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At least 613 records · Page 34Linked to original sources
PubMed2004

Folic acid improves endothelial function in children and adolescents with type 1 diabetes.

OBJECTIVE: To evaluate the effect of folate supplementation on endothelial function in children and adolescents with type 1 diabetes. STUDY DESIGN: Thirty-six subjects with type 1 diabetes age 13.6+/-2.6 years completed a randomized, double-blind, placebo-controlled crossover trial. Each subject received 8 weeks of oral folic acid (5 mg/d) and 8 weeks of placebo, with an 8-week washout period. Before and after each intervention, we assessed endothelial function by using brachial artery responses to flow (flow-mediated dilatation [FMD]) and glyceryl trinitrate, von Willebrand factor, glucose, hemoglobin A1c, total plasma homocyst(e)ine (tHcy), vitamin B(12), serum folate, and red cell folate (RCF). RESULTS: Folic acid increased FMD by 2.58 (3.1-5.7) % (95% confidence interval, 1.28-3.88), whereas placebo did not change FMD (-0.42%; 95% confidence interval, -1.67 to 0.83; P<.001). Folic acid increased serum folate by 14 nmol/L (6.2 ng/mL, P<.001) and RCF by 467.2 nmol/L (206 ng/mL, P<.001). Change in FMD was related to change in serum folate (r=0.46, P=.005) and RCF (r=0.39, P=.02). Glyceryl trinitrate responses, von Willebrand factor, tHcy, and hemoglobin A1c were not affected by the intervention. CONCLUSIONS: Short-term high-dose folic acid improves endothelial function in children and adolescents with type 1 diabetes and normal folate status independently of tHcy.

Administration, Oral↗
PubMed2007

Acute acalculous cholecystitis as the initial presentation of primary Epstein-Barr virus infection.

The case of a 13-year-old girl with primary Epstein-Barr virus (EBV) infection and concomitant cholestatic hepatitis, which initially presented as acute acalculous cholecystitis (AAC), is described. The diagnosis of AAC was documented by clinical and ultrasonographic criteria, whereas acute EBV infection was confirmed serologically. AAC may develop during the course of acute EBV infection, especially in patients with cholestatic hepatitis.

Acalculous Cholecystitis↗
PubMed2007

Predicting the histology of renal masses using preoperative Doppler ultrasonography.

PURPOSE: Traditional imaging techniques cannot differentiate among benign, indolent and malignant renal neoplasms. Since conventional clear cell carcinomas are highly vascular, we used preoperative color and/or power Doppler ultrasonography to evaluate the association between vascular flow in a renal mass and surgical pathology. MATERIALS AND METHODS: Nephrectomies performed at our institution between January 2001 and December 2004 were retrospectively evaluated. Any detection of flow in the renal mass on color Doppler ultrasonography was defined as vascular flow. A prospective validation study was then performed from January 2005 to October 2005 and a nomogram was constructed to predict clear cell histology. RESULTS: Of 299 renal lesions in the retrospective cohort 210 (70%) had evidence of vascular flow, including 156 of 169 conventional clear cell carcinomas (92%) (p <0.0001). On logistic regression analysis vascular flow was associated with conventional clear cell histology (OR 16.9, 95% CI 8.7-32.8; p <0.0001). This finding was validated prospectively in 97 patients. Vascular flow was detected in 54 of 65 renal masses (83%) with conventional clear cell histology (p <0.0001), which was associated with an OR of 10.8 (95% CI 4.0-29.0; p <0.0001). A nomogram incorporating vascular flow along with clinical variables (clinical size, patient sex and age) to predict conventional clear cell histology was constructed on the retrospective cohort and validated on the prospective data set (concordance index 0.82 and 0.76, respectively). CONCLUSIONS: Vascular flow detected by color Doppler ultrasonography is strongly associated with conventional clear cell histology. A nomogram incorporating vascular flow on color Doppler ultrasonography and clinical parameters may aid in the preoperative characterization of renal lesions.

Adult↗
PubMed2004

Assessment of DNA damage by comet assay on frozen total blood: method and evaluation in smokers and non-smokers.

