Curalin supplement for patients with type 2 diabetes mellitus.

OBJECTIVE: To examine the efficacy and safety of Curalin supplement in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adult patients with type 2 diabetes were randomized 1:1 to receive Curalin supplement or placebo. The primary endpoint was HbA1c decrease at 1 month. The secondary endpoint was a decrease in HbA1c by more than 0.5% and 1% and a change in 7 daily blood glucose measurements. A satisfaction questionnaire was used as an exploratory endpoint. Safety variables and adverse events were assessed. RESULTS: After 1 month of intervention, HbA1c was reduced by 0.94% in the Curalin arm versus 0.4% in the placebo arm (P = 0.008). 72% of Curalin patients had decreased HbA1c levels >0.5% versus 35% in the placebo arm (P < 0.05). The Treatment Satisfaction Questionnaire indicated that Curalin arm patients reported higher overall satisfaction. CONCLUSIONS: Curalin treatment significantly reduced HbA1c over a 1-month period and was well-tolerated.

Thyroid function control among pregnant women following a therapeutic thyroidectomy.

OBJECTIVES: The aim of this study was to assess the extent of thyroid function control among pregnant women who had previously undergone a therapeutic thyroidectomy. DESIGN: Retrospective cohort study. SETTING: The largest health maintenance organization in Israel. PARTICIPANTS: All female patients who were pregnant between May, 2001 and September, 2012 and had a medical history of thyroid surgery. MAIN OUTCOME MEASURE: The thyroid-stimulating hormone (TSH) levels throughout the pregnancy were compared to recommended trimestral values. A multivariate analysis was performed to determine risk factors for not attaining TSH recommended range. RESULTS: A total of 477 females with a history of thyroid surgery had given 701 births during the study period. Forty-three percent (n = 203), had thyroidal malignancy. Nearly half of the women underwent total thyroidectomy (43.4%, n = 207). The women's TSH values were within the recommended range in only 60% (n = 350) of the pregnancies during the first trimester (0.1-2.5 mIU/L), in 61% (n = 335) during the second trimester (0.2-3 mIU/L), and in 70% (n = 338) during the third trimester (0.3-3 mIU/L). In multivariate analysis, women that underwent a total thyroidectomy due to a benign thyroid disease, were at the highest risk for not attaining target TSH levels. CONCLUSIONS: This very large cohort of pregnant women with a past history of thyroid surgery demonstrated a significant percentage of pregnancies with TSH values above the recommended range. Women that underwent a total thyroidectomy due to benign thyroid disease were at the highest risk for gestational hypothyroidism.

Improving blood glucose level predictability using machine learning.

This study was designed to improve blood glucose level predictability and future hypoglycemic and hyperglycemic event alerts through a novel patient-specific supervised-machine-learning (SML) analysis of glucose level based on a continuous-glucose-monitoring system (CGM) that needs no human intervention, and minimises false-positive alerts. The CGM data over 7 to 50 non-consecutive days from 11 type-1 diabetic patients aged 18 to 39 with a mean HbA1C of 7.5% ± 1.2% were analysed using four SML models. The algorithm was constructed to choose the best-fit model for each patient. Several statistical parameters were calculated to aggregate the magnitudes of the prediction errors. The personalised solutions provided by the algorithm were effective in predicting glucose levels 30 minutes after the last measurement. The average root-mean-square-error was 20.48 mg/dL and the average absolute-mean-error was 15.36 mg/dL when the best-fit model was selected for each patient. Using the best-fit-model, the true-positive-hypoglycemia-prediction-rate was 64%, whereas the false-positive- rate was 4.0%, and the false-negative-rate was 0.015%. Similar results were found even when only CGM samples below 70 were considered. The true-positive-hyperglycemia-prediction-rate was 61%. State-of-the-art SML tools are effective in predicting the glucose level values of patients with type-1diabetes and notifying these patients of future hypoglycemic and hyperglycemic events, thus improving glycemic control. The algorithm can be used to improve the calculation of the basal insulin rate and bolus insulin, and suitable for a closed loop "artificial pancreas" system. The algorithm provides a personalised medical solution that can successfully identify the best-fit method for each patient.

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). METHODS: An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. RESULTS: Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). CONCLUSION: Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Are bisphosphonates an indispensable tool in the era of targeted therapy for renal cell carcinoma and bone metastases?

