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PubMed2003

Using measurement error models to assess effects of prenatal and postnatal methylmercury exposure in the Seychelles Child Development Study.

Studies of the effects of environmental exposures on human health typically require estimation of both exposure and outcome. Standard methods for the assessment of the association between exposure and outcome include multiple linear regression analysis, which assumes that the outcome variable is observed with error, while the levels of exposure and other explanatory variables are measured with complete accuracy, so that there is no deviation of the measured from the actual value. The term measurement error in this discussion refers to the difference between the actual or true level and the value that is actually observed. In the investigations of the effects of prenatal methylmercury (MeHg) exposure from fish consumption on child development, the only way to obtain a true exposure level (producing the toxic effect) is to ascertain the concentration in fetal brain, which is not possible. As is often the case in studies of environmental exposures, the measured exposure level is a biomarker, such as the average maternal hair level during gestation. Measurement of hair mercury is widely used as a biological indicator for exposure to MeHg and is the only indicator that has been calibrated against the target tissue, the developing brain. Variability between the measured and the true values in explanatory variables in a multiple regression analysis can produce bias, leading to either over or underestimation of regression parameters (slopes). Fortunately, statistical methods known as measurement error models (MEM) are available to account for measurement errors in explanatory variables in multiple regression analysis, and these methods can provide an (either "unbiased" or "bias-corrected") estimate of the unknown outcome/exposure relationship. In this paper, we illustrate MEM analysis by reanalyzing data from the 5.5-year test battery in the Seychelles Child Development Study, a longitudinal study of prenatal exposure to MeHg from maternal consumption of a diet high in fish. The use of the MEM approach was made possible by the existence of independent, calibration data on the magnitude of the variability of the measurement error deviations for the biomarker of prenatal exposure used in this study, the maternal hair level. Our reanalysis indicated that adjustment for measurement errors in explanatory variables had no appreciable effect on the original results.

Adult↗

PubMed2000

Predicting the therapeutic alliance in alcoholism treatment.

OBJECTIVE: Prediction of the therapeutic alliance in alcoholism treatment (as rated by the client and by the therapist) was examined in light of a range of potentially relevant factors, including client demographics, drinking history, current drinking, current psychosocial functioning and therapist demographics. METHOD: The data were gathered in Project MATCH. The present analyses were based on data from 707 outpatients and 480 aftercare clients assigned to one of the three Project MATCH treatments. Potential predictor variables were evaluated by first examining bivariate linear relationships between the variables and ratings of the alliance, and then entering blocks of these predictors into multiple linear regression equations with alliance ratings as the dependent variables. All analysis incorporated adjustments for the nonindependence of ratings pertaining to clients seen by the same therapist. RESULTS: In simple regressions evaluating bivariate relationships, outpatients' ratings of the alliance were positively predicted by client age, motivational readiness to change, socialization, level of perceived social support and therapist age, and were negatively predicted by client educational level, level of depression, and meaning seeking. Therapist ratings in the outpatient sample were positively predicted by the client being female and by level of overall alcohol involvement, severity of alcohol dependence, negative consequences of alcohol use, and readiness to change. Among aftercare clients, ratings of the alliance were positively predicted by readiness to change, socialization and social support, and were negatively predicted by level of depression. Therapist ratings of the alliance in the aftercare sample were positively predicted by the client being female and therapist educational level, and were negatively predicted by pretreatment drinks per drinking day. Of the variables having significant bivariate relationships with alliance scores, only a few were identified as significant predictors in multiple regression equations. Among outpatients, client age and motivational readiness to change remained positive predictors and client education a negative predictor of client ratings of the alliance, while client gender remained a significant predictor of therapist ratings. Among aftercare clients, readiness to change and level of depression remained significant predictors of client ratings, while none of the variables remained a significant predictor of therapist ratings. CONCLUSIONS: While the data indicate that several client variables predict the nature of both the client's and therapist's perception of the therapeutic alliance, the significant relationships are of modest magnitude, and few variables remain predictive after controlling for causally prior variables. The strongest relationship identified in both the outpatient and aftercare samples is that between clients' motivational readiness to change and their ratings of the alliance.

