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Biomedical subjects

J Mandel

Publications and source records attributed to J Mandel.

At least 19 recordsLinked to original sources
PubMed2004

Pre-clinical development of cord blood-derived progenitor cell graft expanded ex vivo with cytokines and the polyamine copper chelator tetraethylenepentamine.

BACKGROUND: We have previously demonstrated that the copper chelator tetraethylenepentamine (TEPA) enables preferential expansion of early hematopoietic progenitor cells (CD34+CD38-, CD34+CD38-Lin-) in human umbilical cord blood (CB)-derived CD34+ cell cultures. This study extends our previous findings that copper chelation can modulate the balance between self-renewal and differentiation of hematopoietic progenitor cells. METHODS: In the present study we established a clinically applicative protocol for large-scale ex vivo expansion of CB-derived progenitors. Briefly, CD133+ cells, purified from CB using Miltenyi Biotec's (Bergisch Gladbach, Germany) CliniMACS separation device and the anti-CD133 reagent, were cultured for 3 weeks in a clinical-grade closed culture bag system, using the chelator-based technology in combination with early-acting cytokines (SCF, thrombopoietin, IL-6 and FLT-3 ligand). This protocol was evaluated using frozen units derived from accredited cord blood banks. RESULTS: Following 3 weeks of expansion under large-scale culture conditions that were suitable for clinical manufacturing, the median output value of CD34+ cells increase by 89-fold, CD34+CD38- increase by 30-fold and CFU cells (CFUc) by 172-fold over the input value. Transplantation into sublethally irradiated non-obese diabetic (NOD/SCID) mice indicated that the engraftment potential of the ex vivo expanded CD133+ cells was significantly superior to that of unexpanded cells: 60+/-5.5% vs. 21+/-3.5% CD45+ cells, P=0.001, and 11+/-1.8% vs. 4+/-0.68% CD45+CD34+ cells, P=0.012, n=32, respectively. DISCUSSION: Based on these large-scale experiments, the chelator-based ex vivo expansion technology is currently being tested in a phase 1 clinical trial in patients undergoing CB transplantation for hematological malignancies.

AC133 Antigen↗
PubMed2001

Evaluation of voxel-based registration of 3-D power Doppler ultrasound and 3-D magnetic resonance angiographic images of carotid arteries.

Spatial registration and fusion of ultrasound (US) images with other modalities may aid clinical interpretation. We implemented and evaluated on patient data an automated retrospective registration of magnetic resonance angiography (MRA) carotid bifurcation images with 3-D power Doppler ultrasound (PD US) and indirectly with 3-D B-mode US. Volumes were initially thresholded to reduce the uncorrelated noise signals. The registration algorithm subsequently maximized the mutual information measure between the PD US and 3-D MRA via iterative simplex search to find best "rigid body" transformation. We rated the performance of the algorithm visually on (n = 5) clinical MRA and 3-D PD US datasets. We also evaluated quantitatively the effect of thresholding, initial misalignment of the paired volumes and the reproducibility registration. We investigated the effect of image artefacts by simulation experiments. Preregistration misalignments of up to 5 mm in the transaxial plane, up to 10 mm along the axis of the carotids and up to 40 degrees resulted in 107 of 110 successful registrations, with translational and rotational errors of 0.32 mm +/- 0.3 mm and 1.6 +/- 2.1 degrees. The algorithm was not affected by missing arterial segments of up to 8 mm in length. The average registration time was 4 min. We conclude that the algorithm could be applied to 3-D US PD and MRA data for automated multimodality registration of carotid vessels without the use of fiducials.

Algorithms↗
PubMed2001

Ultrasensitive quartz crystal microbalance sensors for detection of M13-Phages in liquids.