One third of patients with metastatic renal cell carcinoma (RCC) suffer from bone metastases. Skeletal involvement in RCC is associated with the occurrence of skeletal-related events, and may negatively impact on the outcome of patients treated with systemic therapies. In patients with RCC and bone metastases, therapies that inhibit osteoclasts, as bisphosphonates and denosumab, are used as adjunct to systemic targeted therapies to prevent skeletal-related events. Data suggest that they may also improve the outcome of systemic targeted therapies. Herein we review the preclinical and clinical data on their use, as well as remaining open questions.

Pretreatment neutrophil-to-lymphocyte ratio in metastatic castration-resistant prostate cancer patients treated with ketoconazole: association with outcome and predictive nomogram.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole. METHODS: This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis. RESULTS: Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups. CONCLUSIONS: In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.

Different Factors Are Associated With Sex Hormones and Leydig Cell Function in Israelis and Palestinians in Jerusalem.

Total testosterone (TT) is known to influence health and virility in men. Among men from United States and Europe, numerous sociodemographic and lifestyle factors were reported to be associated with TT. However, associations with TT and Leydig cell function in the Middle East are poorly described. A cross-sectional, population-based sample had a structured interview, physical examinations, and blood tests in two hospitals in Jerusalem, Israel. A subsample (25- to 44-year-old men, n = 286: 124 Israelis, 162 Palestinians) had sex hormone measurements. The primary outcomes were TT and free testosterone/luteinizing hormone (FT/LH) ratio, representing Leydig cell function. Associations with sociodemographic and lifestyle factors, body mass index (BMI), and physical activity (PA) were evaluated using multivariable linear regression. Compared with Palestinians, Israelis had similar TT (4.81 vs. 5.09 ng/mL, p = .405) and higher FT/LH (31.2 vs. 25.8 ng/IU, p = .002). In ln-transformed values, marital status had a stronger association in Palestinians (P for interaction = 0.03). Age, BMI, and PA had a stronger association with TT in Israelis with significant interactions with ethnicity. BMI <25 and a higher PA quartile were associated with a higher TT (p < .001). Among Israelis, age (p = .007), married marital status (p = .007), and BMI <25 were significantly associated with FT/LH. No associations of any factors were identified among Palestinians. Associations with several modifiable factors identified in Western samples were replicated in Israelis and to a lesser degree in Palestinians. Different relationships of several factors with TT and FT/LH could result from ethnically diverse genetic, sociodemographic, and behavioral characteristics that warrant further research.

Vitamin D deficiency prevalence and cardiovascular risk in Israel.

BACKGROUND: Accumulated data in the past years suggest that vitamin D deficiency has an adverse effect on cardiovascular (CVD) health and that its prevalence is significantly higher among patients with CVD risk factors, contributing to the pathogenesis of CVD. MATERIALS AND METHODS: This is a cross-sectional analysis of a relatively large database derived from a health care maintenance organization. The population consisted of individuals 18 years and older who had undergone blood tests for vitamin D levels for any reason during 2001-2008. RESULTS: The study population consisted of 34,874 individuals: 26,699 (76·6%) were women at a mean ± SD age of 55 ± 15 and 8175 men (23·4%) aged 55 ± 17. The mean ± SD vitamin D level was 23·2 ± 10·1 and 22·7 ± 9·9 for men and women, respectively. The prevalence of vitamin D deficiency or insufficiency (vitamin D levels < 30 ng mL(-1)) for the entire study population was surprisingly high for men and women (79·2% and 77·5%, respectively). This remained consistent with only little variation when stratified by age. The group with vitamin D < 15 ng mL(-1) vs. the group with vitamin D levels ≥ 30 ng mL(-1) demonstrated a significant (P < 0·031) age-adjusted odds ratios for the presence of hypertension, diabetes mellitus, dyslipidemia, obesity and peripheral vascular disease for women (OR = 1·19; 1·65; 1·13; 2·28; 1·85, respectively), and the presence of all the above except hypertension in men (OR = 1·51; 1·28; 2·06; 1·73, respectively). CONCLUSIONS: Vitamin D deficiency is associated with CVD and other risk factors in this Israeli study population. The prevalence of the deficiency in Israel is similar to the prevalence found in less sunny regions.

Expression and significance of EGFR in malignant peripheral nerve sheath tumor.

