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Biomedical subjects

L Rosenberg

Publications and source records attributed to L Rosenberg.

At least 19 recordsLinked to original sources
PubMed2006

Autocrine insulin action activates Akt and increases survival of isolated human islets.

AIMS/HYPOTHESIS: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a critical role in promoting the survival of pancreatic beta cells. Akt becomes activated in isolated human islets following overnight culture despite significant levels of cell death. The aim of the current study was to identify the cause of the observed increase in Akt phosphorylation in isolated islets. We hypothesised that a factor secreted by the islets in culture was acting in an autocrine manner to activate Akt. METHODS: In order to identify the stimulus of the PI3K/Akt pathway in culture, we examined the effects of different culture conditions on Akt phosphorylation and islet survival during the immediate post-isolation period. RESULTS: We demonstrated that islet-conditioned medium induced Akt phosphorylation in freshly isolated human islets, whereas frequent medium replacement decreased Akt phosphorylation. Following overnight culture, islet-conditioned medium contained significantly elevated levels of insulin, indicating that insulin may be responsible for the observed increase in Akt phosphorylation. Indeed, treatment with an anti-insulin antibody or with inhibitors of insulin receptor/IGF receptor 1 kinase activity suppressed Akt phosphorylation, leading to decreased islet survival. In addition, dispersion of islets into single cells also suppressed Akt phosphorylation and induced islet cell death, indicating that islet integrity is also required for maximal Akt phosphorylation. CONCLUSIONS/INTERPRETATION: Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets. These findings provide new information on how culturing islets prior to transplantation may be beneficial to their survival by allowing for autocrine activation of the pro-survival Akt pathway.

Cadaver↗
PubMed2006

Evidence for the homeostatic regulation of induced beta cell mass expansion.

AIMS/HYPOTHESIS: Diabetes results from an insufficient insulin-secreting beta cell mass. Restoration of beta cell mass through pharmaceutically induced endogenous beta cell mass expansion may revolutionise diabetes therapy. However, it remains to be determined whether the induced beta cell mass expansion is under homeostatic regulation. METHODS: Beta cell mass expansion rates were derived from three separate studies of continuous stimulation of islet neogenesis, including the partial duct obstruction of euglycaemic Syrian hamsters, administration of a pentadecapeptide with the same amino acid sequence as residues 104-118 of islet neogenesis-associated protein (INGAP(104-118)) to euglycaemic Syrian hamsters, as well as to euglycaemic CD-1 mice. The incidence of islet neogenesis, average beta cell size, and beta cell replication and apoptotic rates were determined. RESULTS: Partial duct obstruction led to a approximately 2.5-fold increase in endocrine tissue at day 56 (p<0.05). From day 0 to day 7 the average rate of change of islet area was 12.7% per day, and this rate decreased to 5.3% per day from day 7 to day 42, and to 2.8% per day from day 42 to day 56. Administration of INGAP(104-118) to adult hamsters led to a 31% increase in total beta cell mass at day 30 (p=0.031). From day 0 to day 10 the average rate of beta cell mass expansion was 148 mug/day, whereas from day 10 to day 30 it decreased to 45 mug/day. INGAP(104-118) administration to adult CD-1 mice resulted in an approximately twofold increase in beta cell mass after 31 days (p=0.021). However, at day 90, there was no significant difference vs age-matched control mice (p=0.30), even though the neogenic beta cell mass was approximately fourfold greater (p=0.026). Beta cell replication was decreased by 56% (p<0.048), whereas beta cell apoptosis was fourfold greater (p<0.003) in 90-day INGAP(104-118)-treated mice compared with age-matched control mice. CONCLUSIONS/INTERPRETATION: These data indicate that in the presence of ongoing islet neogenesis, homeostatic regulatory mechanisms intervene to regulate beta cell mass according to the prevailing metabolic requirements.

Animals↗
PubMed2006

Energy dependence of directed flow over a wide range of pseudorapidity in Au + Au collisions at the BNL Relativistic Heavy Ion Collider.