Adult↗

PubMed1989

The effects of propranolol, phentolamine, and atropine on canine coronary vascular gradients.

The objective of this study was to measure pressure gradients in the coronary circulation following the administration of three receptor-blocking drugs, propranolol, phentolamine, and atropine when administered singly and in sequence. As well, we examined the responses of these gradients to eight interventions: left stellate ganglion or left vagosympathetic trunk stimulation, administration of isoproterenol, acetylcholine, noradrenaline, adenosine, phenylephrine, or adrenaline. Using a multiple linear regression model we examined the actions and interactions of the receptor-blocking agents on hemodynamic variables and vascular gradients. Propranolol reduced heart rate as expected and blocked the responses to isoproterenol administration. As well, it abolished the epicardial coronary artery diastolic gradient. The gradient was restored when propranolol was the second receptor blocker administered but was abolished when it was the third. Phentolamine induced vasodilation with a decrease in coronary small vessel gradients. This effect persisted without regard to the sequence of administration. When it was the second or third agent it decreased the microcirculation and small vein gradients, an action it did not manifest when given singly. Atropine singly did not alter pressures or gradients; but as the second agent it altered the transmural, outflow tract, epicardial diastolic, and microcirculation and small vein diastolic gradients; and as the third agent the changes were in the transmural, epicardial systolic and diastolic, and small artery systolic and diastolic gradients. The pattern of responses was not predictable and that indicates that unique changes occur in the responses of the coronary circulation when multiple receptor-blocking agents are employed. Adrenergic control tends to dominate in the coronary arterial circulation, and muscarinic control in the coronary microcirculation and veins with considerable overlap.

Adenosine↗

PubMed2006

Utilization of rehabilitation therapies by nursing home residents with MS at admission.

OBJECTIVE: To identify factors associated with the utilization of physical and occupational therapies by nursing home residents with multiple sclerosis (MS) at admission to the facility. DESIGN: The study analyzed 27,264 admission assessments for residents with MS recorded in the national Minimum Data Set (MDS) between June, 1998 and June, 2003. A multiple linear regression model was employed to analyze the MDS data. The total number of minutes of physical and occupational therapies provided are the dependent variables. Independent variables are demographic characteristics, payment source, behavioral symptoms, and a range of health-related characteristics. RESULTS: The use of physical and occupational therapies by residents with MS at admission to the nursing facility was significantly associated with payment source, controlling for other independent variables. CONCLUSIONS: When reimbursement is available these therapies are more likely to be prescribed or requested. Since provision of these rehabilitative services diminishes disability and handicap, expanded Medicaid coverage may reduce long term health care costs and also improve the quality of life.

Activities of Daily Living↗

PubMed1999

Artificial neural networks as versatile tools for prediction of MDR-modulatory activity.

Following our ongoing studies on structure-activity relationship studies of propafenone-type modulators of multidrug resistance, we performed both a Free-Wilson analysis and a combined Hansch/Free-Wilson analysis on a set of 48 compounds using artificial neural networks (ANN). In comparison to classical multiple linear regression (MLR) analysis, the ANN showed equal or even slightly better predictive power in leave one out cross validation procedures and was remarkably superior when performing a leave 8 out cross validation. Additionally, it was possible to train a network using only 14 compounds and to properly predict the MDR-modulating activity of the remaining 34 compounds. In this case, the MLR analysis completely failed due to insufficient number of cases. Attempts to extract informations on which input descriptors are important using a genetic input selection algorithm failed. Best results were obtained using those descriptors which showed highest statistical significance in MLR analyses.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Risk assessment in patients with ruptured abdominal aortic aneurysms.

