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A Fernandez

Publications and source records attributed to A Fernandez.

At least 37 records · Page 2Linked to original sources
PubMed2001

Search for rare and forbidden Charm Meson decays D0 --> Vl+l- and hhll.

We report results of a search for flavor-changing neutral current (FCNC), lepton flavor, and lepton-number violating decays of the D0 (and its antiparticle) into three and four bodies. Using data from Fermilab charm hadroproduction experiment E791, we examine modes with two leptons (muons or electrons) and a rho(0), K( *0), or straight phi vector meson or a nonresonant pi(pi), Kpi, or KK pair of pseudoscalar mesons. No evidence for any of these decays is found. Therefore, we present branching-fraction upper limits at 90% confidence level for the 27 decay modes examined (18 new).

Journal Article↗
PubMed2001

Effect of antiangiogenic therapy on slowly growing, poorly vascularized tumors in mice.

BACKGROUND: Angiogenesis is essential for tumor growth and progression. Therefore, inhibition of angiogenesis is being studied as a new anticancer therapy. Because cytotoxic chemotherapy is more effective on rapidly growing tumors than on slowly growing tumors, it has been assumed that antiangiogenic therapy will also be effective only on rapidly growing, highly vascularized tumors. We compared the effects of two angiogenesis inhibitors, TNP-470 and angiostatin, on slowly growing, poorly vascularized and rapidly growing, highly vascularized human tumors in mice. METHODS: Slowly growing (RT-4) and rapidly growing (MGH-U1) human bladder carcinoma cell lines were grown in severe combined immunodeficiency mice. Established tumors were treated with one of the two angiogenesis inhibitors. Tumor volumes, vascularity, and proliferation indices were determined. The in vitro effects of TNP-470 and of angiostatin on the proliferation of RT-4 and MGH-U1 cells were also investigated. All statistical tests were two-sided. RESULTS: RT-4 and MGH-U1 tumor growth was statistically significantly inhibited by both angiogenesis inhibitors (P<.001). Both inhibitors decreased the blood vessel density in both tumor types but did not alter the in vivo proliferation indices of the tumors. TNP-470, but not angiostatin, marginally decreased the in vitro proliferation of MGH-U1 cells. CONCLUSION: Slowly growing, poorly vascularized tumors in animal models respond as well as rapidly growing, highly vascularized tumors to therapy with the angiogenesis inhibitors TNP-470 and angiostatin.

Angiogenesis Inhibitors↗
PubMed2001

Angiogenic potential of prostate carcinoma cells overexpressing bcl-2.

BACKGROUND: Tumors commonly outgrow their blood supply, thereby creating hypoxic conditions, which induce apoptosis and increase expression of angiogenic growth factors. The bcl-2 oncogene inhibits apoptosis induced by a variety of stimuli, including hypoxia. On the basis of bcl-2's role in regulating apoptosis in response to hypoxia, we hypothesized that this oncogene might affect other responses to hypoxia, such as the expression of angiogenic growth factors. METHODS: Three prostate carcinoma cell lines, PC3, LNCaP, and DU-145, were stably transfected with a bcl-2 complementary DNA (cDNA), and transfectants were analyzed in vitro for the expression of angiogenic factors after exposure to either normoxic (19% O(2)) or hypoxic (1% O(2)) conditions. The in vivo angiogenic potential of the transfected cells was determined by analyzing vessel density in xenografts derived from them and by measuring the ability of these xenografts to induce neovascularization when implanted in mouse corneal micropockets. Statistical tests were two-sided. RESULTS: When exposed to hypoxic conditions, prostate carcinoma cells overexpressing bcl-2 expressed statistically significantly higher levels of vascular endothelial growth factor (VEGF), an angiogenic factor, than control-transfected cells (P = .001 for PC3, P = .04 for DU-145 after 48 hours). This effect of bcl-2 was independent of its antiapoptotic activity because increased expression of VEGF was detected in PC3 cells overexpressing bcl-2 even though PC3 cells are inherently resistant to hypoxia-induced apoptosis. In vivo, xenograft tumors derived from the bcl-2-overexpressing prostate carcinoma cell lines displayed increased angiogenic potential and grew more aggressively than tumors derived from the control cell lines (P =.03 for PC3). Treatment of bcl-2-overexpressing and control tumors with the antiangiogenic drug TNP-470 neutralized the aggressive angiogenesis in bcl-2-overexpressing tumors (P = .04 for PC3, P = .004 for DU-145) and the moderate angiogenesis in control tumors (P = .01 for PC3, P = .05 for DU-145), resulting in similar growth rates for both tumors. CONCLUSIONS: bcl-2 may play a dual role in tumorigenesis by suppressing apoptosis and by stimulating angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2001

Study of the D(+)(s)-->pi(-)pi(+)pi(+) decay and measurement of f(0) masses and widths.

