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Dollars and sense: a practical guide to cost analysis for hospital epidemiology and infection control.

This paper explains practical approaches for collecting inpatient cost data for cost-of-illness and cost-effectiveness analyses. The economic definition of cost of an item is the value of the resources that are consumed in its production. Cost analysis should collect the resources hypothesized to be affected by the illness or intervention. The dollar value of these resources can also be estimated. Diagnosis-related group (DRG) reimbursements are not helpful when all study patients have the same DRG or when no DRG exists (e.g., nosocomial infection). Hospital charges are not a good surrogate for costs. Hence, data needed include resources used, charges, and cost-to-charge ratios, so that cost can be estimated. Resources used can be obtained from hospital information systems. For some resource use (e.g., physician services, pharmacy, and intravenous fluids), charges or cost-to-charge ratios may not be available, and an external standard may be needed to estimate the dollar value. For many types of resources, hospital financial systems provide both charges and cost-to-charge ratios. This yields an estimate of average cost (total cost divided by patient days) when marginal cost (change in variable cost per day of patient stay) is a better estimate of the value of the resources consumed. However, cost-to-charge ratios remain the only practical way of estimating cost in many circumstances and are commonly used in economic studies. Cost-of-illness estimates vary among the various nonrandomized study designs used. "Real-world" randomized trials are potentially useful to obtain advantages of randomization but avoid the protocol-induced biases of traditional double-blind controlled trials.

Cost of Illness↗

Diabetes susceptibility at IDDM2 cannot be positively mapped to the VNTR locus of the insulin gene.

An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5' of the INS locus. Patients and control subjects were genotyped at INS/+ 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS/ + 1140 allele '+' were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele '+' (53 vs 31%, p < 0.001) giving an odds ratio of 2.6 (95%CI 1.6-4.2). By multilocus analysis, the TH/RsaI allele '+' identified a subset of INS/ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95%CI 2.9-10.4) than allele + 1140 '+' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.

Adult↗

Is a history of tonsillectomy associated with a decreased risk of Helicobacter pylori infection?

To determine the relation between a history of tonsillectomy and the prevalence of colonization by Helicobacter pylori (HP), we conducted an observational, cohort study at the University of Oklahoma Hospital over a 13-month period. Subjects under-going upper endoscopic evaluation and antral biopsies for HP at the University of Oklahoma Hospital formed the database. The indication of the endoscopy and biopsies was determined by the endoscopist. The antral biopsy specimens were tested for HP using a rapid urease test. We recorded the patient's name, age, gender, race, history of smoking, and history of appendectomy or tonsillectomy. One hundred nine subjects constituted our database. There was no difference in age, gender, or smoking between the HP+ (n = 37) and HP- (n = 72) groups. The ability to pay for healthcare through a third-payor party also was similar. The prevalence of prior tonsillectomy was 30.6% in HP- group versus 5.4% in HP+ group (p < 0.01). In contrast, the prevalence of prior appendectomy was 21.6% in HP+ group versus 23.6% in HP- group (p = not significant). Multiple regression was carried out to account for confounding variables. The model showed that only white race and tonsillectomy were significantly related to the presence of HP colonization. Both appendectomy and health insurance, which were the surrogate markers for access to healthcare and socioeconomic status, were insignificant. We conclude that a history of tonsillectomy is associated with decreased prevalence of HP colonization.

Appendectomy↗

Non-linear dynamics and chaotic indices in heart rate variability of normal subjects and heart-transplanted patients.

