Pharmacological management of South Asians with type 2 diabetes: Consensus recommendations from the South Asian Health Foundation.

South Asians constitute approximately 1.6 billion people from the Indian subcontinent, comprising Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka; and make up the largest diaspora globally. Compared to the White European population, this group is at a higher risk of developing type 2 diabetes along with cardiovascular, renal and eye complications. Over the recent years, a number of new therapies for type 2 diabetes have become available for which cardiovascular outcome trials (CVOTs) have been published. The recent ADA/EASD consensus guidelines on diabetes, pre-diabetes and cardiovascular diseases' offer a transitional shift in type 2 diabetes management. The new consensus recommendations are based on recent CVOTs, many of which had a representation of South Asian cohorts. In light of this new evidence, there is urgent need for an integrated, evidence-based, cost-effective and individualised approach specific for South Asians. This review takes into consideration the evidence from these CVOTs and provides best practice recommendations for optimal management of South Asian people with type 2 diabetes, alongside the previously published consensus report from South Asian Health Foundation in 2014 [1].

An Extension of the Bollinger Scoring System to Analyse the Distribution of Macrovascular Disease of the Lower Limb in Diabetes.

OBJECTIVE: While it is generally considered that patients with diabetes mellitus (DM) have more distal peripheral arterial disease (PAD), there is little information on how individual vessels are affected. The aim of this study was to adapt Bollinger's scoring system for lower limb angiograms (DSAs) to include the distal and planter vessels. The reliability of this extension was tested and was used to compare the distribution of disease in two cohorts of patients with and without DM. METHODS: Patients who had undergone DSA ± angioplasty for PAD at a single centre between September 2010 and April 2014 were identified. Twenty-five patients' images were reviewed by four clinicians and scored using an extended version of the Bollinger score. A total of 153 patients with DM were matched, for age, sex, ethnicity, smoking, and hypertension, with 153 patients without DM. The infrainguinal vessels were divided into 16 arterial segments, including plantar vessels, and scored using the Bollinger score. The score ranges from 0 to 15. Fifteen represents an arterial segment with more than 50% of its length occluded. Interobserver reliability was tested using interclass correlation (ICC) and Cohen's kappa coefficient. RESULTS: The ICC demonstrated good agreement between observers (0.76 [0.72-0.79]) with good internal consistency (Cronbach's alpha 0.93). When the Bollinger scores were categorised, the results were weaker, Cohen's kappa ranged from 0.39 (standard error 0.033) to 0.54 (0.030). Patients with DM had a higher burden of disease in the anterior tibial and posterior tibial arteries with relative sparing of the peroneal artery and no difference in the plantar vessels. CONCLUSION: It has been demonstrated that the Bollinger score can be extended to include the distal vessels. This amended scoring system can be used to compare the burden of distal disease in patients with PAD. How the score relates to clinical presentation and outcomes needs further investigation.

Evaluation of protective efficacy of flaxseed lignan-Secoisolariciresinol diglucoside against mercuric chloride-induced nephrotoxicity in rats.

The toxicity of heavy metals such as mercury (Hg) in humans and animals is well documented. The kidney is the primary deposition site of inorganic-Hg and target organ of its toxicity. The present study investigated the protective efficacy of flaxseed lignan-Secoisolariciresinol diglucoside (SDG) on nephrotoxicity induced by mercuric chloride (HgCl2). Rats were intraperitoneally injected with HgCl2 (2 mg/kg/day) and renal toxicity was induced. Subcutaneous administration of rats with SDG (5 mg/kg/day) as a pre-treatment caused a significant reversal of HgCl2 induced increase in blood urea, creatinine, glutathione s-transferase and catalase (CAT). On the other hand, administration of SDG with HgCl2 restored normal levels of albumin and superoxide dismutase (SOD). Histological examination of kidneys confirmed that pre-treatment of SDG before HgCl2 administration significantly reduced its pathological effects. Thus, the results of the present investigation suggest that SDG can significantly reduce renal damage, serum and tissue biochemical profiles caused by HgCl2 induced nephrotoxicity. Hence, SDG may be recommended for clinical trials in the treatment of kidney disorders caused by exposure to Hg.

