An in vivo role for Rho kinase activation in the tumour vascular disrupting activity of combretastatin A-4 3-O-phosphate

Background and Purpose

Combretastatin A-4 3-O-phosphate (CA4P) is in clinical trial as a tumour vascular disrupting agent (VDA) but the cause of blood flow disruption is unclear. We tested the hypothesis that activation of Rho/Rho kinase (ROCK) is fundamental to the effects of this drug in vivo.

Experimental Approach

Mouse models of human colorectal carcinoma (SW1222 and LS174T) were used. Effects of the ROCK inhibitor, Y27632, alone or in combination with CA4P, on ROCK activity, vascular function, necrosis and immune cell infiltration in solid tumours were determined. Mean arterial BP (MABP) was measured to monitor systemic interactions and the vasodilator, hydralazine, was used to control for the hypotensive effects of Y27632.

Key Results

Y27632 caused a rapid drop in blood flow in SW1222 tumours, with recovery by around 3 h, which was paralleled by MABP changes. Y27632 pretreatment reduced CA4P-induced ROCK activation and partially blocked CA4P-induced tumour vascular effects, in both tumour types. Y27632 also partially inhibited CA4P-induced tumour necrosis and was associated with reduced immune cell infiltration in SW1222 tumours. Hydralazine caused a similar hypotensive effect as Y27632 but had no protective effect against CA4P treatment.

Conclusions and Implications

These results demonstrate that ROCK activity is critical for full manifestation of the vascular activity of CA4P in vivo, providing the evidence for pharmacological intervention to enhance the anti-tumour efficacy of CA4P and related VDAs.     

Andrographolide inhibits human serum albumin fibril formations through site-specific molecular interactions

Protein misfolding and fibrillation are the fundamental traits in degenerative diseases like Alzheimer''s, Parkinsonism, and diabetes mellitus. Bioactives such as flavonoids and terpenoids from plant sources are known to express protective effects against an array of diseases including diabetes, Alzheimer''s and obesity. Andrographolide (AG), a labdane diterpenoid is prescribed widely in the Indian and Chinese health care systems for classical efficacy against a number of degenerative diseases. This work presents an in depth study on the effects of AG on protein fibrillating pathophysiology. Thioflavin T fluorescence spectroscopy and DLS results indicated concentration dependent inhibition of human serum albumin (HSA) fibrillation. The results were confirmed by electron microscopy studies. HSA fibril formations were markedly reduced in the presence of AG. Fluorescence studies and UV-Vis experiments confirmed further that AG molecularly interacts with HSA at site. In silico molecular docking studies revealed hydrogen bonding and hydrophobic interactions with HSA in the native state. Thus AG interacts with HSA, stabilizes the native protein structure and inhibits fibrillation. The results demonstrated that the compound possesses anti-amyloidogenic properties and can be promising against some human degenerative diseases.

Andrographolide inhibited HSA protein fibrillation through site specific interactions.     

The burden of diabetes and impaired fasting glucose in India using the ADA 1997 criteria: prevalence of diabetes in India study (PODIS)

This random multistage cross sectional population survey was undertaken to determine the prevalence of diabetes mellitus (DM) and impaired fasting glycemia/glucose (IFG) in subjects aged 25 years and above in India. The study was carried out in 108 centers (49 urban and 59 rural) to reflect the size and heterogeneity of the Indian population. 41,270 (20,534 males and 20,736 females) subjects were studied. 21,516 (10,865 males and 10,651 females) were from urban areas and 19,754 (9669 males and 10,085 females) from rural areas. Blood samples were taken after a fast of 10-12h and the subjects were categorized as having IFG or DM using the 1997 American Diabetes Association criteria. The age and gender standardized prevalence rate for DM and IFG in the total Indian population was 3.3 and 3.6% respectively (P < 0.001). The standardized prevalence of DM and IFG in urban areas was significantly higher than that for the rural population (urban DM prevalence 4.6% versus rural DM prevalence 1.9%, P < 0.001; urban IFG prevalence 4.8% versus rural IFG prevalence 2.5%, P < 0.001). There was no statistically significant difference in the prevalence between DM (4.6%) and IFG (4.8%) in the urban population. The rural prevalence of IFG (2.5%) was significantly (P <0.001) more than the rural prevalence of DM (1.9%). Type 2 diabetes is a major health problem is India.     