We report on measurements of directed flow as a function of pseudorapidity in Au + Au collisions at energies of square root of SNN = 19.6, 62.4, 130 and 200 GeV as measured by the PHOBOS detector at the BNL Relativistic Heavy Ion Collider. These results are particularly valuable because of the extensive, continuous pseudorapidity coverage of the PHOBOS detector. There is no significant indication of structure near midrapidity and the data surprisingly exhibit extended longitudinal scaling similar to that seen for elliptic flow and charged particle pseudorapidity density.

Journal Article↗
PubMed2005

Energy dependence of elliptic flow over a large pseudorapidity range in Au+Au collisions at the BNL relativistic heavy ion collider.

This Letter describes the measurement of the energy dependence of elliptic flow for charged particles in Au+Au collisions using the PHOBOS detector at the Relativistic Heavy Ion Collider. Data taken at collision energies of square root of s(NN)=19.6, 62.4, 130, and 200 GeV are shown over a wide range in pseudorapidity. These results, when plotted as a function of eta(')=|eta|-y(beam), scale with approximate linearity throughout eta('), implying no sharp changes in the dynamics of particle production as a function of pseudorapidity or increasing beam energy.

Journal Article↗
PubMed2005

Morphogenetic plasticity of adult human pancreatic islets of Langerhans.

The aim of this study was to investigate the phenotypic plasticity of pancreatic islets of Langerhans. Quiescent adult human islets were induced to undergo a phenotypic switch to highly proliferative duct-like structures in a process characterized by a loss of expression of islet-specific hormones and transcription factors as well as a temporally related rise in the expression of markers of both duct epithelial and progenitor cells. Short-term treatment of these primitive duct-like structures with the neogenic factor islet neogenesis-associated protein (INGAP104-118) induced their reconversion back to islet-like structures in a PI3-kinase-dependent manner. These neoislets resembled freshly isolated human islets with respect to the presence and topological arrangement of the four endocrine cell types, islet gene expression and hormone production, insulin content and glucose-responsive insulin secretion. Our results suggest that adult human islets possess a remarkable degree of morphogenetic plasticity. This novel observation may have important implications for understanding pancreatic carcinogenesis and islet neogenesis.

Adult↗
PubMed2004

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity.

AIMS/HYPOTHESIS: We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids. METHODS: Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-kappa B DNA binding was assayed by electrophoretic mobility shift assay. RESULTS: In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagon-like peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-kappa B DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two anti-apoptotic genes under the control of nuclear factor-kappa B. Inhibition of nuclear factor-kappa B by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1. CONCLUSIONS/INTERPRETATION: The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo- and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-kappa B.

Apoptosis↗
PubMed2003

Bone mineral density and lifetime physical activity in South African women.

We investigated the relation between lifetime physical activity and bone mineral density (BMD) in South African women using data collected in a case-control study of breast cancer in relation to BMD. Subjects (n = 144) were of black African or mixed ancestral origin, and <60 years of age (mean age 42.6 +/- 8.9 years). Cases had newly diagnosed breast cancer (n = 62) and controls were referred for conditions unrelated to BMD or breast cancer (n = 82). Physical activity data consisting of household, occupational and leisure-time activity, and activity for transport, were collected via questionnaire at 4 life stages (epochs), viz. 14-21, 22-34, 35-50, and 50+ years of age. Total energy (MET hrs) and peak strain scores were calculated. Lumbar spine and total proximal femur BMD were measured using dual-energy x-ray absorptiometry. BMD measures were similar between groups, therefore data were combined. BMD measures were unrelated to total lifetime physical activity. However, the major determinants of total proximal femur BMD included age, transport activity including walking and bicycling between the ages of 14 and 21 years, and current weight (adjusted r2 = 0.33, P < 0.0001). The major determinants of lumbar spine BMD included age, household energy expenditure between the ages of 14 and 21 years, and current weight (adjusted r2 = 0.23, P < 0.0001). Total peak bone strain score for activities between 14-21 years of age was also significantly correlated with lumbar spine BMD ( r = 0.18, P < 0.05). Intraclass correlation coefficients to assess tracking of activity through epochs 1, 2, and 3 were high for total energy expenditure (0.96; 95%CI: 0.94-0.97), household (0.98; 95%CI: 0.97-0.99) and occupational activity (0.78; 95%CI: 0.71-0.84) and activity for transport (0.92; 95%CI: 0.89-0.94). These data suggest that walking or activities resulting in impact loading at a young age are associated with higher BMD in later years. In addition, our findings suggest tracking of physical activity over time.