Prescribing antibiotics in diabetic foot infection: what is the role of initial microscopy and culture of tissue samples?

The aim of this study was to evaluate the role of microscopy, Gram stain and the culture of tissue samples in the antibiotic treatment of patients with diabetic foot infection. A retrospective review of patients with a diabetic foot infection was undertaken. Data analysed included the severity of infection, antibiotic prescribing patterns, microscopy and culture results. A total of 71 patients were included, from whom 114 tissue samples were collected. Gram stain results were in agreement with final culture results in 45·8% (n = 54) of samples. Overall sensitivity and specificity of the Gram stains were low (74·5% and 69·8%, respectively), although the specificity for Gram-negative rods was high (98·5%). The presence or absence of 'pus cells' on microscopy was a poor predictor of culture results. Empirical prescribing of antibiotics was in accordance with local policy in 31·1% of patients, improving to 86·8 % following culture results. Microscopy, a skilled laboratory procedure, was generally a poor predictor of tissue culture results. However, the presence of Gram-negative rods was suggestive of isolation in the culture of such organisms and could allow the early broadening of antibiotic treatment. Despite initial poor compliance of empirical antibiotic treatment regimens, prescribing was adjusted in light of culture results, suggesting these were important for clinicians.

Flaxseed oil ameliorates mercuric chloride-induced liver damage in rats.

BACKGROUND: Mercury is a relentless pollutant, and its toxicity contributes to significant health problems due to exposure to the environment. The present study has determined the impact of flaxseed oil on mercuric chloride (HgCl2)-mediated hepatic oxidative toxicity in rats. METHODS: Twenty-four healthy male Wistar rats were divided into four groups with six animals in each group. Group-A was the Control group treated with saline; Group-B received 1.0 ml oral dosage of flaxseed oil; Group-C was given 200 µl intraperitoneal injection of HgCl2, and Group-D received 1.0 ml oral dosage of flaxseed oil (one hour after treatment with 200 µl intraperitoneal injection of HgCl2. RESULTS: Mercuric chloride (HgCl2) increased the production of malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH), and the concentration of HgCl2 in the liver tissue with a simultaneous decrease in the activities of Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Furthermore, serum HgCl2 elevated the activity of alanine transaminase (ALT) and Lactate dehydrogenase (LDH). Histopathological changes showed that liver injury was caused by mercuric chloride. Treatment with flaxseed oil ameliorated ROS production and reversed enzymes in serum and liver. Also, a noticeable improvement was observed in all the histopathological characteristics in the rats. CONCLUSIONS: The findings of this study concluded that flaxseed oil had an outstanding remedial effect on mercuric chloride-mediated hepatic cytotoxicity.

Secoisolariciresinol diglucoside protects against cadmium-induced oxidative stress-mediated renal toxicity in rats.