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma. Epidermal growth factor receptor (EGFR) may play a putative role in its pathogenesis, and be targeted for therapeutic purposes. The study was aimed at investigating the expression and prognostic influence of EGFR in MPNST. Primary and metastatic MPNSTs were immunostained with antibodies to EGFR. The total EGFR expression (membranous and cytoplasmic) was analyzed by morphometry, grade of positivity and the intensity (score 0-3). An EGFR composite score (range 0-300) was calculated by multiplying the intensity by the grade. A composite score >10 was considered as EGFR overexpression. Score was correlated with clinical behavior. Forty-three percentage of 46 patients with MPNST overexpressed EGFR in the primary tumor, and had a higher prevalence of advanced-stage tumors (>or=IIc, 46% vs. 80%, P = 0.011). Patients without overexpression had a higher prevalence of tumors with a low mitotic rate (31% vs. 0%, P = 0.049). Neurofibromatosis was more prevalent in patients with EGFR overexpression (75% vs. 42%, P = 0.007). Five year disease free survival (mean 30.1 vs. 17.4 months, P = 0.048), time to progression (mean 9.2 vs. 5.2 months, P = 0.005) and 5 year survival (52% vs. 25%, P = 0.041, mean 54 vs. 43 months) were significantly higher among patients without overexpression. EGFR appeared to play a role in MPNST progression. EGFR overexpression was correlated with worse prognostic variables and course. Clinical trials of targeting EGFR in MPNST are warranted.

Effect of Flash Glucose Monitoring Technology on Glycemic Control and Treatment Satisfaction in Patients With Type 2 Diabetes.

OBJECTIVE: To assess treatment satisfaction and the effectiveness of a flash glucose monitoring (FGM) system in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODS: A total of 101 patients with type 2 diabetes on multiple daily insulin injections (MDI) for at least 1 year were assigned randomly to the FGM intervention (n = 53) or the standard care (control) group (n = 48) and followed for 10 weeks. Both groups were instructed to adjust their insulin doses in face-to-face and telephone visits. Satisfaction with treatment, quality of life, comfort using FGM, HbA1c, and frequency of hypoglycemic events were evaluated. RESULTS: The intervention group found treatment significantly more flexible (P = 0.019) and would recommend it to their counterparts (P = 0.023). Satisfaction using the FGM system was high. The changes in HbA1c were -0.82% (9 mmol/mol) vs. -0.33% (3.6 mmol/mol) in the intervention and control group, respectively (P = 0.005); in nonprespecified post hoc analysis, 68.6% of the patients in the intervention group had their HbA1c reduced by ≥0.5% (5.5 mmol/mol) compared with 30.2% in the control group (P < 0.001), and 39.2% had their HbA1c reduced by ≥1.0% (10.9 mmol/mol) vs. 18.6% in the control group (P = 0.0023) without an increased frequency of hypoglycemia. CONCLUSIONS: FGM tends to improve treatment satisfaction and may lead to amelioration of glycemic control in patients with type 2 diabetes on MDI without increasing the frequency of hypoglycemia.

Severe central obesity or diabetes can replace weight loss in the detection of frailty in obese younger elderly - a preliminary study.

PURPOSE: Unwanted weight loss is one of the established criteria for the diagnosis of frailty. However, the relevance of this criterion to detect frailty in obese older adults has not been assessed. In particular, with the exception of malignancy, unwanted weight loss is not commonly seen in older obese subjects. Therefore, we tested the possibility that some obesity phenotypes and/or diabetes might be more useful in the detection of frailty in this setting. PATIENTS AND METHODS: A preliminary cross-sectional study of 50 consecutive subjects was conducted at The Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center. Inclusion criteria were: young elderly (aged 65-75 years), with general and/or abdominal obesity, without cancer. Frailty was assessed directly using the Fried model, the five-item fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL) scale. Eventually, in the assessment of frailty, the weight loss criterion was replaced by one or several of obesity/diabetes-related variables each time: severity of obesity by body mass index, waist circumference (and their interaction), body fat, and diabetes. The receiver operating characteristic curves for functional impairment indices were plotted to compare the usefulness of the frailty accepted and adjusted models. RESULTS: The prevalence of frailty and pre-frailty in this cohort were 7/50 (14%) and 27/50 (54%), respectively, but unwanted weight loss was seen in three subjects (6%) only. The level of abdominal obesity had the strongest correlation with functional score (r=0.292, P<0.05). Frailty models which included either severe abdominal obesity or diabetes in lieu of unwanted weight loss had good sensitivity rates per each frailty score as compared with the original Fried model. CONCLUSION: For detecting and/or screening for the frailty syndrome in obese young elderly, the level of abdominal obesity or diabetes may provide a useful marker.