Absorptiometry, Photon↗
PubMed2003

Significance of the fragmentation region in ultrarelativistic heavy-ion collisions.

We present measurements of the pseudorapidity distribution of primary charged particles produced in Au+Au collisions at three energies, sqrt[s(NN)]=19.6, 130, and 200 GeV, for a range of collision centrali-ties. The distribution narrows for more central collisions and excess particles are produced at high pseudorapidity in peripheral collisions. For a given centrality, however, the distributions are found to scale with energy according to the "limiting fragmentation" hypothesis. The universal fragmentation region described by this scaling grows in pseudorapidity with increasing collision energy, extending well away from the beam rapidity and covering more than half of the pseudorapidity range over which particles are produced. This approach to a universal limiting curve appears to be a dominant feature of the pseudorapidity distribution and therefore of the total particle production in these collisions.

Journal Article↗
PubMed2003

Signals for death and differentiation: a two-step mechanism for in vitro transformation of adult islets of Langerhans to duct epithelial structures.

Phenotypic change of adult pancreatic islets has been implicated in the development of certain pancreatic cancers and in islet transplant failure. The aim of this study was to characterize intracellular events that mediate changes in adult islet phenotype. Using an in vitro islet-to-duct transformation model, canine islets were induced to undergo phenotypic transformation to duct-like epithelial structures through a two-stage process. Stage one was characterized by widespread islet cell apoptosis associated with the formation of cavitary spaces within the islets. During this stage, c-Jun N-terminal regulated kinase (JNK) and caspase-3 activities were elevated, while extracellular signal-regulated kinase (ERK) and Akt activities were decreased. The second stage of the process was characterized by an inversion in the balance in activity between these signal transduction pathways and by a concomitant decrease in apoptosis. The transformed islets were no longer immunoreactive for islet cell hormones, but expressed the duct epithelial cell marker CK-AE1/AE3. In contrast to islet cells, these duct epithelial cells were highly proliferative. To clarify the role of the identified changes in signal transduction events, we performed additional studies using pharmacological inhibitors of enzyme activity and demonstrated that inhibition of JNK and caspase-3 activity prevented cystic transformation. Our results indicate that the balance in signaling activity between ERK/Akt and JNK/caspase-3 appears to be an important regulator of islet cell death and differentiation.

Animals↗
PubMed2003

Limited Pap screening associated with reduced risk of cervical cancer in South Africa.

BACKGROUND: We investigated the effect of Pap smear screening on the incidence of invasive cancer of the cervix in the Western Cape, South Africa where screening is limited. METHODS: Data were derived from a case-control study of the association of hormonal contraceptives and invasive cervical cancer. Incident cases (n = 524) of invasive cervical cancer who presented at two tertiary hospitals and controls (n = 1540) series matched for age, race, and place of residence were interviewed. Information on a wide range of variables was collected including whether the women had previously had a Pap smear taken and the number and timing of smears. Odds ratios (OR) and 95% CI were calculated using multiple logistic regression. RESULTS: The OR of cervical cancer was reduced among women who had ever had a smear (OR = 0.3, 95% CI: 0.3-0.4). The OR declined with increasing number of smears to 0.2 for >/=>3 smears (trend P = 0.0003). Among women who had a smear <5 years previously the OR was 0.3, but even if the smear was taken >/=15 years previously the women remained at reduced risk (OR = 0.5). CONCLUSION: The data suggest that even limited Pap smear screening reduces the risk of cervical cancer. Should a screening programme be successfully implemented, the incidence of cervical cancer might be reduced by as much as 70%.