OBJECTIVES: Surgery of ruptured abdominal aortic aneurysms is associated with a high mortality rate, mostly related to multi-organ-failure after a prolonged intensive care therapy. In a retrospective study attempts are made to identify individual organ-dysfunction risk profiles influencing the outcome. METHODS: Fifty seven patients (53 men, 4 women, mean age 71.8 +/- 8.8 years) with ruptured abdominal aortic aneurysms underwent graft replacement in a three year period. Fourty eight preoperative, 13 intraoperative and 34 postoperative variables were analyzed. A multi-organ dysfunction (MOD) score was used. RESULTS: The perioperative mortality rate was 31%. Significance of pre-existing risk factors at admission was identified only for cardiovascular diseases. Multiple linear regression analysis indicated that hemoglobin < 90 g/l, systolic blood pressure < 80 mmHg and ECG signs of ischemia at admission are highly significant risk factors. Patients, who died later than 48 hours postoperatively, deceased mainly from MOD (93%) and required intensive care significantly longer than surviving patients (p < 0.0005). All patients with a MOD score > or = 4 died (n = 7). These patients required 26% of all ICU-days and 72% of the ICU-days of the nonsurvivors. CONCLUSION: Patients with ruptured aortic aneurysms should not be excluded from treatment. However, a physiological scoring system after 48 h appears justifiable in order to decide on the appropriateness of continued ICU support.

Aged↗

PubMed1995

Determinants of fetal haemoglobin in newborn infants.

Percentage fetal haemoglobins (% HbF) were measured in 7081 newborns at the University Hospital, Nottingham, between 1990 and 1992 to assess the effects of a range of factors, and to determine if there was an association between % HbF at birth and risk of SIDS (sudden infant death syndrome). Data from the obstetric clinical records were analysed by multiple linear regression to establish the major determinants of % HbF. New findings were the identification of maternal smoking, twin pregnancy, ethnic origin, and season of birth as significant determinants. Alcohol use, drug and vitamin intake, and duration of labour were not found to be important. The previously reported correlations between % HbF and sex, gestational age, and birthweight were confirmed, and the relative effects quantified. Overall, the major determinants of an increase in % HbF in neonates are similar to the known antenatal risk factors for sudden infant death syndrome (SIDS).

Birth Weight↗

PubMed1992

Is age an independent predictor of early and late mortality in patients with acute myocardial infarction?

PURPOSE: To determine whether advancing age is an independent predictor of increased mortality following acute myocardial infarction or simply a marker for more extensive cardiac disease, a higher prevalence of comorbid conditions, and/or differences in therapeutic approach. PATIENTS: A total of 261 consecutive patients with documented acute myocardial infarction admitted to a university teaching hospital during a 1-year interval. METHODS: Seventy-four variables were analyzed to determine univariate predictors of inhospital and 1-year post-discharge mortality. Multiple linear regression models were constructed to determine independent predictors of early and late mortality after adjusting for baseline and therapeutic differences between younger and older patients. RESULTS: Compared with patients less than 70 years (n = 124), patients greater than or equal to 70 years (n = 137) were more likely (all p less than 0.05) to be female and have a prior history of ischemic heart disease. New York Heart Association functional class and Killip class on admission were higher in older patients, as were the admission serum creatinine and blood urea nitrogen levels. Serum albumin and peak creatine kinase levels were lower in older patients, but older patients were more likely to exhibit left ventricular hypertrophy or atrioventricular block on the initial electrocardiogram. Finally, younger patients were three times as likely to receive a thrombolytic agent and 66% more likely to receive intravenous beta-blockade than older patients, and younger patients were also more likely to receive heparin and intravenous nitroglycerin. Hospital mortality was 5.6% in patients less than 70 years versus 16.1% in patients greater than or equal to 70 years (p = 0.013). After adjusting for baseline and therapeutic differences, independent predictors of hospital mortality were systolic blood pressure on admission (inverse correlation, p = 0.0095), beta-blocker therapy (inverse correlation, p = 0.01), age (p = 0.014), peak creatine kinase level (p = 0.015), and Killip class (p = 0.035). Among hospital survivors, 1-year post discharge mortality was 6.8% in patients less than 70 years versus 19.1% in those greater than or equal to 70 years (p = 0.001). Independent predictors of post-discharge mortality after adjusting for age-related baseline and therapeutic differences were admission heart rate (p = 0.0004), age (p = 0.011), left ventricular ejection fraction (inverse correlation, p = 0.012), initial non-Q-wave myocardial infarction (p = 0.026), and the blood urea nitrogen level (p = 0.036). CONCLUSION: After adjusting for multiple baseline and therapeutic differences between older and younger patients, age per se remains a strong independent predictor of both inhospital and 1-year post-discharge mortality rates in patients with acute myocardial infarction.

