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Biomedical subjects

N Nassar

Publications and source records attributed to N Nassar.

At least 19 recordsLinked to original sources
PubMed2007

Evaluation of a decision aid for women with breech presentation at term: a randomised controlled trial [ISRCTN14570598].

OBJECTIVES: To evaluate the effectiveness of a decision aid for women with a breech presentation compared with usual care. DESIGN: Randomised controlled trial. SETTING: Tertiary obstetric hospitals offering external cephalic version (ECV). POPULATION: Women with a singleton pregnancy were diagnosed antenatally with a breech presentation at term, and were clinically eligible for ECV. METHODS: Women were randomised to either receive a decision aid about the management options for breech presentation in addition to usual care or to receive usual care only with standard counselling from their usual pregnancy care provider. The decision aid comprised a 24-page booklet supplemented by a 30-minute audio-CD and worksheet that was designed for women to take home and review with a partner. MAIN OUTCOME MEASURES: Decisional conflict (uncertainty), knowledge, anxiety and satisfaction with decision making, and were assessed using self-administered questionnaires. RESULTS: Compared with usual care, women reviewing the decision aid experienced significantly lower decisional conflict (mean difference -8.92; 95% CI -13.18, -4.66) and increased knowledge (mean difference 8.40; 95% CI 3.10, 13.71), were more likely to feel that they had enough information to make a decision (RR 1.30; 95% CI 1.14, 1.47), had no increase in anxiety and reported greater satisfaction with decision making and overall experience of pregnancy and childbirth. In contrast, 19% of women in the usual care group reported they would have made a different decision about their care. CONCLUSIONS: A decision aid is an effective and acceptable tool for pregnant women that provides an important adjunct to standard counselling for the management of breech presentation.

Adolescent↗
PubMed2006

Test characteristics of placental location screening by transabdominal ultrasound at 18-20 weeks.

OBJECTIVES: To determine the test characteristics of a second-trimester transabdominal fetal anomaly scan in screening for placenta previa. PATIENTS AND METHODS: This was a case-control study carried out at a tertiary obstetric hospital involving 54 women (0.5% of the total number booked for antenatal care and delivery at the center) with clinically significant placenta previa at the time of delivery, and 168 randomly selected controls who attended for antenatal care and delivery in 2000-2003. Sensitivity, specificity and false positive rate of the placenta-os measurement in the second-trimester transabdominal fetal anomaly scan for identification of clinically significant placenta previa were assessed. RESULTS: Women with placenta previa at delivery had significantly different second-trimester placenta-os measurements from those of controls (P < 0.0001). For women with placenta previa, the mean (standard deviation) placenta-os measurement was -0.96 cm (1.95) vs. 4.15 cm (1.77) for controls (P < 0.0001). Using the anomaly scan as a screening test for placenta previa with a placenta-os measurement cut-off point of < or = 2 cm, all cases of placenta previa should be identified, but 11.1% (95% CI, 7.1-14.8) of women without placenta previa would have false positive results. At cut-off points of 3 cm and 1.5 cm the false positive rates were 25.7% (95% CI, 18.8-30.2%) and 6.6% (95% CI, 3.8-9.6%), respectively, but at 1.5 cm 3.8% of cases would be missed. CONCLUSIONS: The second-trimester transabdominal fetal anomaly scan is a useful screening test for placenta previa. However, because of false positives among the much larger population of women without placenta previa, we estimate that with a cut-off point of < or =2 cm, 23 women would have to be followed up to confirm one true placenta previa.

Adolescent↗
PubMed2004

Breast cancer in a male patient after treatment of acute lymphoblastic leukemia including total body irradiation and bone marrow transplantation.

