive proteins are present in a constant amount throughout the contact site subfractions. The enzymatic activity of CPT-II and its associated immunoreactive protein, as well as immunoreactive CACT, is absent in the lighter density gradient subfractions and is present in the higher density subfractions only in trace amounts. This heterogeneity of the contact site fraction is due to unvarying amounts of outer membrane and increasing amounts of attached inner membrane with increasing density of the subfractions.

Animals↗

PubMed2001

Mitochondrial dysfunction in cardiac disease: ischemia--reperfusion, aging, and heart failure.

Mitochondria contribute to cardiac dysfunction and myocyte injury via a loss of metabolic capacity and by the production and release of toxic products. This article discusses aspects of mitochondrial structure and metabolism that are pertinent to the role of mitochondria in cardiac disease. Generalized mechanisms of mitochondrial-derived myocyte injury are also discussed, as are the strengths and weaknesses of experimental models used to study the contribution of mitochondria to cardiac injury. Finally, the involvement of mitochondria in the pathogenesis of specific cardiac disease states (ischemia, reperfusion, aging, ischemic preconditioning, and cardiomyopathy) is addressed.

Aging↗

PubMed2001

Aging skeletal muscle mitochondria in the rat: decreased uncoupling protein-3 content.

The goal of the present study was to discern the cellular mechanism(s) that contributes to the age-associated decrease in skeletal muscle aerobic capacity. Skeletal muscle mitochondrial content, a parameter of oxidative capacity, was significantly lower (25 and 20% calculated on the basis of citrate synthase and succinate dehydrogenase activities, respectively) in 24-mo-old Fischer 344 rats compared with 6-mo-old adult rats. Mitochondria isolated from skeletal muscle of both age groups had identical state 3 (ADP-stimulated) and ADP-stimulated maximal respiratory rates and phosphorylation potential (ADP-to-O ratios) with both nonlipid and lipid substrates. In contrast, mitochondria from 24-mo-old rats displayed significantly lower state 4 (ADP-limited) respiratory rates and, consequently, higher respiratory control ratios. Consistent with the tighter coupling, there was a 68% reduction in uncoupling protein-3 (UCP-3) abundance in mitochondria from elderly compared with adult rats. Congruent with the respiratory studies, there was no age-associated decrease in carnitine palmitoyltransferase I and carnitine palmitoyltransferase II activities in isolated skeletal muscle mitochondria. However, there was a small, significant decrease in tissue total carnitine content. It is concluded that the in vivo observed decrease in skeletal muscle aerobic capacity with advanced age is a consequence of the decreased mitochondrial density. On the basis of the dramatic reduction of UCP-3 content associated with decreased state 4 respiration of skeletal muscle mitochondria from elderly rats, we propose that an increased free radical production might contribute to the metabolic compromise in aging.

Adenosine Diphosphate↗

PubMed2001

The emotional consequences of false positive mammography: African-American women's reactions in their own words.

High false positive rates associated with screening for breast cancer in the United States have an unintended psychological consequence for women (Lerman et al., 1991) that has raised concerns in recent years (Sox, 1998). This study uses inductive qualitative analysis of open-ended interviews with 45 African American women living in New York City who were part of a larger study of women and their experiences after receiving an abnormal mammogram. Themes resulting from the analyses included: inadequate provider-patient communication, anxieties exacerbated by waiting and wondering, and fears of iatrogenic effects of follow-up tests such as biopsies and repeat mammograms. While more research is needed on message-framing strategies for women entering mammographic testing and follow-up, modest changes in service delivery such as improved medical communication can help to alleviate fears and enhance trust.

Adult↗

PubMed2000

Fatty acid import into mitochondria.

