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PubMed1999

Large-artery elastic properties in young men : relationships to serum lipoproteins and oxidized low-density lipoproteins.

Measures of arterial elasticity have been proposed as surrogate markers for asymptomatic atherosclerosis. We investigated the relations of serum lipoproteins, oxidized low-density lipoprotein (ox-LDL), and familial hypercholesterolemia (FH) to arterial elasticity among young men. As a marker of arterial elasticity we measured compliance in the thoracic aorta by using magnetic resonance imaging and in the common carotid artery by using ultrasound. LDL diene conjugation was used as a marker of ox-LDL. In study I, 25 healthy men (aged 29 to 39) were classified into 2 extreme groups according to previously measured high-density lipoprotein cholesterol to total cholesterol ratio (HDL-C/TC ratio). In study II, the healthy men were used as controls for 10 age matched asymptomatic patients with FH. In healthy men, the group with low HDL-C/TC ratio had decreased carotid artery compliance (2. 3+/-0.4% versus 1.9+/-0.5%/10 mm Hg, P=0.034). In univariate analysis, the compliance of the carotid artery associated with ox-LDL (r =-0.49, P=0.016) and HDL-C/TC ratio (r=0.41, P=0.040). In multivariate regression analyses, ox-LDL was the only independent determinant for compliance of the carotid artery (P=0.016). Aortic elasticity was not related to standard lipid variables, but the compliance of the ascending aorta associated with ox-LDL (r=-0.44, P=0.030). In FH patients, arterial elasticity was similar to that in controls. We conclude that elasticity of the common carotid artery is affected by serum lipid profile in young men. The current study demonstrates for the first time an in vivo association between ox-LDL and arterial elasticity suggesting that oxidative modification of LDL may play a role in the alteration of arterial wall elastic properties.

Adult↗
PubMed2004

Does surgical resection of hepatocellular carcinoma accelerate cancer dissemination?

AIM: This study was to investigate whether surgery could increase cancer dissemination and postoperative recurrence in patients with hepatocellular carcinoma (HCC) by detection of human alpha-fetoprotein messenger RNA (hAFP mRNA). hAFP mRNA in the peripheral blood of patients with HCC has been considered as a surrogate marker for circulating tumor cells. METHODS: Eighty-one consecutive patients who underwent curative resection for HCC entered this prospective cohort study. We examined hAFP mRNA from the peripheral blood obtained preoperatively, perioperatively, and postoperatively to correlate the prognosis after curative resections from HCC patients and from the control subjects. Detection of hAFP mRNA by reverse transcriptase and polymerase chain reaction amplification (RT-PCR) was performed with primers specifically. The relations between the clinical variables (age, sex, associated liver cirrhosis, hepatitis B virus infection, hepatitis C virus infection, serum ?-fetoprotein and Child-Pugh class), the histological variables (size, capsule, vascular permeation, grade of differentiation, and daughter nodules), hAFP mRNA in peripheral blood of 3 different sessions, and postoperative course (recurrence, and recurrence related death) were analysed. RESULTS: No hAFP mRNA was detected in control group subjects. Twenty-two (27%), 24 (30%) and 19 (23%) of 81 HCC patients had hAFP mRNA positivity in the preoperative, perioperative and postoperative peripheral blood. The preoperative presence did not influence the risk of HCC recurrence (55% vs 41%, P=0.280). In contrast, patients with postoperative presence had a significantly higher recurrence (90% vs 31%, P<0.001; odds ratio 19.2; 95% confidence interval: 4.0-91.7). In the multivariate analysis by COX proportional hazards model, postoperative positivity had a significant influence on recurrence (P=0.067) and recurrence related mortality (P=0.017). Whereas, the perioperative positivity of hAFP mRNA did not increase HCC recurrence (58% vs.39%, P=0.093). The correlation between perioperative hAFP mRNA positivity and recurrence related mortality had no statistical significance (P=0.836). CONCLUSION: From our study, perioperative detection of hAFP mRNA in peripheral blood of patients has no clinical relevance and significant role in the prediction of HCC recurrence. Surgical resection itself may not accelerate cancer dissemination and does not increase postoperative recurrence significantly either.

Adult↗
PubMed2006

Recovery responses to surrogate slipping tasks differ from responses to actual slips.