BACKGROUND: With increasing numbers of patients subjected to total body irradiation and bone marrow transplantation for treatment of several systemic malignancies more and more patients with second malignancies were observed. CASE REPORT: We report the case of a 29- year-old man who developed breast cancer 13 years after treatment for acute lymphoblastic leukemia. Therapy for leukemia included total body irradiation (TBI) and bone marrow transplantation (BMT). Breast cancer was treated with mastectomy and irradiation of the left chest wall. 17 months later the patient developed malignant pleural effusion and died despite chemotherapy and hormonal therapy due to further tumor progression. CONCLUSION: The increased risk for secondary solid cancers after TBI and BMT and the greater risk among younger patients indicate the need for lifelong careful follow up.

Adolescent↗
PubMed2004

Trofosfamide in the palliative treatment of cancer: a review of the literature.

Trofosfamide is an alkylating agent that is derived from the oxazaphoshorines. It has found application in a broad spectrum of malignancies in the last three decades. The main indications for application were in the palliative situation and as maintenance therapy. Good results were reported from the treatment of non-Hodgkin's lymphomas and soft tissue sarcomas. A lot of small studies and casuistic contributions are available giving treatment results of several solid carcinomas (malignant gliomas, ovarian, lung and prostate cancer, and others). Due to its oral formulation and good tolerability trofosfamide is an attractive candidate for the palliative situation because treatment on an outpatient basis is possible. However, there is still a lack of randomized clinical studies with trofosfamide. Thus, evidence-based conclusions on the therapeutic value of the drug cannot be drawn. In the future, phase III trials should be undertaken.

Antineoplastic Agents↗
PubMed2001

Long-term impact of highly active antiretroviral therapy on HIV-related health care costs.

CONTEXT: Highly active antiretroviral therapy (HAART) is associated with decreased opportunistic infections, hospitalization, and HIV-related health care costs over relatively short periods of time. We have previously demonstrated that decreases in total HIV cost are proportional to penetration of protease inhibitor therapy in our clinic. OBJECTIVE: To determine the effects of HAART on HIV health care use and costs over 44 months. SETTING: A comprehensive HIV service within a Veterans Affairs Medical Center. DESIGN: A cost-effectiveness analysis of HAART. MAIN OUTCOME MEASUREMENTS: The mean monthly number of hospital days, infectious diseases clinic visits, emergency room visits, non-HIV-related outpatient visits, inpatient costs, and antiretroviral treatment costs per patient were determined by dividing these during the period from January 1995 through June 1998 into four intervals. Viral load tests were available from October 1996. Cost-effectiveness of HAART was evaluated by determining the costs of achieving an undetectable viral load over time. RESULTS: Mean monthly hospitalization and associated inpatient costs decreased and remained low 2 years after the introduction of protease inhibitors (37 hospital days per 100 patients). Total cost decreased from $1905 per patient per month during the first quarter to $1090 per patient per month in the third quarter but increased to $1391 per patient per month in the fourth quarter. Antiretroviral treatment costs increased throughout the entire observation period from $79 per patient per month to $518 per patient per month. Hospitalization costs decreased from $1275 per patient per month in the first quarter to less than $500 per patient per month in each of the third and fourth quarters. The percentage of patients with a viral load <500 copies/mL increased from 21% in October 1996 to 47% in June of 1997 (p =.014). The cost of achieving an undetectable viral load decreased from $4438 per patient per month to $2669 per patient per month, but this trend did not reach statistical significance (p =.18). CONCLUSIONS: After an initial decrease, there was an increase in the total monthly cost of caring for HIV patients. Cost increases were primarily due to antiretroviral treatment costs, but these costs were offset by a marked decrease in inpatient-related costs. Increases in costs were not related to antiretroviral treatment failures as measured by the proportion of patients with low or undetectable viral loads. The cost of achieving an undetectable viral load remained stable despite increases in the cost of procuring antiretroviral agents.

Antiretroviral Therapy, Highly Active↗
PubMed2000

Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI.