Age Factors↗

PubMed1999

Hormone replacement therapy affects body composition and leptin differently in obese and non-obese postmenopausal women.

Leptin and oestrogen are both involved in the regulation of adipose tissue deposition and feeding behaviour. We investigated whether 5 years of hormone replacement therapy (HRT) affected serum leptin and body composition differently in 89 postmenopausal women treated with HRT compared with 178 controls. At baseline, leptin was significantly correlated with oestradiol (r=0.13, P<0.05) and in multiple backward regression analysis including oestradiol and any estimate of body fat, oestradiol remained a significant determinant of leptin levels. In the control group, all estimates of body fat determined by dual energy X-ray absorptiometry (DEXA) or anthropometry were increased (3.6-16.9%) and leptin increased 31.3% (16.03+/-1.02 to 20.84+/-1.2 ng/ml (s.e.m.), P<0.001). In the HRT group all estimates of body composition also increased during the 5-year observation but to a lesser extent than observed in the control group (1.0-8.5%). Leptin was raised by 19.7% (17.81+/-1.32 to 20.57+/-1.65 ng/ml, P<0.001). However, the DEXA scans revealed that the control group gained 2.4-fold more fat during the 5-year observation (1.9+/-0.3 vs 0.8+/-0.4 kg, P<0.05), and especially the trunk fat increased (1.4+/-0.2 vs 0.7+/-0.3 kg, P<0.05). This was reflected in the increase in leptin levels, which were increased by 7.4% in the control group compared with the HRT group (4.81+/-0.60 vs 2.76+/-0.87 ng/ml, P<0.05). Adjusting for the difference in adipose tissue revealed that HRT had no independent effect on leptin levels. Comparisons between obese (body mass index>25 kg/m(2)) and non-obese (<25 kg/m(2)) subjects by stratifying for HRT treatment using multiple linear regression revealed that the change in fat mass was significantly less among treated subjects (P=0.038) and especially in the non-obese subjects (P=0.001). The change in trunk fat was similarly correlated with treatment status (P=0.029) and with the degree of obesity (P=0.006). In conclusion, 5 years of HRT treatment significantly reduced fat mass accumulation, especially in the trunk region. This effect of HRT was more pronounced in non-obese as compared with obese subjects. The HRT-induced reduction in fat mass seems not to be mediated by leptin.

Body Composition↗

PubMed1996

US childhood mortality, 1950 through 1993: Trends and socioeconomic diffferentials.

OBJECTIVES: This study examined trends and differentials in US childhood mortality from 1950 through 1993 according to sex, race/ethnicity, education, family income, and cause of death. METHODS: Log-linear, multiple regression, and Cox proportional hazards regression models were applied to the data from the National Vital Statistics System, the National Longitudinal Mortality Study, and the Area Resource File. RESULTS: Substantial declines in US childhood mortality have occurred in the past 4 decades, primarily due to decreases in mortality from unintentional injuries, cancer, pneumonia and influenza, and congenital anomalies. The overall declining trend, however, has been dampened by a twofold to threefold increase in the suicide and homicide rates among children since 1968. Male, Black, American Indian, Hawaiian, and Puerto Rican children and those in the lower socioeconomic strata were at an increased risk of death. CONCLUSIONS: Increasing trends in mortality from violence, firearm injuries, and human immunodeficiency virus/acquired immunodeficiency syndrome pose a major obstacle to continued declines in US childhood mortality. Reducing socioeconomic disparities and improving access to and use of health care may bring about further declines in overall and injury-related childhood mortality.

Adolescent↗

PubMed2002

Brain atrophy in multiple sclerosis: impact of lesions and of damage of whole brain tissue.