Slipping and slip-related falls are a common and potentially dangerous problem, especially for older adults. We believe that it is possible to train compensatory stepping responses of older adults to reduce the incidence of slip-related falls. However, such an approach requires further understanding of the causal biomechanical distinctions between a successful and an unsuccessful recovery effort. Surrogate tasks are often used to study complex biomechanical events associated with large postural disturbances. Although surrogate tasks enhance experimental control over one or more elements of a generally more complex event, such control may change the task of interest by imposing biomechanical constraints that reduce the validity of the surrogate. The purpose of the present study was to quantify the differences in lower extremity and trunk kinematics following a simulated slip versus an actual slip. We hypothesized that the simulated slips would be less variable than real slips and would result in significantly different, and less realistic recovery kinematics. Twenty-two healthy young adults were subjected to unexpected slips using a custom slipping platform and artificial ice. Biomechanical variables associated with the slipping foot were significantly less variable in those slips induced with the platform compared to slips induced with the artificial ice. Significant differences between successful and unsuccessful recovery efforts were found for lower extremity and trunk kinematics on both types of slipping surface. Notably, 40% of the variables for which between surface differences were significant were also those variables that distinguished successful and unsuccessful recovery efforts on the two surfaces. The results suggest that slips induced using artificial ice more accurately reflect the type of slips that occur in the community.

Accidental Falls↗
PubMed2007

The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels.

BACKGROUND: Fabry disease (OMIM 301500) is an X-linked lysosomal storage disorder with characteristic vascular, renal, cardiac and cerebral complications. Globotriaosylceramide (Gb(3)) accumulates in Fabry patients as a result of alpha-galactosidase A deficiency. The phenotypic variability is high, but the relationship between clinical symptoms in individual Fabry patients has not been uniformly documented. Also, the relation between the most prominent biochemical abnormalities, elevated Gb(3) levels in plasma and urine, and clinical symptoms is not firmly established. METHODS: Clinical and biochemical characteristics of 96 (25 deceased) Dutch Fabry patients were collected retrospectively and before the initiation of enzyme therapy. RESULTS: Clinical assessment revealed that median life expectancy was 57 years for male and 72 years for female patients. Cerebral complications, acroparaesthesias and gastrointestinal complications, but not cardiac and auditory complications, were all seen more frequently in male than female patients. Glomerular filtration rate (GFR) was highly variable in male patients, including 2 patients with GFR < 30 ml/min, but median GFR did not differ between males and females (103 and 101 ml/min, respectively). Hyperfiltration was more frequently observed in the female patient group. Microalbuminuria was present in 60% of males and 45% of females. No specific pattern of combined symptoms existed except for a relationship between left ventricular hypertrophy (LVH) and cerebral complications (males 36%, females 32%), or proteinuria (males 35%, females 31%). Gb(3) was found to be more elevated in plasma samples from male (n = 26; median 6.27 micromol/L (1.39-9.74)) than female Fabry patients (n = 37; median 2.16 (0.77-4.18)). This was also observed for urinary Gb(3): males (n = 22) median 1851 nmol/24 h (40-3724); females (n = 29) median 672 (86-2052). Plasma and urinary Gb(3) levels correlated with each other in both males (r = 0.4, p = 0.05) and females (r = 0.4, p = 0.03), but no correlation between elevated Gb(3) levels and clinical symptoms could be detected. CONCLUSION: Analysis of the characteristics of the Dutch Fabry cohort has revealed that a limited relationship between various disease manifestations exists and that individual symptoms do not correlate with elevated urinary or plasma Gb(3) levels, limiting their value as surrogate disease markers.

Adolescent↗
PubMedDate not supplied

Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers.