The RhoGDI proteins serve as key multifunctional regulators of Rho family GTP-binding proteins. The 2.6 A X-ray crystallographic structure of the Cdc42/RhoGDI complex reveals two important sites of interaction between GDI and Cdc42. First, the amino-terminal regulatory arm of the GDI binds to the switch I and II domains of Cdc42 leading to the inhibition of both GDP dissociation and GTP hydrolysis. Second, the geranylgeranyl moiety of Cdc42 inserts into a hydrophobic pocket within the immunoglobulin-like domain of the GDI molecule leading to membrane release. The structural data demonstrate how GDIs serve as negative regulators of small GTP-binding proteins and how the isoprenoid moiety is utilized in this critical regulatory interaction.

Amino Acid Sequence↗
PubMed1999

Protease inhibitor-based therapy is associated with decreased HIV-related health care costs in men treated at a Veterans Administration hospital.

BACKGROUND: Protease inhibitor (PI) therapy for HIV infection is associated with decreased rates of opportunistic infections and death. Statistical models predict that decreased complications will be associated with decreased hospitalization costs. A recent report suggested that the decrease in the HIV hospitalization costs were offset by increases in demand for outpatient services. We performed a study of hospital use and HIV-associated health care costs in our center to determine the following: whether PI therapy is associated with decreased inpatient use; whether PI therapy is associated with decreased outpatient use and costs; whether decreased HIV health care costs are associated with increased use of nucleoside analogues. METHODS: The Dallas Veteran Affairs Medical Center provides comprehensive inpatient and outpatient HIV care and thus can evaluate the relation between inpatient and outpatient costs. The mean monthly number of hospital days, Infectious Diseases clinic visits, emergency department visits, other outpatient clinic visits, inpatient costs, outpatient costs, and PI costs were determined from January 1, 1995 through July 31, 1997. This time period was then divided into three intervals. Comparisons of PI use and HIV-related health care costs were during the three intervals was performed using analysis of variance (ANOVA). Significant differences between the baseline characteristics were further analyzed through multiple linear regression. RESULTS: A decrease in hospital days, and all outpatient visits including emergency visits, and HIV clinic visits was determined. No difference was found in the rate of use of other outpatient services. The per patient costs of HIV care decreased from a monthly average of $1905 U.S. in the first interval to $1122 U.S. in the last interval (p < .01). Linear regression demonstrated an inverse relation between PI use and total HIV costs (B=-0.67, p=.00, adjusted R2=0.52) but no relation between nucleoside use, stage of disease or financial class. CONCLUSIONS: PI therapy is associated with decreased hospital days and use of outpatient services. Total patient costs decreased, but a concomitant rise in outpatient costs took place. This increase was primarily a result of increased costs of acquiring PI. Increases in the number of nucleoside agents prescribed were not associated with decreased costs.

Adult↗
PubMed1999

Crystallization and preliminary X-ray analysis of human RCC1, the regulator of chromosome condensation.

RCC1, the regulator of chromosome condensation, is the guanine nucleotide-exchange factor (GEF) of the GTP-binding protein Ran. Its GEF activity on Ran makes it a key element in nucleo-cytoplasmic transport and cell-cycle regulation. Crystals of human RCC1 suitable for X-ray analysis have been obtained using the seeding technique in hanging drops with sodium citrate as a precipitant. The crystals diffract to 1.7 A at 100 K and belong to the space group P1, with unit-cell parameters a = 49.5, b = 84.3, c = 84.9 A, alpha = 113.0, beta = 103.9,gamma = 103.3 degrees. The Matthews parameter (Vm) and the self-rotation function are consistent with three molecules in the unit cell, which is confirmed by the averaged single isomorphous replacement (SIR) electron-density map.

Cell Cycle Proteins↗
PubMed1999

A retrospective study of the addition of ciprofloxacin to clarithromycin and ethambutol in the treatment of disseminated Mycobacterium avium complex infection.