OBJECTIVES: Heart rate variability (HRV) is characterised by a variety of linear, non-linear, periodical and non-periodical oscillations. The aim of the present study was mainly to investigate the role played by neural mechanisms in determining non-linear and non-periodical components. METHODS: Analysis was performed in 7 recently heart transplanted patients and in 7 controls of similar age whose HRV signal was collected during 24 h. Parameters that quantify non-linear dynamic behaviour, in a time series, were calculated. We first assessed the specific non-linear nature of the time series by a test on surrogate data after Fourier phase randomization. Furthermore, the D2 correlation dimension, K2 Kolmogorov entropy, and H self-similarity exponent of the signal were estimated. From this last parameter, the dimension D = 1/H can be obtained. In order to assess whether the dynamics of the system are compatible with chaotic characteristics, the entire spectrum of Lyapunov exponents was calculated. We used return maps to graphically represent the non-linear and non-periodical behaviours in patients and controls. RESULTS: Surrogate data suggest that the HRV time courses have unique non-linear characteristics. D2, K2 and 1/H parameters were significantly lower in transplanted subjects than in controls. Positivity of the first Lyapunov exponent indicates divergence of trajectories in state-space. Furthermore, the display of return maps on projections obtained after Singular Value Decomposition, especially in low-complexity data (as in transplanted patients), shows a structure which is suggestive of a strange attractor. These findings support the hypothesis that chaotic dynamics underlie HRV. CONCLUSION: These results indicate that non-linear dynamics are likely to be present in HRV control mechanisms, giving rise to complex and qualitatively different behaviours. System complexity decreases in transplanted patients and this may be related to loss of the neural modulation of heart rate.

Adult↗

Differences between carotid wall morphological phenotypes measured by ultrasound in one, two and three dimensions.

Ultrasound measurements are both surrogate markers and risk factors for atherosclerosis end points. Carotid intima-media thickness (IMT) is most commonly used, but ultrasound can also define structures in higher spatial dimensions, such as total plaque area (TPA) and total plaque volume (TPV). Because there are minimal data regarding the relationship between IMT, TPA and TPV, we measured these variables in 272 Oji-Cree subjects. We found pairwise correlations for IMT:TPA, IMT:TPV and TPA:TPV of 0.507, 0.588 and 0.846, respectively (transformed variables, all P <0.0001). In a subset of 168 subjects with complete cardiovascular risk factor data, we performed multivariate regression analysis to identify sources of variation for IMT, TPA and TPV. We found that the ultrasound traits showed different correlations with individual cardiovascular risk factors. In particular, IMT was significantly associated with hypertension, TPA with smoking and plasma cholesterol, and TPV with diabetes. Therefore, these ultrasound measures of carotid artery morphology, while somewhat correlated, likely represent distinctive quantitative traits with different biological determinants, as underscored by different risk factor associations in the multivariate regression analysis. Because the measurements have different implications and determinants, investigators might need to be selective about the particular measurements they choose for specific applications.

Adult↗

Biomarkers and surrogate endpoints in renal transplantation: present status and considerations for clinical trial design.

Of major importance in clinical trials is the ability to predict individual patient outcome or endpoints using biomarkers, also known as variables or predictors, in as safe, efficient, and accurate a manner as possible. This review addresses the concepts and possible strategies for use of predictor and surrogate biomarkers in the design of clinical trials in renal transplantation. The statistical concepts apply equally well to other organ grafts.

Biomarkers↗

Recreational drugs: relationship to AIDS.

Current data suggest that a transmissible agent causes AIDS, but undefined cofactors may also play a role. This paper reviews published data on the relationship between recreational drugs and immune alterations, with particular emphasis on nitrite inhalant (NI) use by homosexual men. In our original cohort of 15 homosexual men, helper:suppressor (H:S) T-cell ratios are stable, but persistently lower in the NI users. A recent analysis of 245 homosexual men shows that NI use is associated with low H:S ratios in homosexual men in Washington, D.C., but not in New York. Although NI use could increase the risk of AIDS by direct or indirect effects, it could also be a surrogate for a lifestyle practice that predisposes homosexual men to the putative AIDS agent. The current evidence concerning use of NI and the risk of AIDS is inconclusive, as is true for two other recreational drugs, heroin and cocaine. Future studies may not be able to dissect the complex interrelationships of drug use and other variables until precise laboratory tests are available for defining exposure to the putative AIDS agent and suspect cofactors.