Polymorphisms in the mu-opioid receptor gene (OPRM1) are primary candidate sources of clinical variability in opioid therapy. Apart from the 118A>G single nucleotide polymorphism, nothing is known about the role of OPRM1 mutations in opioid therapy. The influence of the OPRM1 mutations on opioid pharmacodynamics was assessed in pooled data from 31 healthy volunteers obtained in previous studies with available plasma concentrations and pupil diameters after intravenous administration of morphine or morphine-6-glucuronide (M6G). A total of 24 candidate ORPM1 mutations were screened for and those found at an allelic frequency of at least 5% in the 31 subjects were analyzed for functional consequences, using population pharmacokinetic-pharmacodynamic modeling of the miotic effects of the opioids as a reliable and sensitive surrogate parameter of the central nervous opioid effects. Polymorphisms at an allelic frequency of > or =5% (n=310) were 118A>G in exon 1 (11.5%), the IVS2-31G>A (8.9%) and IVS2-691C>G (44.5%) SNPs in intron 2. The 118A>G SNP significantly increased the values of EC50 by a factor of more than 2 (non-mutated: EC50,morphine=30 nmol/l, EC50,M6G=750 nmol/l, 118G carriers: EC50,morphine=66 nmol/l, EC50,M6G=1650 nmol/l), whereas the IVS2-691C>G SNP had no effect. Based on morphine and M6G, the present analysis encourages focusing on the 118A>G SNP when investigating the role of OPRM1 mutations for the activity of opioid analgesics. Other OPRM1 mutations are probably less important either owing to low allelic frequency or due to poor indications for functional consequences. This applies to opioid potency in the context of opioid therapy but not to pain processing or substance addiction, in which opioid receptors are involved but other or additional OPRM1 mutations may be important.

Alleles↗
PubMed2004

Predicting treatment response in non-Hodgkin's lymphoma from the pretreatment tumor content of phosphoethanolamine plus phosphocholine.

RATIONALE AND OBJECTIVES: Phosphoethanolamine and phosphocholine, shown to be elevated in tumors and possibly related to apoptotic signaling, have the potential to be prognostic variables of cancer treatment. MATERIALS AND METHODS: The sum of phosphoethanolamine and phosphocholine normalized by nucleotide-triphosphates was determined in tumors of non-Hodgkin's lymphoma (NHL) patients via in vivo 31P MR spectroscopy. RESULTS: The normalized sum of phosphoethanolamine and phosphocholine showed significant differences in tumors of patients who had a complete response to treatment against those who did not (t-test: 1.45 +/- 0.15, mean +/- standard error, n = 10 vs. 2.28 +/- 0.15, n = 17, P < .001; Fisher test: P < .04; sensitivity and specificity approximately equal to 70%). This parameter also showed significant differences among treatment responses in the previously untreated and aggressive subgroups and in the low and low-intermediate-risk subgroups determined by the international prognostic index (IPI). Further, distinctly different treatment response cutoffs for the parameter were found in different risk groups. When these risk-dependent cutoffs were used, the Fisher test of the whole group improved (P < .0002, sensitivity 80%, specificity 94%). The normalized sum of phosphoethanolamine and phosphocholine and the IPI were better predictor covariates for time to treatment failure when fitted interactively in a Cox regression (P < .0003) than when fitted independently. When time to treatment failure was used as a surrogate of survival in Kaplan-Meier analysis, the interaction of both covariates segregated the cases significantly (P < .008). There was no significance with each covariate independently. CONCLUSION: The normalized sum of phosphoethanolamine and phosphocholine measured before treatment successfully predicts long-term response to treatment and time to treatment failure in non-Hodgkin's lymphoma, particularly when combined with the IPI.

Chi-Square Distribution↗
PubMedDate not supplied

Quantitative assessment and repeatability of chlorine in exhaled breath condensate.

BACKGROUND: Airway condition is presumably reflected in epithelial lining fluid (ELF). Exhaled breath condensate (EBC) has been used as a surrogate marker of the composition of ELF. OBJECTIVES: This study aimed at assessing the technical repeatability of chlorine measurements in EBC and comparing two separate condensators (Ecoscreen and R Tube regarding recovery and repeatability. Furthermore, the association between condensate recoveries and variations in the airway status were scrutinized. METHODS: EBC was collected using two condensators from 10 healthy volunteers. In addition, 13 asthmatic patients produced EBC with or without an added resistance of 5 cm H2O (Res5), applied to the outflow tract of Ecoscreen. All tests were done in random order. Chlorine levels (analyzed by a coulometric technique) in EBC served as a tool for investigation. RESULTS: Chlorine was measurable in all samples. The coefficient of repeatability of chlorine measurements was <10%. Chlorine levels were higher in EBC obtained from R Tube (p < 0.001), and differences in recoveries and variability in chlorine levels were presumably related to technical differences in the condensators and not to the repeatability of chlorine measurements per se. Air-flow-dependent chlorine levels were obtained from healthy volunteers. Application of Res5, recruiting additional alveoli, resulted in increased recovery of the EBC volume, but not of chlorine, from those that had the most pronounced airway obstruction (p = 0.05). CONCLUSION: We conclude that by employing a sensitive analysis technique, chlorine is repeatedly measurable in EBC. We suggest that the bulk of chlorine in EBC originates from large airways and not from the alveolar area. Both condensators were comparable regarding repeatability but differed regarding chlorine recovery.