Quartz crystal microbalance (QCM) sensors are widely used for determining liquid properties or probing interfacial processes. For some applications the sensitivity of the QCM sensors typically used (5-20 MHz) is limited compared with other biosensor methods. In this study ultrasensitive QCM sensors with resonant frequencies from 39 to 110 MHz for measurements in the liquid phase are presented. The fundamental sensor effect of a QCM is the decrease of the resonant frequency of an oscillating quartz crystal due to the binding of mass on a coated surface during the measurement. The sensitivity of QCM sensors increases strongly with an increasing resonant frequency and, therefore, with a decreasing thickness of the sensitive area. The new kind of ultrasensitive QCM sensors used in this study is based on chemically milled shear mode quartz crystals which are etched only in the center of the blank, forming a thin quartz membrane with a thick, mechanically stable outer ring. An immunoassay using a virus specific monoclonal antibody and a M13-Phage showed an increase in the signal to noise ratio by a factor of more than 6 for 56 MHz quartz crystals compared with standard 19 MHz quartz crystals, the detection limit was improved by a factor of 200. Probing of acoustic properties of glycerol/water mixtures resulted in an increase in sensitivity, which is in very good agreement with theory. Chemically milled QCM sensors strongly improve the sensitivity in biosensing and probing of acoustic properties and, therefore, offer interesting new application fields for QCM sensors.

Acoustics↗
PubMed2001

The transcription factors L-Sox5 and Sox6 are essential for cartilage formation.

L-Sox5 and Sox6 are highly identical Sry-related transcription factors coexpressed in cartilage. Whereas Sox5 and Sox6 single null mice are born with mild skeletal abnormalities, Sox5; Sox6 double null fetuses die with a severe, generalized chondrodysplasia. In these double mutants, chondroblasts poorly differentiate. They express the genes for all essential cartilage extracellular matrix components at low or undetectable levels and initiate proliferation after a long delay. All cartilages are thus extracellular matrix deficient and remain rudimentary. While chondroblasts in the center of cartilages ultimately activate prehypertrophic chondrocyte markers, epiphyseal chondroblasts ectopically activate hypertrophic chondrocyte markers. Thick intramembranous bone collars develop, but the formation of cartilage growth plates and endochondral bones is disrupted. L-Sox5 and Sox6 are thus redundant, potent enhancers of chondroblast functions, thereby essential for endochondral skeleton formation.

Animals↗
PubMed2001

Clinical insights and basic science correlates in sarcoidosis.

More than a century has elapsed since the initial description of sarcoidosis, but critical aspects of the disorder remain poorly understood. Information obtained from epidemiologic observations and basic laboratory research suggests that the disease may represent an immunologic response to an exogenous agent in a genetically susceptible individual. However, a definitive etiologic role for any specific exogenous agent has never been proved, and a "candidate gene" underlying a predisposition to sarcoidosis has not yet been identified. This review presents an historical framework for considering available evidence regarding a transmissible agent in sarcoidosis and host susceptibility to the disease.

Genetic Predisposition to Disease↗
PubMed2000

Mortality among radiologic technologists in the united states (1926-1997). 2(nd) Follow up.

PURPOSE: To evaluate risk for all-cause and cause-specific mortality in a large, primarily female (73%) cohort of radiologic technologists.METHODS: The study consists of 145,915 radiation technologists, certified in the American Registry of Radiologic Technologists (1926-1982) and followed through 1997. Causes of death were obtained from death certificates or, more recently, through NDI Plus. Standardized Mortality Ratios (SMR) were computed and tests of homogeneity were performed to detect differences in mortality among causes. Poisson models were used to estimate risks using an internal comparison group.RESULTS: Significantly low SMRs were observed for all causes (0.76), all cancers (0.82), and diseases of circulatory system (0.69). Compared to U.S. women, the risk for breast cancer mortality bordered around unity (SMR 1.01, 95% CI 0.94-1.09). However, relative to all other cancers, breast cancer mortality was significantly increased (RSMR 1.24, p < 0.01). Elevated risk for breast cancer was associated with certification before 1940 (SMR 1.55, 95% CI 1.24-1.91), and duration of certification of 20-29 (SMR 1.21, 95% CI 1.06-1.37) and 30+ years (SMR 1.77, 95% CI 1.54-2.02). A 35% increase in leukemia risk was evident for women certified for a duration of 20-29 years and a 36% increase among women certified for 30+ years. Poisson analysis revealed a significant increase in breast cancer risk with increasing number of years certified among women first certified before 1940 (p < 0.001) and during 1940-49 (p = 0.05) compared to women first certified in 1950 or later.CONCLUSIONS: Preliminary findings of this study suggest increased breast cancer risk associated with occupational radiation exposures prior to 1950 and with long-term cumulative exposures. However, potential confounding by reproductive and other risk factors needs to be evaluated.

