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Articles by R Agarwal
Total Records ( 6 ) for R Agarwal
  D. J Englot , L Yang , H Hamid , N Danielson , X Bai , A Marfeo , L Yu , A Gordon , M. J Purcaro , J. E Motelow , R Agarwal , D. J Ellens , J. D Golomb , M. C. F Shamy , H Zhang , C Carlson , W Doyle , O Devinsky , K Vives , D. D Spencer , S. S Spencer , C Schevon , H. P Zaveri and H. Blumenfeld

Impaired consciousness requires altered cortical function. This can occur either directly from disorders that impair widespread bilateral regions of the cortex or indirectly through effects on subcortical arousal systems. It has therefore long been puzzling why focal temporal lobe seizures so often impair consciousness. Early work suggested that altered consciousness may occur with bilateral or dominant temporal lobe seizure involvement. However, other bilateral temporal lobe disorders do not impair consciousness. More recent work supports a ‘network inhibition hypothesis’ in which temporal lobe seizures disrupt brainstem–diencephalic arousal systems, leading indirectly to depressed cortical function and impaired consciousness. Indeed, prior studies show subcortical involvement in temporal lobe seizures and bilateral frontoparietal slow wave activity on intracranial electroencephalography. However, the relationships between frontoparietal slow waves and impaired consciousness and between cortical slowing and fast seizure activity have not been directly investigated. We analysed intracranial electroencephalography recordings during 63 partial seizures in 26 patients with surgically confirmed mesial temporal lobe epilepsy. Behavioural responsiveness was determined based on blinded review of video during seizures and classified as impaired (complex-partial seizures) or unimpaired (simple-partial seizures). We observed significantly increased delta-range 1–2 Hz slow wave activity in the bilateral frontal and parietal neocortices during complex-partial compared with simple-partial seizures. In addition, we confirmed prior work suggesting that propagation of unilateral mesial temporal fast seizure activity to the bilateral temporal lobes was significantly greater in complex-partial than in simple-partial seizures. Interestingly, we found that the signal power of frontoparietal slow wave activity was significantly correlated with the temporal lobe fast seizure activity in each hemisphere. Finally, we observed that complex-partial seizures were somewhat more common with onset in the language-dominant temporal lobe. These findings provide direct evidence for cortical dysfunction in the form of bilateral frontoparietal slow waves associated with impaired consciousness in temporal lobe seizures. We hypothesize that bilateral temporal lobe seizures may exert a powerful inhibitory effect on subcortical arousal systems. Further investigations will be needed to fully determine the role of cortical-subcortical networks in ictal neocortical dysfunction and may reveal treatments to prevent this important negative consequence of temporal lobe epilepsy.

  R Agarwal , A. M Gonzalez Angulo , S Myhre , M Carey , J. S Lee , J Overgaard , J Alsner , K Stemke Hale , A Lluch , R. M Neve , W. L Kuo , T Sorlie , A Sahin , V Valero , K Keyomarsi , J. W Gray , A. L Borresen Dale , G. B Mills and B. T. Hennessy

Purpose: We studied the expression levels of cyclins B1, D1, and E1 and the implications of cyclin overexpression for patient outcomes in distinct breast cancer subtypes defined by clinical variables and transcriptional profiling.

Experimental Design: The expression levels of cyclins B1, D1, and E1 were quantified in 779 breast tumors and 53 cell lines using reverse phase protein arrays and/or transcriptional profiling.

Results: Whereas cyclin E1 overexpression was a specific marker of triple-negative and basal-like tumors, cyclin B1 overexpression occurred in poor prognosis hormone receptor–positive, luminal B and basal-like breast cancers. Cyclin D1 overexpression occurred in luminal and normal-like cancers. Breast cancer subgroups defined by integrated expression of cyclins B1, D1, and E1 correlated significantly (P < 0.000001) with tumor subtypes defined by transcriptional profiling and clinical criteria. Across three hormone receptor–positive data sets, cyclin B1 was the dominant cyclin associated with poor prognosis in univariate and multivariate analyses. Although CCNE1 was present in significantly higher copy numbers in basal-like versus other subtypes (ANOVA P < 0.001), CCNB1 gene copy number did not show gain in breast cancer. Instead, cyclin B1 expression was increased in tumors with co-occurrence of TP53 mutations and MYC amplification, a combination that seems to characterize basal-like and luminal B tumors. CCNB1 gene expression was significantly correlated with PLK, CENPE, and AURKB gene expression.

Conclusion: Cyclins B1, D1, and E1 have distinct expressions in different breast cancer subtypes. Novel PLK, CENPE, and AURKB inhibitors should be assessed for therapeutic utility in poor prognosis cyclin B1–overexpressing breast cancers.

  R Agarwal and R. P. Light

Background and objectives: Ambulatory blood pressure (BP) monitoring is commonly used to assess the circadian pattern of BP. Circadian BP pattern is influenced by physical activity and sleep cycle. The effect of BP monitoring itself on the level of physical activity and sleep remains unknown. If BP monitoring affects these parameters, then monitoring itself may influence the circadian BP pattern.

Design, setting, participants, & measurements: To assess the effect of ambulatory BP monitoring on sleep duration, sleep efficiency, and daytime activity, we measured physical activity using wrist actigraphy in 103 veterans with chronic kidney disease. After 6 to 7 days of continuous activity monitoring, participants underwent ambulatory BP monitoring with simultaneous actigraphy. The above experiment was repeated after 1 mo.