Adult↗
PubMed2004

PENTA guidelines for the use of antiretroviral therapy, 2004.

There have been few major advances in paediatric HIV management over the last 2 years. Decisions about starting antiretroviral therapy can now be based on a recent large meta-analysis of the predictive value of CD4 and HIV RNA viral load (VL) in nearly 4000 untreated children, which is discussed in these updated guidelines. Risk estimates for progression to AIDS and death using surrogate markers can now be broken down by age, allowing more accurate discussion with families. In addition, there is increasing recognition of the problems of long-term adherence, drug resistance and cumulative toxicity in adults and children. The controversy over whether to treat asymptomatic infants continues. For older children more data on the efficacy of ritonavir boosted protease inhibitor (PI) regimens suggests that these may be the PI option of first choice. There is still no adult or paediatric trial evidence on which to base decisions about whether to start with PI- or non-nucleoside reverse transcriptase inhibitor (NNRTI)- based regimens, but the PENPACT 1 trial, which is addressing this question, is ongoing. There are increasing moves to provide simpler antiretroviral therapy (ART) regimens, including once daily dosing, but these lag behind adult regimens because of the paucity of pharmacokinetic data. Resistance assays should now be performed in all HIV-infected infants exposed to ART in pregnancy. Therapeutic drug monitoring may be very important in children because of high between- and within-child variability in drug absorption and metabolism. A trial to evaluate this should start shortly in Europe (PENTA 14 trial). The value of resistance tests for choice of second-line and subsequent choices of ART regimens remain unproven (the PERA trial will report late in 2004), but resistance assays are increasingly being used. The issue of when to switch therapy also remains unanswered and is being addressed within the PENPACT 1 trial. Regular formal assessment of adherence is now the standard of care, and routine monitoring in the clinic for lipodystrophy syndrome (LDS) and other ART toxicities is increasingly important. These guidelines will be updated again in 2006.

Anti-HIV Agents↗
PubMed1998

Longitudinal cohort analysis of lethal prostate cancer progression in transgenic mice.

PURPOSE: Human prostate cancer is variably lethal, shows heterogeneous progression, and exhibits a spectrum of histopathology. Traditional rodent models of prostate cancer lack these characteristics. An alternative, autochthonous model of prostate cancer consists of transgenic mice which develop prostate cancer due to prostatic expression of SV40 T antigen. Lethal progression of such cancers in individual mice has not been previously characterized. Studies were undertaken to characterize the longitudinal progression of prostate cancers in these transgenic mice. METHODS: A prospective longitudinal cohort study was undertaken to characterize prostate cancer volume, progression, lethality, and histological heterogeneity in a transgenic mouse model of prostatic adenocarcinoma. Fifty-one transgenic mice were followed prospectively to determine the age at onset of palpable tumor and age at cancer-related death. Tumor volume was followed longitudinally by magnetic resonance imaging (MRI) in a subset of these mice and lethal cancers were evaluated by histopathology. RESULTS: Primary tumors became palpable at 10-38 weeks of age. Palpable tumors always preceded lethal progression. Cancer death followed 2-9 weeks later, and age at cancer death varied from 24 to 39 weeks of age. The histopathological changes were heterogeneous. Primary tumors were detectable by MRI before they became detectable by palpation. MRI showed that, analogous to human prostate cancers, volume of early stage primary tumors did not necessarily predict age at cancer death. CONCLUSION: Prostate cancer in transgenic mice mimics heterogeneic tumor progression in human prostate cancer, providing a uniquely relevant pre-clinical model. Tumor detection by MRI and palpation are valid surrogate measures of tumor progression in this model.

Animals↗
PubMed1999

The reproducibility of central aortic blood pressure measurements in healthy subjects using applanation tonometry and sphygmocardiography.