BACKGROUND: Cadmium is a well known environmental pollutant and strong toxic heavy metal, that causes oxidative damage to various organs of the body, including the kidney. Cadmium (II) chloride (CdCl2) is a water-soluble crystalline form, which exhibits a higher affinity with chlorides at the target site. The current study examined the protective effects of Secoisolariciresinol diglucoside (SDG), a principal lignan extracted from flaxseeds against CdCl2-induced renal toxicity in rats. METHODS: Twenty four healthy male Wistar rats with four groups of six animals each were used in the study. Group-1- Control was administered with saline. Group-2 -was treated with SDG; Group-3 with CdCl2 alone, and Group-4 were treated with CdCl2 plus SDG. The effect of Cd on kidney was assessed in terms of various parameters like lipid peroxidation, production of Nitric oxide (NO) and Myeloperoxidase (MPO), and kidney function markers like uric acid, urea, and creatinine. The levels of antioxidant molecules like glutathione content and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were also measured, apart from histopathological studies. RESULTS: The animals that received CdCl2, exhibited changes in the concentration of Cd in the kidney. The levels of kidney function markers like uric acid, urea, and creatinine were found to be abnormal in serum, and also there was a drastic decrease in the levels of glutathione content and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. The treatment of SDG significantly decreased (p < 0.05) the levels of NO and MPO in the animals treated with CdCl2 plus SDG when compared to the animal group treated with CdCl2 alone. The treatment of SDG before CdCl2 injection exhibited significant changes in the activity of the antioxidant enzymes, which was evidenced by the restoration in their activities, when compared to CdCl2 alone treated group (p < 0.05), as observed in the results of histopathology. CONCLUSIONS: The findings of the present investigation suggested that SDG exhibited anti-oxidant, anti-apoptotic and renoprotective properties. Thus, SDG may act as a supramolecular binding component and naturally occurring metal chelating agent for metal cations like Cd2+. Therefore, flaxseed lignan-SDG can be used as a therapeutic agent against nephrotoxicity caused by cadmium. However, detailed future studies are needed to know the underlying mechanism of action of SDG against the Cd and other heavy metals induced nephrotoxicity.

Albicidin, a potent DNA gyrase inhibitor with clinical potential.

The emergence of multiple antibiotic-resistant bacteria is a serious global problem which requires the development of new effective antimicrobial therapeutics. Albicidin produced by the sugarcane pathogen Xanthomonas albilineans is a potent DNA gyrase inhibitor with inhibitory effects significantly better than most DNA gyrase inhibitors. Albicidin acts primarily by inhibiting the religation of the cleaved DNA intermediate during the gyrase catalytic sequence similar to quinolones. The clinical realization of albicidin has been hampered by limited production and its unsolved structure. In this review, the relationship between albicidin and sugarcane leaf-scald disease is described. Furthermore, the biosynthesis and resistance mechanisms of albicidin are discussed. Finally, recent efforts to solve the structure and produce albicidin in a heterologous host and chemically are summarized.

Managing hypertension in people of African origin with diabetes: Evaluation of adherence to NICE Guidelines.

BACKGROUND: The pathophysiology of hypertension in people of African origin differs from other ethnicities. This effect may be exacerbated in people with type 2 diabetes mellitus (T2DM), hence control of hypertension is particularly important in this population. AIMS: The primary aim was to evaluate the adherence to National Institute of Clinical Excellence (NICE) guidance (National Guidelines NG28) for hypertension management in African origin patients with T2DM. METHODS: This study was done using electronic health records at a large primary care centre based in Birmingham, UK. Strict exclusion criteria were applied to identify individuals with T2DM, African origin patients and a diagnosis of hypertension. Retrospectively participants were identified, and NICE guideline adherence was assessed using descriptive statistics. RESULTS: 78 patients were included in the study of which 28 (36%) were on the NICE recommended combination of antihypertensives, suggesting poor adherence to the guidance in primary care prescribing. The blood pressure control of 35 (44.9%) patients was suboptimal, although this group received more frequent blood pressure monitoring. Microalbuminuria remains a problem in the suboptimal group. CONCLUSION: This study provides insight into adherence to NICE guidance for managing hypertension in African origin patients with diabetes. Further work should be done to explore the effects of hypertension in this ethnic group and if there is a need for a more refined management guideline.

A Review of Distribution of Atherosclerosis in the Lower Limb Arteries of Patients With Diabetes Mellitus and Peripheral Vascular Disease.