From a sample of 848+/-44 D(+)(s)-->pi(-)pi(+)pi(+) decays, we find gamma(D(+)(s)-->pi(-)pi(+)pi(+))/gamma(D(+)(s)-->straight phipi(+)) = 0.245+/-0.028(+0.019)(-0.012). Using a Dalitz plot analysis of this three body decay, we find significant contributions from the channels rho(0)(770)pi(+), rho(0)(1450)pi(+), f(0)(980)pi(+), f(2)(1270)pi(+), and f(0)(1370)pi(+). We also present the values obtained for masses and widths of the resonances f(0)(980) and f(0)(1370).

Journal Article↗
PubMed2001

Experimental evidence for a light and broad scalar resonance in D(+) --> pi(-)pi(+)pi(+) decay.

From a sample of 1172 +/- 61 D(+)-->pi(-)pi(+)pi(+) decays, we find gamma(D(+)-->pi(-)pi(+)pi(+))/gamma(D(+)-->K-pi(+)pi(+)) = 0.0311 +/- 0.0018(+0.0016)(-0.0026). Using a coherent amplitude analysis to fit the Dalitz plot of these decays, we find strong evidence that a scalar resonance of mass 478(+24)(-23) +/- 17 MeV/c(2) and width 324(+42)(-40) +/- 21 MeV/c(2) accounts for approximately half of all decays.

Journal Article↗
PubMed2001

Intravenous metronidazole for the treatment of Clostridium difficile colitis.

PURPOSE: Severe Clostridium difficile colitis may produce abdominal distention and ileus, precluding oral antibiotic therapy. Stimulated by several case reports in which intravenous metronidazole was used, we reviewed our experience. METHODS: Using pharmacy and microbiology laboratory records, we retrospectively identified patients with C. difficile colitis who received intravenous metronidazole as initial monotherapy. To be included, patients had to fulfill the following criteria: 1) at least six doses (equivalent to two days of therapy) of intravenous metronidazole were administered, 2) no other potential cause for colitis was found, and 3) the diagnosis of C. difficile colitis was firmly established. For eligible patients, five clinical parameters were assessed before and after intravenous metronidazole. RESULTS: Our patient group (n = 10) received an average of 13.7 (range, 6-24) doses of intravenous metronidazole as initial therapy for C. difficile colitis. All received a dose of 500 mg three times daily. The majority of patients with vomiting, fever, and/or abdominal pain present at the beginning of therapy had resolution with intravenous metronidazole. Only one patient developed a symptom (vomiting) while on therapy; however, this eventually resolved when oral metronidazole was instituted. No patient required colectomy for refractory colitis or developed toxic megacolon. No patient, including those on prolonged courses, developed toxicity related to intravenous metronidazole such as peripheral neuropathy. CONCLUSIONS: Intravenous metronidazole may be effective therapy in patients with C. difficile colitis. A randomized, prospective study appears warranted.

Adult↗
PubMed2001

Crosstalk between cell cycle regulators and the myogenic factor MyoD in skeletal myoblasts.

During the early process of skeletal muscle differentiation, myogenic factors are not only involved in muscle-specific gene induction but also in regulating the transition from the proliferative stage, when MyoD and Myf5 are already expressed, to the orderly exit from the cell division cycle. This key step in skeletal muscle differentiation involves the down-regulation of cell cycle activators such as cyclins and cdks, and up-regulation of cell cycle inhibitors such as Rb, p21, p27, and p57. In particular, Rb and p21 have been shown to play an important role in the growth arrest of differentiating myoblasts. Their level and/or activity, while being negatively controlled by growth factors, appear to be positively linked with the myogenic factor MyoD, which plays a cooperative role in the induction of growth arrest. MyoD can block proliferation independently of its transcriptional activity. Therefore, the interplay between G1 cyclins and cdk inhibitors, on the one hand, and MyoD and its co-factors, on the other, plays a critical role in myoblast cell cycle withdrawal. Accurate synchronization of dividing myoblasts revealed that MyoD and Myf5 are themselves subject to specific cell cycle-dependent regulation, with MyoD at its highest level in early G1 and its lowest level at the G1 to S phase transition. The time-window when cells exit their cycle into differentiation is in G1, when MyoD is maximal and Myf5 is down. In contrast, quiescent non-differentiating myoblasts (i. e., in G0) present an opposite pattern for the two factors: high Myf5 and no MyoD. Several recent studies have focused on MyoD phosphorylation and its potential role in ubiquitination-mediated degradation of the protein. Linking this phosphorylation to the cell cycle-dependent drop in MyoD protein before S phase leads, to a mechanism implying cdk2-cyclin E and its inhibitors (p57kip and p21cip) in the tight control of MyoD levels and subsequent myoblast cell cycle progression or exit into differentiation.