AIM: Sphygmocardiography via applanation tonometry is a non-invasive, bedside technology which utilises tonometric analysis of the radial artery pulse wave and measurement of peripheral arterial blood pressure (BP) to derive a central arterial pulse wave, central arterial BP and related indices. The present study was designed to determine: (1) the inter-operator variability in measurements obtained using this technique; (2) the relationship between measured peripheral arterial BP and derived central arterial BP. METHOD: Multiple measurements were made from 25 healthy subjects (15 male), mean age 33 (s.d. 10.3) years, mean arterial BP 90 (s.d. 12) mm Hg by two trained observers at the same time of day on three separate occasions. RESULTS: The mean inter-operator difference was 0.1 (s.d. 1.7) mm Hg for derived systolic aortic BP and 0.1 (s.d. 0.7) mm Hg for derived diastolic aortic BP (Bland and Altman analysis). Pulse wave Augmentation Index (AIx) values, ranged from -22% to +40%, with the inter-operator measurement difference being only 0.4 (s.d. 6.4)%. Buckberg ratio measurements ranged from 119% to 254%, with the inter-operator measurement difference being only 2.7 (s.d. 15.4)%. The relationship between derived central systolic BP and peripheral systolic BP readings in individual patients was not constant and showed significant variance when compared on different days (ANOVA, P = 0.03). This was not explained by any significant variance in heart rate (ANOVA, P = 0.39). CONCLUSION: Applanation tonometry has excellent inter-observer reproducibility when used by trained observers. Moreover, the inconsistency in the relationship between peripheral and central aortic BP suggests that the former is not a perfect surrogate for the latter. Further prospective studies are required to define whether derived central aortic BP may be a better predictor of cardiovascular morbidity and mortality and the impact of different antihypertensive therapies on the relationship between peripheral and central arterial BP.

Adult↗
PubMed2005

Clinical and radiographic correlates of primary and reactivation tuberculosis: a molecular epidemiology study.

CONTEXT: The traditional teaching that pulmonary tuberculosis characterized by lymphadenopathy, effusions, and lower or mid lung zone infiltrates on chest radiography represents "primary" disease from recently acquired infection, whereas upper lobe infiltrates and cavities represent secondary or reactivation disease acquired in the more distant past, is not based on well-established clinical evidence. Furthermore, it is not known whether the atypical radiograph common in human immunodeficiency virus (HIV)-associated tuberculosis is due to a preponderance of primary progressive disease or altered immunity. OBJECTIVE: To analyze the relationship between recently acquired and remotely acquired pulmonary tuberculosis, clinical and demographic variables, and radiographic features by using molecular fingerprinting and conventional epidemiology. DESIGN, SETTING, AND POPULATION: A retrospective, hospital-based series of 456 patients treated at a New York City medical center between 1990 and 1999. Eligible patients had to have had at least 1 positive respiratory culture for Mycobacterium tuberculosis and available radiographic data. MAIN OUTCOME MEASURES: Radiographic appearance as measured by the presence or absence of 6 features: upper lobe infiltrate, cavitary lesion, adenopathy, effusions, lower or mid lung zone infiltrate, and miliary pattern. Radiographs were considered typical if they had an upper lobe infiltrate or cavity whether or not other features were present. Atypical radiographs were those that had adenopathy, effusion, or mid lower lung zone infiltrates or had none of the above features. RESULTS: Human immunodeficiency virus infection was most commonly associated with an atypical radiographic appearance on chest radiograph with an odds ratio of 0.20 (95% confidence interval, 0.13-0.31). Although a clustered fingerprint, representing recently acquired disease, was associated with typical radiograph in univariate analysis (odds ratio, 0.68; 95% confidence interval, 0.47-0.99), the association was lost when adjusted for HIV status. CONCLUSIONS: Time from acquisition of infection to development of clinical disease does not reliably predict the radiographic appearance of tuberculosis. Human immunodeficiency virus status, a probable surrogate for the integrity of the host immune response, is the only independent predictor of radiographic appearance. The altered radiographic appearance of pulmonary tuberculosis in HIV is due to altered immunity rather than recent acquisition of infection and progression to active disease.

AIDS-Related Opportunistic Infections↗
PubMed2003

White blood cells as a novel mortality predictor in haemodialysis patients.