The mitochondrial carnitine system plays an obligatory role in beta-oxidation of long-chain fatty acids by catalyzing their transport into the mitochondrial matrix. This transport system consists of the malonyl-CoA sensitive carnitine palmitoyltransferase I (CPT-I) localized in the mitochondrial outer membrane, the carnitine:acylcarnitine translocase, an integral inner membrane protein, and carnitine palmitoyltransferase II localized on the matrix side of the inner membrane. Carnitine palmitoyltransferase I is subject to regulation at the transcriptional level and to acute control by malonyl-CoA. The N-terminal domain of CPT-I is essential for malonyl-CoA inhibition. In liver CPT-I activity is also regulated by changes in the enzyme's sensitivity to malonyl-CoA. As fluctuations in tissue malonyl-CoA content are parallel with changes in acetyl-CoA carboxylase activity, which in turn is under the control of 5'-AMP-activated protein kinase, the CPT-I/malonyl-CoA system is part of a fuel sensing gauge, turning off and on fatty acid oxidation depending on the tissue's energy demand. Additional mechanism(s) of short-term control of CPT-I activity are emerging. One proposed mechanism involves phosphorylation/dephosphorylation dependent direct interaction of cytoskeletal components with the mitochondrial outer membrane or CPT-I. We have proposed that contact sites between the outer and inner mitochondrial membranes form a microenvironment which facilitates the carnitine transport system. In addition, this system includes the long-chain acyl-CoA synthetase and porin as components.

Animals↗

PubMed2000

Growth in human milk-Fed very low birth weight infants receiving a new human milk fortifier.

BACKGROUND/AIMS: Human milk fortification has been advocated to enhance premature infants' growth. We, therefore, undertook this study of a new human milk fortifier containing more protein than a reference one. METHODS: Open, randomized, controlled, multiclinic trial, with weekly growth parameters and safety evaluations in premature infants <1,500 g. RESULTS: The 2 groups did not differ in demographic and baseline characteristics. The adjusted daily milk intake was significantly higher in the infants fed reference human milk fortifier (n = 29; 154.2 +/- 2.1 vs. 144.4 +/- 2.5 ml/kg/day, mean +/- SE; p < 0.05). Both human milk fortifiers produced increases over baseline in weight, length, and head circumference, with greater gains observed in the new human milk fortifier-fed infants for the former two parameters (weight gain 26.8 +/- 1.3 and 20.4 +/- 1.2 g/day, p < 0.05; head circumference 1.0 +/- 0.1 and 0.8 +/- 0.1 cm/week; length 0.9 +/- 0.1 and 0.8 +/- 0.1 cm/week, respectively). Serum chemistries were normal and acceptable for age. Study events were typical for premature infants and similar in both groups. CONCLUSIONS: This new human milk fortifier had comparable safety to the reference human milk fortifier and promoted faster weight gain and head circumference growth.

Body Height↗

PubMed1999

A 22 kDa polyanion inhibits carnitine-dependent fatty acid oxidation in rat liver mitochondria.

The transport of activated fatty acids across the mitochondrial outer membrane has not been fully addressed. A polyanion (M(n)=22 kDa) inhibited the ADP-stimulated carnitine-dependent oxidation of both palmitoyl-CoA and palmitate plus CoA as well as mitochondrial hexokinase binding. In contrast, the oxidation of palmitoylcarnitine plus malate, as well as glutamate oxidation, was essentially unaffected. Mitochondrial carnitine palmitoyltransferase-1 was not inhibited by the polyanion. The data suggest an additional component in carnitine-dependent mitochondrial fatty acid oxidation, possibly porin.

Animals↗

PubMed1999

Breast and cervix cancer screening among multiethnic women: role of age, health, and source of care.

OBJECTIVE: The aim of this study was to evaluate the relationships between age, health status, access to care, and breast and cervical cancer screening among multiethnic elderly and nonelderly women. METHODS: A structured telephone survey of a quota sample of 1,420 New York City women from four Hispanic groups (Columbian, Dominican, Puerto Rican, Ecuadorian) and three black groups (U.S., Caribbean, and Haitian) was performed. Outcome measures included "ever" and "recent" self-reported use of mammography, clinical breast examination (CBE), and Pap smears. Logistic regression models assessed the predictors of screening use. RESULTS: Having a regular source of care significantly predicted all screening use for both elderly and nonelderly, controlling for ethnicity, sociodemographics, health status, access to care, proportion of life in the United States, and cancer attitudes. Elderly women (>/=65 years) were significantly less likely to have ever had (OR = 0.79, 95% CI 0.65-0. 96) and to have recently had (OR = 0.67, 95% CI 0.57-0.79) Pap smears than younger women, controlling for the other variables; being elderly also tended to be an independent predictor of ever and recent mammography and CBE use. Interestingly, there was a trend for health status to act differently in predicting Pap smear use for the two age groups. For younger women, being in poor health increased the odds of Pap smear screening, while for elderly women, being in good health increased the odds of screening. CONCLUSIONS: Elderly women reported being screened less than younger women; interactions between health status and age need further exploration.