Animals↗
PubMed2001

Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium.

Choroidal neovascularization in age-related macular degeneration is a frequent and poorly treatable cause of vision loss in elderly Caucasians. This choroidal neovascularization has been associated with the expression of vascular endothelial growth factor (VEGF). In current animal models choroidal neovascularization is induced by subretinal injection of growth factors or vectors encoding growth factors such as VEGF, or by disruption of the Bruch's membrane/retinal pigment epithelium complex with laser treatment. We wished to establish a transgenic murine model of age-related macular degeneration, in which the overexpression of VEGF by the retinal pigment epithelium induces choroidal neovascularization. A construct consisting of a tissue-specific murine retinal pigment epithelium promoter (RPE(65) promoter) coupled to murine VEGF(164) cDNA with a rabbit beta-globin-3' UTR was introduced into the genome of albino mice. Transgene mRNA was expressed in the retinal pigment epithelium at all ages peaking at 4 months. The expression of VEGF protein was increased in both the retinal pigment epithelium and choroid. An increase of intravascular adherent leukocytes and vessel leakage was observed. Histopathology revealed intrachoroidal neovascularization that did not penetrate through an intact Bruch's membrane. These results support the hypothesis that additional insults to the integrity of Bruch's membrane are required to induce growth of choroidal vessels into the subretinal space as seen in age-related macular degeneration. This model may be useful to screen for inhibitors of choroidal vessel growth.

Age Factors↗
PubMed2001

Primary care physicians' experience with disease management programs.

OBJECTIVE: To examine primary care physicians' perceptions of how disease management programs affect their practices, their relationships with their patients, and overall patient care. DESIGN: Cross-sectional mailed survey. SETTING: The 13 largest urban counties in California. PARTICIPANTS: General internists, general pediatricians, and family physicians. MEASUREMENTS AND MAIN RESULTS: Physicians' self-report of the effects of disease management programs on quality of patient care and their own practices. Respondents included 538 (76%) of 708 physicians: 183 (34%) internists, 199 (38%) family practitioners, and 156 (29%) pediatricians. Disease management programs were available 285 to (53%) physicians; 178 had direct experience with the programs. Three quarters of the 178 physicians believed that disease management programs increased the overall quality of patient care and the quality of care for the targeted disease. Eighty-seven percent continued to provide primary care for their patients in these programs, and 70% reported participating in major patient care decisions. Ninety-one percent reported that the programs had no effect on their income, decreased (38%) or had no effect (48%) on their workload, and increased (48%)) their practice satisfaction. CONCLUSIONS: Practicing primary care physicians have generally favorable perceptions of the effect of voluntary, primary care-inclusive, disease management programs on their patients and on their own practice satisfaction.

Chi-Square Distribution↗
PubMed2001

Effects of tactile-kinesthetic stimulation in preterms: a controlled trial.

BACKGROUND: To determine the effects of tactile-kinesthetic stimulation to preterms on physiologic parameters, physical growth and behavioral development. DESIGN: Controlled trial. SETTING: The premature unit (growing nursery) of a large, teaching hospital. SUBJECTS: 48 well preterms with birth weights between 1000-2000 grams. INTERVENTION: The neonates were systematically allocated into test and control groups. Test babies received tactile-kinesthetic stimulation in the form of a structured baby massage from day 3 to term corrected age. They were observed for changes in vital parameters (heart rate, respiration, temperature and oxygen saturation) during the first few days of stimulation in hospital. Thereafter, massage was continued at home. Changes in weight, length and head circumference and neuro-behavior (Brazelton Neuro-Behavioral Assessment Scale) were assessed in both groups before, during and after the study period. RESULTS: An increase in heart rate (within physiologic range) was seen in the test group during stimulation. This group also showed a weight gain of 4.24 g/day more than controls, which was statistically significant. On the Brazelton Scale the test group showed statistically significant improved scores on the "orientation", "range of state", "regulation of state" and "autonomic stability" clusters at follow-up. No significant complications were noted. A positive correlation was found between the duration of stimulation in days and the weight gain in grams but this did not reach statistical significance. CONCLUSIONS: Tactile-kinesthetic stimulation when administered to well, preterm infants has a beneficial effect on growth and behavioral development with no adverse effects on physiologic parameters.