BACKGROUND: Many conventional cardiovascular risk factors in the general population are not as predictive in end-stage renal disease (ESRD). As absolute neutrophil count and total white blood cell (WBC) count are associated with adverse cardiovascular outcomes and all-cause mortality, this analysis was undertaken to explore the associations of WBC variables with mortality risk in ESRD. METHODS: Of a total study population of 44 114 ESRD patients receiving haemodialysis during 1998 at facilities operated by Fresenius Medical Care, North America, 25 661 patients who underwent differential white cell count and had complete follow-up were included. Information on case mix (age, gender, race), clinical (diabetes, body mass index), and laboratory variables (haematocrit, albumin, creatinine, potassium, calcium, phosphorus, bicarbonate, ferritin, transferrin saturation and differential WBC count) was obtained. Associations between lymphocyte count, neutrophil count and demographic and clinical variables were examined using linear regression. Associations between WBC variables and survival were estimated using Cox proportional hazard regression. RESULTS: A higher lymphocyte count was associated with higher serum albumin and creatinine, lower age and black race. High neutrophil count was associated with lower serum albumin and creatinine, younger age and white race (all Ps <0.0001). Cox proportional hazard regression showed an increased lymphocyte count was associated with reduced mortality risk [HR 0.86 (0.83-0.89) per 500/ml increase in lymphocyte count] and an increased neutrophil count was associated with increased mortality risk [HR 1.08 (1.06-1.09) per 1000/ml increase in neutrophil count]. CONCLUSIONS: An increased neutrophil count is strongly associated with, and reduced lymphocyte count associated less strongly with, many surrogates of both malnutrition and inflammation. An increased neutrophil count and reduced lymphocyte count are independent predictors of increased mortality risk in haemodialysis patients.

Adult↗
PubMed2003

Measuring hospital quality: can medicare data substitute for all-payer data?

OBJECTIVES: To assess whether adverse outcomes in Medicare patients can be used as a surrogate for measures from all patients in quality-of-care research using administrative datasets. DATA SOURCES: Patient discharge abstracts from state data systems for 799 hospitals in 11 states. National MedPAR discharge data for Medicare patients from 3,357 hospitals. State hospital staffing surveys or financial reports. American Hospital Association Annual Survey. STUDY DESIGN: We calculate rates for 10 adverse patient outcomes, examine the correlation between all-patient and Medicare rates, and conduct negative binomial regressions of counts of adverse outcomes on expected counts, hospital nurse staffing, and other variables to compare results using all-patient and Medicare patient data. DATA COLLECTION/EXTRACTION: Coding rules were established for eight adverse outcomes applicable to medical and surgical patients plus two outcomes applicable only to surgical patients. The presence of these outcomes was coded for 3 samples: all patients in the 11-state sample, Medicare patients in the 11-state sample, and Medicare patients in the national Medicare MedPAR sample. Logistic regression models were used to construct estimates of expected counts of the outcomes for each hospital. Variables for teaching, metropolitan status, and bed size were obtained from the AHA Annual Survey. PRINCIPAL FINDINGS: For medical patients, Medicare rates were consistently higher than all-patient rates, but the two were highly correlated. Results from regression analysis were consistent across the 11-state all-patient, 11-state Medicare, and national Medicare samples. For surgery patients, Medicare rates were generally higher than all-patient rates, but correlations of Medicare and all-patient rates were lower, and regression results less consistent. CONCLUSIONS: Analyses of quality of care for medical patients using Medicare-only and all-patient data are likely to have similar findings. Measures applied to surgery patients must be used with more caution, as those tested only in Medicare patients may not provide results comparable to those from all-patient samples or across different samples of Medicare patients.

Aged↗
PubMed1992

Comparative effects of posture on pressure and shear at the body-seat interface.