An unusual cause of recurrent abdominal pain

Abdominal pain is a common complaint with diverse etiologies. We describe an unusual case of recurrent abdominal pain in an adult due to lead poisoning, a condition usually associated with childhood. A previously healthy 42-yr-old man presented with 2 days of severe crampy abdominal pain and a 1-month history of constipation. Physical examination was remarkable for diffuse abdominal pain but peritoneal signs were not present. Blood tests were remarkable for hematocrit of 33 and mean cell volume of 78, with ovalocytes and basophilic stippling on blood smear. Abdominal x-ray showed stool throughout the colon and a nonspecific bowel gas pattern. The patient was treated with intravenous fluids and enemas, and his symptoms resolved within 2 days. Repeat history taking revealed he had been stripping paint from an old Victorian house in the preceding few months. He was discharged after a blood lead level was obtained. Before his clinic appointment he was readmitted 2 days later with recurrent abdominal pain. His blood lead level was elevated at 110 microg/dl (toxic range). After consultation with the Occupational Health and Safety Administration and local poison control service, he was treated with intravenous calcium edetate disodium and intramuscular dimercaprol. He was asymptomatic at discharge, with a level of 56 microg/dl. Two weeks later, a repeat level was elevated at 72 microg/dl, for which he received a 3-wk course of oral dimercaptosuccimer. Subsequent levels were unremarkable, and the patient remains asymptomatic. Abdominal pain secondary to lead poisoning in adults is uncommon. This case highlights the importance of taking a detailed occupational history and appropriately using "routine" blood tests to diagnose a rare condition that presented with a common complaint.     

Myocardial electrophysiological properties in the presence of an AT1 angiotensin II receptor antagonist

Introduction Blockade of the AT₁ angiotensin II (Ang II) receptor has been shown to provide antihypertensive effects. However, whether AT₁ Ang II receptor antagonists influence myocardial electrophysiological properties remains unclear.Methods and results Accordingly, atrial and ventricular myocardial electrophysiological properties were examined in adult rat (n=13) and guinea pig (n=9) myocardial preparations in the presence of the specific AT₁ Ang II receptor antagonist, valsartan (CGP 48933; 0.5, 5, or 500 mol/L). These concentrations reflect up to 100 fold higher drug concentrations than those observed in clinical trials. Transmembrane potential data were recorded using standard microelectrode techniques at baseline and following superfusion with valsartan. The lower concentrations of valsartan (0.5 and 5 mol/L) had minimal effects on myocardial electrophysiology. In the presence of 500 mol/L of valsartan, resting membrane potential increased from baseline in both rat (–82.3±4.1 vs –76.8±5.8 mV, p<0.05) and guinea pig (–81.6±2.9 vs –76.9±2.0 mV, p<0.05) atrial myocardium. Action potential duration at 90% repolarization was increased in guinea pig atrial (91.7±1.4 vs 80.0±5.6 ms, p<0.05) and ventricular (131.1±8.1 vs 118.7±8.3 ms, p<0.05) myocardium following exposure to 500 mol/L of valsartan. In a separate series of experiments Ang II (1.0 mol/L) had no effect on atrial or ventricular action potential characteristics in either species.Conclusion Thus, the effects of valsartan, which were observed only at concentrations 100 fold higher than those reported in clinical trials, may be due to non-specific drug interactions with the myocyte sarcolemma.     

Chronic low-level arsenic exposure reduces lung function in male population without skin lesions

Objectives

The respiratory effects of chronic low-level arsenic exposure from groundwater have been investigated in West Bengal, India.

Methods

The participants (834 non-smoking adult males) were subdivided in two groups: an arsenic-exposed group (n = 446, mean age 35.3 years) drinking arsenic-contaminated groundwater (11–50 μg/L) and a control group of 388 age-matched men drinking water containing <10 μg/L of arsenic. Arsenic in water samples was measured by atomic absorption spectroscopy. The prevalence of respiratory symptoms was documented by structured, validated questionnaire. Pulmonary function test (PFT) was assessed by portable spirometer.

Results

Compared with control, the arsenic-exposed subjects had higher prevalence of upper and lower respiratory symptoms, dyspnea, asthma, eye irritation and headache. Besides, 20.6 % of arsenic-exposed subjects had lung function deficits (predominantly restrictive and combined types) compared with 13.6 % of control (p < 0.05). A positive association was observed between arsenic concentration in drinking water and the prevalence of respiratory symptoms, while a negative association existed between arsenic level and spirometric parameters.

