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Articles by Constantine Daskalakis in JoVE

 JoVE Clinical and Translational Medicine

Non-invasive Assessment of Microvascular and Endothelial Function

1Department of Family and Community Medicine, Thomas Jefferson University, 2Department of Pharmacology and Experimental Therapeutics, Biostatistics Division, Thomas Jefferson University, 3Department of Internal Medicine, Thomas Jefferson University


JoVE 50008

Capillaroscopy is a non-invasive, relatively inexpensive methodology for directly visualizing the microcirculation. The forearm blood flow technique provides accepted non-invasive measures of endothelial function.

Other articles by Constantine Daskalakis on PubMed

Regression Analysis of Multiple-source Longitudinal Outcomes: a "Stirling County" Depression Study

Epidemiologic studies of psychiatric disorders have increasingly relied on multiple sources of information to improve the validity of diagnoses and repeated assessments over time to provide a longitudinal perspective. In this paper, the authors present a general multivariate logistic regression method for the simultaneous analysis of discrete outcomes that exhibit such features. This approach permits risk factor and agreement analyses within a unified framework and appropriately uses data from subjects who may be missing some outcomes. The authors use this approach to analyze data from a "Stirling County" study of depression. During a 3- to 4-year period in the early 1990s, 631 subjects were assessed in two separate interviews, on each occasion with two diagnostic schedules (the DePression and AnXiety schedule (DPAX) and the Diagnostic Interview Schedule (DIS)). The female:male ratio of depression was found to be different for the DPAX and the DIS (0.8 and 1.6, respectively). Education was inversely associated with depression, while the effects of time, the subject's age, and the interviewer's sex were essentially null. With respect to the outcomes' association, agreement between the DPAX and the DIS was low. In addition, stability of the DPAX over time was significantly higher than that of the DIS. No covariates were found to affect significantly the association between outcomes.

Tumor Oxygenation and Acidification Are Increased in Melanoma Xenografts After Exposure to Hyperglycemia and Meta-iodo-benzylguanidine

Tumor oxygen tension and extracellular pH (pH(e)) are physiological parameters that can be manipulated to improve current cancer therapies. Many human tumors consist of cells that are chronically exposed to low pH(e). Exposure of tumor cells in culture to glucose decreases oxygen consumption (oxygen sparing or Crabtree effect), and while this effect is absent in low pH-adapted tumor cells, it can be restored by combining the respiratory inhibitor meta-iodo-benzylguanidine (MIBG) with glucose (Burd et al., Cancer Res. 61, 5630-5635, 2001). The effects of hyperglycemia and MIBG on tumor oxygen tension and on pH(e) were investigated in human melanoma xenografts in SCID mice. An oral gavage of 1 M glucose (2 g/kg) increased the average blood glucose concentration from <140 mg/dl to approximately 400 mg/dl. Although tumor pH(e) decreased from pH 6.7 to pH 6.5 (P < 0.01) after about 60 min, no change in tumor oxygen tension was observed. However, when oral glucose and MIBG (15 mg/kg) were administered together, oxygen tension increased from 2.8 mmHg to approximately 17 mmHg, and tumor pH(e) decreased from pH 6.7 to pH 6.3 (P < 0.01) after about 115 min. In conclusion, administration of glucose together with MIBG increases tumor oxygen tension and also increases the magnitude and duration of acidification. Hyperglycemia plus MIBG has the potential to improve response to radiation therapy as well as to hyperthermia and some chemotherapies.

Intracellular Acidification Abrogates the Heat Shock Response and Compromises Survival of Human Melanoma Cells

This study tests the hypothesis that lowering intracellular pH (pHi) in melanoma cells grown at low extracellular pH (pHe) selectively abrogates 42 degrees C-induced heat shock protein (HSP) expression and reduces survival. Cells were acidified by a combination of a 0.2-pH-unit decrease in pHe coupled with the lactate/H+ transport inhibitor alpha-cyano-4-hydroxy-cinnamic acid (CNCn). A mild acute extracellular acidification was used to mimic the acute extracellular acidification observed in tumors that can be induced in vivo by oral glucose administration. CNCn blocks the activity of H(+)-linked monocarboxylate transporters (MCTs), particularly MCT isoform 1 (MCT-1). This transporter removes lactic acid from cells and has a high activity in DB-1 melanoma cells grown at low pHe. The effect of extracellular acidification combined with CNCn on pHi was measured in cells grown at pHe 6.7 and pHe 7.3. Cells grown at pHe 6.7 serve as an in vitro model for cells in an acidic tumor microenvironment. When cells were grown at pHe 6.7 and incubated with CNCn at pHe 6.5, the pHi decreased from 6.9 to below 6.5, and the 42 degrees C induction of HSP70 and HSP27 was blocked. The abrogation of HSP induction correlated positively with decreased clonogenic survival. In contrast, when cells growing at pHe 7.3 were acidified by a 0.2-pH unit to pHe 7.1, the inhibitor had less effect on pHi, which remained above 7.0. Under these conditions, the 42 degrees C-induction of HSPs was not inhibited, and cytotoxicity was not enhanced. These results indicate that a significant decrease in the pHi of melanoma cells can selectively sensitize the cells to 42 degrees C hyperthermia, possibly through the inhibition of HSP expression. This strategy could result in a therapeutic gain, because normal tissues, existing at a pHe above 7.0, would not be sensitized.