INTRODUCTION: In multiple sclerosis (MS), brain atrophy measurement on magnetic resonance imaging (MRI) reflects overall tissue loss, especially demyelination and axonal loss. We studied which factor contributes most to the development of brain atrophy extent and severity of lesions or damage of whole brain issue (WBT). METHODS: Eighty-six patients with MS [32 primary progressive (PP), 32 secondary progressive (SP)] and 22 relapsing-remitting (RR) were studied MRI included T1- and T2-weighted imaging to obtain hypointense T1 lesion volume (T1LV) and two brain volume measurements: 1) the parenchymal fraction (PF; whole brain parenchymal volume/intracranial volume) as a marker of overall brain volume, and 2) the ventricular fraction (VF; ventricular volume/intracranial volume) as a marker of central atrophy. From magnetization transfer ratio (MTR) histograms, the relative peak height (rHp) was derived as an index of damage of WBT (a lower peak height reflects damage of WBT). RESULTS: Multiple linear regression analysis revealed that damage of WBT explains most of the variance of PF (standardized coeffcient beta = 0.59, p < 0.001 for WBT and beta = -0.19, p < 0.05 for T1LV). These findings are independent of disease phase; even in RR patients, damage of WBT plays a dominant role in explaining the variance in overall brain volume. By contrast the variance in VF is explained by both T1LV and damage of WBT (standardized coefficient beta = 0.43, p < 0.001 for T1LV and beta =-0.38, p < 0.001 for WBT). CONCLUSION: This study shows that overall brain volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss. Central atrophy (VP) is determined by both lesion volume and damage of WBT. Our results underline the importance of nonfocal pathology even in the early (RR) phase of the disease.

Adult↗

PubMed2001

The predictive parameters of erythropoietin hyporesponsiveness in patients on continuous ambulatory peritoneal dialysis.

BACKGROUND: The present study was aimed at investigating the predictive parameters of erythropoietin (epoetin) hyporesponsiveness in patients on continuous ambulatory peritoneal dialysis (CAPD). METHODS: We studied 40 patients with end-stage renal disease who had been receiving CAPD for at least 6 months and epoetin therapy for at least more than 2 months. Pearson's simple correlation and multiple stepwise linear regression analysis was used to discover what parameter can predict epoetin resistance. We expressed epoetin resistance index (ERI) as weekly epoetin dose/hematocrit/body weight'. The dose of epoetin is titrated by about 25% every 2 to 4 weeks to maintain a target hematocrit level between 33% and 36%. RESULTS: We analyzed the relationship between ERI and other predictive parameters by Pearson's correlation. These results showed ERI has a statistically significant correlation with transferrin saturation (TS) (r = -0.327, p = 0.042), total weekly Kt/Vurea (r = -0.423, p = 0.018), serum albumin level (r = -0.458, p = 0.003), normalized protein catabolic rate (nPCR) (r = -0.479, p = 0.006), normalized protein equivalent of total nitrogen appearance (nPNA) (r = -0.488, p = 0.005) and serum C-reactive protein (CRP) (r = 0.332, p = 0.036). Regression analysis was performed using stepwise linear regression for multiple variables to discover the most independent variable which is correlated with ERI. ERI was entered as a dependent variable, whereas the other parameters (age, duration of peritoneal dialysis, serum albumin level, CRP, serum ferritin, total weekly Kt/Vurea, nPCR, nPNA, serum iPTH, serum aluminium, TS) were entered as independent variables. This analysis showed CRP is the most significant variable and, if CRP is excluded, nPNA is the significant variable. CRP has a statistically significant correlation with serum albumin level (r = -0.418, p = 0.007) and total weekly Kt/Vurea (r = -0.366, p = 0.043). High CRP group has more increased level of ERI (p < 0.05), age (p < 0.05) and serum creatinine level (p < 0.05) than normal control, but more decreased level of serum albumin (p < 0.01) and serum iron levels (p < 0.05). CONCLUSION: These results indicate that CRP is the most important predictor of epoetin hyporesponsiveness.

Adult↗

PubMed1991

Effects of intoxication on the catecholamine response to multisystem injury.