Acculturation↗

PubMed1999

Correlation between pre-operative periprosthetic bone density and post-operative bone loss in THA can be explained by strain-adaptive remodelling.

Periprosthetic adaptive bone remodelling after total hip arthroplasty can be simulated in computer models, combining bone remodelling theory with finite element analysis. Patient specific three-dimensional finite element models of retrieved bone specimens from an earlier bone densitometry (DEXA) study were constructed and bone remodelling simulations performed. Results of the simulations were analysed both qualitatively and quantitatively. Patterns of predicted bone loss corresponded very well with the DEXA measurements on the retrievals. The amount of predicted bone loss, measured quantitatively by simulating DEXA on finite element models, was found to be inversely correlated with the initial bone mineral content. It was concluded that the same clinically observed correlation can therefore be explained by mechanically induced remodelling. This finding extends the applicability of numerical pre-clinical testing to the analysis of interaction between implant design and initial state of the bone.

Absorptiometry, Photon↗

PubMed1999

Acculturation and breast cancer screening among Hispanic women in New York City.

OBJECTIVES: This study investigated whether acculturation was associated with the receipt of clinical breast examinations and mammograms among Colombian, Ecuadorian, Dominican, and Puerto Rican women aged 18 to 74 years in New York City in 1992. METHODS: A bilingual, targeted, random-digit-dialed telephone survey was conducted among 908 Hispanic women from a population-based quota sample. Outcome measures included ever and recent use of clinical breast examinations and mammograms. Multivariate logistic regression models were used to assess the effect of acculturation on screening use. RESULTS: When demographic, socioeconomic, and health system characteristics and cancer attitudes and beliefs were controlled for, women who were more acculturated had significantly higher odds of ever and recently receiving a clinical breast examination (P < or = .01) and of ever (P < or = .01) and recently (P < or = .05) receiving a mammogram than did less acculturated women. For all screening measures, there was a linear increase in the adjusted probability of being screened as a function of acculturation. CONCLUSIONS: Neighborhood and health system interventions to increase screening among Hispanic women should target the less acculturated.

Acculturation↗

PubMed1999

Racial differences in testing motivation and psychological distress following pretest education for BRCA1 gene testing.

OBJECTIVES: We conducted a randomized trial to investigate racial differences in response to two alternate pretest education strategies for BRCA1 genetic testing: a standard education model and an education plus counseling (E + C) model. MATERIALS AND METHODS: Two hundred twenty-eight Caucasian women and 70 African American women with a family history of breast or ovarian cancer were contacted for a baseline telephone interview to assess sociodemographic characteristics, number of relatives affected with cancer, and race before pretest education. Outcome variables included changes from baseline to 1-month follow-up in cancer-related distress and genetic testing intentions, as well as provision of a blood sample after the education session. RESULTS: African American women were found to differ significantly from Caucasian women in the effects of the interventions on testing intentions and provision of a blood sample. Specifically, in African American women, E + C led to greater increases than education only in intentions to be tested and provision of a blood sample. These effects were independent of socioeconomic status and referral mechanisms. In Caucasian women, there were no differential effects of the interventions on these outcomes. Reductions in cancer-specific distress were evidenced in all study groups. However, this decrease, although not significantly different, was smallest among African American women who received E + C. CONCLUSIONS: In low- to moderate-risk African American women, pretest education and counseling may motivate BRCA1 testing. Further research is needed to explore the mechanisms of impact of the alternate pretest education strategies and to increase the cultural sensitivity of education and counseling protocols.