Acquired Immunodeficiency Syndrome↗

1H-MRS quantification of tNA and tCr in patients with multiple sclerosis: a meta-analytic review.

Meta-analysis was performed on the results of 75 comparisons from the 30 peer-reviewed publications that used proton magnetic resonance spectroscopy (1H-MRS) or spectroscopic imaging to (i) quantify the mean concentrations of total creatine (tCr, found in neurons, astrocytes and oligodendrocytes), and/or total N-acetyl groups (tNA, found only in neurons), in the lesional and/or non-lesional white matter (WM) and/or the grey matter (GM) of patients with multiple sclerosis (MS) and (ii) compare these values with those in the homologous tissues of normal controls (NC). For mean [tNA] values, there was (i) a large-effect-sized overall decrease in patients' lesional WM relative to NC WM (25 comparisons), (ii) a medium-effect-sized overall decrease in patients' non-lesional WM relative to NC WM (36 comparisons) and (iii) a medium-effect-sized overall decrease in patients' GM relative to NC GM (14 comparisons). Patients' mean [tNA] values were sometimes statistically normal but were never statistically increased. For mean [tCr] values, there was (i) no statistically significant overall change in the patients' lesional WM relative to NC WM (24 comparisons), although statistically significant increases and decreases were sometimes found, (ii) a medium-effect-sized overall increase in patients' non-lesional WM relative to NC WM (33 comparisons) and (iii) no statistically significant overall change in patients' GM relative to NC GM (12 comparisons), although a significant decrease was found in one comparison. Of 41 comparisons with statistically significant changes, 38 combined in a way that would probably result in decreased mean [tNA]/[tCr] ratios such that (i) 66% had statistically decreased mean [tNA] and statistically unchanged mean [tCr] values, (ii) 13% had statistically decreased mean [tNA] and statistically increased mean [tCr] values and (iii) 21% had statistically unchanged mean [tNA] values and statistically increased mean [tCr] values. Of the 25 comparisons that came from studies that also analysed [tNA]/[tCr] ratios, the direction of change in mean [tNA] values and mean [tNA]/[tCr] ratios was concordant in 84%. In comparisons that quantified both [tNA] and [tCr], there was a similar amount of variability in both measures in each of the different tissue types studied, both in patients and NCs. Together, these results suggest that within-voxel tNA/tCr ratios can be interpreted as valid and accurate surrogate measures of 'cerebral tissue integrity'-with decreased tNA/tCr ratios indicating some combination of neuroaxonal disturbance, oligodendroglial disturbance, and astrocytic proliferation. These results also suggest that, although within-voxel tNA/tCr ratios are not perfect indicators of [tNA] content, they do represent a practical compromise to acquiring surrogate measures of within-voxel neuroaxonal integrity.

Aspartic Acid↗

C-reactive protein and dietary nutrients in urban Asian Indian adolescents and young adults.

OBJECTIVE: The relationship between C-reactive protein (CRP), a surrogate marker of cardiovascular risk, and dietary nutrients is not known. We investigated the relationship between serum CRP levels and dietary nutrients in young Asian Indians residing in a major metropolitan city in north India. METHODS: Dietary nutrient intake values (24-h dietary recall and monthly consumption data) and serum CRP levels were studied in 359 healthy adolescents and young adults (312 male and 47 female) (mean age, 18.0 +/- 2.3 y; range, 14-25 y), after carefully excluding those with history of infections and smoking. Bivariate and multivariate logistic regression analysis was performed with CRP [raised (>3.0 mg/L)/normal] as the outcome variable and various dietary nutrients and anthropometric variables as covariates. RESULTS: Mean CRP level was 1.3 +/- 2.3 mg/L (range, 0.02-17.5 mg/L). Raised CRP levels (>3 mg/L) were noted in 9% study subjects (8.6% males and 12.8% females). After adjustment for other covariates, saturated fat emerged as the single most important nutrient contributing to increase in serum CRP levels. The odds of having a raised CRP level in subjects consuming more than 10% energy as saturated dietary fat were twice as compared to subjects having a normal saturated fat intake [Adjusted odds ratio (OR) (95% CI) = 2.0 (0.94-4.1)]. For every one percent decrease in energy intake by saturated fat, CRP level was calculated to decrease by 0.14 mg/L. For decreasing CRP levels to <1.0 mg/L (low risk for cardiovascular disease), Asian Indian adolescents and young adults should ensure saturated fat intake <7% of caloric intake. CONCLUSION: We suggest that daily saturated fat intake should be limited to <7% of caloric intake in urban adolescents and young adult Asian Indians to decrease their future cardiovascular risk.