The Cyclooxygenase-2 Inhibitor, Celecoxib, Prevents the Development of Mammary Tumors in Her-2/neu Mice

Evidence is now available showing that cyclooxygenase (COX)-2, which is involved in prostaglandin production, is overexpressed in many types of tumors including breast. Several reports have indicated that HER-2/neu-positive breast tumors are associated with an increased amount of COX-2 protein. In this study, we evaluated the effectiveness of the select COX-1 and COX-2 inhibitors in preventing mammary tumor development in HER-2/neu transgenic mice. At 4 weeks of age, female HER-2/neu mice were fed a #5020 rodent diet supplemented with 900 ppm celecoxib, a COX-2 inhibitor, 64 ppm of SC560, a COX-1 inhibitor, or the unsupplemented #5001 diet (control). The incidence of mammary tumors was significantly lower in the celecoxib-fed mice (71%; P = 0.001 versus control) than in the control mice (95%) or in the SC560-fed mice (91%). Celecoxib-treated mice also developed fewer tumors (1.3 +/- 1.1 SD; P = 0.039 versus control) than the control mice (2.2 +/- 1.2) or the SC560 treated mice (2.3 +/- 1.3). The median time to tumor development was 266 days in the control group versus 291 days in the celecoxib-treated group (P = 0.003 versus control). Lung metastasis was also reduced by treatment with celecoxib. The COX-1 inhibitor SC560 had no protective effect. The protection offered by celecoxib was associated with significantly lower concentrations of prostacyclin and prostaglandin E(2) in mammary tumors and their adjacent mammary glands. Our findings provide additional preclinical evidence to support the clinical studies to investigate the potential effectiveness of COX-2 inhibitors in protecting woman who are at high risk for breast cancer.

Behaviors Used by Men to Protect Themselves Against Prostate Cancer

This paper reports on behaviors men use to protect themselves against prostate cancer. Data were collected via a telephone or mailed survey from 353 men enrolled in two studies of prostate cancer screening. Respondents reported behaviors they used to protect themselves against prostate cancer, and responses were coded as conventional care, self-care, or nothing. Men who reported using both conventional care and self-care were categorized as conventional care users. Polytomous logistic regression was conducted to evaluate the association between sociodemographic background, prior prostate screening, and cognitive, affective, and social support and influence factors with protective behavior type. The distribution of protective behaviors was as follows: conventional care, 63%; self-care only, 19%; and nothing, 18%. In multivariable analyses, higher education level was found to be positively associated with conventional care use. Perceived salience and coherence of prostate cancer screening was positively associated with conventional care use among men in one of the two studies. Low concern about screening was positively associated with self-care use, as was mailed survey completion. This study presents self-report data regarding prostate cancer protection behaviors. Most men in the study reported using some type of prostate cancer protective behavior. Decision-making about whether or not to take protective action and what type of behavior to use may be influenced by socioeconomic background, cognitive perceptions related to behavioral options, and concern about risk.

Smoking Prevention: Implications of Study Design, Research Setting, and Goals

Collaborations among various disciplines concerned with smoking prevention are gaining in currency. Such collaborations are predicated, in part, on recognizing both the implicit assumptions in different fields and the consequences of these assumptions. These issues, however, are often ignored in transdisciplinary research. In this article, we demonstrate how simple indices, such as the risk ratio, attributable fraction, or R(2), may have different implications for causal inference and interventions, depending on study setting and research goals.

Effect of the Tumor Vascular-damaging Agent, ZD6126, on the Radioresponse of U87 Glioblastoma

The effect of ZD6126 on tumor oxygen tension and tumor growth delay in combination with ionizing radiation was examined in the human U87 glioblastoma tumor model. Resistance to ZD6126 treatment was investigated with the nitric oxide synthase inhibitor, l-N(G)-nitroarginine methyl ester (hydrochloride; l-NAME/active form, l-NNA).Methods: U87 human xenografts were grown in athymic nude mice. ZD6126 was given with or without l-NNA. Tumor oxygen tension was measured using the Oxford Oxylite (Oxford, England) fiberoptic probe system. Tumor volume was determined by direct measurement with calipers and calculated by the formula [(smallest diameter(2) x widest diameter)/2].

GATA-3 Expression As a Predictor of Hormone Response in Breast Cancer

Expression of estrogen receptor-alpha (ERalpha) as determined by immunohistochemistry of tumor tissue is currently the most clinically useful test to predict hormone responsiveness of breast cancer. Thirty percent of ERalpha-positive breast cancers do not respond to hormonal therapy. GATA-3 is a transcription factor that is expressed in association with ERalpha and there is evidence that GATA factors influence response to estrogen. In this pilot study, we investigated whether GATA-3 expression is associated with hormone response in breast cancer.