Adolescent↗

PubMed1998

The malonyl-CoA-sensitive form of carnitine palmitoyltransferase is not localized exclusively in the outer membrane of rat liver mitochondria.

The data used to support the idea that malonyl-coenzyme A (CoA)-sensitive carnitine palmitoyltransferase (CPT-I) is localized on the outer mitochondrial membrane are based on harsh techniques that disrupt mitochondrial physiology. We have turned to the use of the French press, which produces a shearing force that denudes mitochondria of their outer membrane without the physiologically disruptive effects characteristic of phosphate swelling. Our results indicate that the mitoplasts contain just 15-19% of the outer membrane marker enzyme activity while retaining 85% of the total CPT activity and 50% of both CPT-I, as well as long-chain acyl-CoA synthase activity, the latter two supposed outer membrane enzymes. These mitoplasts were shown by electron microscopy to have the configuration of mitochondria that merely have been divested of their outer membranes. Carnitine-dependent fatty acid oxidation was retained in the mitoplasts, showing that they were physiologically intact. Moreover, protein immunoblotting analysis showed that CPT-I, as well as the inner CPT-II, was localized in the mitoplast fraction. The outer membrane fraction, which consisted of membrane "ghosts," contained most (50-60%) of marker enzyme activity, monoamine oxidase-B and porin proteins, but only about 27-29% CPT-I activity. Because CPT-I and long-chain acyl-CoA synthetase appear to be associated with both inner and outer membranes, we postulate that these enzymes reside in contact sites, which represent a melding of both limiting membranes.

2,4-Dinitrophenol↗

PubMed1998

Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure.

BACKGROUND: Pharmacological inhibition of carnitine palmitoyl transferase I (CPT-I), the enzyme controlling the rate of fatty acid transport into the mitochondria, prevents the contractile dysfunction, myosin isozyme shift and deterioration in sarcoplasmic reticulum Ca2+ handling that occurs in rat models of left ventricular hypertrophy. In this study we examine whether the improved cardiac function with beta blockade therapy in heart failure is associated with an alteration in CPT-I activity. METHODS AND RESULTS: We examined dogs with coronary microembolism-induced heart failure treated for 12 weeks with metoprolol (25 mg twice daily). Myocardial activities of CPT-I, medium-chain acyl co-enzyme A dehydrogenase (MCAD, a beta-oxidation enzyme), citrate synthase, and triglyceride content were measured. The progressive decrease in cardiac function was prevented by treatment with metoprolol, as reflected by an improved ejection fraction over 12 weeks in the metoprolol group (from 35% to 40%) compared to the untreated heart failure dogs (decrease from 36% to 26%). Dogs treated with metoprolol had a marked decrease in CPT-I activity (0.46 +/- 0.03 vs. 0.64 +/- 0.02 micromol min(-1) g(-1) wet weight; P < .02) along with an increase in triglyceride concentration compared to untreated heart failure dogs (3.9 +/- 0.3 v 4.9 +/- 0.2 micromol/g wet weight, respectively; P < .003). By contrast, MCAD and citrate synthase activities did not change. CONCLUSION: Metoprolol induced a decrease in CPT-I activity and an increase in triglyceride content. These results suggest that the improved function observed with beta blockers in heart failure could be due, in part, to a decrease in CPT-I activity and less fatty acid oxidation by the heart.

Adrenergic beta-Antagonists↗

PubMed1998

Genetic disorders of carnitine metabolism and their nutritional management.