In patients suffering isolated head trauma, we have previously shown that levels of circulating catecholamines obtained within 48 hours of trauma correlate with the severity of brain injury and predict outcome and that intoxication blunts this response. The effects of alcohol on the increase in catecholamines in systematically injured patients, however, have not been well defined. From 1983 to 1990, 78 patients (74% male; median age 30 years) with blunt head and multisystem injury, who also had alcohol levels measured within 5 hours of injury, were studied. Norepinephrine and epinephrine levels were assayed by a radioenzymatic technique. Injury severity was assessed by the admission Glasgow Coma Scale (GCS) score (4-15; median, 12), the Injury Severity Score (ISS) (13-50; median, 25) and the volume of blood products administered within the first 24 hours (0-14.4 L; median, 0.5 L). The impact of alcohol on the norepinephrine response to injury was analyzed using multiple linear regression models, including polynomial interaction terms. Norepinephrine levels significantly (p less than 0.0001) correlated with the GCS score and ISS. However, alcohol significantly lowered the norepinephrine response to decreasing GCS score (R = 0.49, p less than 0.002) and to increasing ISS (R = 0.51, p less than 0.0006). The blunting of the catecholamine response was most marked in those severely injured. The rise in norepinephrine concentrations seen with increasing volume of blood replacement was not affected by intoxication. An association between injury severity and epinephrine levels was also present, but not as consistently. Epinephrine concentrations rose with falling GCS score and with increasing ISS values, but unlike norepinephrine, there were no apparent effects of alcohol on changes in epinephrine levels. Thus, in patients suffering head and multisystem injury, catecholamine changes reflect the severity of injury using three different scalers. Furthermore, intoxication blunts only the norepinephrine component of this important biologic response.

Adolescent↗

PubMed2003

Mortality after reamed intramedullary nailing of bilateral femur fractures.

We performed retrospective review of 743 patients treated with reamed intramedullary nailing of a femoral shaft fracture was done to assess the clinical impact of bilateral femur fractures on the mortality, hospital stay, and length of intensive care treatment in patients with blunt trauma. Unilateral injuries occurred in 689 patients and bilateral injuries occurred in 54 patients. Mortality in patients with bilateral femur fractures was 5.6% compared with 1.5% in patients with unilateral femur fractures. The two groups were analyzed using multiple linear regression and logistic regression with age and Injury Severity Scores as covariants to allow for comparison of similarly injured groups as predicted by the Injury Severity Scores. Bilateral femur fractures still were associated with a significantly higher mortality, longer length of stay in the hospital, and longer length of stay in the intensive care unit. As expected, when analyzed separately, patients with bilateral femur fractures had significantly higher Injury Severity Scores, longer lengths of stay in the intensive care unit, and longer lengths of stay in the hospital. Patients with bilateral femur fractures have an increased mortality when compared with patients with unilateral femur fractures after controlling for Injury Severity Score and age. When used alone, the Injury Severity Score underestimates the contribution of a second femur fracture.

Adolescent↗

PubMedDate not supplied

[Health Search--Research Institute of the Italian Society of General Practice: the creation of a research database in general practice].

