Biomedical subjects

Viswanathan Ramakrishnan

Publications and source records attributed to Viswanathan Ramakrishnan.

16 recordsLinked to original sources

PubMed2006

Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin's) lymphoma.

PURPOSE: Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase II studies. EXPERIMENTAL DESIGN: Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events. RESULTS: Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m(2)/d x 5). The recommended bryostatin 1 phase II dose is 50 microg/m(2) for both sequences, bryostatin 1 --> fludarabine and fludarabine --> bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells. CONCLUSIONS: Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration.

Adult↗

PubMed2006

Audio-visual biofeedback for respiratory-gated radiotherapy: impact of audio instruction and audio-visual biofeedback on respiratory-gated radiotherapy.

PURPOSE: Respiratory gating is a commercially available technology for reducing the deleterious effects of motion during imaging and treatment. The efficacy of gating is dependent on the reproducibility within and between respiratory cycles during imaging and treatment. The aim of this study was to determine whether audio-visual biofeedback can improve respiratory reproducibility by decreasing residual motion and therefore increasing the accuracy of gated radiotherapy. METHODS AND MATERIALS: A total of 331 respiratory traces were collected from 24 lung cancer patients. The protocol consisted of five breathing training sessions spaced about a week apart. Within each session the patients initially breathed without any instruction (free breathing), with audio instructions and with audio-visual biofeedback. Residual motion was quantified by the standard deviation of the respiratory signal within the gating window. RESULTS: Audio-visual biofeedback significantly reduced residual motion compared with free breathing and audio instruction. Displacement-based gating has lower residual motion than phase-based gating. Little reduction in residual motion was found for duty cycles less than 30%; for duty cycles above 50% there was a sharp increase in residual motion. CONCLUSIONS: The efficiency and reproducibility of gating can be improved by: incorporating audio-visual biofeedback, using a 30-50% duty cycle, gating during exhalation, and using displacement-based gating.

Adult↗

PubMed2006

Anal sphincter defects and bowel symptoms in women with and without recognized anal sphincter trauma.

OBJECTIVE: The purpose of this study was to determine the rate of new bowel symptoms and anal sphincter defects in primiparous women with and without recognized anal sphincter (AS) injury. STUDY DESIGN: One hundred seventeen primiparous women classified with increasing degrees of perineal trauma and 21 controls delivered by cesarean section were enrolled immediately postpartum and demographic and delivery data were collected. At 6 weeks' postpartum, subjects completed a bowel function questionnaire and endoanal ultrasonography was performed. Logistic regression, chi-square, and 2-sample t tests were used for statistical analysis. RESULTS: A significant difference in new bowel symptoms was reported in women with (39%) and without (11%) recognized AS injury (P = .002). AS defects were present in 0%, 15%, 23%, 37%, and 67% of women with C/S, first-, second-, third-, and fourth-degree lacerations, respectively. Combined defects of the internal and external AS were associated with the greatest risk of new bowel symptoms (OR 32.1 [95% CI 9.6-107], P < .001). CONCLUSION: In women with and without recognized AS trauma, new bowel symptoms were strongly correlated with the presence of anatomic AS defects postpartum.

Adult↗

PubMed2006

Paternal relatives and family history of breast cancer.

BACKGROUND: Reported family medical history may be the most widely accessible genomics screen currently available. The worth of any population-screening tool may be measured by parameters such as sensitivity and specificity. There is some evidence and theory suggesting that family history of breast cancer may be more frequently communicated about maternal (versus paternal) lines. If true, a discrepancy in reporting family history of breast cancer could mean suboptimal accuracy for this genomics-screening tool. METHODS: A cross-sectional analysis of reported family history of breast cancer was conducted beginning in early fall 2005 of data collected from April 2003 to March 2005. Study participants were Women's Health Clinic patients without breast cancer aged at least 40 years. The number of women reporting extended paternal relatives (e.g., aunts, grandmothers) with breast cancer was compared to the number of women reporting maternal relatives. RESULTS: More women reported a maternal relative with breast cancer (16%) compared to those reporting paternal relatives (10%) (McNemar odds ratio = 1.71, 95% confidence interval = 1.26 to 2.34). A discrepancy remained in analyses adjusting for potential covariates (race/ethnicity, awareness of breast cancer, family communication about breast cancer, and perceived risk). CONCLUSIONS: Self-reported family history of breast cancer may not optimally capture inherited risk from the father's side of the family. Further research is needed to look for modifiable contributors to this discrepancy to optimize screening for familial breast cancer.