This study was undertaken with the aim to develop an optimised protocol for the evaluation of DNA damage in frozen whole blood. This was achieved by use of the single-cell gel electrophoresis (SCGE) or comet assay in its alkaline version. After collection of blood, the total blood sample was mixed with dimethyl sulfoxide (DMSO), a cryoprotectant commonly used for prevention of freezing-induced damage to living cells, and then stored at -80 degrees C. We observed no statistically significant differences in the level of DNA damage between fresh blood samples and frozen blood samples, as assessed by the comet assay. Considering the absence of effects of the freezing step, a frozen blood sample was included as a control sample in subsequent experiments. Thus the protocol was applied to blood samples of twenty healthy subjects including smokers and non-smokers. The comparative analysis indicated that the level of DNA damage was 56% higher in smokers than in non-smokers (P = 0.01). Altogether, this study strongly suggests that frozen whole blood could be utilised in association with the comet assay in human epidemiological bio-monitoring for the assessment of genetic damage in populations at risk.

Blood↗
PubMed2026

Targeting SUV4-20H2-mediated H4K20 methylation restrains growth and migration in pediatric high-grade astrocytomas.

Pediatric astrocytomas are characterized by increased molecular and clinical heterogeneity with epigenetic alterations contributing to aggressiveness and therapy resistance. The repressive histone mark H4K20 trimethylation (H4K20me3) and the methyltransferase SUV4-20H2 (KMT5C) are critical regulators of chromatin integrity and genome stability, with limited investigation in pediatric astrocytomas. KMT5C mRNA levels were evaluated in a publicly available pediatric gliomas database using bioinformatic analysis. Investigation of SUV4-20H2 and H4K20me3 expression was performed in a cohort of 43 pediatric astrocytoma tissues by immunohistochemistry. Their functional role and mechanism of action was investigated in pediatric glioma cell lines by using the substrate-competitive inhibitor of SUV4-20, A-196. Cell viability, apoptosis and migration were assessed using XTT, cleaved PARP, and wound healing assays, respectively. Effects of treatment on H4K20 methylation, DNA damage, mitotic stress [Polo-like kinase (PLK1) expression], and invasion markers (N-cadherin, &#x3b2;-catenin expression) were examined by western immunoblotting. KMT5C mRNA was significantly enriched in pediatric high-grade astrocytomas compared to low-grade tumors. A significant elevation of SUV4-20H2 and H4K20me3 expression was detected in astrocytoma tissues indicating epigenetic dysregulation contributing to malignancy. Treatment with A-196 reduced cell proliferation of pediatric glioma cell lines and induced apoptosis in a dose-dependent manner. It further impaired cell migration, accompanied by reduced N-cadherin and &#x3b2;-catenin expression. Mechanistically, inhibition of SUV4-20 depleted H4K20me3, inducing chromatin destabilization, replication-associated DNA damage and was associated with increased PLK1 expression, consistent with activation of a mitotic stress response. Our findings indicate that SUV4-20H2-mediated H4K20 activity in pediatric high-grade astrocytomas maintains their growth and migratory potential by regulating chromatin integrity and may serve as potential therapeutic target.

H4K20me2/3↗
PubMedDate not supplied

Transformation for health: a framework for health disparities research.

The task of generating knowledge addressing disparities in health among vulnerable populations in American society is explored. The community-based participatory approach as an alternate paradigm to traditional research is mentioned as a process for understanding the realities of the populations of interest. Identification and testing of mediating and moderating variables is suggested to guide the process of increasing knowledge regarding health disparities. Transformation for Health is proposed as a conceptual framework to study how these third variables influence the relationship between the primary variables of interest. A theoretical example is offered describing the application of the framework to study the mediators and moderators in an investigation of childhood obesity. Analytical challenges in the exploration of "third variables" are described, and the authors recommend that salient methodological issues should be addressed when conducting these types of investigations.

Attitude of Health Personnel↗
PubMed2006

Homozygous MTHFR C677T gene mutation and recurrent stroke in an infant.