Child Development↗
PubMed2001

Bilateral diaphragmatic paralysis after open heart surgery.

The purpose of the present case report is to present a case of bilateral diaphragmatic paralysis as a complication of open-heart surgery. A 47-year-old male was operated for aortic and mitral valve replacement. After discontinuation of sedation, bilateral diaphragmatic paralysis as well as motor and sensitive dysfunction in the four extremities was observed. The patient remained with mechanical ventilation support for twenty months. Two years after the operation a complete normalisation of the diaphragmatic motion was observed. Although uncommon, bilateral diaphragmatic paralysis after open-heart surgery could take place, being necessary long term mechanical ventilation support until recovery.

Aortic Valve↗
PubMed2000

Protein kinase B beta/Akt2 plays a specific role in muscle differentiation.

Insulin-like growth factors positively regulate muscle differentiation through activation of the phosphatidylinositol 3-kinase/protein kinase B (PKB/Akt) signaling pathway. Here, we compare the role of the two closely related alpha (Akt1) and beta (Akt2) isoforms of PKB in muscle differentiation. During differentiation of C2.7 or L6D2 myoblasts, PKBbeta was up-regulated whereas expression of PKBalpha was unaltered. Although the two isoforms were found active in both myoblasts and myotubes, cell fractionation experiments indicated that they displayed distinct subcellular localizations in differentiated cells with only PKBbeta localized in the nuclei. In a transactivation assay, PKBbeta (either wild-type or constitutively active) was more efficient than PKBalpha in activating muscle-specific gene expression. Moreover, microinjection of specific antibodies to PKBbeta inhibited differentiation of muscle cells, whereas control or anti-PKBalpha antibodies did not. On the other hand, microinjection of the anti-PKBalpha antibodies caused a block in cell cycle progression in both non muscle and muscle cells, whereas anti-PKBbeta antibodies had no effect. Taken together, these results show that PKBbeta plays a crucial role in the commitment of myoblasts to differentiation that cannot be substituted by PKBalpha.

Cell Differentiation↗
PubMed2000

Friend or foe? How primary care physicians perceive hospitalists.

BACKGROUND: Increased use of hospitalists is redefining the role of primary care physicians. Whether primary care physicians welcome this transition is unknown. We examined primary care physicians' perceptions of how hospitalists affect their practices, their patient relationships, and overall patient care. METHODS: A mailed survey of randomly selected general internists, general pediatricians, and family practitioners with experience with hospitalists practicing in California. MAIN OUTCOME MEASURES: Physicians' self-reports of hospitalists' effects on quality of patient care and on their own practices. RESULTS: Seven hundred eight physicians were eligible for this study, and there was a 74% response rate. Of the 524 physicians who responded, 34% were internists, 38% were family practitioners, and 29% were pediatricians. Of the 524 respondents, 335 (64%) had hospitalists available to them and 120 (23%) were required to use hospitalists for all admissions. Physicians perceived hospitalists as increasing (41%) or not changing (44%) the overall quality of care and perceived their practice style differences as neutral or beneficial. Twenty-eight percent of primary care physicians believed that the quality of the physician-patient relationship decreased; 69% reported that hospitalists did not affect their income; 53% believed that hospitalists decreased their workload; and 50% believed that hospitalists increased practice satisfaction. In a multivariate model predicting physician perceptions, internists, physicians who attributed loss of income to hospitalists, and physicians in mandatory hospitalist systems viewed hospitalists less favorably. CONCLUSIONS: Practicing primary care physicians have generally favorable perceptions of hospitalists' effect on patients and on their own practice satisfaction, especially in voluntary hospitalist systems that decrease the workload of primary care physicians and do not threaten their income. Primary care physicians, particularly internists, are less accepting of mandatory hospitalist systems. Arch Intern Med. 2000;160:2902-2908

Attitude of Health Personnel↗
PubMed2000

Research on factors allowing a risk assessment of spore-forming pathogenic bacteria in cooked chilled foods containing vegetables: a FAIR collaborative project.

Vegetables are frequent ingredients of cooked chilled foods and are frequently contaminated with spore-forming bacteria (SFB). Therefore, risk assessment studies have been carried out, including the following: hazard identification and characterisation--from an extensive literature review and expertise of the participants, B. cereus and C. botulinum were identified as the main hazards; exposure assessment--consisting of determination of the prevalence of hazardous SFB in cooked chilled foods containing vegetables and in unprocessed vegetables, and identification of SFB representative of the bacterial community in cooked chilled foods containing vegetables, determination of heat-resistance parameters and factors affecting heat resistance of SFB, determination of the growth kinetics of SFB in vegetable substrate and of the influence of controlling factors, validation of previous work in complex food systems and by challenge testing and information about process and storage conditions of cooked chilled foods containing vegetables. The paper illustrates some original results obtained in the course of the project. The results and information collected from scientific literature or from the expertise of the participants are integrated into the microbial risk assessment, using both a Bayesian belief network approach and a process risk model approach, previously applied to other foodborne hazards.