OBJECTIVE: To describe a database used in general practice by analysing the characteristics of the physicians providing the data and the completeness of the data recording on the basis of the indicators of interest (smoking habits, weight, height, and the prevalence of hypertension). DESIGN: Descriptive study and multiple linear regression analysis of the relationships between structural variables and outcomes. SETTING: General practitioners (GPs) belonging to the Italian Society of General Medicine (SIMG), and enrolled in Health Search (HS). POPULATION: Six hundred and ninety-five voluntarily enrolled GPs and their patients. PRINCIPAL OUTCOMES: Descriptive statistics (mean and median values, standard deviation, frequencies) concerning the general characteristics of the GPs, the ways in which they connect to the network and their use of the clinical data management software, and epidemiological measures concerning the prevalence of hypertension among their patients, and the recording of weight, height and tobacco smoking habits. RESULTS: The geographic distribution of the GPs is homogeneous: 317 in Northern Italy (12.52 physicians per 10(6) patients), 134 in Central Italy (12.30 physicians per 10(6) patients) and 244 in Southern Italy and the Islands (11.89 physicians per 10(6) patients). Five hundred and ninety-five (85.6%) are males; their mean age is 46.7 years (SD +/- 3.8); the mean number of patients per physician is 1128; 69% have at least one post-graduate specialisation; 49% practise alone; and they work for a mean of 30 hours per week (SD +/- 13). Five hundred and fifty-three GPs were actually connected to the network as of January 2003. The data relating to the years 2000-2001 show an increase in the number of connected physicians (34 in 2000 and 261 in 2001) and in the number of connections (a median of 12 in 2000 and 17 in 2001). The GPs contact more than 80% of their patients every year. The frequency of the recording of data concerning smoking habits, weight and height increases in proportion with the frequency of connections. The prevalence of hypertension among the patients included in the survey is 5.4%. Multiple regression analysis showed that the variability in the prevalence of hypertension was not influenced by the frequency of PC use but by the different structure of the age classes of the patients. CONCLUSIONS: This study of the variables relating to GPs, their clinical practices, and their use of computerised records (examined by means of the chosen indicators) shows that the regular and complete recording of the principal data of health interest is feasible insofar as it is not biased by the characteristics of the GPs, and advantageous. The construction of the database therefore represents a first step towards the initiation of routine research into general practice in Italy.

Biomedical Research↗

PubMed2005

Quantitative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 1,4-dihydropyridines and pyridines as multidrug resistance modulators.

PURPOSE: The aim of this study was to develop quantitative structure-activity/pharmacokinetic relationships (QSAR/QSPKR) for a series of synthesized 1,4-dihydropyridines (DHPs) and pyridines as P-glycoprotein (P-gp) inhibitors. METHODS: Molecular descriptors of test compounds were generated by 3D molecular modeling using SYBYL and KowWin programs. Forward inclusion coupled with multiple linear regression (MLR) was used to derive a QSAR equation for Ca2+ channel binding. A multivariate statistical technique, partial least square (PLS) regression, was applied to derive a QSAR model for P-gp inhibition and QSPKR models. Cross-validation using the "leave-one-out" method was performed to evaluate the predictive performance of models. RESULTS: For Ca2+ channel binding, the MLR equation indicated a good correlation between observed and predicted values (R2 = 0.90), and cross-validation confirmed the predictive ability of the model (Q2 = 0.67). For P-gp reversal, the model obtained by PLS could account for most of the variation in P-gp inhibition (R2 = 0.76) with fair predictive performance (Q2 = 0.62). Nine structurally related 1,4-DHP drugs were used for QSPKR analysis. The models could explain the majority of the variation in clearance (R2 = 0.90), and cross-validation confirmed the prediction ability (Q2 = 0.69). CONCLUSION: QSAR/QSPKR models were developed, and the QSAR models were capable of identifying synthesized 1,4-DHPs and pyridines with potent P-gp inhibition and reduced Ca2+ channel binding. The QSPKR models provide insight into the contribution of electronic, steric, and lipophilic factors to the clearance of DHPs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Whole-brain T1 mapping in multiple sclerosis: global changes of normal-appearing gray and white matter.