This study considers the effects of seated posture and body orientation on the pressure-distribution and surface shear (tangential) forces acting at the body-seat interface. Nine postures typically assumed by wheel-chair users were studied. Comparisons were made within and between two study groups, made up of 12 subjects with spinal cord injuries (SCI) and 10 nondisabled subjects. Both interface pressure and the surface shear were measured simultaneously in each of nine reproducible, seated postures. The same seat cushion was used for all trials. The Oxford Pressure Monitor, a pneumatic cell device, was used to measure and record the interface pressures. Instrumentation for measuring and recording the surface shear force was constructed specifically for the study. Analysis consisted of statistically comparing changes in pressure values and shear forces derived from eight sitting postures with reference to values recorded in a defined neutral sitting posture. The pressure-distribution findings suggest that in the postures studied SCI subjects have maximum pressures that are higher than nondisabled subjects in all postures, ranging from 6% to 46% depending on the posture. Maximum pressures can be reduced by postural changes: forward flexion to 50 degrees, -9%; backrest recline to 120 degrees, -12%; and, full body tilt, -11%. On average, the SCI group members have peak pressure gradients (PPG) that are 1.5 to 2.5 greater than the nondisabled group. The maximum reduction in PPG occurred at backrest recline of 120 degrees, -18%. Tangential shear force acts at the body-seat interface in all nine postures studied. Extrapolation of results suggests that full-body tilt to approximately 25 degrees reduces the surface shear force to near zero. In contrast, a backrest-only recline of 20 degrees causes a 25% increase in the surface shear force. These results suggest that caution must be taken when using nondisabled subjects as surrogates for people with SCI because of the inherent differences between the groups. Also, researchers and clinicians should recognize that posture and body orientation in space are additional variables that can have a profound effect on the interaction between a seated person and his or her supporting surface.

Adult↗
PubMed2001

Proof of principle trials: EEG surrogate endpoints.

Pivotal studies in man require prolonged administration to demonstrate efficacy for most seizure types. Earlier evidence of human efficacy can be of value for decision making, and EEG surrogate endpoints can be of value in this respect. Studies of spontaneous EEG discharges under standard recording conditions can demonstrate meaningful acute EEG effects of antiepileptic drugs (AEDs). These require a rapidly effective formulation of the product, preferably intravenous. The EEG recording conditions are standardised and the subject is required to perform a task to maintain a constant level of vigilance. The outcome measure of efficacy is spike count per minute or, if the discharges are more protracted (as generalised no spike and wave), the percentage of recording time occupied by discharges. Sub-acute experiments are conducted under less rigorously standardised conditions, but over longer periods, using ambulatory monitoring or telemetry to record the EEG. The photoparoxysmal responses (PPRs) of photosensitive subjects, evoked using a standardised stimulation protocol, are subject to less variability than spontaneous epileptiform activity. The PPR is elicited over a range of flash rates that can be used as a measure of sensitivity, and an effective treatment will reduce the range or abolish the PPR. Reduction in photosensitivity is demonstrable after a single dose of various AEDs, at clinically relevant plasma concentrations, even using drugs that are not generally effective for long-term treatment of photosensitive epilepsy. Evoked potential and nerve conduction studies and electronystagmography can be used to assess possible neurotoxicity, and quantitative EEG analysis can be employed to assess sedative effects.

Animals↗
PubMed2000

Activation (tyrosine phosphorylation) of ErbB-2 (HER-2/neu): a study of incidence and correlation with outcome in breast cancer.

PURPOSE: We hypothesize that phosphorylated ErbB-2 (P-ErbB-2, identified by a novel antibody PN2A) may provide either more significant or additional prognostic marker data for breast cancer patients. This study was designed to compare the incidence and prognostic value of ErbB-2 (HER-2/neu) and P-ErbB-2 immunoexpression in archival breast cancer samples. MATERIALS AND METHODS: Eight hundred sixteen invasive breast cancers with a median of 16.3 years of follow-up were immunostained for ErbB-2 (using antibody CB11) and P-ErbB-2 (using antibody PN2A). ErbB-2 and P-ErbB-2 data were compared with clinical, histologic, immunohistochemical, and outcome variables. RESULTS: Of 816 primary breast cancers, 307 (38%) were positive for ErbB-2 and 37 (12% of ErbB-2 positive and 5% of the study population) expressed P-ErbB-2. P-ErbB-2 was not detected in ErbB-2-negative cases (n = 509). ErbB-2 immunohistochemical data were bimodal; patients with > or = 80% cellular expression had the shortest disease-free and disease-specific survival. P-ErbB-2 was associated with a higher percentage of ErbB-2-positive cells, a higher number of positive lymph nodes, and cellular proliferation. ErbB-2 and P-ErbB-2 were indicators of poor prognosis in node-positive patients in both univariate and multivariate analyses. We found that either P-ErbB-2 expression or high (> or = 80%) ErbB-2 expression provided the most significant prognostic value in node-positive cases by multivariate analyses. There were too few P-ErbB-2-positive cases and events in the node-negative patient group to allow statistical analysis of P-ErbB-2 in that subgroup. CONCLUSION: PN2A immunostaining identified a subset (approximately 12% of ErbB-2-positive breast cancers) with activation (phosphorylation) of the receptor ErbB-2. P-ErbB-2 expression was strongly associated with higher levels of ErbB-2 expression (> or = 80%), although it was not a surrogate. Identification of cases with a high percentage of invasive breast cancer cells expressing ErbB-2 or determination of receptor activation via P-ErbB-2 may provide additional prognostic value in node-positive breast cancers.