Adult↗

PubMed2006

Preliminary results of subintimal angioplasty for limb salvage in lower extremities with severe chronic ischemia and limb-threatening ischemia.

OBJECTIVE: This study examined the hypothesis that superficial femoral artery (SFA) subintimal angioplasty (SI-PTA) can maintain limb salvage with minimal complications in patients with symptomatic occlusive arterial disease. METHODS: From March 1, 2004, until April 28, 2006, 78 patients with rest pain (62.2%), gangrene (25.6%), or severe progressive claudication (12.2%) were treated consecutively with 82 SFA SI-PTAs (4 bilateral). The mean age was 59 +/- 1.2 years, and 21 (27%) of the patients were female. All patients were treated in the operating room under local anesthesia by using fluoroscopic guidance, and the percentage SFA that was occluded was measured during the diagnostic portion of the procedure. Selective stent placement was performed after successful recanalization of the occluded arterial segments. Patients were treated with chronic aspirin and clopidogrel bisulfate for 3 months and followed up at 30 days and then every 3 months with physical examination and arterial duplex scan. RESULTS: Of the 82 SFA SI-PTA attempts, 76 (92%) were initially successful, with an increase in the ankle-brachial index from 0.46 +/- 0.02 to 0.88 +/- 0.01 (P < .001). Five of the six patients with a failed SFA SI-PTA were female, two of the six had had previous bypass attempts, and one of the six had had a previous SFA SI-PTA attempt by another physician. Forty-nine (64%) of the 76 initially successful SFA SI-PTAs required placement of a stent, and 43 (56.5%) of the successful 76 SFA SI-PTAs required additional PTA of 1 or more arterial segments. The group treated with a successful SFA SI-PTA had 42.5% +/- 3.5% SFA occlusion, compared with 82% +/- 10% (P < .05) in the group with a failed attempt at SFA SI-PTA. Two of the six patients with initial SI-PTA failure underwent leg amputation within 30 days, three were treated with successful leg bypass surgery, and one was lost to follow-up. Of the 76 successful SFA SI-PTAs, 5 (6.5%) failed within 90 days, and the patients were treated successfully with leg bypass surgery. Of the 71 limbs with patent SI-PTAs at 90 days, 68 have remained patent with a mean follow-up 10.4 +/- 0.7 months (range, 2-24 months). Three of the 71 SFA SI-PTAs failed between 4 and 7 months (mean, 5 +/- 0.7 months): 1 patient was treated with successful bypass surgery, 1 patient is currently considering further intervention, and 1 patient was treated with amputation. Ten (14%) of the 71 successful SFA SI-PTAs required limited PTA for asymptomatic restenosis, as identified by the arterial duplex scan (7.4 +/- 1.4 months; range, 2-16 months). There were no perioperative deaths, and three patients have died during follow-up with patent SFA SI-PTAs (9.3 +/- 1.4 months). CONCLUSIONS: These data suggest that SFA SI-PTA can be successfully used for limb salvage with minimal morbidity and mortality in a group of patients with severe lower extremity occlusive vascular disease.

Adult↗

PubMed2005

Transient exposure of mammary tumors to PD184352 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth.

