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PubMed1995

Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. AIDS Clinical Trials Group Protocol 116B/117 Team and the Virology Committee Resistance Working Group.

OBJECTIVE: To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression. DESIGN: Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous zidovudine therapy. SETTING: Participating ACTG virology laboratories. PATIENTS: 187 patients with baseline HIV-1 isolates. MEASUREMENTS: Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional hazards regression models. RESULTS: Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhibitory zidovudine concentration > or = 1.0 microM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4+ T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 isolates. CONCLUSIONS: High-level resistance of HIV-1 to zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from zidovudine to didanosine whether high-level HIV-1 resistance to zidovudine is present or absent, and laboratory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Didanosine compared with continued zidovudine therapy for HIV-infected patients with 200 to 500 CD4 cells/mm3. A double-blind, randomized, controlled trial. Canadian HIV Trials Network Protocol 002 Study Group.

OBJECTIVE: To compare the safety and efficacy of didanosine with that of continued zidovudine therapy in persons with human immunodeficiency virus (HIV) infection who had received zidovudine for at least 6 months and had CD4 cell counts of 200 to 500 CD4 cells/mm3. DESIGN: Double-blind, randomized controlled trial. SETTING: 10 Canadian university-affiliated specialty clinics. PATIENTS: 246 patients were assigned to receive standard doses of either zidovudine or didanosine. OUTCOME MEASURES: The primary clinical end point was the occurrence of a new, previously undiagnosed acquired immunodeficiency syndrome (AIDS)-defining illness or death. RESULTS: 245 of 246 patients were eligible (118 receiving didanosine and 127 receiving zidovudine). Sixty-six percent were asymptomatic, 30% had AIDS-related complex, and 4% had AIDS. The median baseline CD4 count was 320 cells/mm3. The median previous duration of zidovudine therapy was 471 days. Nine new AIDS-defining illnesses developed during the study; all but one were in the zidovudine group (relative risk, 7.9 [95% CI, 1.0 to 63.3; P = 0.02]). A change to didanosine led to a statistically significant increase in CD4 counts by week 2 that persisted until the end of the study at week 48 (P < or = 0.01). Viral sensitivity studies (done in 102 patients) showed that 28% of the zidovudine group and 21% of the didanosine group had high-level in vitro resistance to zidovudine (50% inhibitory concentration greater than 0.8 microM) at baseline (P = 0.49). Only one patient in the didanosine group developed high-level resistance to zidovudine during the study. In the zidovudine group, the cumulative probability of developing high-level resistance to zidovudine was 59% at 1 year (P = 0.01). Abdominal pain, leukopenia, and neutropenia were more frequent in the zidovudine group, and hyperuricemia was more frequent in the didanosine group (P < 0.05). CONCLUSION: In clinically stable patients with 200 to 500 CD4 cells/mm3 who had tolerated zidovudine for at least 6 months, a change to didanosine led to a decrease in the rate of disease progression, a sustained increase in CD4 counts, and a decrease in the chances of developing high-level resistance to zidovudine. Both drugs were generally well tolerated.

Adult↗

PubMed2000

Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy.

BACKGROUND: The prognostic value of discordant immunologic (CD4 cell increase) and virologic (plasma HIV RNA level decrease) responses to antiretroviral treatment is not known. OBJECTIVE: To study the relation between clinical outcome of HIV-infected patients receiving highly active antiretroviral therapy (HAART) and early immunologic and virologic responses to such therapy. DESIGN: Prospective cohort study. SETTING: 68 hospitals in France. PATIENTS: 2236 protease inhibitor-naive patients. INTERVENTION: Initiation of HAART with one protease inhibitor and two nucleoside analogues between July 1996 and March 1997. MEASUREMENTS: Immunologic and virologic response at 6 months. Multivariate Cox models were used to assess the relation between these responses and progression to a new AIDS-defining event or death. RESULTS: On the basis of 6-month immunologic and virologic responses, patients were classified into four groups: complete response (47.5%), complete nonresponse (16.2%), immunologic response only (19.0%), and virologic response only (17.3%). After month 6 and within a median of 18 months, 69 patients died and 123 experienced a new AIDS-defining event. After adjustment, complete nonresponders and those with only a virologic response had significantly higher risks for clinical progression at 6 months (relative risk, 3.38 [95% CI, 2.28 to 5.02] and 1.98 [CI, 1.26 to 3.10], respectively) than complete responders. The difference between complete responders and those with only an immunologic response at 6 months was weaker and nonsignificant (relative risk, 1.55 [CI, 0.96 to 2.50]). CONCLUSIONS: Immunologic response after 6 months of HAART indicates a favorable clinical outcome in HIV-infected patients regardless of virologic response. This suggests that both immunologic and virologic markers should be used in clinical practice to evaluate treatment response.