Adult↗
PubMed2003

Assessment of strategies for identifying diagnosed cases of systemic lupus erythematosus through self-report.

The objective of this work was to assess the optimal way to identify potential systemic lupus erythematosus (SLE) cases in large epidemiologic studies through self-reported information about diagnosis of SLE, symptoms and medications, and to investigate the utility of a criteria checklist sent directly to participants' physicians. We used data collected in 1997 from 53322 participants in a study of African-American women, the Black Women's Health Study, including a lupus screening questionnaire (LSQ) and questions about SLE diagnosis and medications. We confirmed self-reported SLE through medical records and criteria checklists sent to participants' physicians. Among those for whom we received medical records and/or criteria checklists, we compared the predictive value and proportion of missed cases of several algorithms using combinations of self-reported SLE diagnosis, LSQ score and medication use to self-reported SLE diagnosis alone. We obtained a physician checklist or medical chart for 251 individuals who reported SLE, of whom 212 (84%) fulfilled ACR criteria for definite or probable SLE, or had clinical lupus (SLE diagnosis recorded in medical charts plus appropriate medication use). The use of LSQ score or medication use in addition to self-report of SLE tended to decrease the false positive rate but also to reduce the proportion of true cases identified. Checklists of ACR criteria completed by subjects' physicians documented more criteria than medical records. In conclusion, among participants who consented to medical record review, SLE prediction algorithms using questions about lupus symptoms and medications offered slightly higher predictive value for detecting cases than self-reported diagnosis alone, but at the cost of case detection. SLE case confirmation strategies can be complemented by the use of criteria checklists sent directly to participants' physicians.

Adult↗
PubMed2002

Pseudorapidity and centrality dependence of the collective flow of charged particles in Au+Au collisions at sqrt[s(NN)]=130 GeV.

This paper describes the measurement of collective flow for charged particles in Au+Au collisions at sqrt[s(NN)]=130 GeV using the PHOBOS detector at the Relativistic Heavy Ion Collider (RHIC). The measured azimuthal hit anisotropy is presented over a wide range of pseudorapidity (-5.0<eta<5.3) for the first time at this energy. The result, averaged over momenta and particle species, is observed to reach 7% for peripheral collisions at midrapidity, falling off with centrality and increasing |eta|. These results call into question the common assumption of longitudinal boost invariance over a large region of rapidity in RHIC collisions.

Journal Article↗
PubMed2002

Altered islet homeostasis before classic insulitis in BB rats.

Young diabetes-prone BioBreeding (BBdp) rats fed a diabetes-promoting, cereal-based, NIH-07 (NIH) diet have decreased islet area compared with rats fed a diabetes-retardant diet at a time when classic insulitis is minimal. This finding raised the possibility that islet homeostasis in BBdp rats may be abnormal. To investigate this possibility further, comparisons were made between BBdp and BB control (BBc) rats fed a diabetes-promoting NIH diet for 22 days after weaning. Pancreatic sections were fixed in Bouin's solution and evaluated using immunohistochemistry and image analysis by staining with antibodies for islet hormones: insulin, glucagon; cell proliferation markers: PCNA, BrdU; markers of islet neogenesis: PDX-1, cytokeratin 20; apoptosis was assessed by morphological changes and TUNEL staining. Body weight of BBdp rats was significantly smaller than BBc rats. Although the total number of islets was higher in BBdp compared with BBc, both islet and beta-cell fraction were similar. BBdp rats had a lower beta-cell mass than BBc rats, although this was not statistically significant. Alpha-cell fraction and beta-cell size were similar. Apoptotic bodies were rare in beta-cells but more frequent in acinar tissue of BBdp rats. When the day-night cycle was reversed to synchronize the apoptotic process, the number of apoptotic bodies in islets and in acinar cells was increased. Apoptotic bodies and BrdU+ or PCNA+ beta-cells were more frequently encountered in islets of BBdp rats. Although the frequency of CK20+ islets in BBdp rats was not different, CK20+ area fraction was smaller in BBdp. The number of extra-islet insulin+ and glucagon+ clusters (<4 cells) was significantly greater in BBdp rats. These data are consistent with an enhanced compensatory or "repair" process in the pancreas of BBdp rats that attempts to maintain islet cell mass by altering homeostasis through increased islet neogenesis.

