Biomedical subjects

S Haddad

Publications and source records attributed to S Haddad.

At least 37 records · Page 2Linked to original sources

PubMed2000

Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures.

The objective of this study was to predict and validate the theoretically possible, maximal impact of metabolic interactions on the blood concentration profile of each component in mixtures of volatile organic chemicals (VOCs) [dichloromethane (DCM), benzene (BEN), trichloroethylene (TCE), toluene (TOL), tetrachloroethylene (PER), ethylbenzene (EBZ), styrene (STY), as well as para, ortho-, and meta-xylene (p-XYL, o-XYL, m-XYL)] in the rat. The methodology consisted of: (1) obtaining the validated, physiologically based toxicokinetic (PBTK) model for each of the mixture components from the literature, (2) substituting the Michaelis-Menten description of metabolism with an equation based on the hepatic extraction ratio (E) for simulating the maximal impact of metabolic interactions (i.e., by setting E to 0 or 1 for simulating maximal inhibition or induction, respectively), and (3) validating the PBTK model simulations by comparing the predicted boundaries of venous blood concentrations with the experimental data obtained following exposure to various mixtures of VOCs. All experimental venous blood concentration data for 9 of the 10 chemicals investigated in the present study (PER excepted) fell within the boundaries of the maximal impact of metabolic inhibition and induction predicted by the PBTK model. The modeling approach validated in this study represents a potentially useful tool for screening/identifying the chemicals for which metabolic interactions are likely to be important in the context of mixed exposures and mixture risk assessment.

Administration, Inhalation↗

PubMed2000

Validation of a physiological modeling framework for simulating the toxicokinetics of chemicals in mixtures.

The objective of this study was to investigate the usefulness of a physiologically based toxicokinetic (PBTK) modeling framework for simulating the kinetics of chemicals in mixtures of varying complexities and composition. The approach involved the simulation of the kinetics of components in two situations: (i) when one of the mixture components was substituted with another (i.e., benzene in the benzene (B)-toluene (T)-ethyl benzene (E)-m-xylene (X) mixture was substituted with dichloromethane (D)), and (ii) when another chemical was added to the existing four-chemical mixture model (i.e., when D was added to the existing BTEX mixture model). In both cases, differing compositions of mixtures were used to obtain simulations and to generate experimental data on kinetics for validation purposes. Since the quantitative and qualitative mechanisms of interaction among B, T, E, and X have already been established, the mechanisms of binary interactions between D and the BTEX components (e.g., competitive, noncompetitive, or uncompetitive metabolic inhibition) were investigated in the present study. The analysis of rat blood kinetic data (4-h inhalation exposures, 50-200 ppm each) to all binary combinations (D-B, D-T, D-E, and D-X) investigated in the present study was suggestive of competitive metabolic inhibition as the plausible interaction mechanism. By incorporating the newly estimated values of metabolic inhibition constant (K(i)) for each of these binary combinations within the five-chemical PBTK model (i.e., for the DBTEX mixture), the model adequately predicted the venous blood kinetics of chemicals in rats following a 4-h inhalation exposure to various mixtures (mixture 1:100 ppm of D and 50 ppm each of T, E, and X; mixture 2: 100 ppm each of D, T, E, and X; mixture 3: 100 ppm of D and 50 ppm each of B, T, E, and X; mixture 4: 100 ppm each of D, B, T, E, and X). The results of the present study suggest that the PBTK model framework is useful for conducting extrapolations of the kinetics of chemicals from one mixture to another differing in complexity and composition, based on mechanistic considerations of interactions elucidated at the binary level.

Administration, Inhalation↗

PubMed2000

Relative lipid content as the sole mechanistic determinant of the adipose tissue:blood partition coefficients of highly lipophilic organic chemicals.

The adipose tissue:blood partition coefficient (PCat:b) refers to the ratio of chemical concentration or solubility in adipose tissue and blood. The solubility of a chemical in adipose tissue or whole blood is equal to the sum total of its solubility in lipid and water fractions of these matrices. For highly lipophilic organic chemicals (HLOCs, i.e., chemicals with log n-octanol:water partition coefficients (PCo:w) greater than four), their solubility in the water fractions of both tissue and blood is negligible, and therefore their solubility in lipid fractions of tissue and blood alone determines PCat:b. Since the numerical value representing chemical solubility in lipids is likely to be the same for both blood lipids and adipose tissue lipids, the PCat:b values should be hypothetically, equal to the ratio of lipid content of adipose tissue and blood. The objective of the present study was therefore to verify whether the PCat:bs of HLOCs (volatile organics, dioxins, PCBs, PBBs, DDT) are equal to the ratio of adipose tissue and blood lipid levels. The data on lipid content of rat and human blood and adipose tissues were obtained from the literature. The calculated tissue:blood lipid ratios were comparable to the human and rat PCat:b of volatile organic chemicals, dioxins, PCBs, PBBs and/or DDT obtained from the literature. These results then suggest that, regardless of the identity and PCo:w of HLOCs, their PCat:b is equal to the ratio of lipid in adipose tissues and blood.