Adult↗

PubMed1997

Principles for including or excluding 'mechanisms' of death when writing cause-of-death statements.

OBJECTIVE: To develop principles and refined definitions designed to improve the content of cause-of-death statements regarding inclusion or exclusion of so-called mechanisms of death. DATA SOURCES: Survey of readily available instruction manuals and other literature regarding mechanisms of death and instructions for death certificate completion. DATA SYNTHESIS: Definitions and principles contained in the information sources were reviewed, and a set of specific principles, criteria, and definitions were written. These principles are consistent with, but are more extensive and practically applicable than, those found in each of the information sources surveyed and may be used to decide which conditions to report in cause-of-death statements. CONCLUSIONS: Mechanisms of death include a defined list of terminal events (such as asystole) and a larger group of nonspecific physiologic derangements (such as portal hypertension) and are differentiated by definition from nonspecific anatomic processes (such as cirrhosis). Three principles may be applied in individual cases. Principle 1 states that terminal events are not reported in cause-of-death statements. Principle 2 states that a nonspecific physiologic derangement or a nonspecific anatomic process should be reported if (1) it is a recognized, potentially fatal complication of the underlying cause of death; (2) it constitutes part of the sequence of conditions that led to the death of the patient in question; (3) it is not a symptom or sign; (4) its existence in the patient would not be apparent unless included and explicitly stated in the cause-of-death statement; (5) its inclusion does not constitute an oversimplification of the facts; and (6) an etiologically specific underlying cause of death is also reported. Principle 3 states that if the existence of the complication is obvious based on the underlying cause of death or another reported complication, it need not be reported.

Autopsy↗

PubMed1997

Suicide among foreign-born minorities and Native Swedes: an epidemiological follow-up study of a defined population.

The increasing number of immigrants in Sweden during the past four decades has brought the health of ethnic groups into focus. The purpose of this study was to analyse the influence of ethnicity, age, sex, marital status and date of immigration on suicide rates. The study population consisted of all individuals over 15 years of age, N = 6,725,274, from the Swedish census of 1985 and is based on individual data. Suicides and undetermined deaths, during the follow-up period 1986-1989, were taken from the central Cause of Death Register. Ethnicity, defined as being foreign-born, was a risk factor for suicide for both men and women with risk ratios of 1.21 (1.11-1.31) and 1.36 (1.21-1.53), respectively, with control for age and marital status. Being unmarried was also a risk factor for both males and females with risk ratios from 1.26 to 5.55 in different age groups. The highest risk ratios for suicide in Sweden, adjusted for age, were found among males born in Russia and Finland. They also showed higher suicide risks than in their countries of birth. Females born in Hungary, Russia, Finland and Poland all had high risks of committing suicide in Sweden and they also had higher risks than in their countries of birth. Further, being of male sex, aged 45-54 or 75 and older, and born in Eastern Europe or Finland were significant risk factors for suicide. The same was true for those who had immigrated to Sweden in 1967 or earlier and were born in Finland, Eastern Europe or in non-European countries. These findings are of great importance for primary health care and psychiatric care planning.

Adolescent↗

PubMed1999

Caspase structure, proteolytic substrates, and function during apoptotic cell death.

Caspases play an essential role during apoptotic cell death. These enzymes define a new class of cysteine proteases and comprise a multi-gene family with more than a dozen distinct mammalian family members. The discrete and highly limited subset of cellular polypeptides that are cleaved by these proteases is sufficient to account for the majority of cellular and morphological events that occur during cell death. In some cases, caspases also play a contributory role in escalating the propensity for apoptosis, and in doing so may exacerbate disease pathogenesis.

Amino Acid Sequence↗

PubMed1997

Persistent vegetative state and brain stem death.

