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Biomedical subjects

P Becker

Publications and source records attributed to P Becker.

At least 55 records · Page 3Linked to original sources
PubMed1999

Lymphohematopoietic stem cell engraftment.

Traditional dogma has stated that space needs to be opened by cytoxic myeloablative therapy in order for marrow stem cells to engraft. Recent work in murine transplant models, however, indicates that engraftment is determined by the ratio of donor to host stem cells, i.e., stem cell competition. One hundred centigray whole body irradiation is stem cell toxic and nonmyelotoxic, thus allowing for higher donor chimerism in a murine syngeneic transplant setting. This nontoxic stem cell transplantation can be applied to allogeneic transplant with the addition of a tolerizing step; in this case presensitization with donor spleen cells and administration of CD40 ligand antibody to block costimulation. The stem cells that engraft in the nonmyeloablated are in G0, but are rapidly induced (by 12 hours) to enter the S phase after in vivo engraftment. Exposure of murine marrow to cytokines (IL-3, IL-6, IL-11 and steel factor) expands progenitor clones, induces stem cells into cell cycle, and causes a fluctuating engraftment phenotype tied to phase of cell cycle. These data indicate that the concepts of stem cell competition and fluctuation of stem cell phenotype with cell cycle transit should underlie any new stem cell engraftment strategy.

Animals↗
PubMed1999

Alendronate increases spine and hip bone mineral density in women with postmenopausal osteoporosis who failed to respond to intermittent cyclical etidronate.

In a U.S. multicenter study of intermittent cyclical etidronate treatment for postmenopausal osteoporosis, approximately 20% of patients were nonresponders, defined as failure to increase spine bone mineral density. In contrast, essentially all patients who received 10 mg of alendronate daily in U.S. phase III trials showed some increase in spine bone mineral density. The current study was undertaken to determine the response to alendronate therapy in women with postmenopausal osteoporosis who were nonresponders to intermittent cyclical etidronate therapy. Twenty-five women with postmenopausal osteoporosis (mean +/- SD: 65.1+/-1.9 years of age), previously treated with intermittent cyclical etidronate with no increase of spine bone mineral density, and who agreed to be changed to alendronate, were recruited from a university out-patient clinic specializing in the treatment of osteoporosis for a prospective observational study. Measurements included bone mineral density of the lumbar spine and proximal femur (by dual-energy X-ray absorptiometry) and biochemical markers of bone remodeling (serum bone-specific alkaline phosphatase by immunoassay and urine deoxypyridinoline by high-pressure liquid chromatography). Patients had received intermittent cyclical etidronate for 3.3+/-0.4 years, during which time their bone density declined at spine and hip sites. They were then changed to alendronate 10 mg/day, which they received for 1.3+/-0.1 years; after treatment with alendronate, bone mineral density increased significantly at the lumbar spine (4.4+/-0.7% annualized,p < 0.0001) and at all hip sites. Bone markers also changed significantly after alendronate treatment: urine deoxypyridinoline fell from 6.8+/-0.8 to 5.5+/-0.6 micromol/mol creatinine (p < 0.0001) and serum bone-specific alkaline phosphatase rose from 4.6+/-0.5 to 11.9+/-1.0 ng/mL (p < 0.0001). Upper gastrointestinal side effects forced 4 of 25 patients (16%) to discontinue alendronate. Alendronate increases bone density at the spine and hip in patients who have not responded to intermittent cyclical etidronate therapy. Changes in bone markers suggest that alendronate causes more complete suppression of bone resorption and less inhibition (or stimulation) of bone formation.

Absorptiometry, Photon↗
PubMed1999

Cyclophosphamide, cytosine arabinoside and TBI as a conditioning regimen for allogeneic bone marrow transplantation in patients with leukemia.