Adolescent↗

EEG spike and wave modelled by a stochastic limit cycle.

Many reports based upon correlation dimension studies have suggested the chaotic nature of electroencephalographic spike and wave activity (SW). Another study found no evidence for this, showing that surrogate stochastic data generated from SW have the same dynamical properties as the original data. The present paper explicitly models SW as the output of a non-linear stochastic system. Non-linear non-parametric kernel autoregression is used to show that the attractor of this system may be a limit cycle. The addition of system noise originates a simulated time series with the same interspike interval variability originally hypothesized as chaotic. Tests performed on the correlation dimension obtained from the original data as well as from both linear and non-linear surrogates show that the noise-perturbed limit cycle model achieves the best fit to the original data. We conclude that SW is likely to be a form of stochastic disturbed limit cycle behaviour rather than chaos.

Animals↗

Differential sensitivity of children and adults to chemical toxicity. II. Risk and regulation.

Animals can be useful predictors of chemical hazards to humans. Growth and development are compressed into a shorter period in animals, which makes interpretation of animal testing inherently more difficult. However, similar events occur in both humans and laboratory animals and testing that covers the full period of animal development can reasonably be considered an appropriate surrogate for human development. Some have proposed an additional 10-fold factor for the extra protection of children when estimating safe exposures. Use of such an additional factor, as required by the Food Quality Protection Act (FQPA), is meant to address the same issues covered by the EPA's database uncertainty factor, UF(D), and additional issues related to exposure uncertainty. Thus, when UF(D) has already been deployed, the EPA modifies its use of the FQPA factor. Based on our analysis, we agree with the EPA. Drawing conclusions about the adequacy of UF(H), the uncertainty factor used to account for intrahuman variability, in terms of its ability to protect children on the basis of the modest data available is challenging. However, virtually all studies available suggest that a high percentage of the population, including children, is protected by using a 10-fold uncertainty factor for human variability or by using a 3.16-fold factor each for toxicokinetic and toxicodynamic variability. Based on specific comparisons for newborns, infants, children, adults, and those with severe disease, the population protected is between 60 and 100%, with the studies in larger populations that include sensitive individuals suggesting that the value is closer to 100%.

Adolescent↗

Subclinical atherosclerosis in rheumatoid arthritis in India.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have high cardiovascular morbidity and mortality as compared to the general population. Indians are also at increased risk of developing early and severe atherosclerotic coronary artery disease. Carotid intima-media thickness as measured by ultrasound is a validated surrogate marker of atherosclerosis. We studied the prevalence of subclinical atherosclerosis in Indian patients with RA. METHODS: Common carotid IMT (CCA IMT) was measured at the level of carotid bifurcation along with fasting lipid profile in 57 RA patients and 45 age and sex matched controls. Values of mean CCA IMT above mean + 2 SD of the control group were defined as abnormal IMT. Variables of disease activity and severity were measured in RA patients. Patients and controls with known traditional cardiovascular risk factors were excluded from the study. Student t test and chi-square test for proportion were used for statistical analysis. A logistic regression analysis was done to find out independent predictors of abnormal IMT. RESULTS: Nineteen RA patients (33.3%) and 2 controls (4.44%) had abnormal IMT values. RA patients had significantly increased mean CCA IMT (0.558 +/- 0.137 mm) as compared to controls (0.416 +/- 0.002 mm; p < 0.0001). Age > or = 42 years, duration of disease > or= 6 years, and tender joint count > or = 5 predicted increased risk of having abnormal CCA IMT in a logistic regression analysis. CONCLUSION: One-third of Indian RA patients had subclinical atherosclerosis. Age and tender joint count were independent predictors of abnormal CCA IMT.