Adipose Tissue↗

PubMed2000

Patient perception of quality following a visit to a doctor in a primary care unit.

BACKGROUND: Assessment of the quality of primary care services may be enhanced by including patient perceptions as well as professional judgment of quality. There is a need for reliable and valid instruments to measure these perceptions. OBJECTIVES: (i) To present a scale for measuring patient perception of quality of care following a visit to a doctor; and (ii) to analyse the responses given by patients recruited in primary care units in the Montreal region. The scale is composed of 22 items regrouped into three sub-scales referring to the patient-physician relationship (five items); the technical aspects of care (12 items); and the outcomes of the visit (five items). Distinctive features of the scale are that it focuses on patients' opinions about quality rather than on satisfaction, and that it includes items related to outcomes of the visit. METHODS: A survey was conducted on 473 patients who visited a physician in 11 primary care units in the Montreal region. Randomly selected patients received mailed questionnaires 5-7 days following their visit. Various statistical procedures were used to assess the reliability and the validity of the global scale and the sub-scales, and to analyse patients' patterns of response. RESULTS: The analysis of the psychometric properties of the global scale and the three sub-scales provides favourable evidence concerning their reliability and validity. The results of the factor analysis, the inter-item correlations and the Cronbach's alpha coefficients all support the distinction made between the interpersonal processes, the technical processes and the outcomes, and, at the same time, confirm the complex nature of the notion of perceived quality. The analysis of patients' responses allows the identification of items associated with global perception about quality of care. This global perception results from patients' perception of the physician's professional and interpersonal skills as well as from the outcomes of care. CONCLUSION: The scale can be used by physicians or primary health care units and has a wide range of applications.

Attitude to Health↗

PubMed2000

The effect of thrombophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.

OBJECTIVE: To observe the effect of thrombophylaxis on pregnancy in women with a history of unexplained recurrent pregnancy loss also carrying the factor V Leiden mutation. METHODS: Between 1 January and 31 December 1996, activated protein C (APC) resistance and factor V Leiden mutation were prospectively measured in 56 nonpregnant women, with a history of two or more unexplained recurrent pregnancy losses. During the same study period, seven women carrying the factor V Leiden mutation conceived, and were subsequently followed throughout their pregnancy. Subcutaneous low molecular weight heparin (LMWH, enoxaparin, 40 mg/day) and oral low dose aspirin (100 mg/day) were administered throughout the pregnancies, starting at early first trimester. Ultrasound and Doppler umbilical and fetal middle cerebral arterial flow studies were performed in the second and third trimesters, and the course and outcome of the pregnancies were documented. RESULTS: Activated protein C resistance and factor V Leiden were found in 20 (36%) and 12 (21%) women of the study, respectively. Five of the seven pregnancies occuring progressed uneventfully to term with normal fetal growth, normal Doppler flow studies and uneventful neonatal outcome. Two of the seven women had early missed abortions. CONCLUSIONS: Thrombophylaxis, beginning in early pregnancy, in women with unexplained recurrent pregnancy loss associated with factor V Leiden mutation, seems to be safe and allow normal fetal development and good neonatal outcome. To prove the efficacy of thrombophylaxis by LMWH and low dose aspirin in this setting prospective controlled studies seem to be justified.

Abortion, Habitual↗

PubMed1999

Physiological modeling of the toxicokinetic interactions in a quaternary mixture of aromatic hydrocarbons.