Interest in the persistent vegetative state has focused on the accuracy of diagnosis and prognosis. Retrospective studies in both adult and paediatric groups have raised questions about the most appropriate clinical methods to diagnose patients in the vegetative state and about the length of time before recovery from such a state can be regarded as hopeless. Although no absolute answers have been forthcoming, the debate engendered by the work has been informative and the need for further prospective studies is apparent. Following the publication of guidelines on the management of patients in the vegetative state, the views of physicians in the USA and Europe have been sought in relation to ethical problems and, although they highlight some areas of inconsistency, they show the potential for consensus. Clinically, the field of brain stem death is reasonably defined and consistently managed but the search for methods of technical confirmation of diagnosis continues. It is suggested that the use of magnetic resonance imaging and angiography might provide additional confirmatory evidence.

Animals↗

PubMed2002

Confounding factors in diagnosing brain death: a case report.

BACKGROUND: Brain death is strictly defined medically and legally. This diagnosis depends on three cardinal neurological features: coma, absent brainstem reflexes, and apnea. The diagnosis can only be made, however, in the absence of intoxication, hypothermia, or certain medical illnesses. CASE PRESENTATION: A patient with severe hypoxic-ischemic brain injury met the three cardinal neurological features of brain death but concurrent profound hypothyroidism precluded the diagnosis. Our clinical and ethical decisions were further challenged by another facet of this complex case. Although her brain damage indicated a hopeless prognosis, we could not discontinue care based on futility because the only known surrogate was mentally retarded and unable to participate in medical planning. CONCLUSION: The presence of certain medical conditions prohibits a diagnosis of brain death, which is a medicolegal diagnosis of death, not a prediction or forecast of future outcome. While prognostication is important in deciding to withdraw care, it is not a component in diagnosing brain death.

Brain↗

PubMed1996

Heat-related deaths in Philadelphia--1993.

A study of heat-related deaths associated with the 1993 heat wave in Philadelphia, Pennsylvania, was conducted. Most of these deaths were in the susceptible elderly with preexisting natural diseases who lived alone without air conditioning in upstairs bedrooms with windows shut, thus creating an even hotter environment. These excessive deaths under such conditions did not meet the standard clinical criteria for hyperthermia because of varying postmortem intervals. Therefore, the authors stress the utility of a postmortem definition of heat-related death to better define the magnitude of health risk posed by hot weather and warn public health and other agencies to take preventative measures.

Adult↗

PubMed2003

Arsenic trioxide uses caspase-dependent and caspase-independent death pathways in myeloma cells.

Arsenic trioxide (ATO) is emerging as a standard therapy for refractory acute promyelocytic leukemia. Consequently, ATO-based therapies are being investigated in other cancers. We have reported that the combination of ATO and ascorbic acid is an effective strategy in chemoresistant myeloma cell lines and in plasma cells from patients. ATO action is multimodal and appears to involve thiol depletion, increased reactive oxygen species production, loss of mitochondrial membrane potential (DeltaPsi(m)), and activation of caspases. To better define the ATO death pathway, we asked whether caspase activity is required for ATO-mediated cell death. Here we report that ATO exerts cytotoxic effects in myeloma cell lines via both caspase-dependent and caspase-independent pathways. We monitored ATO-induced changes in cell viability, caspase activity, superoxide production, and DeltaPsi(m) in the presence or absence of the caspase inhibitors t-butoxy carbonyl-Asp.fluoromethylketone (BocD.fmk) and Z-Val-Ala-Asp.fluoromethylketone (zVAD.fmk) and the anti-oxidant N-acetylcysteine. Consistent with glutathione levels dictating ATO action, N-acetylcysteine abrogated ATO-induced changes in cell death, caspase activation, free radical production, and loss of DeltaPsi(m) in all the cell lines we tested. Experiments with caspase inhibitors suggested at least two models for ATO death signaling. In 8226/S cells, blockade of caspases had no effect on loss of cell viability, increase in reactive oxygen species production, and minimal effects on the loss of DeltaPsi(m). In contrast, BocD.fmk or zVAD.fmk conferred significant protection from the effects of ATO in U266 cells and MM1.S cells. Chemoresistant variants of 8226/S and MM1.S displayed similar ATO-induced death pathways as their respective parental lines. Studies with myeloma cells from bone marrow biopsies indicated that ATO initiates a caspase-independent pathway in the majority of samples.

Acetylcysteine↗

PubMed1995

Apoptosis in substantia nigra following developmental hypoxic-ischemic injury.