Adult↗

An assessment of peak expiratory flow as a surrogate measurement of FEV1 in stable asthmatic children.

We examined the relationship over 24 hours between percent-predicted values (PPV) of peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) in a group of 23 stable untreated asthmatic children 6 to 17 years of age by means of regression analysis as well as the percentage difference between the PPV of these two measurements. Although the Pearson correlation coefficient between the PPV was consistently high, ranging between 0.854 and 0.892, the assumption that such a finding substantiates the substitution of PEF for FEV1 is called into question. Over 50 percent of the subjects displayed a 10 percent or greater difference in the PPV between the two measurements, regardless of the time of day the two respiratory variable were determined, while over one-third of all subjects evidenced a 20 percent or greater discrepancy between the PPV of the two measures. While, on a group basis, there was no statistically significant difference in the mean percentage difference over 24 hours between the PPV of FEV1, when compared with the corresponding measurement of PEF, reliance on PEF alone in individual subjects may result in a false impression of the patency of the airways in comparison to the FEV1.

Adolescent↗

Matching based on quantitative coronary angiography as a surrogate for randomized studies: comparison between stent implantation and balloon angioplasty of native coronary artery lesions.

Although intracoronary stenting has been advocated as an adjunct to balloon angioplasty to circumvent late restenosis, its effectiveness has not yet been verified. Therefore the aim of this study was to determine the differences in the immediate and long-term changes in stenosis geometry between Wallstent implantation and balloon angioplasty in native coronary artery lesions. To obtain two study populations with identical baseline stenosis characteristics, patients were matched for lesion site, vessel size, and minimal luminal diameter. Only patients undergoing elective and successful coronary intervention of a native coronary artery, in whom a control angiographic study had been performed, were included. A total of 186 patients (93 in each group) were selected. The coronary angiograms were analyzed with the computer-assisted cardiovascular angiographic analysis system. Matching was considered adequate, since there was an equal number of lesion sites in each study population and there were no differences in baseline reference diameter and minimal luminal diameter. Wallstent implantation resulted in a significantly greater increase in minimal luminal diameter (from 1.22 +/- 0.34 mm to 2.49 +/- 0.40 mm, p < 0.00001) compared with balloon angioplasty (from 1.21 +/- 0.29 mm to 1.92 +/- 0.35 mm, p < 0.00001). Despite a greater decrease in minimal luminal diameter after Wallstent implantation (0.48 +/- 0.74 mm) than after balloon angioplasty (0.20 +/- 0.46 mm), the minimal luminal diameter at follow-up was significantly greater after stent implantation (2.01 +/- 0.75 mm vs 1.72 +/- 0.54, p < 0.0001). It was concluded that Wallstent implantation results in a superior immediate and long-term increase in minimal luminal diameter compared with balloon angioplasty. The larger initial gain after stent implantation compensates for the late loss, and thus an improved initial result and not lessened neointimal hyperplasia is responsible for a reduced incidence of restenosis. Studies based on matching of angiographic variables are a surrogate for randomized studies, forecasting their results and offering insight into the effects of different interventional techniques. Moreover, these studies yield statistical information that may be helpful for the proper design of a randomized study (sample size, type II error).

Angioplasty, Balloon, Coronary↗

The integrated use of pharmacokinetic and pharmacodynamic models for the definition of breakpoints.