Conclusions

The findings suggest that even low-level arsenic exposure has deleterious respiratory effects.     

Evaluation of the relationship between weight change and glycemic control after initiation of antidiabetic therapy in patients with type 2 diabetes using electronic medical record data

Aims

This study evaluates the relationship between HbA1c and weight change outcomes by anti-diabetic weight-effect properties in patients newly treated for type 2 diabetes; a relationship not previously characterized.

Methods

Electronic medical records of patients with type 2 diabetes newly prescribed anti-diabetic monotherapy were assessed to identify HbA1c goal attainment [(<53 mmol/mol)] and weight change at 1-year. Anti-diabetics were categorized by weight-effect properties: weight-gain (sulfonylureas, thiazolidinediones) and weight-loss/neutral (metformin, DPP-4 inhibitors, GLP-1 agonists). Logistic regression analyses identified likelihood of attaining HbA1c goal or ≥3% weight loss by anti-diabetic category controlling for baseline characteristics. MANOVA was used to identify correlation between changes in weight and HbA1c.

Results

The study included 28,290 patients. Mean age ± sd was 61 years ± 11.8. Baseline HbA1c was 7.4% ± 1.6 (57 mmol/mol ± 17); 67.3% were prescribed a weight-loss/neutral anti-diabetic. At 1-year, more patients in the weight-loss/neutral anti-diabetic category lost weight (≥3%) than in the weight-gain anti-diabetic category (40.4% vs. 24.2%, p < 0.001) or had an HbA1c < 7.0% (<53 mmol/mol) (71.1% vs. 63.8%, p < 0.001). Those prescribed a weight-gain anti-diabetic were 53% less likely to lose weight and 29% less likely to be at HbA1c goal than those prescribed a weight-loss/neutral anti-diabetic (p < 0.001). Weight loss and HbA1c outcomes were significantly correlated (p < 0.001).

Conclusions

Weight loss of ≥3% was associated with better glycemic control in patients newly treated for type 2 diabetes. Anti-diabetics associated with weight-loss/neutrality were associated with greater weight loss and HbA1c goal attainment and may facilitate efforts to co-manage weight and glycemia in the ambulatory-care setting.     

Predictive factors for latency period and a prognostic model for survival in patients with therapy‐related acute myeloid leukemia

Therapy‐related acute myeloid leukemia (t‐AML) is an increasingly recognized sequela in patients receiving chemotherapy or radiotherapy for a primary malignancy or autoimmune disease. This study assessed factors related to the latency period (LP) between the antecedent disorder (AD) and t‐AML diagnosis and developed a comprehensive prognostic model to predict overall survival (OS). We evaluated a cohort of newly diagnosed t‐AML patients treated with cytarabine‐based induction therapy from 2001 to 2011. Multivariable linear and proportional hazards models were used to assess the impact of different classes of chemotherapy on the LP and to identify independent prognostic factors for OS. Of 730 treated AML patients, 58 (7.9%) had t‐AML. Median LP to t‐AML was 5.6 years (range, 0.5–38.4). 64% of patients achieved CR and median OS was 10.7 months. Independent prognostic factors of short LP were age at AD (P < 0.0001) and prior treatment with mitotic inhibitors (P = 0.05). Unfavorable cytogenetics (P = 0.004), antecedent hematologic or autoimmune disease (P = 0.01), age >60 (P = 0.03), and platelet count <30,000 μL (P = 0.04) at the time of t‐AML diagnosis were prognostic for inferior OS. A prognostic model using these factors was developed that risk stratified t‐AML patients into two groups: favorable and unfavorable. Patients in the favorable group had a median OS of 37.6 months compared with 6.4 months in patients comprising the unfavorable group (P < 0.0001). Multicomponent prognostic models integrating disease or treatment‐related covariates can help better understand how t‐AML evolves; and can be clinically useful in risk stratifying t‐AML patients undergoing induction therapy. Am. J. Hematol. 89:168–173, 2014. © 2013 Wiley Periodicals, Inc.     

A diabetes perception study among rural and urban individuals of West Bengal,India: are we ready for the pandemic?

International Journal of Diabetes in Developing Countries - Type 2 diabetes is a pandemic in India, yet studies regarding knowledge, attitude, and practices in diabetes in various Indian...