Correction: The effect of CAG repeats length on differences in hirsutism among healthy Israeli women of different ethnicities.

[This corrects the article DOI: 10.1371/journal.pone.0195046.].

The effect of CAG repeats length on differences in hirsutism among healthy Israeli women of different ethnicities.

PURPOSE: Variations in the degree of hirsutism among women of different ethnic backgrounds may stem from multiple etiologies. Shorter length of the polymorphic CAG repeats of the androgen receptor (AR) gene may be associated with increased activity of the receptor leading to hirsutism. We hypothesized that there are ethnic differences in the degree of hirsutism that is unrelated to androgen levels among Israeli women, and that the CAG repeats length may contribute to these differences. Anti-androgenic therapies, such as spironolactone, could be suggested if a shorter CAG repeats length is found to affect the difference in the degree of hirsutism between the ethnic groups. METHODS: Healthy Israeli Jewish women aged 18-45 years of Ashkenazi and non-Ashkenazi origin were invited to participate. Hirsutism was assessed using the simplified Ferriman-Gallwey (sFG) score, and serum total testosterone levels were measured as well. The CAG repeats length was determined by PCR. Methylation-sensitive methods were used to detect the fractional activity of each allele, and the weighted mean was calculated for the CAG repeats length. RESULTS: One-hundred and eight women were recruited (49 Ashkenazi and 59 non-Ashkenazi). The Ashkenazi women had a significantly lower degree of hirsutism (P<0.01), lower mean BMI (P = 0.003), total testosterone levels (P = 0.017), and longer weighted bi-allelic CAG repeats mean (P = 0.015) compared to non-Ashkenazi women. For the group as a whole, there was a significant negative correlation between the number of CAG repeats in the AR gene and the sFG score, while the number of repeats was not related to testosterone levels. Stepwise logistic regression revealed that ethnic origin and the CAG repeats length were the strongest factors affecting hirsutism (P<0.001, P = 0.03, respectively). CONCLUSIONS: There is a significant difference in the degree of hirsutism between Ashkenazi and non-Ashkenazi women in Israel that is partially explained by CAG repeats length.

Metformin Use and Outcome of Sunitinib Treatment in Patients With Diabetes and Metastatic Renal Cell Carcinoma.

BACKGROUND: Although studies in several cancer types suggest that metformin has antitumor activity, its effect on the outcome of targeted therapies in metastatic renal cell carcinoma (mRCC) is poorly defined. We aimed to analyze the effect of metformin use on the outcome of sunitinib treatment in diabetic patients with mRCC. PATIENTS AND METHODS: We performed a retrospective study of diabetic patients with mRCC, who were treated with sunitinib in 8 centers across 2 countries. Patients were divided into metformin users and nonusers. The effect of metformin use on response rate, progression-free survival (PFS), and overall survival (OS), was tested. Furthermore, univariate and multivariate analyses of the association between clinicopathologic factors and metformin use, and outcome were performed using the entire patient cohort. RESULTS: Between 2004 and 2014, 108 diabetic patients with mRCC were treated with sunitinib. There were 52 metformin users (group 1) and 56 nonusers (group 2). The groups were balanced regarding clinicopathologic factors. Clinical benefit (partial response + stable disease) in group 1 versus 2 was 96% versus 84% (P = .054). Median PFS was 15 versus 11.5 months (P = .1). Median OS was 32 versus 21 months (P = .001). In multivariate analyses of the entire patient cohort (n = 108), factors associated with PFS were active smoking and pretreatment neutrophil to lymphocyte ratio > 3. Factors associated with OS were metformin use (hazard ratio, 0.21; P < .0001), Heng risk, active smoking, liver metastases, and pretreatment neutrophil to lymphocyte ratio > 3. CONCLUSION: Metformin might improve the OS of diabetic patients with mRCC who are treated with sunitinib.

Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug.