The role of homozygosity for the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene as an independent risk factor for primary and recurrent stroke has been questioned, although recent data appear to be supportive. However, the association of homozygous C677T MTHFR mutation with silent brain infarctions in infancy has not been reported. The authors describe an 11-month-old male who had suffered a silent brain infarction followed by a symptomatic arterial stroke. The evaluation revealed mildly elevated homocysteine levels secondary to homozygous C677T alleles for MTHFR and iron deficiency anemia. An extensive evaluation for other causes of infarction was negative. We suggest that the mother's homozygous MTHFR status played a role in the early onset of stroke and that iron deficiency anemia may have contributed to the recurrence. The patient was treated with anticoagulation therapy, folic acid, and iron supplementation and has not had a recurrent event during 3 years of follow-up. This case provides further evidence that homozygous MTHFR mutation is a predisposing factor for early and recurrent pediatric stroke, including silent infarcts, especially in the presence of other risk factors.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed2005

Under the skin: Biotransformation of para-aminophenol and para-phenylenediamine in reconstructed human epidermis and human hepatocytes.

We investigated the biotransformation of the oxidative arylamine (AA) hair dye ingredients [14C]-para-aminophenol (PAP) and [14C]-para-phenylenediamine (PPD) in reconstructed human epidermis and human hepatocytes. Human epidermis quantitatively transformed PAP to its N-acetylated derivative (APAP), whereas hepatocytes transformed PAP to sulfate or glucuronic acid conjugates of APAP or PAP as well as free APAP. Epidermis and hepatocytes converted PPD to N-mono- (MAPPD) and N,N'-di-acetylated (DAPPD) derivatives. At higher concentrations of PPD (250-1000 microM), epidermis or hepatocytes produced more of the MAPPD, whereas concentrations below 250 microM and lower favoured formation of the DAPPD metabolite. When compared with epidermis, human hepatocytes had a three-fold or eight-fold greater capacity for generation of MAPPD or DAPPD, respectively. No evidence of transformation of PAP or PPD to N-hydroxylated derivatives was found in epidermis or hepatocytes. Our results suggest that (i) after dermal absorption of PAP or PPD, humans are systemically exposed to acetylated derivatives; (ii) current in vitro skin absorption studies may be inadapated for determination of human systemic exposure to AAs due to reduced or absent metabolic capacity of non-viable skin; (iii) due to qualitative differences between dermal and hepatic metabolism, oral toxicity studies may be unsuited for the hazard assessment of dermal exposure to AAs; and (iv) use of induced rodent liver S9 metabolic activation systems for in vitro genotoxicity studies may produce misleading results on the hazard of human dermal exposure to AAs. In conclusion, our data support the growing evidence that AAs are transformed in human skin and suggest that current practices of safety assessment of AAs should take these findings into account.

Aminophenols↗
PubMed2004

Age-structured optimal control in population economics.

This paper brings both intertemporal and age-dependent features to a theory of population policy at the macro-level. A Lotka-type renewal model of population dynamics is combined with a Solow/Ramsey economy. We consider a social planner who maximizes an aggregate intertemporal utility function which depends on per capita consumption. As control policies we consider migration and saving rate (both age-dependent). By using a new maximum principle for age-structured control systems we derive meaningful results for the optimal migration and saving rate in an aging population. The model used in the numerical calculations is calibrated for Austria.

Adult↗
PubMed2006

Insulin-like growth factor-I stimulates H4II rat hepatoma cell proliferation: dominant role of PI-3'K/Akt signaling.

Although hepatocytes are the primary source of endocrine IGF-I and -II in mammals, their autocrine/paracrine role in the dysregulation of proliferation and apoptosis during hepatocarcinogenesis and in hepatocarcinomas (HCC) remains to be elucidated. Indeed, IGF-II and type-I IGF receptors are overexpressed in HCC cells, and IGF-I is synthesized in adjacent non-tumoral liver tissue. In the present study, we have investigated the effects of type-I IGF receptor signaling on H4II rat hepatoma cell proliferation, as estimated by 3H-thymidine incorporation into DNA. IGF-I stimulated the rate of DNA synthesis of serum-deprived H4II cells, stimulation being maximal 3 h after the onset of IGF-I treatment and remaining elevated until at least 6 h. The IGF-I-induced increase in DNA replication was abolished by LY294002 and only partially inhibited by PD98059, suggesting that phosphoinositol-3' kinase (PI-3'K) and to a lesser extent MEK/Erk signaling were involved. Furthermore, the 3- to 19-fold activation of the Erks in the presence of LY294002 suggested a down-regulation of the MEK/Erk cascade by PI-3'K signaling. Finally, the effect of IGF-I on DNA replication was almost completely abolished in clones of H4II cells expressing a dominant-negative form of Akt but was unaltered by rapamycin treatment of wild-type H4II cells. Altogether, these data support the notion that the stimulation of H4II rat hepatoma cell proliferation by IGF-I is especially dependent on Akt activation but independent on the Akt/mTOR signaling.