Bacillus cereus↗
PubMed2000

Efficacy of antiangiogenic therapy with TNP-470 in superficial and invasive bladder cancer models in mice.

OBJECTIVES: To evaluate the efficacy of antiangiogenic therapy with O-(chloracetyl-carbamoyl) fumagillol (TNP-470) in a superficial and an invasive bladder cancer model in mice. The control of recurrent superficial and metastatic bladder cancer constitutes a major problem in urologic practice. Although the established therapies for these cases (immunotherapy, chemotherapy, and radiation therapy) have improved during the previous decades, further improvement and the reduction of existing side effects are needed. The inhibition of angiogenesis represents a new concept in cancer therapy. METHODS: We evaluated the in vitro effect of TNP-470 on the proliferation of bovine capillary endothelial cells (BCE), the superficial transitional cell carcinoma (TCC) cell line (KK-47), and the invasive TCC cell line (MGH-U1). To evaluate the in vivo effect of TNP-470 on the growth of advanced TCCs, both cell lines were injected subcutaneously into SCID mice. When tumors grew to a size of 100 to 200 mm(3), therapy either with TNP-470 or phosphate-buffered saline was initiated. RESULTS: TNP-470 strongly inhibited endothelial cell proliferation in vitro. The in vitro proliferation of both bladder carcinoma cell lines was also inhibited by TNP-470. However, the doses inhibitory to bladder carcinoma cells were 100-fold higher than the doses that were effective in the inhibition of endothelial cell proliferation. In vivo, TNP-470 significantly inhibited the growth of advanced KK-47 (67%) and MGH-U1 (68%) tumors in SCID mice. CONCLUSIONS: Our results indicate that antiangiogenic therapy with TNP-470 is equally effective in advanced superficial and invasive bladder carcinoma models in mice. When our results are taken together with the reports of other laboratories, TNP-470 appears to be a promising candidate as a tumor suppressor in superficial and invasive bladder cancer.

Angiogenesis Inhibitors↗
PubMed2000

Cyclin E-cdk2 phosphorylation promotes late G1-phase degradation of MyoD in muscle cells.

Proliferating myoblasts already express MyoD before the induction of differentiation. Overexpression of MyoD in normal and transformed cell lines was shown to block cells from entering S phase, suggesting that the MyoD growth suppressive effect must be tightly controlled in growing myoblasts. Here we show that during G1 phase, but not in G2, MyoD abundance is down-regulated by the ubiquitin-proteasome pathway through phosphorylation of serine 200. Roscovitine, a specific inhibitor of cyclin-Cdk2 complexes, prevents both phosphorylation and degradation of MyoD in G1. Inhibition of the ubiquitin-dependent proteasome pathway by MG132 results in stabilization of MyoD-wt, with little effect on a MyoD mutant where serine 200 is replaced by an alanine. Our results show that MyoD Ser200 is the substrate for phosphorylation by cyclin E-Cdk2 stimulating its degradation by the ubiquitin-proteasome system which controls MyoD levels in G1. Phosphorylation/degradation of MyoD at the end of G1 thus represents the regulatory checkpoint in growing myoblasts allowing progression into S phase in a manner similar to the recently examplified cdk2-phosphorylation/degradation of p27(Kip1).

Animals↗
PubMed2000

Mutation of MyoD-Ser237 abolishes its up-regulation by c-Mos.

Recently we have shown that Mos could activate myogenic differentiation by promoting heterodimerisation of MyoD and E12 proteins. Here, we demonstrate that MyoD can be efficiently phosphorylated by in vitro kinase assay with purified Mos immunoprecipitated from transfected cells. Comparative two-dimensional tryptic phosphopeptide mapping combined with site-directed mutagenesis revealed that Mos phosphorylates MyoD on serine 237. Mutation of serine 237 to a non-phosphorylable alanine (MyoD-Ala237) abolished the positive regulation of MyoD by Mos following overexpression in proliferating 10T1/2 cells. Taken together, our data show that direct phosphorylation of MyoD-Ser237 by Mos plays a positive role in increasing MyoD activity during myoblast proliferation.

Amino Acid Substitution↗