OBJECTIVE: There is a generally accepted hypothesis that patients with diabetes mellitus (DM) have a higher burden of atherosclerotic disease below the knee compared to patients without DM (NDM). The aim of this review was to summarize the evidence regarding this hypothesis. METHODS: The literature was searched for papers that compared the anatomical distribution of atherosclerotic disease in patients with DM and those without using radiological imaging. Search terms used included "diabetes mellitus," "peripheral vascular disease," "distribution of disease," "angiography," "computed tomography angiography," and "magnetic resonance angiography." Where possible, the number of patients with disease in each arterial segment was extracted and included in a forest plot. A descriptive approach was taken when this was not possible or a scoring system was used. RESULTS: Fourteen studies were included in the review and it was possible to summarize data from 9 of these in a forest plot. Fifteen different arterial segments were described; however, the most commonly used segments that differentiated between proximal and distal disease were aortoiliac (A-I; DM = 466 patients, NDM = 458), femoropopliteal (F-P; DM = 568, NDM = 585), tibial (DM = 306, NDM = 417). The resulting forest plot showed that those with DM were significantly less likely to have disease in the A-I segment (odds ratio [OR]: 0.25 [0.15-0.42]) and significantly more likely to have disease in the tibial segment (OR 1.94 [1.27-2.96]). In the DM group, there was a trend toward relative sparing in the F-P segment, but this does not reach significance (0.66 [0.33-1.31]). CONCLUSIONS: These results support the hypothesis that patients with DM are more likely to have atherosclerotic disease in the tibial vessels than NDM. There is however limited information on how individual vessels are affected. Further information on this and a greater understanding of why the distal vessels are more affected are avenues for future research.

Assessing stemness and proliferation properties of the newly established colon cancer 'stem' cell line, CSC480 and novel approaches to identify dormant cancer cells.

To date two questions that remain unanswered regarding cancer are the following: i) how is it initiated, and ii) what is the role that cancer stem cells (CSCs) play in the disease process? Understanding the biology of CSCs and how they are generated is pivotal for the development of successful treatment regimens. To date, the lack of a representative cell model has prevented the successful identification and eradication of CSCs in vivo. The current methods of CSC identification are dependent on the protocol used to generate these cells, which has introduced variation and made the identification process more complicated. Furthermore, the list of possible markers is increasing in complexity. This is further confounded by the fact that there is insufficient information to determine whether the cells these markers detect are truly self­renewing stem cells or, instead, progenitor cells. In the present study, we investigated a novel cell line model, CSC480, which can be employed to assess CSC markers and for testing novel therapeutic regimens. CSC480 cells have been revealed to express markers of CSCs such as CD44, ALDH1 and Sox2, that have lower expression in the SW480 cell line. CSC480 cells also expressed higher levels of the cancer resistance marker, ABCG2 and had higher proliferative and growth capacity than SW480 cells. In the present study, we also evaluated a novel approach to identify different cell types present in heterogeneous cancer cell populations according to their proliferative ability using the proliferation marker 5­ethynyl­2'­deoxyuridine (EdU). Furthermore, using EdU, we identified dormant cells with a modified label­retaining cell (LRC) protocol. Through this novel LRC method, we assessed newly discovered markers of stemness to ascertain their capability to identify quiescent from dividing CSCs. In conclusion, the CSC480 cell line was an important model to be used in unravelling the underlying mechanisms that control fast­dividing and partially self­renewing stem cells (SCs) that may give rise to cancer.

The Difference Between the Healing and the Nonhealing Diabetic Foot Ulcer: A Review of the Role of the Microcirculation.