Adult↗
PubMed2005

Predictors of noncompliance with warfarin therapy in an outpatient anticoagulation clinic.

STUDY OBJECTIVES: To test variables associated with the Health Belief Model, the Patient Satisfaction Model, and patient demographics in predicting compliance with warfarin therapy. DESIGN: Descriptive study using chart and pharmacy database review as well as patient questionnaires. SETTING: Outpatient anticoagulation clinic in an academic medical center. PATIENTS: Seventy-five patients who had received warfarin therapy over the previous 6 months. MEASUREMENTS AND MAIN RESULTS: Clinicians interviewed patients using a subscale of the Beliefs About Anticoagulation Survey and a Patient Satisfaction Model. Perceived barriers to compliance with warfarin therapy and marital status explained 21.7% of the variance in calculations of refill adherence (p<0.001). Compliance with warfarin therapy was assessed using a validated compliance self-report survey and outpatient pharmacy dispensing data. Perceived barriers and current living conditions explained 33.2% of the variance in self-reported noncompliance (p<0.001). Logistic regression analysis, conducted to attempt to predict patients with an 80% refill adherence threshold, correctly classified compliance 85.3% of the time. CONCLUSION: This investigation provided some insight into the factors predictive of noncompliance in a low-income, outpatient population. Perceived barriers, marital status, living arrangements, and drug regimen played significant roles in warfarin noncompliance. Our results provide more evidence supporting the use of refill adherence and patient self-report as measures of noncompliance. This linkage helps validate compliance as a useful surrogate of patient health outcomes. This study also offers a model that can help clinicians identify patients at significant risk of noncompliant behavior.

Anticoagulants↗
PubMed2005

Identification of outcome predictors in diffuse large B-cell lymphoma. Immunohistochemical profiling of homogeneously treated de novo tumors with nodal presentation on tissue micro-arrays.

BACKGROUND AND OBJECTIVES: Patients with diffuse large B-cell lymphoma (DLBCL) could benefit from integration of well-established bioclinical prognostic factors with new tools - such as micro-arrays - exploring aberrant gene and/or protein expression. DESIGN AND METHODS: Tissue micro-arrays (TMA) were constructed for the paraffin blocks of 68 patients with de novo DLBCL with nodal presentation, who underwent MACOP-B and were provided with complete clinical information. TMA were tested with specific antibodies against CD10, CD20, CD30, CD79a, CD138, Bcl-2, Bcl-6, IRF4, and IRTA1. RESULTS: The following phenotypic subclassification was made: a) CD10 +/Bcl-6 + or Bcl-6+/IRF4 +, but Bcl-2-/CD30-/CD138-- suggesting B-cells gathering/leaving the germinal center (group 1; n=36); b) Bcl-2+/CD10-/Bcl-6- and CD30+ or CD138+ corresponding to putative non-germinal center B-cells with features of activation or plasmablastic/plasmacellular differentiation (group 2; n=17); c) CD30-/CD138- with extensive Bcl-2 positivity and variable CD10, Bcl-6 and IRF4 combinations (group 3; n=15). Mean IPI scores were 0.6, 1.9 and 1.1 for groups 1, 2 and 3, respectively (p= 0.001). Complete remission (CR) rates were 89%, 53% and 73% (p= 0.015). The 3-year relapse-free survival (RFS) rates are 86%, 41% and 63% (p=0.001) and 42-month overall survival (OS) rates are 91%, 38% and 66% (p=0.0002). INTERPRETATION AND CONCLUSIONS: The present TMA-based study suggests an immunophenotypic profiling system for patients with de novo DLBCL that seems to provide additional prognostic information and contributes to the existing debate on the identification of suitable immunohistochemical surrogates of gene expression profiling results.

Adult↗