OBJECTIVES: The goal of this study was to determine how often atrioventricular (AV) block is really caused by medications. BACKGROUND: Beta-blockers, verapamil, and diltiazem are considered a cause of AV block for which pacemaker implantation is not indicated. However, it is not known if such patients can expect a benign course after discontinuation of the culprit medication. METHODS: Consecutive patients with II or III degree AV block not related to acute myocardial infarction, digitalis toxicity, or vasovagal syncope were studied. The level of AV block (AV-nodal or infranodal) was defined by electrocardiographic criteria. The cause and effect relation between AV block and drugs was defined according to the response to drug discontinuation. RESULTS: Of 169 patients with AV block, 92 (54%) were receiving beta-blockers and/or verapamil or diltiazem. Patients receiving medications had similar clinical and electrocardiographic characteristics with patients who had AV block in the absence of drugs. Drug discontinuation was followed by resolution of AV block in 41% of cases, whereas spontaneous improvement of AV conduction occurred in 23% of patients who had AV block in the absence of drugs. However, 56% of the patients for whom drug discontinuation led to resolution of AV block had recurrence of AV block in the absence of therapy. Atrioventricular block that was "truly caused by drugs" was found in only 15% of patients who had II or III degree AV block during therapy with beta-blockers, verapamil, or diltiazem. CONCLUSIONS: Atrioventricular block is commonly "related to drugs" but is rarely "caused by drugs."

Intravenous chlorpromazine for the emergency treatment of uncontrolled symptomatic hypertension in the pre-hospital setting: data from 500 consecutive cases.

BACKGROUND: Chlorpromazine is a dopamine-receptor antagonist antipsychotic agent. Because of its strong alpha-blocking and sedative actions, it has also been used as emergency therapy for extreme arterial hypertension. Published reports to date have included very small numbers of patients (i.e., 5-30). OBJECTIVES: To analyze data on almost 500 patients who received intravenous chlorpromazine for the emergency treatment of uncontrolled symptomatic hypertension in the pre-hospital setting. METHODS: We reviewed data from 496 consecutive patients who received intravenous chlorpromazine as emergency therapy for uncontrolled symptomatic hypertension. Chlorpromazine was injected intravenously. The dose was 1 mg every 2-5 minutes until the systolic pressure was < or =140 mmHg and the diastolic pressure < or =100 mmHg with alleviation of symptoms. RESULTS: The mean dose of chlorpromazine administered was 4.5 +/- 5 mg (range 1-50 mg). Only 33 patients (7%) required >10 mg. Chlorpromazine reduced systolic BP from 222.82 +/- 26.31 to 164.93 +/- 22.66 mmHg (P< 0.001) and diastolic BP from 113.5 +/-16.63 to 85.83 +/- 11.61 mmHg (P< 0.001). The sinus rate decreased from 97.9 +/- 23.5 to 92.2 +/- 19.7 beats per minute (P< 0.001). These results were achieved within the first 37 +/- 11 minutes. CONCLUSIONS: Intravenous chlorpromazine is safe and effective when used as emergency treatment for uncontrolled symptomatic hypertension.

Is idiopathic ventricular fibrillation a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls.

OBJECTIVE: The purpose of this study was to determine if patients with idiopathic ventricular fibrillation (VF) have shorter QT intervals than comparable healthy controls. BACKGROUND: The upper limit of the normal QT is well defined. Less is known about the lower limit of the normal QT. Patients with the recently described "short QT syndrome" have characteristics resembling those of patients with idiopathic VF. METHODS: The ECGs of 28 consecutive patients with idiopathic VF (17 men and 11 women, age 31 +/- 17 years) were compared to those of 270 age- and gender- matched healthy controls. Based on published literature, we defined "short QT" as QTc < or = 360 ms for males and < or = 370 ms for females. RESULTS: Despite significant overlapping, the QTc of males with idiopathic VF was shorter than the QTc of healthy males (371 +/- 22 ms vs 385 +/- 19 ms, P = .034). Short QT intervals were found more frequently among males with idiopathic VF (35% vs 10%, P = .003). No such differences were apparent among women. Short QTc intervals were more commonly seen during bradycardia. However, the correlation between short QT and a history of VF was independent of heart rate. CONCLUSIONS: "Short" QTc values are commonly seen in male patients with idiopathic VF. However, "short" QTc values are not rare among healthy adults, especially at slow heart rates. Further studies are needed to define when a given QT is really "too short."