Animals↗
PubMed2006

The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center.

OBJECTIVES: To describe the incidence of symptomatic postoperative lower-extremity lymphedema in women treated for uterine corpus cancer, and to evaluate its relationship to regional lymph node removal and postoperative therapy. METHODS: A retrospective chart review of all patients with uterine corpus cancer managed over a 12-year period (1/93-12/04). All patients had a hysterectomy as part of their therapy. We identified patients with leg lymphedema - as described by the physician or reported by the patient - through medical records. We excluded cases of leg edema that developed secondary to medical conditions such as cardiovascular and renal disease, venous thrombosis, and end-stage recurrent malignancy. Lymphedema dermal changes and related fibrosis were graded using the common terminology criteria for adverse events. RESULTS: In all, 1,289 patients with uterine corpus malignancy were evaluated. We excluded other chronic lower-extremity edema that was related to a variety of medical conditions in 74 patients (5.7%). With a median follow-up of 3 years (interquartile range, 1.1-5.4 years), new symptomatic post-treatment lower-extremity lymphedema was noted in 16 patients. Patients who had lymph nodes removed at initial surgery had a higher rate of developing lymphedema (16/670, 2.4%) than those who did not (0/619, 0%) (P = 0.0001). Furthermore, symptomatic lymphedema was limited to patients who had 10 or more regional lymph nodes removed 16/469 (3.4%). Lymphedema was noted at a median of 5.3 months after surgery (range, 1-32 months). Lymphedema was unilateral in 11 patients (69%) and bilateral in 5 (31%); moreover, it was considered grade 1 in 12 patients (75%) and grade 2 in 4 (25%). Age, weight, stage, type of hysterectomy, and type of postoperative adjuvant therapy were not associated with lymphedema. CONCLUSIONS: To date, this is the largest series evaluating symptomatic lower-extremity lymphedema in women with uterine corpus cancer. Patients who had 10 or more regional lymph nodes removed at initial surgery appeared to be at higher risk for developing new symptomatic leg lymphedema. Patients undergoing surgery with lymphadenectomy for uterine corpus malignancy should be informed about the possibility of postoperative new symptomatic leg lymphedema. A prospective evaluation of leg lymphedema is needed to accurately determine the incidence, severity, and risk factors of this complication.

Adult↗
PubMed2006

CA125 level as a predictor of progression-free survival and overall survival in ovarian cancer patients with surgically defined disease status prior to the initiation of intraperitoneal consolidation therapy.