Carnitine functions as a substrate for a family of enzymes, carnitine acyltransferases, involved in acyl-coenzyme A metabolism and as a carrier for long-chain fatty acids into mitochondria. Carnitine biosynthesis and/or dietary carnitine fulfill the body's requirement for carnitine. To date, a genetic disorder of carnitine biosynthesis has not been described. A genetic defect in the high-affinity plasma membrane carnitine-carrier(in) leads to renal carnitine wasting and primary carnitine deficiency. Myopathic carnitine deficiency could be due to an increase in efflux moderated by the carnitine-carrier(out). Defects in the carnitine transport system for fatty acids in mitochondria have been described and are being examined at the molecular and pathophysiological levels. the nutritional management of these disorders includes a high-carbohydrate, low-fat diet and avoidance of those events that promote fatty acid oxidation, such as fasting, prolonged exercise, and cold. Large-dose carnitine treatment is effective in systemic carnitine deficiency.

Animals↗

PubMed1997

Continuity of care and the use of breast and cervical cancer screening services in a multiethnic community.

OBJECTIVE: To examine how continuity of care affects the use of breast and cervical cancer screening in a multiethnic population. METHODS: All data came from a structured telephone survey of a population-based quota sample designed to determine the cancer prevention needs of multiethnic blacks and Hispanics in New York, NY, in 1992. The study included 1420 women of 7 racial/ethnic groups: US-born blacks, English-speaking Caribbean-born blacks, Haitian blacks, and Puerto Rican, Dominican, Colombian, and Ecuadorian Hispanics. The main outcome measures were ever and recently having had a Papanicolaou smear, clinical breast examination (CBE), or mammogram. RESULTS: Among respondents who qualified for the survey on the basis of age and ethnicity, the refusal rate for completing the interview was 2.1%. Compared with women without a usual site of care, those with a usual site, but no regular clinician, were 1.56, 2.45 (P < or = .01), and 2.32 (P < or = .05) times as likely ever to have received a Papanicolaou smear, CBE, or mammogram, respectively and 1.84, 1.92 (P < or = .05), and 1.75 times as likely to have received a recent Papanicolaou smear, CBE, or mammogram, respectively. Compared with women without a usual site of care, women with a regular clinician at that usual site of care were 2.63 (P < or = .01), 2.83 (P < or = .01), and 2.30 (P < or = .05) times as likely ever to have received a Papanicolaou smear, CBE, or mammogram, and were 2.00 (P < or = .05), 2.65 (P < or = .01), and 1.40 times as likely to have recently received a Papanicolaou smear, CBE, or mammogram, respectively (adjusted odds ratios). For uninsured women, presence of a usual site of care was associated with increases in recent use of cancer screening for all screening tests. CONCLUSIONS: There is a linear trend in increasing breast and cervical cancer screening rates when one goes from having no usual source of care, to having a usual source, and to having a regular clinician at that usual source. Emphasis on continuity of care, especially on usual source of care, may help to bridge the gap in access to cancer prevention services faced by minority women.

Adult↗

PubMed1997

Controlled trial of pretest education approaches to enhance informed decision-making for BRCA1 gene testing.

BACKGROUND: In response to the isolation of the BRCA1 gene, a breast-ovarian cancer-susceptibility gene, biotechnology companies are already marketing genetic tests to health care providers and to the public. Initial studies indicate interest in BRCA1 testing in the general public and in populations at high risk. However, the optimal strategies for educating and counseling individuals have yet to be determined. PURPOSE: Our goal was to evaluate the impact of alternate strategies for pretest education and counseling on decision-making regarding BRCA1 testing among women at low to moderate risk who have a family history of breast and/or ovarian cancer. METHODS: A randomized trial design was used to evaluate the effects of education only (educational approach) and education plus counseling (counseling approach), as compared with a waiting-list (control) condition (n = 400 for all groups combined). The educational approach reviewed information about personal risk factors, inheritance of cancer susceptibility, the benefits, limitations, and risks of BRCA1 testing, and cancer screening and prevention options. The counseling approach included this information, as well as a personalized discussion of experiences with cancer in the family and the potential psychological and social impact of testing. Data on knowledge of inherited cancer and BRCA1 test characteristics, perceived risk, perceived benefits, limitations and risks of BRCA1 testing, and testing intentions were collected by use of structured telephone interviews at baseline and at 1-month follow-up. Provision of a blood sample for future testing served as a proxy measure of intention to be tested (in the education and counseling arms of the study). The effects of intervention group on study outcomes were evaluated by use of hierarchical linear regression modeling and logistic regression modeling (for the blood sample outcome). All P values are for two-sided tests. RESULTS: The educational and counseling approaches both led to significant increases in knowledge, relative to the control condition (P < .001 for both). The counseling approach, but not the educational approach, was superior to the control condition in producing significant increases in perceived limitations and risks of BRCA1 testing (P < .01) and decreases in perceived benefits (P < .05). However, neither approach produced changes in intentions to have BRCA1 testing. Prior to and following both education only and education plus counseling, approximately one half of the participants stated that they intended to be tested; after the session, 52% provided a blood sample. CONCLUSIONS: Standard educational approaches may be equally effective as expanded counseling approaches in enhancing knowledge. Since knowledge is a key aspect of medical decision-making, standard education may be adequate in situations where genetic testing must be streamlined. On the other hand, it has been argued that optimal decision-making requires not only knowledge, but also a reasoned evaluation of the positive and negative consequences of alternate decisions. Although the counseling approach is more likely to achieve this goal, it may not diminish interest in testing, even among women at low to moderate risk. Future research should focus on the merits of these alternate approaches for subgroups of individuals with different backgrounds who are being counseled in the variety of settings where BRCA1 testing is likely to be offered.