PURPOSE: To prospectively investigate whether T1 changes in normal-appearing white matter (WM) and normal-appearing gray matter (GM) in multiple sclerosis (MS) are global or regional and their relationship to disease type. MATERIALS AND METHODS: The institutional ethics review board approved study; written informed consent was obtained. Whole-brain T1 maps were obtained in 67 patients with MS and 24 healthy control subjects with three-dimensional fast low-angle shot flip angle-array method, with correction for B(1) imperfections. Analysis of variance was performed on T1 histogram parameters of global normal-appearing WM and GM. Regional mean T1 values were analyzed with a multilevel approach. Multiple linear regression analysis was performed to investigate associations with clinical disability and overall atrophy. For patients, T2 lesion load was determined. RESULTS: T1 histograms of normal-appearing WM had significantly higher peak positions for patients with MS (792 msec +/- 36 in secondary progressive [SP] MS) than for control subjects (746 msec +/- 23) and were significantly broader and lower (all P < .001). Histograms for cortical normal-appearing GM were significantly shifted (peak positions, 1263 msec +/- 44 in control subjects and 1355 msec +/- 62 in patients with SP MS) (P < .001). Histogram peak positions were significantly higher in SP MS than in relapsing-remitting (RR) and primary progressive MS (P < .05). In SP disease, at least 31% of normal-appearing WM and 20% of cortical normal-appearing GM were affected. In MS, T1 was significantly elevated in all normal-appearing WM and cortical normal-appearing GM regions (all P < .01) but was elevated only in the thalamus in deep GM (P < .05). Cortical T1 histogram peak position was associated with clinical disability; T2 lesion load was not. CONCLUSION: Results suggest that a global disease process affects large parts of both normal-appearing WM and GM in MS and effects are worse for SP MS than for RR MS.

Adult↗

PubMed1998

Serum ferritin as a component of the insulin resistance syndrome.

OBJECTIVE: In epidemiological studies, serum ferritin was the second-strongest determinant of blood glucose (after BMI) in regression models and the third-strongest determinant of serum insulin (after BMI and age). Its concentration also correlated positively with plasma triglycerides and apolipoprotein B concentrations, and negatively with HDL2 cholesterol. We hypothesized that serum ferritin could be a marker of insulin resistance. RESEARCH DESIGN AND METHODS: Oral glucose tolerance and insulin sensitivity (SI, minimal model method) were prospectively evaluated in 36 healthy subjects. The relationship between serum ferritin and metabolic control (as measured by HbA1c levels) was also studied in 76 consecutive NIDDM patients. RESULTS: In healthy subjects, log-transformed serum ferritin (LOGFER) correlated with basal serum glucose (r = 0.44, P = 0.007), but not with BMI, age, systolic or diastolic blood pressure, total cholesterol, VLDL cholesterol, HDL cholesterol, total triglycerides, VLDL triglycerides, serum insulin, or HbA1c (all P = NS). Identical results were obtained when the two lowest quartiles of serum ferritin were evaluated separately. However, in the two highest quartiles, LOGFER correlated with BMI (0.50, P = 0.02), diastolic blood pressure (r = 0.8, P < 0.0001), serum LDL cholesterol (r = 0.57, P = 0.01), VLDL cholesterol (r = 0.48, P = 0.03), total cholesterol and HDL2 and HDL3 subtractions of HDL cholesterol (r = -0.68, -0.76, -0.55, P = 0.001. < 0.0001, and 0.01, respectively), total triglycerides (r = 0.60, P = 0.006), HDL2/HDL3 quotient (P = -0.71, P = 0.001), VLDL triglycerides (r = 0.65, P = 0.004), and serum uric acid (r = 0.51, P = 0.03), but not with systolic blood pressure (r = 0.38, P = 0.15). After adjusting for BMI, only the correlations between LOGFER and diastolic blood pressure (r = 0.7, P = 0.002) and HDL2/HDL3 quotient (r = -0.63, P = 0.01) remained significant. Strong correlations between LOGFER and glucose area under the curve during oral glucose tolerance test (Pearson's r = 0.73, P = 0.001) and SI (r = -0.68, P = 0.001), which remained significant after controlling for BMI, were observed. LOGFER (beta = -0.44, P = 0.01) and BMI (beta = -0.52, P = 0.004) constituted independent predictors of insulin sensitivity in a multivariate analysis (R2 = 0.68). In 76 consecutive NIDDM outpatients, serum glucose (P < 0.00001) and LOGFER (P = 0.03) independently predicted the value of HbA1c (R2 = 0.40) in a multiple linear regression analysis. CONCLUSIONS: The correlations among serum ferritin and diastolic blood pressure, HDL quotient, glucose area under the curve, and SI suggest that serum ferritin could be a marker of the insulin resistance syndrome. Serum ferritin may also be an independent determinant of poor metabolic control in the diabetic patient.

Adult↗