Previous studies from our group have demonstrated in vitro that UCN-01 (7-hydroxystaurosporine) and inhibitors of MEK1/2 interact to cause tumor cell death in a wide variety of malignant, but not in nontransformed, cell types. The present studies determined whether UCN-01 and MEK1/2 inhibitors interacted to cause tumor cell death in vivo. In vitro colony formation studies demonstrated that UCN-01 and the MEK1/2 inhibitor PD184352 interacted to synergistically kill human mammary carcinoma cells (MDA-MB-231, MCF7) with similar combination index values. Athymic mice were implanted in the rear flank with either MDA-MB-231 or MCF7 cells and tumors permitted to form to a volume of approximately 100 mm3 prior to a two day exposure of either Vehicle, PD184352 (25 mg/kg), UCN-01 (0.1-0.2 mg/kg) or the drug combination. Tumor volume was measured every other day and tumor growth determined over the following approximately 30 days. Transient exposure of MDA-MB-231 tumors or MCF7 tumors to either PD184352 or UCN-01 did not significantly alter tumor growth rate or the mean tumor volume in vivo approximately 15-30 days after drug administration. In contrast, combined treatment with PD184352 and UCN-01 significantly reduced MDA-MB-231, and largely abolished MCF7 tumor growth. Tumor control values for both cell lines were 0.36. Tumor cells isolated approximately 30 days after combined drug exposure exhibited a significantly greater reduction in plating efficiency using ex vivo colony formation assays than tumor cells that were exposed to either drug individually. Reduced tumor growth correlated with profound tumor cell death within five days of combined drug exposure, which was also evident approximately 30 days after exposure. In addition, tumor cell death correlated with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31. Collectively, these findings argue that UCN-01 and MEK1/2 inhibitors have the potential to suppress mammary tumor growth in vivo which is independent of p53 status, estrogen dependency, caspase 3 levels or oncogenic K-RAS expression.

Apoptosis↗

PubMed2005

Assessing quality of hybridized RNA in Affymetrix GeneChip experiments using mixed-effects models.

The technology for hybridizing archived tissue specimens and the use of laser-capture microdissection for selecting cell populations for RNA extraction have increased over the past few years. Both these methods contribute to RNA degradation. Therefore, quality assessments of RNA hybridized to microarrays are becoming increasingly more important. Existing methods for estimating the quality of RNA hybridized to a GeneChip, from resulting microarray data, suffer from subjectivity and lack of estimates of variability. In this article, a method for assessing RNA quality for a hybridized array which overcomes these drawbacks is proposed. The effectiveness of the proposed method is demonstrated by the application of the method to two microarray data sets for which external verification of RNA quality is known.

Biometry↗

PubMed2005

Differences in outcomes after third- versus fourth-degree perineal laceration repair: a prospective study.

OBJECTIVE: The purpose of this study was to compare outcomes after third- versus fourth-degree laceration repair. STUDY DESIGN: Fifty-six primiparous women who sustained a third- or fourth-degree tear were enrolled at delivery and demographic and obstetric data were collected. At 6 weeks' postpartum, subjects completed a bowel function questionnaire and endoanal ultrasonography was performed. Fisher exact test and chi-square were used for statistical analysis. RESULTS: Thirty-nine women with third- and 17 with fourth-degree tears were enrolled. Subjects with fourth- were more likely to report bowel symptoms (59% vs 28%, P = .03), and to demonstrate persistent combined defects of the internal (IAS) and external anal sphincter (EAS) (48% vs 8%, P = .002) than third-degree tears. Combined defects were associated with the highest risk of bowel symptoms (OR 18.7, 95% CI 3-101, P < .001). CONCLUSION: Bowel symptoms were more common after fourth- than third-degree repair, and may be secondary to higher rates of combined defects of the IAS and EAS.

Adult↗

PubMed2005

Anal incontinence in women with and those without pelvic floor disorders.