Adult↗

PubMed1997

The costs and effects of cervical and breast cancer screening in a public hospital emergency room. The Cancer Control Center of Harlem.

OBJECTIVES: This study assessed the cost-effectiveness of cervix and breast cancer screening in a public hospital emergency room. METHODS: Age-eligible women with nonurgent conditions and without recent screening were offered screening by a nurse. A decision analysis compared the costs and outcomes of emergency room screening and standard hospital screening efforts. RESULTS: The undiscounted cost-effectiveness results for establishing new programs were $4050 (cervical cancer), $403,203 (breast cancer), and $4375 (joint cervix and breast cancer) per year of life saved. If screening is added to an existing program, results are more favorable ($429, $21,324, and $479 per year of life saved for cervix, breast, and joint screening, respectively). Results were most sensitive to volume and probability of receiving treatment after an abnormal screen. CONCLUSIONS: Emergency room screening was cost-effective for cervical cancer; breast cancer screening was relatively expensive given the low number of women reached. More intensive recruitment and follow-up strategies are needed to maximize the cost-effectiveness of such programs.

Breast Neoplasms↗

PubMed1996

Implementation of a breast and cervical cancer screening program in a public hospital emergency department. Cancer Control Center of Harlem.

STUDY OBJECTIVE: To assess the feasibility and yields of screening for breast and cervical cancer in an urban public hospital emergency department. METHODS: Women who presented to the ED of a large, urban public hospital during the study period with nonurgent conditions were eligible for a Papanicolaou test (Pap smear) and a clinical breast examination (CBE) if they were 18 years of age or older and for a mammogram if they were 40 years of age or older, provided they had not had the screening examination within the past year. The Pap smear and CBE were performed by a nurse, and mammography was scheduled for a later date. Women with gynecologic complaints were excluded. RESULTS: On the basis of screening history, medical status, and age, 1,850 (32%) of the 5,830 women seen in the ER during the 23-month study period were eligible for both mammography and CBE, and 2,361 (41%) were eligible for Pap smears. Of these women, 116 (6%) completed mammography and CBE, and 644 (27%) received Pap smears. Among screened women, 10 (9%) and 20 (3%), respectively, had results that were suspicious or positive for breast or cervical cancer. Follow-up rates were low: 20% for breast screening and 50% for Pap smears. Among those receiving follow-up, 1 woman was found to have breast cancer and 8 were found to have cervical neoplasia. CONCLUSION: ED cancer screening was feasible and yielded a high rate of cancer detection. Program efficiency was hampered by low volume and high numbers of patients lost to follow-up after abnormal screening results. Greater integration into the acute care setting and more intensive recruitment and follow-up strategies are needed to maximize the potential yield and cost effectiveness of such programs.

Adolescent↗