For fluoroquinolones AUC/MIC ratios are known to correlate with clinical outcomes for patients suffering from respiratory tract infections (RTI) and complicated skin and skin structure infections (cSSSI). This paper describes the results of a population PK/PD analysis followed by Monte Carlo simulations to estimate clinical outcome and the microbiological breakpoints for a 400 mg once-daily moxifloxacin (MFX) treatment schedule. Based on PK data from 416 subjects, a non-compartmental population PK model was developed first to describe the expected exposure (AUC) distribution in humans. Height and gender were the main population covariates with moderate influence on PK variability. Albumin, bilirubin, and creatinine clearance (as derived from serum creatinine according to Cockroft and Gault) had a mild effect on AUC. Residual unexplained variability of AUC was low (13.1%). To describe the PD function the MIC distribution pattern of more than 3,000 isolates of S. pneumoniae as the representative pathogen for RTI (MIC90, range: 0.125; 0.006-4 mg/l) was built into the population PK/PD model for RTI, while 126 isolates of methicillin-susceptible Staphylococcus aureus strains (MIC90, range: 0.125; 0.03-4 mg/l) were the basis for the PD function in cSSSI. Simulations for 20,000 (RTI) and 4,000 (cSSSI) subjects were performed to evaluate the AUC/MIC characteristics for moxifloxacin for these two diseases. Overall, a target hit rate was THR = 99% for RTI, while it amounted to THR = 97.5% for cSSSI when applying a threshold of AUIC > 30 [h] as the PK/PD surrogate parameter which is predictive for a positive clinical outcome. A target hit rate of THR = 93.6 % (RTI) and 97.3% (cSSSI), respectively, was predicted when assuming that an AUIC of > 125 [h] is indicative of clinical success (as shown for ciprofloxacin and severe RTIs due to gram-negative infections). In clinical trials with patients receiving 400 mg moxifloxacin once daily for the treatment of community-acquired pneumonia (CAP) success rate was approximately 93.5%. From the simulations performed for RTI an analysis of the overall likelihood of therapeutic failure broken down according to MICs suggests that the risk of a negative clinical outcome at a MIC = 1 mg/l is approximately 0.25% (for MIC = 2 mg/l: predicted likelihood approximately 0.5%) assuming that a cutoff of AUIC = 30 [h] is applicable. Likewise, for cSSSI the probability to fail is predicted as 1.6% at a MIC = 2 mg/l (no strains with MICs between 0.5 and 1 mg/l available from the clinical isolates). These findings are in line with the breakpoint definition of the former National Committee for Clinical Laboratory Standards (NCCLS) for MFX (=1 mg/L to differentiate between susceptible and intermediately susceptible microorganisms; = 2 mg/l to separate intermediate from resistant pathogens). The results of the investigation indicate that the noncompartmental PK/PD model for MFX is suitable to predict clinical outcomes in CAP and cSSSI caused by gram-positive aerobe pathogens. They confirmed that a 400 mg once-daily dosing regimen is suitable to treat these diseases successfully. They are in agreement with the microbiological breakpoints determined by independent methods by the Clinical and Laboratory Standards Institute (CLSI) (former NCCLS).

Anti-Bacterial Agents↗

In microdissected ductal carcinoma in situ, HER-2/neu amplification, but not p53 mutation, is associated with high nuclear grade and comedo histology.