The available data on binary interactions are yet to be considered within the context of mixture risk assessments because of our inability to predict the effect of a third or fourth chemical in the mixture on the interacting binary pairs. Physiologically based toxicokinetic (PBTK) models represent a framework that can be potentially used for predicting the impact of multiple interactions on component kinetics at any level of complexity. The objective of this study was to develop and validate an interaction-based PBTK model for simulating the toxicokinetics of the components of a quaternary mixture of aromatic hydrocarbons [benzene (B), toluene (T), ethylbenzene (E), m-xylene (X)] in the rat. The methodology consisted of: (1) obtaining and refining the validated individual chemical PBTK models from the literature, (2) interconnecting all individual chemical PBTK models at the level of liver on the basis of the mechanism of binary chemical interactions (e.g., competitive, noncompetitive, or uncompetitive metabolic inhibition), and (3) comparing the a priori predictions of the interaction-based model to corresponding experimental data on venous blood concentrations of B, T, E, and X during mixture exposures. The analysis of blood kinetics data from inhalation exposures (4 h, 50-200 ppm each) of rats to all binary combinations of B, T, E, and X was suggestive of competitive metabolic inhibition as the plausible interaction mechanism. The metabolic inhibition constant (K(i)) for each binary combination was quantified and incorporated within the mixture PBTK model. The binary interaction-based PBTK model predicted adequately the inhalation toxicokinetics of all four components in rats following exposure to mixtures of BTEX (50 ppm each of B, T, E, and X, 4 h; 100 ppm each of B, T, E and X, 4 h; 100 ppm B + 50 ppm each of T, E, and X, 4 h). The results of the present study suggest that data on interactions at the binary level alone are required and sufficient for predicting the kinetics of components in complex mixtures.

Administration, Inhalation↗

PubMed1999

Antitumor effects of bis(ethyl)polyamine analogs on mammary tumor development in FVB/NTgN (MMTVneu) transgenic mice.

We studied the therapeutic potential of two polyamine analogs on breast cancer using FVB/NTgN (MMTVneu), a transgenic mouse model with neu/erb-B2 oncogene overexpression. Treatment was initiated at 31 weeks of age with bis(ethyl)norspermine (BE333) and its higher homolog, BE3333 as i.p. injections once weekly. There was a 40% reduction in the average number of tumors per mouse in both treatment groups, by 10 weeks of treatment. BE3333-treated mice had 70-75% lower tumor volume than controls. Spermidine/spermine acetyl transferase activity was significantly higher in tumor tissues and kidneys of treated animals, whereas polyamine levels were lower than controls. Beneficial effects were also evident from the mortality rates in control and treatment groups. Our results suggest a potential use of selected bis(ethyl) polyamine analogs as antitumor agents in breast cancer.

Acetyltransferases↗

PubMed1999

A modeling approach to account for toxicokinetic interactions in the calculation of biological hazard index for chemical mixtures.

Biological hazard index (BHI) is defined as biological level tolerable for exposure to mixture, and is calculated by an equation similar to the conventional hazard index. The BHI calculation, at the present time, is advocated for use in situations where toxicokinetic interactions do not occur among mixture constituents. The objective of this study was to develop an approach for calculating interactions-based BHI for chemical mixtures. The approach consisted of simulating the concentration of exposure indicator in the biological matrix of choice (e.g. venous blood) for each component of the mixture to which workers are exposed and then comparing these to the established BEI values, for calculating the BHI. The simulation of biomarker concentrations was performed using a physiologically-based toxicokinetic (PBTK) model which accounted for the mechanism of interactions among all mixture components (e.g. competitive inhibition). The usefulness of the present approach is illustrated by calculating BHI for varying ambient concentrations of a mixture of three chemicals (toluene (5-40 ppm), m-xylene (10-50 ppm), and ethylbenzene (10-50 ppm)). The results show that the interactions-based BHI can be greater or smaller than that calculated on the basis of additivity principle, particularly at high exposure concentrations. At lower exposure concentrations (e.g. 20 ppm each of toluene, m-xylene and ethylbenzene), the BHI values obtained using the conventional methodology are similar to the interactions-based methodology, confirming that the consequences of competitive inhibition are negligible at lower concentrations. The advantage of the PBTK model-based methodology developed in this study relates to the fact that, the concentrations of individual chemicals in mixtures that will not result in a significant increase in the BHI (i.e. > 1) can be determined by iterative simulation.

Animals↗

PubMed1999

An improved method for screening alpha-acetolactate producing mutants.

Alpha-Acetolactate-deficient Lactococcus lactis ssp. lactis biovar. diacelylactis are utilised in several industrial processes for producing diacetyl and alpha-acetolactate. They can be selected by screening after random mutagenesis. We improved a previously described screening method [Monnet, C., Schmitt, P., Diviès, C., 1997. Appl. Environ. Microbiol. 63, 793-795], which makes it possible to screen up to 1000 colonies per agar plate, whereas the previous method allowed to screen only 60 colonies per agar plate. The new screening method facilitates selection of alpha-acetolactate-deficient mutants.

Filtration↗

PubMed1999

Nutricel as an additive solution for neonatal transfusion.