Results: Among the top tertile of patients (most sleep), when wearing ambulatory BP patients spent less time in bed at night (–92 min, P < 0.0001), were less asleep during those hours (–98 min, P < 0.0001), and had reduced sleep efficiency (82% versus 77%, –5% P = 0.02). On the day of ambulatory BP monitoring, patients were more sedentary during waking hours (+27 minutes, P = 0.002). During ambulatory BP monitoring, waking after sleep onset more than median was associated with greater odds for nondipping (odds ratio 10.5, P = 0.008).

Conclusions: Ambulatory BP monitoring is associated with disturbed sleep and reduced physical activity, characteristics that influence dipping. Ambulatory BP monitoring may itself induce nondipping and may thus mitigate the prognostic significance of the dipping phenomenon.

  R Agarwal and R. P. Light

Background: Median BP obtained over a single dialysis treatment can diagnose hypertension among hemodialysis patients. Whether median BP is as useful to track change in BP is unknown.

Design, setting, participants, & measurements: Among patients participating in the dry-weight reduction in hypertensive hemodialysis patients (DRIP) trial, interdialytic ambulatory BP was recorded at baseline, 4 weeks, and 8 weeks. The mean interdialytic ambulatory BP was compared to the following recordings: predialysis on one dialysis treatment (Pre1), predialysis averaged over 2 weeks of dialysis treatment (Pre6), postdialysis on one dialysis treatment (Post1), postdialysis averaged over 2 weeks of dialysis treatment (Post6), and median intradialytic BP over one treatment.

Results: Pre1 was unable to detect change in ambulatory BP. Although Pre6 was able to detect change, it overestimated the ambulatory BP. On average, the magnitude of reduction in Post1 in response to probing dry-weight was nearly twice that obtained by ambulatory BP monitoring. Even Post6 overestimated the magnitude of reduction in BP at 8 weeks. Median systolic BP was responsive to probing dry-weight and neither overestimated nor underestimated the interdialytic ambulatory systolic BP at baseline or over time. However, the SD of the differences between median systolic BP and interdialytic ambulatory systolic BP varied from 16 to 20 mmHg.

Conclusions: Median intradialytic BP recordings can detect change in ambulatory BP evoked by reduction in dry-weight at the population level. Because of wide agreement limits between intradialytic and interdialytic BP, the individual prediction of ambulatory BP from median intradialytic BP can be misleading.

  R Agarwal and M. R. Weir

Background and objectives: Achieving and maintaining dry-weight appears to be an effective but forgotten strategy in controlling and maintaining normotension among hypertensive patients on hemodialysis.

Methods: Qualitative review of literature to define dry-weight and its utility in achieving blood pressure control.

Results: The concept of dry-weight has evolved over time and its definition has changed. One such definition defines dry-weight as the lowest tolerated postdialysis weight achieved via gradual change in postdialysis weight at which there are minimal signs or symptoms of hypovolemia or hypervolemia. Although clinical examination does not perform well in detecting latent increase in dry-weight, several technologies such as relative plasma volume monitoring and body impedance analysis are emerging that may help in assessing dry-weight in the future. Sodium restriction is a modifiable risk factor that can lead to better blood pressure (BP) control. However, dietary sodium restriction requires lifestyle modifications that are difficult to implement and even harder to sustain over the long term. Restricting dialysate sodium is a simpler but underexplored strategy that can reduce thirst, limit interdialytic weight gain, and assist the achievement of dry-weight. Achievement of dry-weight can improve interdialytic BP, reduce pulse pressure, and limit hospitalizations.

Conclusions: Avoiding medication-directed control of BP may enhance the opportunity to probe dry-weight, facilitate removal of volume, and limit the risk for pressure-volume overload, which may be a significant concern leading to myocardial remodeling in the hemodialysis patient. Probing dry-weight among patients with ESRD has the potential to improve dismal cardiovascular outcomes.

  R. K Elespuru , R Agarwal , A. H Atrakchi , C. A. H Bigger , R. H Heflich , D. R Jagannath , D. D Levy , M. M Moore , Y Ouyang , T. W Robison , R. E Sotomayor , M. C Cimino and K. L. Dearfield

With the advent of new technologies (e.g., genomics, automated analyses, and in vivo monitoring), new regulations (e.g., the reduction of animal tests by the European REACH), and new approaches to toxicology (e.g., Toxicity Testing in the 21st Century, National Research Council), the field of regulatory genetic toxicology is undergoing a serious re-examination. Within this context, Toxicological Sciences has published a series of articles in its Forum Section on the theme, "Genetic Toxicity Assessment: Employing the Best Science for Human Safety Evaluation" (beginning with Goodman et al.). As a contribution to the Forum discussions, we present current methods for evaluating mutagenic/genotoxic risk using standard genotoxicity test batteries, and suggest ways to address and incorporate new technologies. We recognize that the occurrence of positive results in relation to cancer prediction has led to criticism of in vitro mammalian cell genetic toxicity assays. We address criticism of test results related to weak positives, associated only with considerable toxicity, only seen at high concentrations, not accompanied by positive results in the other tests of standard test batteries, and/or not correlating well with rodent carcinogenicity tests. We suggest that the problems pointed out by others with these assays already have been resolved, to a large extent, by international groups working to update assay protocols, and by changes in data interpretation at regulatory agencies. New guidances at the U.S. Environmental Protection Agency and the U.S. Food and Drug Administration improve data evaluation and help refocus risk assessment. We discuss the results of international groups working together to integrate new technologies and evaluate new tests, including human monitoring. We suggest that strategies for identifying human health risks should naturally change to integrate new technologies; however, changes should be made only when justified by strong scientific evidence of improvement in the risk assessment paradigm.

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