Animals↗
PubMed2001

Energy dependence of particle multiplicities in central Au+Au collisions.

We present the first measurement of the pseudorapidity density of primary charged particles in Au+Au collisions at root square[s(NN)] = 200 GeV. For the 6% most central collisions, we obtain dN(ch)/d(eta)/(/eta/<1) = 650+/-35(syst). Compared to collisions at root square[s(NN)] = 130 GeV, the highest energy studied previously, an increase by a factor of 1.14+/-0.05 at 90% confidence level, is found. The energy dependence of the pseudorapidity density is discussed in comparison with data from proton-induced collisions and theoretical predictions.

Journal Article↗
PubMed2001

Changes in neuronal activation with increasing attention demand in healthy volunteers: an fMRI study.

Several lines of evidence suggest that structures involved in mediating attention differentially respond to increasing processing demand. Investigation of differences in neuronal activation, however, has been complicated by methodological inconsistencies and concomitant discrepancies in degree of difficulty and subject effort between disparate tasks. In this study, we utilized fMRI to compare neural activation patterns associated with two related attention tasks associated with different degrees of processing load while controlling for degree of performance difficulty. Healthy volunteers performed two continuous performance tasks, utilizing an identical pairs paradigm (CPT-IP) and a matched simple number recognition paradigm with degraded stimuli (CPT-DS) during a single fMRI scan. Degree of stimulus resolution degradation in the latter CPT was designed to equalize degree of performance difficulty between the two tasks. CPT-IP and CPT-DS were both associated with activation of frontal, limbic, subcortical, and sensory integratory structures. CPT-IP administration was associated with significantly greater activation of left dorsolateral prefrontal cortex, bilateral posterior temporal cortex, bilateral putamen, and thalamus. This study demonstrates both that differing attention tasks are associated with a high degree of functional overlap and that increasing processing demand is associated with increased activation of specific portions of attentional networks.

Adult↗
PubMed2001

Follow-up of a large cohort of Black women.

High retention rates in follow-up studies reduce the potential for biased data due to selective losses. The Black Women's Health Study began in 1995 when 64,500 participants aged 21-69 years enrolled by completing postal health questionnaires. Follow-up is carried out biennially. On the basis of data collected between enrollment and completion of the first follow-up, the authors assessed the usefulness of various follow-up methods and compared the characteristics of respondents, nonrespondents, and women lost to follow-up because of an unknown address. The 1997 questionnaire was completed by 82.8% of the participants. The study population was highly mobile: 56.5% moved at least once, and 1.5% moved at least four times. Moving was associated with younger age: A total of 71.7% of participants aged 21-29 years moved at least once compared with 43.2% of women aged 50-69. The most successful and cost-effective method for eliciting completed questionnaires from participants was sending multiple waves of questionnaires. Telephone calls to nonrespondents were successful but were highly labor intensive. Demographic and health characteristics of the women were similar regardless of which mailing was completed, except that early respondents had higher levels of education. Respondents were more highly educated and older than were nonrespondents and lost subjects but were quite similar in all other characteristics. These data suggest that follow-up of a mobile population of African-American women can be successful.

Adult↗
PubMed2001

Charged-particle pseudorapidity density distributions from Au+Au collisions at sqrt[s(NN)]=130 GeV.

The charged-particle pseudorapidity density dN(ch)/d eta has been measured for Au+Au collisions at sqrt[s(NN)] = 130 GeV at RHIC, using the PHOBOS apparatus. The total number of charged particles produced for the 3% most-central Au+Au collisions for /eta/<or=5.4 is found to be 4200+/-470. The evolution of dN(ch)/d eta with centrality is discussed, and compared to model calculations and to data from proton-induced collisions. The data show an enhancement in charged-particle production at midrapidity, while in the fragmentation regions, the results are consistent with expectations from pp and pA scattering.

Journal Article↗