Preparing African-American Men in Community Primary Care Practices to Decide Whether or Not to Have Prostate Cancer Screening

This study was a randomized trial to test the impact of an informed decision-making intervention on prostate cancer screening use.

Utility of Indices of Gun Availability in the Community

To estimate the degree to which the proportion of homicides and suicides committed with a gun is associated with reported availability of firearms across Chicago neighbourhoods.

Racial and Socioeconomic Differences in Psychiatric Symptoms in Nursing Home Residents: a Minimum Data Set-based Pilot Study

Little research has explored racial and socioeconomic differences in the presence, detection, and treatment of neuropsychiatric symptoms in nursing home residents.

Surgeon-performed Ultrasound for Preoperative Localization of Abnormal Parathyroid Glands in Patients with Primary Hyperparathyroidism

The introduction of portable ultrasound equipment enables surgeons to perform ultrasound examinations in a clinic setting. This study was undertaken to evaluate surgeon-performed ultrasound (SP-US) in patients with primary hyperparathyroidism (PHPT).

Increasing Access to Clinical and Educational Studies

In 2001, the National Cancer Institute (NCI) provided funds to support the Increasing Access to Clinical and Educational Studies (ACES) Project of the Thomas Jefferson University, Kimmel Cancer Center in Philadelphia. The ACES Project enabled the Center to engage in the systematic development of approaches for reducing cancer health disparities among African Americans in Philadelphia. This project brought together community partners, clinical partners, cancer prevention and control experts, and staff from an NCI-designated cancer center to develop and implement a community-based outreach education program, a special populations investigator (SPI) training program, and SPI pilot studies in cancer screening and clinical trials participation. At the end of 5 years, the ACES Project had 1) organized a steering committee, expert panel, and a network of community collaborators and clinical partners; 2) implemented a clinical trials education program for community-based nurses, lay health advocates active in community organizations, and health ministries in community churches; 3) mentored 4 SPIs in cancer prevention and control research; 4) completed SPI pilot studies; and 5) leveraged these activities to gain support for cancer health disparities related research. The Project established a successful dialogue between an NCI-designated cancer center and the African American population related to cancer research, and enabled SPIs from the community to adapt evidence-informed interventions for application in cancer prevention and control research. Lessons learned from the Project can guide the implementation of such projects in the future. Cancer 2006. (c) 2006 American Cancer Society.

VEGF Trap in Combination with Radiotherapy Improves Tumor Control in U87 Glioblastoma

To determine the effect of vascular endothelial growth factor VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, NY), a humanized soluble vascular endothelial growth factor (VEGF) receptor protein, and radiation (RT) on tumor growth in U87 glioblastoma xenografts in nude mice.

A Five-year, Retrospective, Comparison Review of Survival in Neurosurgical Patients Diagnosed with Venous Thromboembolism and Treated with Either Inferior Vena Cava Filters or Anticoagulants

[corrected] The optimal role of inferior vena cava filters (IVCF) in the management of venous thromboembolism (VTE) is not well defined. The purpose of this study was to compare mortality risk for VTE patients treated with IVCF or anticoagulants.

Multifocal Glioblastoma Multiforme: Prognostic Factors and Patterns of Progression

To assess the progression patterns in patients with multifocal glioblastoma multiforme who had undergone whole brain radiotherapy (WBRT), the historical standard, versus three-dimensional conformal radiotherapy, and to identify predictive treatment and pretreatment factors.

Gestational Age at Cervical Length Measurement and Incidence of Preterm Birth

To estimate the risk of spontaneous preterm birth based on transvaginal ultrasound cervical length and gestational age at which cervical length was measured.

Dampness and Mold in the Home and Depression: an Examination of Mold-related Illness and Perceived Control of One's Home As Possible Depression Pathways

We evaluated a previously reported association between residence in a damp and moldy dwelling and the risk of depression and investigated whether depression was mediated by perception of control over one's home or mold-related physical illness.

Human Leukocyte Antigen and Adult Living-donor Liver Transplantation Outcomes: an Analysis of the Organ Procurement and Transplantation Network Database