This is a prospective study designed to determine the toxicity, efficacy and antileukemic effect of high-dose cytosine arabinoside (ara-C), cyclophosphamide and total body irradiation (TBI) as a myeloablative regimen prior to allogeneic bone marrow transplantation for patients with hematologic malignancies. Fifty-eight patients with hematologic malignancies were treated with cyclophosphamide, high-dose ara-C and total body irradiation (TBI) followed by allogeneic bone marrow transplantation. Fifty patients had good prognosis disease and eight had poor prognosis disease. Cyclosporine and short-course methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. The conditioning regimen consisted of ara-C 3000 mg/m2 twice a day x six doses on days -7, -6, and -5; cyclophosphamide 1800 mg/m2 on days -4 and -3; and TBI 1400 cGy midline dose at 5 cGy/min in eight total fractions administered twice a day on days -4, -3, -2, and -1. The bone marrow was infused on day 0 (zero). Toxicity related to the conditioning regimen was comparable to that reported with other conditioning regimens, except for diarrhea which appears to be more frequent. The actuarial survival at 1 year was 69% (58-82) and at 5 years was 54% (42-69) with the numbers in parentheses representing the 95% confidence interval of the Kaplan-Meier estimate. After a median follow-up of 28 months, 31 of 58 (53%) patients are alive without evidence of disease. Only four of the 58 patients (7%) have relapsed. Cyclophosphamide, ara-C and TBI is a safe and effective myeloablative regimen for patients with leukemia. The overall relapse rate in our study was 7% with a median follow-up of 28 months and appears to be lower than relapse rates reported in other series. This is probably due to the added antileukemic effect of ara-C. This regimen should be compared with other myeloablative regimens in a controlled study.

Adolescent↗
PubMed1999

Safety and cost of hyperhydration for the prevention of hemorrhagic cystitis in bone marrow transplant recipients.

Hemorrhagic cystitis is a major cause of morbidity after bone marrow transplantation. Traditional methods of prevention have included mesna (2-mercaptoethane sodium sulfonate) and bladder irrigation. We report the use of hyperhydration as an alternative to these prophylactic measures. One hundred consecutive patients who underwent autologous or allogeneic bone marrow transplantation received high dose cyclophosphamide with hyperhydration using 5% dextrose normal saline at the rate of 250 ml/h and furosemide to maintain a urine output of >150 ml/h. Seventy-one of these patients also received high dose cyclophosphamide as mobilization chemotherapy. There were no episodes of hemorrhagic cystitis following mobilization chemotherapy. The incidence of hemorrhagic cystitis after transplant conditioning was 7% with 2 patients developing clinically significant hemorrhagic cystitis; one was a severe episode. The cost of hyperhydration was US$ 20 per course as opposed to US$ 1,500 per course for mesna, based on acquisition costs at our institution. We conclude that hyperhydration is a safe, inexpensive means of preventing hemorrhagic cystitis associated with high dose cyclophosphamide in bone marrow transplant recipients.

Adult↗
PubMed1999

Discrimination between viral and nonviral meningitis by visually analyzed and quantitative electroencephalography.

A prospective study was conducted to assess the ability of the visually analyzed electroencephalogram (VEEG), the quantitative EEG (QEEG) and the Glasgow Coma Scale (GCS) to discriminate between patients with viral and nonviral meningitis. The 55 subjects, aged 14-75 years, fell into one of the following categories: viral (n = 12), bacterial (n = 19), tuberculous (n = 16) or cryptococcal (n = 8) meningitis. EEG recordings and Glasgow Coma Scale (GCS) scores were obtained within 48 hours of admission to hospital. The sensitivity of the VEEG and QEEG for the prediction of patients with nonviral meningitis (true positives in this context) attained reasonably high values of 70% and 80%, respectively. In contrast, the sensitivity of the GCS was only 38%. Each of the three tests achieved high degrees of consistency in this regard with positive predictive values of 94% or better. The specificity for each of the three tests was high, 100% for the VEEG and the GCS and 82% for the QEEG indicating a high probability for the correct prediction of viral meningitis (true negatives). The consistency of this prediction was, however, poor due to negative predictive values of only 53% for the QEEG, 48% for the VEEG and 32% for the GCS. The QEEG results did not reveal any obvious advantages over the VEEG. Rather the assessment of the occurrence of particular VEEG abnormalities showed that patients with delta abnormalities had a very high probability of nonviral meningitis. At the other end of the spectrum, all normal VEEGs occurred in viral meningitis. In important respects the predictive ability of the EEG was superior to that of the GCS. While there was statistically significant agreement between the VEEG and GCS, the degree of agreement was poor. This study indicates that the EEG is a valuable and probably underestimated test in the acute phase of meningitis and provides complementary information to the GCS.

Adolescent↗
PubMed1999

[Minimally invasive coronary artery surgery].