OBJECTIVES: Recent data suggest that differences in CA125 levels within the normal range may predict progression-free survival (PFS), but limited information is available regarding the value of these differences in predicting overall survival (OS) in patients with epithelial ovarian cancer. The objective of this study was to determine whether CA125 is an independent predictor of OS in patients with surgically defined disease status at the end of primary therapy prior to intraperitoneal (IP) consolidation chemotherapy. A secondary objective was to assess the relationship of CA125 level to PFS. METHODS: Using data from a retrospective cohort of 433 patients who received intraperitoneal (IP) therapy following primary treatment for ovarian cancer between 1984 and 1998, we identified 241 patients with a complete clinical response and CA125 data at the time of second-look surgery prior to IP chemotherapy. Patient demographics and updated follow-up status were abstracted from medical records. Kaplan-Meier survival curves were compared using the log-rank test, and Cox regression models were used for multivariate analysis. RESULTS: The majority of patients had advanced stage III or IV disease (n=201, 83%) and high-grade histology (n=163, 68%). Taxane was used as part of primary platinum-based therapy in 56% (n=134) of patients, and subsequent IP chemotherapy was platinum-based in 85% (n=206). When considered as a continuous variable, CA125 was a predictor of OS (P=0.029). Using the median CA125 level in our study group as a cut-off, OS was increased in patients with CA125 < or =12 U/ml (median 5.8 years) compared with >12 (3.7 years) (P=0.0027). CA125 level was an independent predictor of OS (HR: 1.410; 95% CI, 1.044, 1.904, P=0.0248) in a multivariate model that included stage (P=0.0166), grade (P=0.0001), and findings at second-look surgery (P=0.0003). CA125 level was also a predictor of clinical PFS (radiographic or CA125 elevation criteria alone) in a subset of 161 patients as a continuous variable (P=0.0036), and when divided at the median (< or = or >12; median 2.8 years vs. 1.7 years; P=0.0017). CONCLUSIONS: In our study population, CA125 level at the end of primary therapy was a predictor of OS and PFS when considered as a continuous variable, or when divided at the median (< or = or >12 U/ml). Further prospective study is required to optimize clinically significant cut-off values within the normal range of CA125 levels for both OS and PFS endpoints.

Adult↗
PubMed2006

Preoperative serum YKL-40 is a marker for detection and prognosis of endometrial cancer.

OBJECTIVE: YKL-40 is a secreted glycoprotein of the chitinase family that has been previously described as a diagnostic and prognostic marker for a number of cancers, including epithelial ovarian cancer. In this study, we examined the frequency of serum elevation as well as the diagnostic and prognostic significance of this serum marker in endometrial cancer. MATERIALS AND METHODS: Preoperative serum levels of YKL-40 and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) for all endometrial cancer patient samples (34) available in the Memorial Sloan-Kettering Cancer Center Gynecology Service Tissue Bank between the years 1987 and 2002, and compared to a cohort of normal individuals. A YKL-40 value of 61 ng/mL has previously been determined to represent the upper limit of normal. YKL-40 values were correlated with clinical characteristics, including patient age, tumor grade, histology, clinical stage, and clinical outcome (progression-free survival [PFS] and overall survival [OS]). RESULTS: YKL-40 was elevated (>61 ng/mL) in 26 (76%) of 34 endometrial cancer patients compared with elevations of CA125 in 21 (62%) of 34 patients (P=0.09). Twenty-eight (82%) of all 34 patients had elevations of either CA125 or YKL-40 or both; 16 (89%) of 18 advanced-stage endometrial cancer patients had elevation of at least one of these two markers. Median preoperative YKL-40 value was 137 ng/mL (range, 22-1738 ng/mL) for endometrial cancer patients compared with 28 ng/mL (range, 15-72 ng/mL) for normal healthy subjects (P<0.0001). There was no statistically significant association of YKL-40 with patient age, tumor grade, histology, or stage. Elevation of YKL-40 (>80 ng/mL) was correlated with poor clinical outcome in univariate analysis, but was not demonstrated in multivariate analysis. At 5 years' follow-up, the PFS rate was 80% for patients with YKL-40<80 ng/mL compared with 43% for patients with YKL-40>80 ng/mL (P=0.004). The 5-year OS rate for patients with YKL-40<80 ng/mL was 79% compared with 48% for patients with YKL-40>80 ng/mL (P=0.047). CONCLUSION: Preoperative serum YKL-40 is frequently elevated and may represent a novel marker for the detection of endometrial cancer and the identification of high-risk subsets of patients with worse clinical outcome. Further investigation of this promising endometrial cancer marker in larger studies is warranted.

Adipokines↗
PubMed2002

A co-culture-based model of human blood-brain barrier: application to active transport of indinavir and in vivo-in vitro correlation.