Human leukocyte antigen (HLA) compatibility has no clinically significant impact in cadaveric liver transplantation. Less is known regarding living-donor liver transplantation (LDLT). Our prior analysis of the Organ Procurement and Transplantation Network (OPTN) database suggested a higher graft failure rate in patients who underwent LDLT from donors with close HLA match. We further investigated the effect of HLA-A, -B, and -DR matching on 5-yr graft survival in adult LDLT by analyzing OPTN data regarding adult LDLT performed between 1998 and 2005. We evaluated associations between 5-yr graft survival and total, locus-specific, and haplotype match levels. Separate analyses were conducted for recipients with autoimmune (fulminant autoimmune hepatitis, cirrhosis secondary to autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) or nonautoimmune liver disease. Multivariable Cox proportional hazard models were used to evaluate interactions and adjust for potential confounders. Among 631 patients with available donor/recipient HLA data, the degree of HLA match had no significant effect on 5-yr graft survival, even when analyzed separately in recipients with autoimmune vs. nonautoimmune liver disease. To be able to include all 1,838 adult LDLTs, we considered a first-degree related donor as substitute for a close HLA match. We found no difference in graft survival in related vs. unrelated pairs. In conclusion, our results show no detrimental impact of close HLA matching on graft survival in adult LDLT, including in recipients with underlying autoimmune liver disease.

Modifiable Cardiovascular Risk Factors Among Individuals in Low Socioeconomic Communities and Homeless Shelters

To understand cardiovascular health in low socioeconomic populations, we analyzed the data from 426 low socioeconomic community-dwelling males and females and 287 homeless males in Philadelphia. Despite higher prevalence of smoking and hypertension, the proportion of homeless participants at increased risk for coronary heart disease was comparable with that of low socioeconomic community-dwelling participants. Among various characteristics, emotional stress was significantly associated with coronary heart disease risk in low socioeconomic community-dwelling participants only, suggestive of a differential psychosocial effect of stress. Our findings suggest that low socioeconomic populations are heterogeneous with respect to their risk factors and needs for interventions.

Racial Disparity in the Relationship Between Hospital Volume and Mortality Among Patients Undergoing Coronary Artery Bypass Grafting

To examine whether the volume-mortality relationship in coronary artery bypass grafting (CABG) differs by race and operative risk.

Capillary Rarefaction in Treated and Untreated Hypertensive Subjects

This study aimed to determine if capillary rarefaction is detectable and associated with endothelial dysfunction in persons with mild systolic blood pressure (SBP) elevation. Capillary density and endothelial function were quantified for 150 nondiabetic participants, grouped by blood pressure (BP) as normotensive, untreated high BP, and treated high BP. Structural capillary rarefaction measures were not different between the three groups. Functional capillary rarefaction measures were significantly lower in both high BP groups compared to normotensives, and correlated inversely with endothelial function. The study findings indicate that the hypertensive vascular pathologic process is already underway at modest levels of blood pressure elevation.

A Validation Study of 3 Grading Systems to Evaluate Small-bowel Cleansing for Wireless Capsule Endoscopy: a Quantitative Index, a Qualitative Evaluation, and an Overall Adequacy Assessment

Capsule endoscopy (CE) is a powerful tool for evaluating the small bowel. Assessment of small-bowel cleansing for CE is an essential quality measure.

The Significance of GATA3 Expression in Breast Cancer: a 10-year Follow-up Study

GATA3 is a transcription factor closely associated with estrogen receptor alpha in breast carcinoma, with a potential prognostic utility. This study investigated the immunohistochemical expression of GATA3 in estrogen receptor alpha-positive and estrogen receptor alpha-negative breast carcinomas. One hundred sixty-six cases of invasive breast carcinomas with 10-year follow-up information were analyzed. Positive GATA3 and estrogen receptor alpha cases were defined as greater than 20% of cells staining. Time to cancer recurrence and time to death were analyzed with survival methods. Of 166 patients, 40 were estrogen receptor alpha negative and 121 estrogen receptor alpha positive. Thirty-eight (23%) recurrences and 51 (31%) deaths were observed. In final multivariable analyses, GATA3-positive tumors had about two thirds the recurrence risk of GATA3-negative tumors (hazard ratio = 0.65, P = .395) and comparable mortality risk (hazard ratio = 0.86, P = .730). In prespecified subgroup analyses, the protective effect of GATA3 expression was most pronounced among estrogen receptor alpha-positive patients who received tamoxifen (hazard ratio = 0.57 for recurrence and 0.68 for death). We found no statistically significant differences in recurrence or survival rates between GATA3-positive and GATA3-negative tumors. However, there was a suggestion of a modest-to-strong protective effect of GATA3 expression among estrogen receptor alpha-positive patients receiving hormone therapy.

Safety of Selective Serotonin Reuptake Inhibitor in Adults Undergoing Coronary Artery Bypass Grafting