BACKGROUND: HER-2/neu and p53 are two molecular markers that have been the focus of investigation in patients with invasive breast carcinoma. However, most of the published data have relied on immunohistochemical detection of the proteins as a surrogate marker of the underlying genetic alterations, a detection method that often gives variable results due to technical factors. In addition, there are limited data documenting HER-2/neu amplification and p53 mutations in the various histologic subtypes of ductal carcinoma in situ (DCIS). The authors evaluated a series of microdissected, pure DCIS lesions comprising a spectrum of morphologic subtypes (comedo, micropapillary, papillary, cribriform, and solid) and their corresponding normal breast tissue for genetic aberrations in HER-2/neu and p53. METHODS: HER-2/neu amplification was determined by differential polymerase chain reaction, and p53 mutations were identified by single-strand conformation polymorphism analysis. RESULTS: HER-2/neu amplification was identified in 12 of 30 DCIS samples (40%), and p53 mutations were identified in 6 of 30 DCIS samples (20%). The genetic alterations were not present in any of the normal breast tissue samples. HER-2/neu amplification occurred predominantly in the comedo subtype (69% vs. 18% of the noncomedo subtype; P = 0.008) and in lesions of high nuclear grade (63% vs. 14% of low grade; P = 0.01). There was no difference in the frequency of p53 mutations among the subtypes or between low grade and high grade lesions. No correlation between the presence of the two genetic alterations was observed. CONCLUSIONS: The presence of HER-2/neu amplification, but not p53 mutations, correlates with histologic subtype and nuclear grade. The relatively frequent occurrence of HER-2/neu amplification and p53 mutations in DCIS tissue and their absence in normal breast tissue suggest that these genetic aberrations are important early in breast duct carcinogenesis.

Breast Neoplasms↗

Baroreflex stabilization of the double (pressure-rate) product at 0.05 Hz in conscious rabbits.

The product of heart rate (HR) and systolic blood pressure (SBP), the double product (DP), is an indirect index of cardiac oxygen consumption. We used spectral analysis to test the hypothesis that baroreflex adjustments of HR stabilize the DP during spontaneous variations in SBP. SBP and HR were recorded by telemetry in five male conscious rabbits. HR and SBP power spectra each exhibited a low frequency peak at approximately 0.05 Hz that was associated with high (>0.5) spectral coherence and a positive phase relationship between SBP and HR (SBP leading). A prominent peak was absent in the spectra of their product, suggesting that SBP and HR interacted to reduce DP variability in this frequency region. In contrast, a prominent 0.05-Hz peak was present in the power spectrum of calculated surrogates of the DP in which reflex interactions between HR and SBP had been removed. Our results suggest that baroreflex adjustments of HR stabilize the DP during spontaneous low-frequency variations in SBP in conscious rabbits.

Animals↗

Seizure-induced neuronal injury: human data.

Evidence that recurrent epileptic seizures may cause neuronal injury in some patients has been inferred from clinical observation, neuropsychological assessments, and neuroimaging studies. Cross-sectional investigations have yielded conflicting results and it is not possible to draw conclusions regarding causation, rather than merely association, from such designs. However, there is also evidence from in vivo biochemical studies that seizures may cause neuron injury. The heterogeneity of the epilepsies, epileptic seizures, co-morbidities, treatment regimens, and individual patient susceptibility all complicate the picture and inhibit the drawing of conclusions that are uniformly applicable. Longitudinal neuroimaging studies have the potential to objectively identify structural changes in the brain that are markers of neuronal injury. Such studies are a major undertaking, requiring age-matched control groups and consistent image acquisition and analysis techniques. One needs to analyze not only changes in group means but also the number of patients who show significant changes in imaging parameters that exceed the limits of test-retest reliability and changes in age-matched controls. Quantitative analysis of MRI T(1)-weighted volumetric datasets can reliably identify changes in cerebral and hippocampal volumes of 1-3% in individual subjects. The sensitivity of such quantitative analysis of structural data to identify functionally significant changes is not yet certain. Functional imaging techniques such as MR spectroscopy, PET, and SPECT may be more sensitive for detecting cerebral abnormalities, but their test-retest reliability is inferior. Other MRI tools, such as diffusion tensor imaging, may be useful for evaluating secondary cerebral damage after seizures, both acutely and chronically. Present evidence suggests that, to detect significant treatment effects, longitudinal studies of putative neuroprotective agents, using neuroimaging methods as a surrogate end point, would require at least a 3-year observation period, include large numbers of patients, and provide stratification for important clinical variables.

Brain Injuries↗