OBJECTIVE: To compare the prevalence of anal incontinence and anal sphincter injury in women with pelvic floor disorders (cases) with those in a group of normal control subjects and to evaluate the relationship between sphincter injury and anal incontinence in each group. METHODS: We previously reported the results of a cross-sectional study of 100 women with pelvic floor disorders (> or = stage II pelvic organ prolapse and/or urinary incontinence). In this study, we compared those cases with 90 controls (stage 0 or I pelvic organ prolapse and no urinary incontinence) who completed the Rockwood-Thompson fecal incontinence severity index, in which scoring (0-61) is based on the frequency and type of anal incontinence. All women underwent endoanal ultrasonography, and the internal and external anal sphincters were reported as intact versus disrupted. Chi-square test, Student t test, and logistic regression were used for statistical analysis. RESULTS: Women with pelvic floor disorders were significantly more likely to report anal incontinence (54% versus 17.8%, odds ratio [OR] 5.4, 95% confidence interval [CI] 2.8-10.6, P < .001) and had higher mean fecal incontinence severity index scores (22.3 +/- 13 versus 12.7 +/- 6.3, P = .006) than controls. Cases demonstrated higher rates of anal sphincter defects on ultrasound examination than did controls (52% versus 30%, P = .007). Anal incontinence was significantly associated with anal sphincter injury in women with pelvic floor disorders (OR 36.4, 95% CI 12-114, P < .001) and in controls (OR 5.9, 95% CI 3-11, P = .002). CONCLUSION: Anal incontinence was more common in women with pelvic floor disorders than normal controls and may be due to higher rates of anatomic anal sphincter disruption in this group.

Age Distribution↗

PubMed2005

Frameless stereotaxy using bone fiducial markers for deep brain stimulation.

OBJECT: Functional neurosurgical interventions such as deep brain stimulation (DBS) are traditionally performed with the aid of a stereotactic frame. Although frameless techniques have been perceived as less accurate, data from a recent phantom study of a modified frameless approach demonstrated a laboratory accuracy exceeding that obtained using a common frame system. The present study was conducted to evaluate the accuracy of a frameless system in routine clinical use. METHODS: Deep brain stimulation leads were implanted in 38 patients by using a skull-mounted trajectory guide and an image-guided workstation. Registration was accomplished with bone fiducial markers. Final lead positions were measured on postoperative computerized tomography scans and compared with the planned lead positions. The accuracy of the Leksell frame within the clinical situation has been reported on in a recent study; these raw data served as a comparison data set. The difference between expected and actual lead locations in the x plane was 1.4 mm in the frame-based procedure and 1.6 mm in the frameless procedure. Similarly, the difference in the y plane was 1.6 mm in the frame-based system and 1.3 mm in the frameless one. The error was greatest in the z plane, that is, 1.7 mm in the frame-based method and 2 mm in the frameless system. Multivariate analysis of variance demonstrated no statistically significant difference in the accuracy of the two methods. CONCLUSIONS: The accuracy of the frame-based and frameless systems was not statistically significantly different (p = 0.22). Note, however, that frameless techniques offer advantages in patient comfort, separation of imaging from surgery, and decreased operating time.

Deep Brain Stimulation↗

PubMed2004

Graphical technique for identifying a monotonic variance stabilizing transformation for absolute gene intensity signals.

BACKGROUND: The usefulness of log2 transformation for cDNA microarray data has led to its widespread application to Affymetrix data. For Affymetrix data, where absolute intensities are indicative of number of transcripts, there is a systematic relationship between variance and magnitude of measurements. Application of the log2 transformation expands the scale of genes with low intensities while compressing the scale of genes with higher intensities thus reversing the mean by variance relationship. The usefulness of these transformations needs to be examined. RESULTS: Using an Affymetrix GeneChip dataset, problems associated with applying the log2 transformation to absolute intensity data are demonstrated. Use of the spread-versus-level plot to identify an appropriate variance stabilizing transformation is presented. For the data presented, the spread-versus-level plot identified a power transformation that successfully stabilized the variance of probe set summaries. CONCLUSION: The spread-versus-level plot is helpful to identify transformations for variance stabilization. This is robust against outliers and avoids assumption of models and maximizations.