Selective serotonin reuptake inhibitors (SSRIs) are commonly used in patients with coronary artery disease and depression, but they have been reported to increase the risk for bleeding. However, data on the short-term outcomes comparing SSRI and non-SSRI antidepressant use after coronary artery bypass grafting (CABG) are limited. A retrospective analysis was conducted of 1,380 adults who received any antidepressants before CABG from 2003 to 2006 at academic medical centers participating in the University HealthSystem Consortium. The primary end point was defined as a composite of in-hospital mortality or any bleeding events, including postprocedural hemorrhage or hematoma, gastrointestinal hemorrhage, and reopening of surgical site. A total of 1,076 adults (78%) received SSRIs. After controlling for propensity of receiving SSRIs compared with non-SSRIs, no significant differences were found in the primary end point (9.4% vs 8.2%, adjusted odds ratio [OR] 1.03, 95% confidence interval [CI] 0.60 to 1.78), any bleeding events (6.5% vs 7.2%, OR 0.93, 95% CI 0.50 to 1.76), or in-hospital mortality (3.1% vs 2.3%, OR 0.88, 95% CI 0.47 to 1.65). There was no increased risk associated with SSRI use when the analysis was restricted to patients who received antiplatelet and anticoagulant therapy for acute coronary syndromes (OR 1.03, 95% CI 0.40 to 2.61) and when examined by age, gender, nonsteroidal anti-inflammatory drug use, and type of CABG (on pump or off pump). In conclusion, compared with non-SSRIs, the preoperative use of SSRIs does not seem to increase the risk for bleeding or in-hospital mortality after CABG.

Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

The tumor growth kinetics of the human LoVo colorectal xenograft model was assessed in response to vandetanib, an orally available receptor tyrosine kinase inhibitor, radiotherapy (RT), or irinotecan (CPT-11), as single therapies and in combination.

The Role of Head Computer Tomographic Scans on the Management of MICU Patients with Neurological Dysfunction

Neurological dysfunction is common in patients admitted to the medical intensive care unit (MICU). However, the indications for head imaging in those patients are unclear. The objective of this study was to assess whether clinical variables would be useful in selecting patients who are likely to have an abnormality on head computerized tomographic (CT) scanning and to determine the impact of such scans on management decisions. We reviewed the charts of 740 patients admitted to our MICU between October 2002 and July 2004. A total of 123 patients (16.6%) had a head CT scan performed, with a new finding being present in 26 (21.1%) patients. In the patients with a new CT finding, there was a change in diagnosis in 11 (42%) patients and a change in treatment in 6 (23%) patients. Logistic regression analysis failed to determine any clinical characteristic that could predict a new finding on the CT scan. This study suggests that clinicians should have a low threshold for ordering a CT scan in MICU patients with acute neurological dysfunction.

Aspirin and Clopidogrel Use in the Early Postoperative Period Following On-pump and Off-pump Coronary Artery Bypass Grafting

Preoperative use of clopidogrel increases the risk of bleeding, but its postoperative use has not been studied. We studied early postoperative clopidogrel use in on-pump and off-pump coronary artery bypass grafting.

Ablation of Tumor Progression Locus 2 Promotes a Type 2 Th Cell Response in Ovalbumin-immunized Mice

The protein kinase encoded by the Tpl2 proto-oncogene regulates ERK activation and cytokine gene expression in macrophages in response to LPS and TNF-alpha. In this study we show that OVA-immunized Tpl2(-/-) mice express high levels of IgE and develop more severe bronchoalveolar eosinophilic inflammation than Tpl2(+/+) controls, when challenged with OVA intranasally. Bronchoalveolar exudates and supernatants of OVA-stimulated splenocytes from immunized Tpl2(-/-) mice express elevated levels of IL-4 and IL-5, suggesting that Tpl2 ablation promotes the Th2 polarization of the T cell response. Anti-CD3 stimulation of CD4(+) T cells of wild-type and Tpl2 knockout mice revealed that Tpl2 ablation gives rise to a cell autonomous T cell defect that is primarily responsible for the Th2 polarization of the T cell response to Ag. This observation was further supported by experiments addressing the expression of Th1 and Th2 cytokines in OVA-stimulated mixed cultures of CD4(+) T cells from Tpl2(+/+)/OT2 or Tpl2(-/-)/OT2 mice and dendritic cells from Tpl2(+/+) or Tpl2(-/-) mice. Further studies revealed that Th1 cells express significantly higher levels of Tpl2 than Th2 cells. As a result, Tpl2(-/-) Th1 cells exhibit a stronger defect in ERK activation by anti-CD3 than Th2 cells and express low levels of T-bet. Given that the development of Th1 and Th2 cells depends on positive feedback signals from the T cells, themselves, the functional defect of the Tpl2(-/-) Th1 cells provides a mechanistic explanation for the T cell autonomous Th2 polarization in Tpl2(-/-) mice.

Association of Capillary Density and Function Measures with Blood Pressure, Fasting Plasma Glucose, and Insulin Sensitivity

The pathophysiology underlying the association between hypertension and insulin resistance remains unclear. The study purpose was to determine whether reduced capillary density and/or function underlie, and may therefore explain, this association. The study was conducted on 115 black and non-black participants aged 18 to 55 years: 91 with normal blood pressure (systolic blood pressure [SBP] <130 mm Hg) and 24 with mild blood pressure elevation (SBP 130-159 mm Hg). Capillary density and function were quantified using direct capillaroscopy measures. Insulin sensitivity (IS) was estimated using the Quantitative Insulin Sensitivity Check Index (QUICKI). Endothelial function (EF) was measured using strain-gauge plethysmography. Data were analyzed by linear regression adjusted for age, sex, race, and body mass index (BMI). After adjustment for BMI, capillary density and function measures were significant predictors of SBP ( P<.01), fasting plasma glucose (P=.012, P=.03, and P=.004, respectively), and EF (P=.033, P=.001, and P=.009, respectively). However, none of the capillary measures were significant predictors of fasting insulin or IS. These capillaroscopy data demonstrated an association with SBP but not insulin resistance, suggesting that capillary measures are unlikely to explain the association between hypertension and insulin resistance, at least with modest degrees of blood pressure elevation.