The growing array of in vitro models of the blood-brain barrier (BBB) which have been used makes it difficult to draw firm conclusions concerning the BBB penetration of HIV-1 protease inhibitors. What is needed is a combined in vivo and in vitro study on biological models that mimic as closely as possible the normal human BBB, to establish whether and how indinavir crosses the BBB. We developed a new human BBB model using primary endothelial cells and astrocytes. The biological relevance of this model was checked with respect on the one hand, to the close relationship between the log of drug permeability coefficient normalized to molecular weight and the log of the 1-octanol/water partition coefficient, and on the other hand to the functional P-glycoprotein (P-gp) expression. We employed this model to perform transport studies with indinavir and showed that the rate of in vitro indinavir transport from the basal to apical compartment was higher than the rate of apical to basal transport. Pretreatment of the BBB model with the P-gp inhibitor, quinidine, significantly increased apical to basal transport. Intracellular indinavir accumulation was increased in BBB as a result of inhibition of active transport. These data were correlated with the indinavir-mediated P-gp ATPase modulation showing that indinavir specifically interacted with a binding site on P-gp. Moreover, the activation of P-gp ATPase by indinavir was inhibited by quinidine. In addition, the in vivo brain to plasma concentration ratio of indinavir into mice showed that indinavir concentration was up to five times higher in the brain of mdr1a(-/-) mice than in the brain of mdr1a(+/+) mice. All these results confirm the role of P-gp in preventing the passage of indinavir across BBB and thus its entry into the central nervous system (CNS). Our human BBB model represents a useful tool for the evaluation of drug penetration into the CNS.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

[Cardiovascular disease in HIV-infected patients on highly active antiretroviral therapy].

BACKGROUND AND OBJECTIVE: Our goal was to assess the main characteristics of cardiovascular disease in HIV-infected patients on highly active antiretroviral therapy (HAART). PATIENTS AND METHOD: Retrospective analysis of the clinico-epidemiological characteristics of 16 HIV-infected patients treated with HAART who had suffered a cardiovascular event from a 1,459 patients' cohort. RESULTS: Clinical presentation of cardiovascular disease was an acute coronary syndrome in 12 cases, ischemic stroke in 2 and peripheral vascular disease in 2. Patients included in the study had a mean of 3.2 cardiovascular risk factors, smoking and low HDL levels being the more prevalent risk factors. Eight (50%, 95% CI, 25-75%) patients fulfilled the criteria of metabolic syndrome. The mean CD4 count was 548 x 10(6)/l. CONCLUSIONS: HIV-infected patients on HAART ha-ve a high cardiovascular risk. A strict management of modifiable risk factors must be warranted in these patients.

Adult↗
PubMed2002

Visually- and motor-based knowledge of letters: evidence from a pure alexic patient.

We describe a patient, VSB, whose reading was impaired as a consequence of a left temporal-parietal lesion, whereas writing was relatively preserved. At variance with other pure alexic patients described in the literature, VSB claimed to have become unable to mentally visualise letters and words. Indeed, his performance on a series of tests tapping visual mental imagery for orthographic material was severely impaired. However, performance on the same tests was dramatically ameliorated by allowing VSB to trace each item with his finger. Visual mental imagery for non-orthographic items was comparatively spared. The pattern of dissociation shown by VSB between impaired visual mental imagery and relatively preserved motor-based knowledge for orthographic material lends support to the view that separate codes, respectively based on visual appearance and on motor engrams, may be used to access knowledge of the visual form of letters and words.

Alexia, Pure↗
PubMed2003

Actin dynamics control SRF activity by regulation of its coactivator MAL.

Rho GTPases regulate the transcription factor SRF via their ability to induce actin polymerization. SRF activity responds to G actin, but the mechanism of this has remained unclear. We show that Rho-actin signaling regulates the subcellular localization of the myocardin-related SRF coactivator MAL, rearranged in t(1;22)(p13;q13) AML. The MAL-SRF interaction displays the predicted properties of a Rho-regulated SRF cofactor. MAL is predominantly cytoplasmic in serum-starved cells, but accumulates in the nucleus following serum stimulation. Activation of the Rho-actin signaling pathway is necessary and sufficient to promote MAL nuclear accumulation. MAL N-terminal sequences, including two RPEL motifs, are required for the response to signaling, while other regions mediate its nuclear export (or cytoplasmic retention) and nuclear import. MAL associates with unpolymerized actin through its RPEL motifs. Constitutively cytoplasmic MAL derivatives interfere with MAL redistribution and Rho-actin signaling to SRF. MAL associates with several SRF target promoters regulated via the Rho-actin pathway.

3T3 Cells↗