Computational Biology↗

PubMed2004

Effects of Freund's complete adjuvant on the physiology, histology, and activity of New Zealand White Rabbits.

The purpose of this study was to determine whether Freund's complete adjuvant causes adverse effects on the physiology, histology, and activity of rabbits used for polyclonal antibody production. Rabbits in the experimental groups were immunized intradermally and subcutaneously with keyhole limpet hemacyanin with or without Freund's adjuvant. Booster immunizations were administered 28 days after the initial immunizations. No immunizations were administered to rabbits in the control group. Body weight, food consumption, activity, rectal temperature, white blood cell count, corticosterone concentration, and induration around immunization sites were measured. Histologic changes in the lung, kidney, liver, lymph node, and skin were evaluated after euthanasia. There were significant differences in white blood cell count, induration around immunization sites, and lipid droplet deposition in pulmonary microgranulomas in some rabbits that received Freund's adjuvant. These differences did not affect well-being of the rabbits. Freund's complete adjuvant caused no adverse effects on physiologic parameters and activity levels in rabbits; thus, its use in polyclonal antibody production should not be discouraged.

Analysis of Variance↗

PubMed2003

Melanoma differentiation-associated 7 (interleukin 24) inhibits growth and enhances radiosensitivity of glioma cells in vitro and in vivo.

PURPOSE: Despite therapeutic interventions including surgery, chemotherapy, and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. EXPERIMENTAL DESIGN: Melanoma differentiation-associated 7 (mda-7) (interleukin 24), when expressed via a recombinant replication-defective adenovirus, adenovirus (Ad).mda-7, has profound antiproliferative and cytotoxic effects in a variety of tumor cells but not in nontransformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cell lines. RESULTS: Ad.mda-7 caused a dose-dependent reduction in the proliferation of glioma cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The antiproliferative effects of Ad.mda-7 were enhanced by radiation in a greater than additive fashion. These effects were not observed in cultures of nontransformed primary astrocytes. Purified MDA-7 protein caused a similar dose-dependent reduction in GBM cell growth that was enhanced after radiation exposure. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. These modifications in cell phenotype correlated with reduced expression of Bcl-(XL) and enhanced expression of BAX. Overexpression of Bcl-(XL) protected cells from the antiproliferative and cytotoxic effects of Ad.mda-7 + radiation. Incubation of cells with N-acetyl cysteine abolished the enhancing effects of radiation. In vitro, Ad.mda-7 and radiation reduced colony formation ability, which was significantly increased when the two treatments were combined. In vivo, Ad.mda-7 enhanced the survival of Fischer 344 rats implanted intracranially with glioma cells. Radiation did not alter survival in control infected animals, whereas it prolonged survival in those infected with Ad.mda-7. CONCLUSIONS: These findings demonstrate that mda-7 reduces the proliferation and enhances the radiosensitivity of GBM cells in vitro and in vivo.

Acetylcysteine↗

PubMed2002

Salvage radiotherapy for rising or persistent PSA after radical prostatectomy.

OBJECTIVES: To assess the effectiveness of salvage radiotherapy (RT) for a persistent or rising prostate-specific antigen (PSA) level after radical prostatectomy, and to identify the pretreatment factors that may predict for patients likely to benefit from this treatment. METHODS: Seventy-three consecutive patients were treated during a 10-year period (1989 to 1999) with RT after radical prostatectomy. Twelve patients were excluded from analysis because of either an undetectable PSA level before RT or lack of follow-up data. No patients had clinical or radiographic evidence of distant disease. An undetectable PSA level (less than 0.1 ng/mL) was required to be considered disease free. RESULTS: The median PSA level before RT was 0.8 ng/mL (range 0.1 to 63). The median radiation dose prescribed was 66.6 Gy. The actuarial PSA-free survival rate at 4 years was 39%. Failure was uncommon in patients followed up beyond 4 years. Univariate analysis revealed that a pre-RT PSA level of less than 1.0 ng/mL (P = 0.001), Gleason score less than 8 (P = 0.003), and achievement of an undetectable PSA level after prostatectomy (P = 0.018) were significant predictors of improved disease-free survival. On multivariate analysis, both a pre-RT PSA level of less than 1.0 ng/mL and a Gleason score less than 8 maintained statistical significance. CONCLUSIONS: Salvage RT provides a reasonable chance of intermediate-term disease-free survival in patients with PSA persistence or relapse after radical prostatectomy. Patients with a higher PSA level (greater than 1 ng/mL) and Gleason score of 8 or more are less likely to benefit from this treatment, and improved therapies are needed for this subset of patients. Patients should be referred promptly for salvage RT after detection of relapse.