GM1 Ganglioside in Parkinson's Disease: Results of a Five Year Open Study

Previous work demonstrated that short-term (i.e., 16 weeks) use of GM1 ganglioside resulted in significant symptom reduction in Parkinson's disease (PD) patients. As GM1 use may have long-term benefit for PD patients, the present study was conducted to evaluate the long-term safety and efficacy of GM1 in PD patients. Twenty-six patients who concluded a previous randomized double blind placebo controlled trial of GM1 volunteered for this open-extension study. At the end of 5 years of GM1 use, patients generally had lower Unified Parkinson's Disease Rating Scale (UPDRS) motor scores (assessed during a practically defined "off" period) than at baseline prior to randomization into the original study. A similar result was found for UPDRS Activities of Daily Living scores. Performance of timed motor tests also remained mostly stable over the 5 year observation period. No consistent clinically significant changes in blood chemistry, hematologic indices or urine chemistry were noted over the course of this study. These results suggest that long-term GM1 use by PD patients is safe and may provide some clinical benefit for PD patients. Additional study is required to more completely assess the degree to which GM1 treatment may be a symptomatic and/or disease-modifying agent for treatment of PD.

Over-the-counter Analgesics in Cirrhotic Patients: a Case-control Study Examining the Risk of Hospitalization for Liver-associated Events

To assess the association between over-the-counter analgesic (OTCA) use and hospitalization for liver-associated events in cirrhotic patients.

Regulation of Transforming Growth Factor-beta1 by Insulin in Prediabetic African Americans

Insulin resistance has been associated with kidney disease even in the absence of diabetes; however, pathways linking insulin resistance to kidney disease are unclear. The purpose of this study was to determine if transforming growth factor (TGF)-beta1, a key cytokine associated with kidney disease, responds to circulating levels of glucose and/or insulin. Urinary TGF-beta1 levels were measured in 249 young adult African Americans (mean age 40) at baseline, after an oral glucose tolerance test and after a euglycemic hyperinsulinemic clamp procedure. Baseline urinary geometric mean TGF-beta1 levels were somewhat lower in those with normal compared with the impaired glucose tolerance. The urinary TGF-beta1 level increased by 56% followed by a 23% decrease in the normal glucose tolerance group, changes that were significant and corresponded to the changes in the plasma glucose and insulin concentrations. The impaired tolerance group showed little change in the urinary TGF-beta1 level following glucose ingestion. All participants had a significant increase in urinary TGF-beta1 level after steady-state hyperinsulinemia, with sustained euglycemia during the clamp procedure in both of the groups. At baseline, there was a significant correlation between the urinary TGF-beta1 level and urinary albumin excretion. Thus our results suggest that insulin contributes to increased TGF-beta1 production and possible early renal injury in prediabetic young African Americans.

Efficacy of Morning-only Compared with Split-dose Polyethylene Glycol Electrolyte Solution for Afternoon Colonoscopy: a Randomized Controlled Single-blind Study

Administering a purgative close to the time of colonoscopy is optimal for cleansing. The aim of this study was to compare the efficacy and tolerability of morning-only (AM-only) polyethylene glycol electrolyte solution (PEG-ELS) to split-dose (PM/AM) PEG-ELS for afternoon colonoscopy.

Alterations in Capillary Morphology Are Found in Mild Blood Pressure Elevation

Remodeling of small resistance arteries is an early sign of target organ damage in hypertension. Peripheral capillary morphology abnormalities in hypertension are not well studied. The study objective was to determine whether altered capillary morphology is associated with SBP, DBP, or both in individuals without and with mild blood pressure elevation (SBP = 130-160 mmHg). Another objective was to determine whether capillary morphology is associated with minimum forearm vascular resistance, a measure of altered resistance artery structure.