The Proatherogenic Effect of Chronic Nitric Oxide Synthesis Inhibition in ApoE-Null Mice Is Dependent on the Presence of PPAR α.

Inhibition of endothelial nitric oxide synthase (eNOS) accelerates atherosclerosis in ApoE-null mice by impairing the balance between angiotensin II (AII) and NO. Our previous data suggested a role for PPAR α in the deleterious effect of the renin-angiotensin system (RAS). We tested the hypothesis that ApoE-null mice lacking PPAR α (DKO mice) would be resistant to the proatherogenic effect of NOS inhibition. DKO mice fed a Western diet were immune to the 23% worsening in aortic sinus plaque area seen in the ApoE-null animals under 12 weeks of NOS inhibition with a subpressor dose of L-NAME, P = 0.002. This was accompanied by a doubling of reactive oxygen species (ROS-) generating aortic NADPH oxidase activity (a target of AII, which paralleled Nox1 expression) and by a 10-fold excess of the proatherogenic iNOS, P < 0.01. L-NAME also caused a doubling of aortic renin and angiotensinogen mRNA level in the ApoE-null mice but not in the DKO, and it upregulated eNOS in the DKO mice only. These data suggest that, in the ApoE-null mouse, PPAR α contributes to the proatherogenic effect of unopposed RAS/AII action induced by L-NAME, an effect which is associated with Nox1 and iNOS induction, and is independent of blood pressure and serum lipids.

The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma.

BACKGROUND: Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). The neutrophil to lymphocyte ratio (NLR), an index of systemic inflammation, is associated with outcome in several cancer types. AIMS: To study the association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival (PFS) and overall survival (OS) of patients treated with sunitinib for mRCC. METHODS: We retrospectively studied an unselected cohort of patients with mRCC, who were treated with sunitinib. Logistic regression model was used to analyse response rate. Cox regression models were fitted to identify risk factors associated with PFS and OS. We investigated how pre-treatment NLR is associated with these clinical outcomes after adjusting for confounding covariates. Regression tree for censored data method was used to find the best NLR cut-off value. RESULTS: Between 2004 and 2011, 133 patients with mRCC were treated with sunitinib. One hundred and nine were included in the NLR analysis, from which were excluded patients without available data on pre-treatment NLR or with comorbidities/recent treatments known to be associated with a change of blood counts. Factors associated with PFS were low NLR ≤ 3 (HR = 0.285, p < 0.001), past nephrectomy (HR = 0.38, p = 0.035), sunitinib dose reduction/treatment interruption (HR = 0.6, p = 0.014) and the use of antiotensin system inhibitors (HR = 0.537, p = 0.008). Low NLR ≤ 3 was associated with OS (HR = 0.3, p = 0.043). CONCLUSIONS: In patients with mRCC treated with sunitinib, pre-treatment NLR may be associated with PFS and OS. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.

Low-dose calcitriol decreases aortic renin, blood pressure, and atherosclerosis in apoe-null mice.

AIMS: To determine whether low-dose calcitriol attenuates atherosclerosis in apoE-null mice and, if so, through which predominant mechanism. METHODS: Starting at the age of 6 weeks, mice received intraperitoneal injections of either 0.25 ng/g body weight of calcitriol or the vehicle, every other day for 8 weeks. RESULTS: Calcitriol treatment resulted in 35% reduction of atherosclerosis at the aortic sinus, and in a significant decrease in blood pressure. These effects were possibly mediated by downregulation of the renin-angiotensin system (RAS), as there was a 64% decrease in the aortic level of renin mRNA. None of the other components of the RAS or the prorenin receptor were affected by treatment. Low-dose calcitriol treatment did not modify the plasma level of monocyte chemoattractant protein-1, interferon γ, interleukin-4 and interleukin-10, which were similar in control and treated mice. Likewise, there was no difference in the percentage of splenic Foxp3+ regulatory T cells. Calcitriol treatment resulted in an unfavorable metabolic profile (glucose and lipids), as determined after a limited fast, a difference that disappeared after food was withheld for a longer time. CONCLUSIONS: At a relatively low dosage, calcitriol attenuates the development of atherosclerosis in apoE-null mice, most probably by down regulation of RAS, and not through immunomodulation; however, even at this low dose, calcitriol appears to elevate calcium and to have potentially adverse metabolic effects. Exploring the potential antiatherogenic effects of non-calcemic and safer analogues is therefore warranted.