Analysis of Variance↗

PubMed2002

Defining the photochemical contribution to particulate matter in urban areas using time-series analysis.

The objective of this project is to demonstrate how the ambient air measurement record can be used to define the relationship between O3 (as a surrogate for photochemistry) and secondary particulate matter (PM) in urban air. The approach used is to develop a time-series transfer-function model describing the daily PM10 (PM with less than 10 microm aerodynamic diameter) concentration as a function of lagged PM and current and lagged O3, NO or NO2, CO, and SO2. Approximately 3 years of daily average PM10, daily maximum 8-hr average O3 and CO, daily 24-hr average SO2 and NO2, and daily 6:00 a.m.-9:00 a.m. average NO from the Aerometric Information Retrieval System (AIRS) air quality subsystem are used for this analysis. Urban areas modeled are Chicago, IL; Los Angeles, CA; Phoenix, AZ; Philadelphia, PA; Sacramento, CA; and Detroit, MI. Time-series analysis identified significant autocorrelation in the O3, PM10, NO, NO2, CO, and SO2 series. Cross correlations between PM10 (dependent variable) and gaseous pollutants (independent variables) show that all of the gases are significantly correlated with PM10 and that O3 is also significantly correlated lagged up to two previous days. Once a transfer-function model of current PM10 is defined for an urban location, the effect of an O3-control strategy on PM concentrations is estimated by calculating daily PM10 concentrations with reduced O3 concentrations. Forecasted summertime PM10 reductions resulting from a 5 percent decrease in ambient O3 range from 1.2 microg/m3 (3.03%) in Chicago to 3.9 microg/m3 (7.65%) in Phoenix.

Air Pollutants↗

PubMedDate not supplied

Effect of ozone and aeroallergens on the respiratory health of asthmatics.

The effect of ambient air pollutants, pollens, and mold spores on respiratory health was studied in an area with low concentrations of chemical pollutants and abundant aeroallergens. A panel of 40 asthmatic subjects living near East Moline, Illinois, recorded peak expiratory flow rates (PEFRs), respiratory symptoms, frequency of asthma attacks, and asthma medication use between April and October 1994. Daily outdoor concentrations of pollutants and aeroallergens were measured, and indoor levels of bioaerosols were measured on several occasions in each participant's home. Ozone was associated with increased morning and evening symptom scores and decreased evening PEFR, and these associations remained significant with adjustment for weather and aeroallergens. The association between ozone and asthma medication use was increased in magnitude and significance with adjustment for weather and aeroallergens; however, the association between ozone and morning PEFR became nonsignificant with weather and aeroallergen adjustment. Significant associations were also found between pollen concentration and decreased evening PEFR, as well as between increased morning and evening symptom scores and asthma medication use. In addition, associations were noted between total spore concentration and increased morning PEFR and decreased morning and evening symptom scores. The inverse associations found with mold spore concentrations were not consistent with the results of other studies; however, the associations between ozone and pollen concentration were consistent with previous studies. When results were stratified by a number of independent risk factors, no differences were noted relative to allergic status or presence of dampness or flooding in the home; however, the associations with outdoor ozone and pollens were seen mainly among participants with low levels of exposure to indoor bioaerosols (< 1,800 spores/m3) or with no environmental tobacco smoke exposure.

Adolescent↗