We have previously observed that either hypoxic-ischemic or excitotoxic striatal injury during development is associated with a reduction in the adult number of dopaminergic neurons in the substantia nigra. This decrease occurs in the presence of preserved striatal dopaminergic markers and in the absence of direct nigral injury. We have also observed that natural cell death, with the morphology of apoptosis, occurs in the substantia nigra, and that there is an induced apoptotic cell death event following early striatal excitotoxic injury. We now report that forebrain hypoxic-ischemic injury is also associated with an induced cell death event in the substantia nigra, with both morphological and histochemical features of apoptosis. Induced apoptotic cell death occurs in immunohistochemically defined dopaminergic neurons. While the mechanisms for this induced cell death are not yet known, in the case of the pars compacta it may be related to the loss of normal striatal target-derived developmental support. Since dopaminergic neurons are postmitotic at the time of the injury, we conclude that this induced cell death is responsible for the diminished adult number of dopaminergic neurons. We also conclude that hypoxic-ischemic injury to the developing brain in general causes not only direct, necrotic injury to vulnerable regions, but also induced apoptotic death at remote sites. The significance of this finding is that apoptosis is a distinct death mechanism, with unique regulatory pathways, which can potentially be modified by approaches different from those which might influence cell death in regions of direct injury. In view of the present finding that apoptosis can occur in the setting of hypoxic-ischemic injury, and our previous work demonstrating its occurrence following excitotoxic injury, it seems likely that it may occur following other forms of injury to the immature brain in which excitotoxic injury plays a role, such as seizures, head trauma and hypoglycemia.

Animals↗

PubMed1999

Cryopreserved homograft valves in the pulmonary position: risk analysis for intermediate-term failure.

OBJECTIVE: The purpose of this study was to examine the durability of cryopreserved homografts used to replace the "pulmonary" valve and to identify factors associated with their late deterioration. METHODS: We reviewed our entire experience (1985-1997) with 331 survivors in whom cryopreserved homograft valves (pulmonary, n = 304; aortic, n = 27) were used to reconstruct the pulmonary outflow tract. Median age was 14 years (range, 2 days-62 years). Operations included Ross operation (n = 259), tetralogy of Fallot (n = 41), truncus arteriosus (n = 14), Rastelli operation (n = 11), and others (n = 6). Median follow-up was 3.8 years (range, 0.2-11.2 years); late echographic follow-up was complete for 97% of patients. Homograft failure was defined as the need for explantation and valve-related death; homograft dysfunction was defined as a pulmonary insufficiency grade 3/4 or greater and a transvalvular gradient of 40 mm Hg or greater. RESULTS: Homograft failure occurred in 9% (30 of 331 patients; Kaplan-Meier); freedom from failure was 82% +/- 4% at 8 years. Homograft dysfunction occurred in 12% (39 of 331 patients), although freedom from dysfunction was 76% +/- 4% at 8 years. For aortic homografts, this was 56% +/- 11%, compared to 80% +/- 4% for pulmonary homografts (P =.003). For patients aged less than 3 years (n = 38), this was 51% +/- 12%, compared with 87% +/- 4% for older patients (P =.0001). By multivariable analysis, younger age of homograft donors, non-Ross operation, and later year of operation were associated with homograft failure; younger age of homograft donors, later year of operation, and use of an aortic homograft were associated with homograft dysfunction. CONCLUSIONS: Homograft valves function satisfactorily in the pulmonary position at mid-term follow-up. The pulmonary homograft valve appears to be more durable than the aortic homograft valve in the pulmonary position.

Adolescent↗

PubMed2000

Palmitate-induced apoptosis in cardiomyocytes is mediated through alterations in mitochondria: prevention by cyclosporin A.