Disseminated Mycobacterium avium complex (DMAC) infection is associated with increased morbidity and mortality in HIV-infected individuals. The combination antibiotic regimens containing clarithromycin can decrease symptoms and improve survival in patients with DMAC, however, optimal therapy remains to be defined. Quinolones have been widely used in the treatment of DMAC but their utility has not been established. A retrospective cohort study of DMAC infection was established in a metropolitan hospital providing comprehensive care to over 3000 HIV-infected individuals. Medical records of patients with DMAC diagnosed at the Parkland Memorial Hospital from 1991 to 1994 were reviewed for therapeutic regimens for DMAC, concomitant therapy for HIV and Pneumocystis carinii prophylaxis and date of death. Subjects were included if they were treated with clarithromycin and ethambutol. Cases were defined as those patients who received more than 30 days of ciprofloxacin as therapy for DMAC in addition to the other drugs that they received. The primary endpoint was the time to death from the data of DMAC diagnosis. Covariates effecting survival were analysed through the Cox proportional hazards model. Eighty-nine subjects with DMAC who were treated with clarithromycin and ethambutol were identified. Fifty-eight received ciprofloxacin in addition to clarithromycin and ethambutol. The time to death was significantly better in those subjects who were treated with ciprofloxacin than those who were not (489 days vs 281 days, P=0.01). The sole significant predictor of improved survival on Cox proportional hazards model was ciprofloxacin therapy. Subjects treated with combination of clarithromycin, ethambutol and ciprofloxacin had improved survival over those treated with clarithromycin and ethambutol alone.

Anti-Bacterial Agents↗
PubMed1998

The 1.7 A crystal structure of the regulator of chromosome condensation (RCC1) reveals a seven-bladed propeller.

The gene encoding the regulator of chromosome condensation (RCC1) was cloned by virtue of its ability to complement the temperature-sensitive phenotype of the hamster cell line tsBN2, which undergoes premature chromosome condensation or arrest in the G1 phase of the cell cycle at non-permissive temperatures. RCC1 homologues have been identified in many eukaryotes, including budding and fission yeast. Mutations in the gene affect pre-messenger RNA processing and transport, mating, initiation of mitosis and chromatin decondensation, suggesting that RCC1 is important in the control of nucleo-cytoplasmic transport and the cell cycle. Biochemically, RCC1 is a guanine-nucleotide-exchange factor for the nuclear Ras homologue Ran; it increases the dissociation of Ran-bound GDP by 10(5)-fold. It may also bind to DNAvia a protein-protein complex. Here we show that the structure of human RCC1, solved to 1.7-A resolution by X-ray crystallography, consists of a seven-bladed propeller formed from internal repeats of 51-68 residues per blade. The sequence and structure of the repeats differ from those of WD40-domain proteins, which also form seven-bladed propellers and include the beta-subunits of G proteins. The nature of the structure explains the consequences of a wide range of known mutations. The region of the protein that is involved in guanine-nucleotide exchange is located opposite the region that is thought to be involved in chromosome binding.

Amino Acid Sequence↗
PubMed1998

Fluoride activation of the Rho family GTP-binding protein Cdc42Hs.

Aluminum tetrafluoride (AlF4-) activation of heterotrimeric G-protein alpha-subunits is a well established aspect of the biochemistry of these proteins; however, until recently it has been thought that AlF4- does not mediate effects on the Ras superfamily of low molecular weight GTP-binding proteins. Recent work demonstrating aluminum fluoride-induced complex formation between Ras and its GTPase-activating proteins (RasGAP and NF1) has provided important insights into the mechanism of GAP-stimulated GTP hydrolysis. We have characterized the AlF4--induced complex formation between the GDP-bound form of the Rho subfamily G-protein Cdc42Hs and a limit functional domain of the Cdc42-GAP using a variety of biochemical techniques. Our results indicate that the apparent affinity of GAP for the AlF4--mediated complex is similar to the affinity observed for the activated (GTP-bound) form of Cdc42 and that beryllium (Be) can replace aluminum in mediating fluoride-induced complex formation. Additionally, the AlF4--induced interaction is weakened significantly by the catalytically compromised GAP(R305A) mutant, indicating that this arginine is critical in transition state stabilization. Unlike Ras, we find that AlF4- and BeF3- mediate complex formation between Cdc42Hs.GDP and downstream target/effector molecules, indicating that there are important differences in the mechanism of effector binding between the Ras and Rho subfamily G-proteins.