BACKGROUND: There is a growing interest to perform a left internal mammary artery (LIMA) graft to the left anterior descending coronary artery (LAD) on a beating heart through a minimally invasive access to the chest cavity. AIM: To report the experience with minimally invasive coronary artery surgery. PATIENTS AND METHODS: Analysis of 11 patients aged 48 to 79 years old with single vessel disease that, between 1996 and 1997, had a LIMA graft to the LAD performed through a minimally invasive left anterior mediastinotomy, without cardiopulmonary bypass. A 6 to 10 cm left parasternal incision was done. The LIMA to the LAD anastomosis was done after pharmacological heart rate and blood pressure control and a period of ischemic pre conditioning. Graft patency was confirmed intraoperatively by standard Doppler techniques. Patients were followed for a mean of 11.6 months (7-15 months). RESULTS: All patients were extubated in the operating room and transferred out of the intensive care unit on the next morning. Seven patients were discharged on the third postoperative day. Duplex scanning confirmed graft patency in all patients before discharge; in two patients, it was confirmed additionally by arteriography. There was no hospital mortality, no perioperative myocardial infarction and no bleeding problems. After follow up, ten patients were free of angina, in functional class I and pleased with the surgical and cosmetic results. One patient developed atypical angina on the seventh postoperative month and a selective arteriography confirmed stenosis of the anastomosis. A successful angioplasty of the original LAD lesion was carried out. CONCLUSIONS: A minimally invasive left anterior mediastinotomy is a good surgical access to perform a successful LIMA to LAD graft without cardiopulmonary bypass, allowing a shorter hospital stay and earlier postoperative recovery. However, a larger experience and a longer follow up is required to define its role in the treatment of coronary artery disease.

Adult↗
PubMed1999

[Long-term results of reconstructive surgery for mitral insufficiency].

BACKGROUND: Surgical repair is the procedure of choice for mitral insufficiency since it preserves better left ventricular structure and function. AIM: To assess the long term clinical and echocardiographic results of mitral valve reconstructive surgery. MATERIAL AND METHODS: A review of clinical and echocardiographic data of 68 patients (34 male, age range 17 to 82 years), subjected to surgical mitral valve repair between December 1991 and March 1998. Preoperative functional capacity of these patients was 2.96 +/- 0.7. Surgical repair was assessed using transesophagic echocardiography in all subjects. RESULTS: The etiology of mitral insufficiency was degenerative in 43 patients, rheumatic in 10, infectious in 6, ischemic in 5 and miscellaneous in 4. The most frequent pathological findings were dilatation of the mitral ring in 42% of patients, chordae tendinae rupture in 32% and enlargement in 24%. A mitral anuloplasty was done in 90% of patients, a cuadrilateral resection of posterior leaflet in 52% and chordae tendinae transference in 12%. An additional surgical procedure was done in 34% of subjects. Three patients died during hospitalization (4.4%). During the follow up of 36.5 +/- 22.3 months, five patients died and one required a mitral valve replacement. The actuarial survival probability was 95.3 +/- 2.6% at one year and 83.5 +/- 6.5% at five years. The reoperation free survival was 100% at one year and 97.4 +/- 2.5% at five years. At the end of follow up the functional capacity improved to 1.25 +/- 0.4. Echocardiography showed absence of mitral insufficiency in 48.4% of patients, minimal, mild and moderate insufficiency in 35.5, 14.5 and 1.6% of patients respectively. CONCLUSIONS: Surgical valve reconstruction in mitral insufficiency has satisfactory long term results and should be the procedure of choice for eligible patients.

Adolescent↗
PubMed1998

Behavioral thermoregulatory responses of single- and group-housed mice.

The ambient temperature (Ta) to house and study laboratory rodents is critical for nearly all biomedical studies. The ideal Ta for housing rodents and other animals should be based on their thermoregulatory requirements. However, fundamental information on the behavioral thermoregulatory responses of single- and group-housed rodents is meager. To address this issue, thermoregulatory behavior was assessed in individual and groups of CD-1 mice housed in a temperature gradient. Mice were housed in groups of five or individually while selected Ta and motor activity were monitored. Single- and group-housed mice displayed a circadian oscillation of selected Ta and motor activity with relatively warm T(a)s of approximately 29 degrees C selected during the light phase; during the dark phase selected Ta was reduced by 4 degrees C, whereas motor activity increased. Selected Ta of aged (11 months old) mice housed individually was approximately 1.0 degrees C warmer than the group-housed mice. Thermal preference of younger mice (2 months old) was similar for single- and group-housed animals. The operative Ta of mice housed in standard facilities was estimated by measuring the cooling rate of "phantom" mice modeled from aluminum cylinders. The results show that the typical housing conditions for single- and group-housed mice are cooler than their Ta for ideal thermal comfort.