Endothelin-1 Response to Glucose and Insulin Among African Americans

Endothelin-1 (ET-1) is implicated in the pathogenesis of hypertension. In vitro studies demonstrate that ET-1 is upregulated by insulin and glucose. The purpose of this study was to determine the effects of insulin and glucose on ET-1 levels in young adult African Americans, a population with a high burden of hypertension and diabetes. Plasma and urine ET-1 levels were measured before and after an oral glucose tolerance test (OGTT) and insulin clamp procedure in 288 participants. Subjects were classified according to glucose tolerance and blood pressure (BP) status. Plasma and urine ET-1 were not significantly different among the glucose tolerance groups. There was a trend toward increased plasma ET-1 among those with diabetes compared with impaired glucose tolerance and normal glucose tolerance; however, this was not statistically significant (P = .085). According to BP status, plasma ET-1 was highest among the high BP group compared with the normal BP group (P = .01). After glucose challenge, plasma ET-1 levels decreased and urine ET-1 increased in all three BP groups (P = .037). Our data show that plasma ET-1 is higher among young adult African Americans with hypertension compared with normotension. Urine ET-1 levels increased in response to glucose challenge, possibly indicating early renal injury.

Mediated Decision Support in Prostate Cancer Screening: a Randomized Controlled Trial of Decision Counseling

This randomized trial was conducted to assess the impact of a mediated decision support intervention on primary care patient prostate cancer screening knowledge, decisional conflict, informed decision making (IDM), and screening.

A Retrospective Analysis of the Use of Caspofungin in Recipients of Liver Transplant with a Modified High Index of Suspicion for Fungal Infection. A Critical Review of Mortality, Acute Cellular Rejection, Infections, and Changes in the Liver Function Tests While on Caspofungin

This study is a retrospective analysis of death, adverse events (AE), fungal infections, and hepatic function among recipients of liver transplantation at high risk of fungal infection who received prophylactic treatment with caspofungin. After reviewing data of 105 patients who had received isolated liver transplant between January 2003 and April 2007, we identified and analyzed 82 high-risk patients. Post-transplant patients at high risk for fungal infection are commonly defined by the presence of at least one of the following: (i) re-transplantation; (ii) re-operation; (iii) renal dysfunction. However, in our practice, patients are also considered at high risk for developing fungal infections if they present with the following: (iv) fever of unknown origin; (v) hypothermia; (vi) positive random culture for fungus at the time of transplant (bile and/or ascites); (vii) sepsis; (viii) use of vasopressors; (ix) re-intubation, during the first hospitalization after liver transplant; (x) prolonged intubation (>24 h), and (xi) acute respiratory distress syndrome, until negative fungal cultures are obtained. Exact conditional logistic regression was used to compare the risk of death, AEs, and fungal infections between patients who received caspofungin, other antifungal drugs, and no antifungal drugs. Analyses were then performed with SAS 9.1 (SAS Institute Inc., Cary, NC, USA). Patients were between 27 and 72 yr old (mean = 55), with two-thirds male and three-quarters Caucasian. Sixteen patients received caspofungin (11 preventively), and 32 received other antifungal (26 preventively). There were no proven fungal infections among the patients who received caspofungin, three infections among patients who received other antifungal (3/26 = 12%), and 14 infections among patients who were not preventively treated (14/45 = 31%). These infection rates were significantly different across the three groups (p = 0.029), with caspofungin and other antifungal preventive treatment comparable (p = 0.540), and both better than no preventive treatment at all (OR = 0.15, p = 0.049, for caspofungin versus no preventive treatment; OR = 0.29, p = 0.085, for other antifungal versus no preventive treatment). Caspofungin appears to be an effective preventive agent against fungal infections when used in recipients of liver transplant designated as high risk for fungal infection. Usage of caspofungin in these patients does not carry an apparent increase in risk of death or acute cellular rejection, although we observed a significantly higher risk of AEs, especially acute renal failure (p = 0.001), in patients who received this agent.

Obesity and Other Predictors of Absenteeism in Philadelphia School Children

Limited data indicate that obese children are absent from school more than their normal-weight peers. We analyzed administrative data from a large urban school district to investigate the association of obesity and student sociodemographic characteristics with absenteeism.

Race/Ethnicity, Gender, Weight Status, and Colorectal Cancer Screening

Background. The literature on colorectal cancer (CRC) screening is contradictory regarding the impact of weight status on CRC screening. This study was intended to determine if CRC screening rates among 2005 National Health Interview Survey (NHIS) respondent racial/ethnic and gender subgroups were influenced by weight status. Methods. Univariable and multivariable logistic regression analyses were performed to determine if CRC screening use differed significantly among obese, overweight, and normal-weight individuals in race/ethnic and gender subgroups. Results. Multivariable analyses showed that CRC screening rates did not differ significantly for individuals within these subgroups who were obese or overweight as compared to their normal-weight peers. Conclusion. Weight status does not contribute to disparities in CRC screening in race/ethnicity and gender subgroups.

Measuring Informed Decision Making About Prostate Cancer Screening in Primary Care

To measure the extent of informed decision making (IDM) about prostate cancer screening in physician-patient encounters, describe the coding process, and assess the reliability of the IDM measure.