Palmitate, a C16 fatty acid found in high concentrations in the blood in acute myocardial infarction, induces apoptotic cell death. To more completely define the nature and mechanism underlying palmitate-induced cell death, cardiomyocytes were cultured from embryonic chick heart and were treated with palmitate. Concentration-dependent loss of cell viability was established by loss of the ability of palmitate-treated cells to exclude propidium iodide (PI), metabolize 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and retain fluorescein diacetate (FDA). Dual staining with PI and FDA and subsequent analysis by FACS established that palmitate-induced cell death was predominantly necrosis whereas apoptosis occurred in 13% of all dead cells. The low proportion of palmitate-induced apoptosis was confirmed by evaluation of the DNA content or PI fluorescent staining of the DNA of permeabilized cardiomyocytes. A critical role for mitochondria in the pathogenesis of palmitate-induced cell death was demonstrated, for the first time, based on palmitate-induced reduction of mitochondrial activity as assessed by the mitochondrial-selective dye chloromethyl-X-Rosamine and the presence of a greater amount of the mitochondrial marker cytochrome C in the cytosol of palmitate-treated cardiomyocytes than in control cells. Further, cyclosporin that inhibits the development of mitochondrial transition pores blocked palmitate-induced alteration in mitochondrial function and palmitate-induced cell death. We further demonstrated the selectivity of cyclosporin A for the prevention of apoptotic cell death in the heart as there was no alteration in necrotic cell death produced by palmitate with cyclosporin pretreatment. Our data demonstrate the nature of palmitate-induced cell death in cardiomyocytes (both apoptotic and necrotic), propose a mitochondrial basis for its pathogenesis and show that cyclosporin A prevents palmitate-induced apoptotic cardiomyocyte cell death.

Animals↗

PubMed2003

Mitochondrial cytochrome c release is a key event in hyperoxia-induced lung injury: protection by cyclosporin A.

Hyperoxia is known to induce extensive alveolar cell death by still poorly defined mechanisms. In this study, the mitochondria-dependent cell death pathway was explored during hyperoxia-induced lung injury in mice. We observed a progressive release of cytochrome c from the mitochondria into the cytosol of alveolar cells. This release was accompanied by the translocation of the proapoptotic protein Bax from cytosol to mitochondria without detectable activation of caspase-3. As cytochrome c release can be induced by mitochondrial membrane alteration and permeability transition (MPT), mice were treated with cyclosporin A, which specifically inhibits MPT. Cyclosporin A treatment prevented mitochondrial release of cytochrome c during hyperoxia and concomitantly preserved mitochondria from extensive swelling and crista disorganization, as assessed by electron microscopy analysis of alveolar epithelial cells. These morphological and biochemical observations correlated with decreased lung tissue damage, as evaluated by morphological score and lung weight. In conclusion, mitochondrial damage and cytochrome c release are important linked events in hyperoxia-induced lung injury and can be efficiently blocked by cyclosporin A.

Animals↗

PubMed2005

Weight, weight gain, and survival after breast cancer diagnosis.

PURPOSE: To determine whether weight prior to diagnosis and weight gain after diagnosis are predictive of breast cancer survival. METHODS: Patients included 5,204 Nurses' Health Study participants diagnosed with incident, invasive, nonmetastatic breast cancer between 1976 and 2000; 860 total deaths, 533 breast cancer deaths, and 681 recurrences (defined as secondary lung, brain, bone, or liver cancer, and death from breast cancer) accrued to 2002. We computed the change in body mass index (BMI) from before to the first BMI reported > or = 12 months after the date of diagnosis. Cox proportional hazards models were used to evaluate associations of categories of BMI before diagnosis and of BMI change with time to event. We stratified by smoking, menopausal status, and breast cancer-related variables. RESULTS: In multivariate-adjusted analyses, weight before diagnosis was positively associated with breast cancer recurrence and death, but this was apparent only in never smokers. Similarly, among never-smoking women, those who gained between 0.5 and 2.0 kg/m(2) (median gain, 6.0 lb; relative risk [RR], 1.35; 95% CI, 0.93 to 1.95) or more than 2.0 kg/m(2) (median gain, 17.0 lb; RR, 1.64; 95% CI, 1.07 to 2.51) after diagnosis had an elevated risk of breast cancer death during follow-up (median, 9 years), compared with women who maintained their weight (test for linear trend, P = .03). Associations with weight were stronger in premenopausal than in postmenopausal women. Similar findings were noted for breast cancer recurrence and all-cause mortality. CONCLUSION: Weight and weight gain were related to higher rates of breast cancer recurrence and mortality, but associations were most apparent in never-smoking women.

Adult↗

PubMed1996

Prognosis of hypertrophic cardiomyopathy.