Red cell concentrates stored in additive solutions have limitations for use in the pediatric population. Our survey of 10 pediatric institutions found that Nutricel supernatant was often removed prior to infusion. Examination of packed red cells showed a potassium concentration in excess of 15 mmol/l by day 7 in AS-3 and 40 mmol/l by day 35. Comparison with cells stored in CP2D and CPDA1 showed that the total mass of potassium was highest in AS-3 (5.6 mmol/l) as was the phosphate. The total mass of citrate and glucose was considerably increased in the AS-3 system at 1.73 mmoles and 3.23 mmoles. All had a pH less than 6.6 at day 35. The high concentration of potassium in AS-3 raises concern for the potential for hyperkalemic dysrhythmias during massive transfusion while the citrate load has clinical implications for divalent cation homeostasis during rapid infusion or exchange; the glucose may induce hyperglycemic sequelae.

Erythrocyte Transfusion↗

PubMed1999

Ten-year heart transplantation experience at the MARITIME HEART CENTER: does volume affect results?

OBJECTIVE: To evaluate the experience of a small volume Canadian heart transplantation centre. DESIGN: Ninety-four consecutive primary heart transplants were performed from 1988 to 1998 at the Maritime Heart Center, Halifax, Nova Scotia, with 100% follow-up. Kaplan-Meier survival analysis was used. RESULTS: The mean recipient age was 48.5+/-12.3 years and donor age 33+/-13.2 years. Eighty per cent of recipients were men. The prevalence of elevated pulmonary vascular resistance (4 or more Wood units) was 20.2%. Etiology of heart failure was ischemic cardiomyopathy (50%), dilated cardiomyopathy (40.9%) and congenital heart disease (9.1%). Survival was 85.9% at one year (n=71), 75.3% at five years (n=33) and 60.5% at eight years (n=8). There was a trend toward survival benefit with human leukocyte antigen (HLA) -DR matching, body mass index ratio of donor to recipient greater than 0.8, ischemic time less than 90 mins and male donors. There was no effect on survival with donor or recipient age, recipient sex, diabetes, hypertension, hypercholesterolemia, elevated pulmonary vascular resistance and HLA-A/B mismatch. CONCLUSIONS: Excellent survival at one and five years following heart transplantation is reported that compares favourably with results published by the International Society for Heart and Lung Transplantation.

Adolescent↗

PubMed1999

[Venous malformation of the corpus adiposum buccae].

We report on a venous malformation (previously known as a cavernous angioma) with an unusual location in the corpus adiposum buccae. Diagnosis, histologic classification and management of these rare lesions are discussed.

Adipose Tissue↗

PubMed1998

Premature luteinization: could it be an early manifestation of low ovarian reserve?

OBJECTIVE: To gain insight into the physiologic significance of premature luteinization and to evaluate whether it could be a manifestation of low ovarian reserve. DESIGN: Retrospective evaluation. SETTING: Reproductive medicine unit. PATIENT(S): Thirty-one consecutively seen women with normal ovulation and unexplained infertility. INTERVENTION(S): Induction of superovulation with hMG coupled with synchronized IUI. A GnRH agonist was not used during the study. MAIN OUTCOME MEASURE(S): Premature luteinization was defined as a progesterone/estradiol ratio of > 1 on the day of hCG administration. Patients were evaluated during their first cycles of hMG treatment and then were divided into those with (study group) and those without (control group) premature luteinization. The ovarian reserve parameters were compared between the two groups. RESULT(S): Nineteen of the 31 patients with unexplained infertility demonstrated premature luteinization. Patient characteristics were similar between the study and control groups. Mean (+/- SD) day 3 FSH levels were 8.2 +/- 3.3 and 6.6 +/- 1.7 mIU/mL in the study and control groups, respectively. Mean (+/- SD) day 3 estradiol levels were significantly higher in the study than in the control group (74 +/- 49 pg/mL vs. 30 +/- 17 pg/mL, respectively). Mean (+/- SD) estradiol levels on the day of hCG administration also differed significantly between the study and control groups (760 +/- 539 pg/mL vs. 1,568 +/- 675 pg/mL, respectively). Likewise, the number of follicles that were > or = 15 mm on the day of hCG administration was significantly lower in the study than in the control group (2.9 +/- 1.5 vs. 4.3 +/- 1.3, respectively). The total dose of hMG and duration of administration were similar in the two groups. The clinical pregnancy rates after four cycles of treatment were 15.8% and 41.7% in the study and control groups, respectively. CONCLUSION(S): This preliminary work suggests that, in cycles that are not treated with a GnRH agonist, signs of premature luteinization in patients with unexplained infertility could be an early manifestation of low ovarian reserve. It appears that hMG treatment in this group of patients could uncover the pathogenesis of their infertility.

Adult↗

PubMed1998

What does quality mean to lay people? Community perceptions of primary health care services in Guinea.