Aging↗
PubMed1998

Physical interaction between retinoic acid receptor and the oncoprotein myb inhibits retinoic acid-dependent transactivation.

The c-myb protooncogene is predominantly expressed in hematopoietic cells and plays a vital role in hematopoiesis. Retinoic acid (RA) is able to induce differentiation of several hematopoietic cells. This differentiation is linked to decreased c-myb expression, suggesting that retinoid receptors (RAR/RXR) may down-regulate c-myb gene expression. Furthermore, recent data indicate that RAR inhibits the function of the Myb protein itself. In addition, the Myb-Ets oncogenic fusion protein has been shown to inhibit transcriptional activation by RAR and thyroid hormone receptor. Myb-Ets also antagonizes the biological response of erythrocytic progenitor cells to RA and thyroid hormone. This prompted us to investigate a possible cross talk between RAR and Myb. Here, we demonstrate that RA inhibits the expression of the endogenous Myb target gene tom-1. Conversely, Myb functions as a potent inhibitor of RA-induced biological responses. Functional analysis of Myb mutants in transfection studies revealed that the Myb DNA-binding domain (DBD) is necessary for repression whereas the transactivation domain is dispensable. Furthermore, we show that v-Myb and RAR interact in vitro and in vivo. This interaction requires the DBD of RAR. In contrast, glutathione S-transferase-pulldown assays with v-Myb mutants indicate that the DBD and the C terminus of Myb directly interact with RAR. Our results suggest that the physical interaction between Myb and RAR may play a role in the regulation of hematopoietic gene expression.

3T3 Cells↗
PubMed1998

Phenotype of the engrafting stem cell in mice.

The present data on engraftment into non-myeloablated mice strongly suggest that engraftment is determined by host-donor ratios as opposed to opening space. Theoretically, if the ratios of donor to host stem cells could be altered, especially without causing toxicity to the host animal, then the phenotypic readout could be increased in a clinically applicable manner. To research this further, we investigated low-dose irradiation (100 cGy) for its effects on marrow, spleen and peripheral blood counts, as well as engrafting stem cell levels. We found a transient but significant depression in the white blood cell and platelet counts in the peripheral blood which returned to normal by two weeks, with no apparent deleterious effect on the animals. However, the same irradiation dose after two months impaired marrow repopulation and reduced engraftment potential to less than 20% capacity. These results suggested that we could obtain much higher phenotypic readouts after engraftment with this model; thus, we assessed the engraftment of 40 million male BALB/c marrow cells into female hosts exposed to 100 cGy at two, five and eight months after cell infusion. The resultant high levels of chimerism, reaching 100% in many cases, strongly suggest that the key to engraftment in these models is host-donor stem cell ratios. One important issue relative to the above finding is whether cytokine-stimulated proliferating stem cells have irreversibly lost engraftment capacity or whether changes in the engraftment capacity are of a plastic nature, possibly related to cell cycle transit. A number of experiments following engraftment have shown that the engraftment defect is reversible and can be repeatedly lost and regained during the initial portions of a cytokine-stimulated culture. The above results suggest that, at least at the more primitive stem cell level, hematopoietic stem cell regulation may in part be based on a cell cycle model rather than a hierarchical system.

Animals↗
PubMed1998

Adhesion molecules in tissue injury: kinetics of expression and shedding and association with cytokine release in humans.