Journal Article↗
PubMed2000

Trends in reproductive, smoking, and other chronic disease risk factors by birth cohort in a large occupational study.

PURPOSE: To illustrate the value of using large cohort studies to identify birth cohort trends in several chronic disease risk factors.METHODS: In collaboration with the American Registry of Radiologic Technologists (ARRT) and the University of Minnesota, the National Cancer Institute (NCI) initiated a cohort study of radiologic technologists who were certified by ARRT for at least two years between 1926 and 1982. Over 90,000 technologists (nearly four-fifths female) from all 50 states responded to a mailed questionnaire on reproductive, medical, work, and lifestyle factors. Ten, mostly five-year, birth cohorts, from before 1920 through 1960 and later, were evaluated.RESULTS: In this population, the mean height of both men and women generally rose in each subsequent birth cohort. The proportion of men who smoked before age 18 fell among those born since the late 1920s. In contrast, the proportion of women smoking before age 18 rose among those born since the early 1950s, reaching 14.2% among those born in 1960 and later. The mean age at menarche fell, until leveling off at 12.5, among those born after 1940. Recent birth cohorts (since 1950) show among the highest mean ages at birth of first child (>26 yeras), highest rates of nulliparity at age 25 (>/=63%), and lowest mean parity levels (</=1.7), compared with earlier birth cohorts. The proportion of women ever using oral contraceptives rose steadily by birth cohort, reaching 86 percent in the most recent birth cohort.CONCLUSIONS: Some of the trends observed may help explain historic chronic disease incidence patterns and predict future disease burdens.

Journal Article↗
PubMed2000

Effects of combined angiotensin II and endothelin receptor blockade with developing heart failure: effects on left ventricular performance.

BACKGROUND: The goal of this study was to determine the comparative effects of angiotensin II type 1 (AT(1)) receptor inhibition alone, endothelin-1 (ET) receptor blockade alone, and combined receptor blockade on left ventricular (LV) function, contractility, and neurohormonal system activity in a model of congestive heart failure (CHF). METHODS AND RESULTS: Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant AT(1) receptor blockade (valsartan, 3 mg/kg per day) and rapid pacing (n=8), (3) concomitant ET receptor blockade (bosentan, 50 mg/kg BID) and rapid pacing (n=8), (4) concomitant combined AT(1) and ET receptor inhibition and rapid pacing (n=8), and (5) sham-operated control (n=9). LV stroke volume was reduced from the control value after rapid pacing, was unchanged with either AT(1) or ET receptor blockade alone, but was improved with combination treatment. LV peak wall stress was reduced in both groups with ET receptor blockade compared with the rapid pacing group. Plasma norepinephrine levels were increased by >3-fold after rapid pacing, remained increased in the monotherapy groups, but were reduced after combination treatment. LV myocyte velocity of shortening was reduced after rapid pacing-induced CHF, remained reduced after AT(1) receptor blockade, increased after ET receptor blockade (compared with rapid pacing-induced CHF values), and returned to within control values after combined blockade. CONCLUSIONS: Combined AT(1) and the ET receptor blockade in this model of CHF improved LV pump function, and contributory factors included the effects of LV loading conditions, neurohormonal system activity, and myocardial contractile performance. Thus, combined receptor blockade may provide a useful combinatorial therapeutic approach in CHF.

Angiotensin II↗
PubMed1999

Treatment delay and reliance on private physicians among patients with sexually transmitted diseases in China.

We examined health-care seeking practices among patients with sexually transmitted diseases (STDs) in south China. In 1995, we recruited a consecutive sample of 939 STD patients attending the STD clinics of the Municipal STD Control Centers of Guangzhou and Shenzhen, 'special economic zones' near Hong Kong. Attending physicians interviewed patients face-to-face using a standard survey questionnaire. Twenty-seven per cent of all subjects had sought treatment elsewhere for their presenting complaints, before visiting a study clinic. The main sources of prior treatment were private physicians followed by public clinics and drugstores. Women were more likely than men to delay in presenting their current symptoms to a study clinic (32% vs 25%, P=0.046). Factors associated with treatment delay differed by gender. Among men, seeking prior treatment from private physicians (OR=3.31; 95% CI=1.70, 6.43), having no urethral discharge (OR=4.00; 95% CI=2.33, 6.85), having engaged in sex trade (OR=1.64; 95% CI=1.03, 2.63), or being a resident in Shenzhen (OR=1.80; 95% CI=1.12, 2.89) were more likely to delay seeking treatment. Among women, only living in Shenzhen (OR=2.86; 95% CI=1.56, 5.25) was associated with treatment delay. Promotion of appropriate health-seeking behaviours and better management of STDs must be a top priority to slow a rapid spread of STD/HIV in China. Health education, improvement of STD care in the public and private sectors, and regulations of unauthorized private physicians, may help with STD control and HIV prevention.