Central Blood Pressures Are Associated with Left Ventricular Mass Index Among African-American Adolescents

There is a high burden of premature cardiovascular disease (CVD) among African Americans. Measures of central aortic blood pressure (CASP) and wave reflection are predictive of CVD risk in adults, but there is a paucity of data regarding the relation of these measures to target organ damage among adolescents. The objective of this study was to examine the relationship between CASP, central pulse pressure (CPP), and augmentation index (AI) with left ventricular mass index (LVMI).

Autophagy Inhibition Synergistically Enhances Anticancer Efficacy of RAMBA, VN/12-1 in SKBR-3 Cells, and Tumor Xenografts

VN/12-1 is a novel retinoic acid metabolism blocking agent discovered in our laboratory. The purpose of the study was to elucidate the molecular mechanism of anticancer activity of VN/12-1 in breast cancer cell lines and in tumor xenografts. We investigated the effects of VN/12-1 on induction of autophagy and apoptosis in SKBR-3 cells. Furthermore, we also examined the impact of pharmacologic and genomic inhibition of autophagy on anticancer activity of VN/12-1. Finally, the antitumor activity of VN/12-1 was evaluated as a single agent and in combination with autophagy inhibitor chloroquine in an SKBR-3 mouse xenograft model. Short exposure of low dose (<10 μmol/L) of VN/12-1 induced endoplasmic reticulum stress, autophagy, and inhibited G(1)-S phase transition and caused a protective response. However, a higher dose of VN/12-1 initiated apoptosis in vitro. Inhibition of autophagy using either pharmacologic inhibitors or RNA interference of Beclin-1 enhanced anticancer activity induced by VN/12-1 in SKBR-3 cells by triggering apoptosis. Importantly, VN/12-1 (5 mg/kg twice weekly) and the combination of VN/12-1 (5 mg/kg twice weekly) + chloroquine (50 mg/kg twice weekly) significantly suppressed established SKBR-3 tumor growth by 81.4% (P < 0.001 vs. control) and 96.2% (P < 0.001 vs. control), respectively. Our novel findings suggest that VN/12-1 may be useful as a single agent or in combination with autophagy inhibitors for treating human breast cancers. Our data provides a strong rationale for clinical evaluation of VN/12-1 as single agent or in combination with autophagy inhibitors.

Stage of Change and Other Predictors of Participant Retention in a Behavioral Weight Management Program in Primary Care

High attrition often limits the efficacy of weight management programs, particularly those that serve primary care patients. We investigated stage of change and other predictors of retention in a behavioral intervention program that enrolled adult obese patients at three primary care sites. The program included practice improvements and provider training, as well as individual lifestyle counseling and educational group classes for participants. We analyzed predictors of whether participants returned for counseling visits and whether they attended group classes. The 461 participants were mainly women (84%) and minorities (87%), and most of them were in the preparation stage for dietary and physical activity changes. A total of 134 (29%) participants returned for at least one follow-up visit with their counselor and 85 (18%) attended at least one class. Baseline stage of change was not significantly associated with either return visits or class attendance (p = .875 and .182, respectively). Men and participants with children in the household were less likely to return for subsequent counseling sessions (p = .012 and .027, respectively). Age and employment were associated with class attendance (p = .099 and .034, respectively). Focus groups with participants confirmed that reasons for dropout included physical limitations or health issues, family issues, stress, and lack of social support. We conclude that prescreening of patients for readiness to participate and attention to personal barriers related to family and work might improve program retention. More frequent contacts between visits and stronger provider engagement might also strengthen the intervention.

Identifying Potential Adverse Effects by Patients' Ratings: a Proof-of-concept Study of a Novel Approach

Methods to evaluate adverse effects of medications are significantly underdeveloped compared to those for efficacy. In this pilot proof-of-concept study, we preliminarily compared a novel approach-the Symptom Assessment Tool (SAT)-to a systematic and detailed assessment by a physician for identifying symptoms that were potentially adverse effects (sensitivity) and excluding symptoms that were unlikely to be adverse effects (specificity).

Limited Sampling Estimates of Epigallocatechin Gallate Exposures in Cirrhotic and Noncirrhotic Patients with Hepatitis C After Single Oral Doses of Green Tea Extract

Epigallocatechin-3-gallate (EGCG) has antiangiogenic, antioxidant, and antifibrotic properties that may have therapeutic potential for the treatment of cirrhosis induced by hepatitis C virus (HCV). However, cirrhosis might affect EGCG disposition and augment its reported dose-dependent hepatotoxic potential.

The Effect on Colon Visualization During Colonoscopy of the Addition of Simethicone to Polyethylene Glycol-electrolyte Solution: a Randomized Single-blind Study

Colonic bubbles associated with polyethylene glycol-electrolyte solution (PEG-ELS) are common and obscure mucosal visualization. This study aimed to determine whether adding simethicone decreases the incidence of bubbles.

A Randomized Controlled Trial of a Tailored Navigation and a Standard Intervention in Colorectal Cancer Screening

This randomized, controlled trial assessed the impact of a tailored navigation intervention versus a standard mailed intervention on colorectal cancer screening adherence and screening decision stage (SDS).

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