Adhesion molecules are responsible for leukocyte recruitment in injured tissues. Here, the kinetics of expression and shedding of endothelial (sE-selectin-1, sP-selectin, and sICAM-1) and neutrophil (CD11b, CD62L, and CD54) adhesion molecules was investigated by serial determinations of serum concentrations in 20 patients with elective hip arthroplasty as an exemplary condition of acute inflammation in humans. Changes were related to secretion of proinflammatory cytokines (IL-1beta, IL-6, IL-8, and TNF-alpha) as their possible inducing signals. sE-selectin-1 responded to injury with a significant increase in concentrations already after 20 min, followed by sP-selectin and sICAM-1, which increased at Hour 10 and Day 1. Expression of CD11b and CD62L acutely responded to injury (within 1 h) by a parallel increase and decrease, respectively, and normalized by Day 1. Increases in concentrations of IL-1beta and TNF-alpha preceded the increase in adhesion molecules and significantly correlated with the response of sE-selectin-1 and sICAM-1. In conclusion, the close associations between release of IL-1beta and TNF-alpha and sE-selectin and sICAM-1 shown in this kinetic study indicates a key role of these cytokines in upregulation of endothelial rather than neutrophil adhesion molecules in vivo.

Aged↗
PubMed1998

TGF beta-1 mRNA expression and proliferation of human osteoblastic cells in nonosteoporotic and osteoporotic women under influence of TGF beta-1 and IGF-I.

Currently, primary osteoporosis is the most frequent metabolic disease in women after menopause [1]. The resulting loss of bone mass is accompanied by an increased risk of skeletal fragility. One reason for the development of osteoporosis might be an impaired function of mature osteoblasts. To evaluate the involvement of specific growth factors in bone remodeling, cell cultures of osteoblastic cells derived from nonosteoporotic and osteoporotic postmenopausal women were established. The influences of TGF beta-1 and IGF-I on proliferation and mRNA expression of TGF beta-1 were investigated by [3H]-thymidine incorporation and competitive RT-PCR. We found IGF-I to have no significant effect on proliferation in cells of osteoporotic and nonosteoporotic patients. In contrast, differences were found in TGF beta-1 mRNA expression after application of IGF-I. Application of TGF beta-1 enhanced its own mRNA expression in both groups in a similar manner. Whereas the proliferation of cells of nonosteoporotic patients was inhibited by (10(-10) M) TGF beta-1, this treatment led to an increased proliferation of cells of osteoporotic patients.

Aged↗
PubMed1998

Coverage of bone marrow transplant patients: a survey of American and Canadian institutions.

Personnel involved in supportive care of bone marrow transplant (BMT) patients include fellows (F), medical house-staff (HS), nurse practitioners (NP), physician assistants (PA), and moonlighting physicians (MP). We have obtained surveys from 108 American and Canadian transplant centers on the composition of inpatient support teams. Eighty-seven percent of institutions responding to the survey were university-based programs. Eighty-eight percent of the centers performed both allogeneic and autologous transplants, and 60% performed unrelated donor grafts. The mean number of transplants performed annually at each center was 101 (range 4-515). For daytime coverage, the percent of programs involving F, HS, NP, PA, or MP was 57, 50, 35, 25, and 0%, respectively, and for nighttime coverage, the composition was 50, 56, 7, 6, and 13%, respectively. Medical HS were incorporated into the care of BMT patients at some level in 93% of the programs. Involvement by HS included full 24-hour coverage (44%), full nighttime coverage (8%), stat coverage (18%), and code blue only coverage (21%). HS involvement was similar in small and large transplant programs. HS were more involved in university-based programs. Programs on the East Coast had more HS involvement, with 54% of the programs reporting full 24-hour coverage by HS compared with 32% of the programs in the Pacific region. Coverage of transplant patients varies throughout the country, and nonphysician providers are often used. HS are more active in university-based programs, and their role is similar in both large and small programs.

Bone Marrow Transplantation↗
PubMed1998

Special feature: a multifacet circumplex model of personality as a basis for the description and therapy of personality disorders.

A new circumplex model of personality, based upon two higher order personality factors, mental health and behavior control, is presented. This eight-octant model, which also includes the two multifacet dimensions of "social adaptation vs. unrestraint" and "self-actualization vs. inhibition," should not be confused with two other well-known circumplex models: the interpersonal model and the Eysenck model. Mental health, a multifacet construct, is defined as the ability to cope with external and internal demands. Behavior control, also a multifacet construct, is characterized by self-control (norm-, future-, work-, and reason-orientation; orderliness) vs. spontaneity (hedonism, excitement seeking, feeling orientation, liveliness). The theoretical background and facets of these constructs are presented. The model is useful for the description of personality disorders, and etiological hypotheses are formulated from the combination of this model with a circumplex model of interpersonal behavior. Finally, some therapeutic implications of the model are discussed.

Behavior Therapy↗