Aluminum Compounds↗
PubMed1998

Structures of Cdc42 bound to the active and catalytically compromised forms of Cdc42GAP.

The Rho-related small GTP-binding protein Cdc42 has a low intrinsic GTPase activity that is significantly enhanced by its specific GTPase-activating protein, Cdc42GAP. In this report, we present the tertiary structure for the aluminum fluoride-promoted complex between Cdc42 and a catalytically active domain of Cdc42GAP as well as the complex between Cdc42 and the catalytically compromised Cdc42GAP(R305A) mutant. These structures, which mimic the transition state for the GTP hydrolytic reaction, show the presence of an AIF3 molecule, as was seen for the corresponding Ras-p120RasGAP complex, but in contrast to what has been reported for the Rho-Cdc42GAP complex or for heterotrimeric G protein alpha subunits, where AIF4- was observed. The Cdc42GAP stabilizes both the switch I and switch II domains of Cdc42 and contributes a highly conserved arginine (Arg 305) to the active site. Comparison of the structures for the wild type and mutant Cdc42GAP complexes provides important insights into the GAP-catalyzed GTP hydrolytic reaction.

Aluminum Compounds↗
PubMed1998

An interstitial nucleolus organizer region in the long arm of human chromosome 7: cytogenetic characterization and familial segregation.

An unusual NOR-bearing chromosome 7 was detected in a phenotypically normal, healthy 29-year-old male proband. Differential banding techniques as well as in situ hybridization employing various DNA-probes were performed in order to characterize the chromosome in detail. The nucleolus organizer region was found to be located between bands 7q21.3 and 7q22.1. No further rearrangements were detected in this chromosome. Analysis of spontaneously occurring micronuclei revealed 9% of them to contain a 7q fragment distal to (or including) the inserted NOR, suggesting that the inserted secondary constriction represents a potential hot spot for chromosomal breakage and rearrangement. Segregation analysis of the variant chromosome 7 in 51 members of the probands' family showed transmission in a Mendelian fashion. 27 individuals were found to be heterozygous for the inserted chromosome. A three-year-old child in the consanguineous marriage of two heterozygous carriers exhibited the NOR-insertion in both of his chromosome 7 homologues. To our knowledge, this is the first report on a homozygous carrier of a non-acrocentric NOR-bearing chromosome.

Adult↗
PubMed1996

How Ras-related proteins talk to their effectors.

More and more effectors for the Ras-related protein superfamily are being discovered and it is emerging that these GTP-binding proteins interact with more than one effector to generate more than one cellular signal. Atomic details for the interaction of Rap/Ras with one of the effectors, the protein kinase c-Raf-1, have recently become available by X-ray structure analysis. The implications for the specificity of the signal transduction pathway, and how the GTP-dependent switch mechanism modulates the interaction with effectors will be discussed here, using Ras as a paradigm.

Animals↗
PubMed1996

Quantitative structure-activity analysis correlating Ras/Raf interaction in vitro to Raf activation in vivo.

Binding of Ras to c-Raf-1 is a pivotal step of many mitogenic signalling pathways. Based on the recent crystal structure of the complex of Rap1A with the Ras-binding domain of Raf, mutations were introduced in c-Raf-1 and their effects on Ras/Raf binding affinity in vitro and Ras/Raf regulated gene expression in vivo were analysed. Our data reveal an empirical semilogarithmic correlation between dissociation constants and Raf-induced gene activity. The functional epitope that primarily determines binding affinity consists of residues Gln 66, Lys 84 and Arg 89 in Raf. This quantitative structure-activity investigation may provide a general approach to correlate structure-guided biochemical analysis with biological function of protein-protein interactions.

Amino Acid Sequence↗