BACKGROUND: The actual prognosis of hypertrophic cardiomyopathy, a disorder previously thought of to be notorious for an increased risk of untimely death is poorly defined. OBJECTIVE: The present study describes the findings of patients with Hypertrophic Cardiomyopathy followed for more than nineteen years in a large clinic population. MATERIALS AND METHODS: A clinic population of 113 patients with Hypertrophic Cardiomyopathy was prospectively studied to assess cardiac mortality in the overall groups and in selected subgroups commonly thought to be at high risk for sudden death. Diagnosis of hypertrophic cardiomyopathy was based on the presence of left ventricular hypertrophy without a known cause. Left ventricular hypertrophy was determined by echocardiography. RESULTS: During follow-up there were 11 cardiac and 2 non cardiac deaths. The annual cardiac mortality was 1% (95% confidence interval 0.2-1.8%). Relative risk for cardiac death was not significantly different in the presence of young age (< 30 years), family history for Hypertrophic Cardiomyopathy (HCM) and sudden death, history for syncope or previous cardiac arrest or both, ventricular tachyeardia on 24-hour, holter monitoring or operation for refractory symptoms and out-flowtract obstruction. CONCLUSION: HCM has a relatively benign prognosis (1% cardiac annual mortality) that is 2-4 times less than previously thought. These findings might have important consequences for risk assessment in individual patients. Echocardiography is obligatory to determine the presence, and extent of myocardial hypertrophy. In addition, the technique allows differentiation between Hypertrophic Cardiomyopathy and Athlete's Heart.

Adolescent↗

PubMed1995

Body height, body mass index, and fatal hip fractures: 16 years' follow-up of 674,000 Norwegian women and men.

We studied the relations between body height, body mass index (BMI), and fatal hip fractures prospectively in a large, representative population. During the years 1963-1975, a nationwide compulsory mass x-ray examination including standardized height and weight measurements took place in Norway covering all persons age 15 years and older. In the study presented here, we selected women (N = 357,807) and men (N = 316,041) age 50-89 years at screening. We matched the file to the national death register containing causes of death throughout 1991; we defined cases as persons with hip fracture mentioned on their death certificates. During an average follow-up of 16.4 years, we identified a total of 6,087 fatal hip fractures in the study population. There was a distinct inverse relation between BMI and fatal hip fracture, with an age-adjusted relative risk (RR) in the three highest vs the low quartile of 0.68 [95% confidence interval (CI) = 0.63-0.72] in women and 0.57 (95% CI = 0.52-0.62) in men. The risk of fatal hip fractures increased slightly with increasing body height [RR = 1.10 (95% CI = 1.04-1.16) in women and RR = 1.08 (95% CI = 1.01-1.16) in men per 10-cm increase in body height]. This study indicates that low BMI is an important risk factor for fatal hip fractures and that body height has a weak, positive association.

Aged↗

PubMed2005

Metabolic profiling by 13C-NMR spectroscopy: [1,2-13C2]glucose reveals a heterogeneous metabolism in human leukemia T cells.

Metabolic profiling is defined as the simultaneous assessment of substrate fluxes within and among the different pathways of metabolite synthesis and energy production under various physiological conditions. The use of stable-isotope tracers and the analysis of the distribution of labeled carbons in various intermediates, by both mass spectrometry and NMR spectroscopy, allow the role of several metabolic processes in cell growth and death to be defined. In the present paper we describe the metabolic profiling of Jurkat cells by isotopomer analysis using (13)C-NMR spectroscopy and [1,2-(13)C(2)]glucose as the stable-isotope tracer. The isotopomer analysis of the lactate, alanine, glutamate, proline, serine, glycine, malate and ribose-5-phosphate moiety of nucleotides has allowed original integrated information regarding the pentose phosphate pathway, TCA cycle, and amino acid metabolism in proliferating human leukemia T cells to be obtained. In particular, the contribution of the glucose-6-phosphate dehydrogenase and transketolase activities to phosphoribosyl-pyrophosphate synthesis was evaluated directly by the determination of isotopomers of the [1'-(13)C], [4',5'-(13)C(2)]ribosyl moiety of nucleotides. Furthermore, the relative contribution of the glycolysis and pentose cycle to lactate production was estimated via analysis of lactate isotopomers. Interestingly, pyruvate carboxylase and pyruvate dehydrogenase flux ratios measured by glutamate isotopomers and the production of isotopomers of several metabolites showed that the metabolic processes described could not take place simultaneously in the same macrocompartments (cells). Results revealed a heterogeneous metabolism in an asynchronous cell population that may be interpreted on the basis of different metabolic phenotypes of subpopulations in relation to different cell cycle phases.

Carbon Isotopes↗