Adult↗
PubMed1999

Can we predict recovery in chronic fatigue syndrome?

PURPOSE: To determine if selected demographic or clinical features of chronic fatigue syndrome (CFS) are associated with recovery. PATIENTS AND METHODS: A follow-up questionnaire was mailed to 341 patients who had been ill on average for nine years to ascertain "recovery" rate (defined as self-reported recovery on a visual analog scale). Baseline demographic and clinical features (functional status and psychological status) recorded at the time of the initial (baseline) clinical visit were analyzed for their association with recovery at the time of follow-up. RESULTS: Of the 177 patients who responded to the follow-up questionnaire, only 21 (12%) reported "recovery." Patients with higher levels of physical and social functioning and lower levels of anxiety and obsessive-compulsiveness at baseline were more likely to report recovery at follow-up (p < 0.05). No specific demographic characteristics were associated with recovery. CONCLUSION: These findings support previous research that complete recovery from CFS is rare and that patients with less severe illness at the initial clinic visit are more likely to have a positive prognosis for recovery. However, considerable overlap in illness severity was observed between the recovered and nonrecovered groups, suggesting that accurate prediction of recovery in individual CFS patients is not currently feasible.

Activities of Daily Living↗
PubMed1998

Cohort mortality study of prostate cancer among chemical workers.

A retrospective cohort mortality study was conducted at a chemical plant producing acetic acid and acetic anhydride, two chemicals essential in the synthesis of cellulose triacetate fiber. Previously, we reported excess mortality from biliary tract and prostate cancers among workers in cellulose triacetate fiber manufacturing plants. In the present investigation, an excess of prostate cancer (SMR = 330.4; 95% confidence interval = 121.3-719.1) was observed among former chemical plant workers, some of whom had been exposed to both acetic acid and acetic anhydride. These apparent increases in mortality are difficult to interpret biologically, particularly in light of recent suggestions concerning the role of endocrine factors. Additional work is planned to more fully characterize potential occupational exposures that might explain the etiology of prostate cancer.

Acetic Acid↗
PubMed1998

Novel isoforms of the fragile X related protein FXR1P are expressed during myogenesis.

The fragile X syndrome results from transcriptional silencing of the FMR1 gene and the absence of its encoded FMRP protein. Two autosomal homologues of the FMR1 gene, FXR1 and FXR2, have been identified and the overall structures of the corresponding proteins are very similar to that of FMRP. Using antibodies raised against FXR1P, we observed that two major protein isoforms of relative MW of 78 and 70 kDa are expressed in different mammalian cell lines and in the majority of mouse tissues. In mammalian cells grown in culture as well as in brain extracts, both P78and P70isoforms are associated with mRNPs within translating polyribosomes, similarly to their closely related FMRP homologues. In muscle tissues as well as in murine myoblastic cell lines induced to differentiate into myotubes, FXR1P78and P70isoforms are replaced by novel unpredicted isoforms of 81-84 kDa and a novel FXR1 exon splice variant was detected in muscle RNA. While P81-84isoforms expressed after fusion into myotubes in murine myoblast cell lines grown in culture are associated with polyribosomes, this is not the case when isolated from muscle tissues since they sediment with lower S values. Immunohistochemical studies showed coexpression of FMRP and FXR1P70and P78in the cytoplasm of brain neurons, while in muscle no FMRP was detected and FXR1P81-84were mainly localized to structures within the muscle contractile bands. The complex expression pattern of FXR1P suggests tissue-specific expression for the various isoforms of FXR1 and the differential expression of FMRP and FXR1Ps suggests that in certain types of cells and tissues, complementary functions may be fulfilled by the various FMRP family members.

3T3 Cells↗