The success of strategies to revitalize primary health care services such as those advocated by the Bamako Initiative requires a response adapted to the expectations of the population, especially in terms of quality. The goal of this study, conducted in two rural communities in Guinea, was to identify, characterize, and classify the criteria that the public uses to judge the quality of primary health care (PHC) services. This study included 180 participants in 21 focus group discussions. Forty-four main criteria were identified. These criteria vary depending on the respondents' sex and age, and their ability to access primary health care services. Some of the criteria correspond to those used by health care providers, while others do not. The general public places considerable emphasis on outcomes, but little emphasis on preventive services. The users appear very sensitive to aspects of the interpersonal relations they have with professionals and the technical quality of the care provided. A taxonomy of perceived quality is developed, which includes the following five categories: (1) technical competence of the health care personnel; (2) interpersonal relations between the patients and care providers; (3) availability and adequacy of resources and services; (4) accessibility and (5) effectiveness of care. It is a major challenge to refocus on quality in the development of health care services. This will require considerable changes for which training may be an effective, but certainly not a sufficient means. Promoting professionalism and changing the relations between public authorities and the general public are the only means of improving the quality of health care services as well as user perception.

Adult↗

PubMed1998

Prenatal ultrasonography: clinical and radiological findings in a boy with fibrochondrogenesis.

Fibrochondrogenesis, a rare lethal chondrodysplasia has been reported on nine patients. We report on a boy with fibrochondrogenesis whose parents were second cousins. Prenatal ultrasonography performed at 22 weeks of gestation revealed an intrauterine growth retardation, an apparently large head, an hypoplasia of the thorax, a prominent abdomen, rhizomelic limbs, and wide metaphysis. The latest have never been reported in other lethal dysplasias.

Bone and Bones↗

PubMed1998

Measuring lay people's perceptions of the quality of primary health care services in developing countries. Validation of a 20-item scale.

INTRODUCTION: Methodologies that have been developed and validated in accordance with accepted scientific standards are needed to monitor and assess the quality of primary health care in developing countries. OBJECTIVE: To present the results of reliability and validity testing of a new instrument of measurement intended to document the user's opinion on the quality of primary health care services. METHODS: The 20-item scale includes three subscales related to health care delivery personnel and facilities. There were 241 people in one city and two villages in Upper Guinea who responded to the questionnaire. An item analysis preceded the test of psychometric properties of the three subscales and of the total score. Reliability was estimated by analyses of internal consistency and the Cronbach's alpha coefficient. A variety of statistical procedures were used to test factorial validity, trait validity (convergent and discriminant) and nomological validity. RESULTS: The reliability of the subscales ranged from 0.71 to 0.88. The validity analyses supported the initial dimensionality and suggested good construct validity. CONCLUSION: Results confirm the value of the use of the scale developed and highlight the need to take into account the diversity of how quality is perceived by lay people in developing countries. It is suggested that the process of formalization of this type of measurement scale be pursued.

Adult↗

PubMed1998

Spontaneous resolution of subdural hematoma. MRI findings.

A 33-year-old man suffered a traumatic subdural hematoma with complete spontaneous resolution, as demonstrated by computed tomography scanning and magnetic resonance imaging. After resolution, there was obliteration of the subarachnoid space on the affected side, giving rise to relative dilation of the subarachnoid space over the uninvolved convexity. A resolved subdural hematoma should be considered in the differential diagnosis of such an asymmetry.

Accidental Falls↗

PubMed1998

Physiological modeling of toxicokinetic interactions: implications for mixture risk assessment.

Most of the available data on chemical interactions have been obtained in animal studies conducted by administering high doses of chemicals by routes and scenarios different from anticipated human exposures. A mechanistic approach potentially useful for conducting dose, scenario, species, and route extrapolations of toxic interactions is physiological modeling. This approach involves the development of mathematical descriptions of the interrelationships among the critical determinants of toxicokinetics and toxicodynamics. The mechanistic basis of the physiological modeling approach not only enables the species, dose, route, and scenario extrapolations of the occurrence of toxicokinetic interactions but also allows the extrapolation of the occurrence of interactions from binary to multichemical mixtures. Examples are presented to show the feasibility of predicting changes in toxicokinetics of the components of complex chemical mixtures based on the incorporation of binary interaction data within physiologically based models. Interactions-based mixture risk assessment can be performed by simulating the change in the tissue dose of the toxic moiety of each mixture component during combined exposures and calculating the risk associated with each tissue dose estimate using a tissue dose versus response curve for all components. The use of such a mechanistic approach should facilitate the evaluation of the magnitude and relevance of chemical interactions in assessing the risks of low-level human exposures to complex chemical mixtures.

Algorithms↗