BACKGROUND: Diabetic foot disease carries a high morbidity and is a leading cause of lower limb amputation. This may in part be due to the effect diabetes mellitus (DM) has on the microcirculation including in the skin. METHOD: We conducted a review of studies that have examined the relationship between microcirculatory function and wound healing in patients with DM. A search of the Medline, Embase, and Web of Science databases was performed coupled with a review of references for the period 1946 to March 2015. RESULTS: Nineteen studies of diverse methodology and cohort selection were identified. Poor function of the microcirculation was related to poor outcome. Transcutaneous oxygen pressure (TcPO2) was the most commonly used method to measure the microcirculation and thresholds for poor outcome proposed ranged from 10 mmHg to <34 mmHg. Two studies reexamined microcirculatory function following revascularization. Both found an increase in TcPO2, however only 1 reached statistical significance. No significant difference in the results of microcirculation tests was found between diabetic and nondiabetic patients. CONCLUSIONS: While it is not possible to draw firm conclusions from the evidence currently available there are clear areas that warrant research. Good microcirculation unsurprisingly appears to associate with better wound healing. The influence of DM is not clear, and neither is the degree of improvement required to achieve healing. Studies that examine a clearly defined cohort both with and without DM are urgently required. Accurate quantitative assessment of microcirculation will aid prediction of wound healing identifying those at greatest risk of amputation.

Dapagliflozin for the treatment of type 2 diabetes: a review of the literature.

OBJECTIVE: Dapagliflozin was the first drug in a class of therapies that took a new approach to glycemic control in adults with type 2 diabetes (T2D). It is an inhibitor of the sodium glucose cotransporter, resident in the proximal nephron, which is responsible for the recovery of filtered glucose back into circulation. Inhibiting this cotransporter reduces glucose recovery, increases glucose excretion, and reduces hyperglycemia. Here, we review some of the literature relating to the action, efficacy, and clinical use of dapagliflozin. MATERIALS AND METHODS: A Medline search was conducted within date, animal, and language limits, and relevant papers were selected for review. Conference proceedings were reviewed to obtain up-to-date literature on this drug. Clinical trial websites were reviewed for ongoing studies. RESULTS: On average, treatment with dapagliflozin results in improvement in glycated hemoglobin by 0.50%, fasting plasma glucose by 1 mmol/L, weight by 2 kg, body mass index by 1.1%, and systolic/diastolic blood pressure by 4/2 mmHg over 24-52 weeks. The weight benefit is greater when used in association with sulfonylureas. It is generally well tolerated, but comes with an increased risk of genitourinary and urinary tract infections. In addition, it is associated with reversible changes to renal function that need to be explored. Early reports of an association with cancer also need to be carefully monitored. CONCLUSION: Dapagliflozin is a useful therapy for adult patients with T2D. It also holds potential for a broader range of patients with T2D (such as the elderly and pediatric populations), as well as those with other forms of diabetes, such as type 1 diabetes. While longer-term outcome studies of safety and efficacy are awaited, dapagliflozin forms a very useful and welcome addition to our armamentarium for managing patients with T2D.

In-hospital mortality and length of stay in patients with diabetes having foot disease.

OBJECTIVE: We aimed to determine whether in-patient mortality and length of stay were greater in diabetes patients with foot disease compared to those without foot disease. METHODS: Retrospective data analysis of admissions over four years (2007-2010) to University Hospital Birmingham. Based on discharge diagnostic codes we grouped admissions into those 1) with amputation, 2) with foot disease and 3) without foot disease. Inpatient mortality and length of stay were compared between the three groups, adjusting for confounders. RESULTS: We identified 25,118 admissions with diabetes of which 1149 admissions (4.6%) had foot disease and another 195 (0.8%) had a code for lower limb amputation. When compared to those without foot disease the adjusted odds ratio for inpatient mortality was 1.31 (95% CI 1.04-1.65 P=0.02) in the foot disease group, and 1.02 (95% CI 0.56-1.85 P=0.95) in the amputation group; and the adjusted relative ratio for length of stay was 2.01 (95 CI 1.86-2.16 P<0.001) in the foot disease group and 3.08 (95% CI 2.60-3.65 P<0.001) in the amputation group. CONCLUSION: Foot disease in hospitalised patients with diabetes is associated with increased length of stay and inpatient mortality. Our study adds to evidence on excess mortality associated with diabetic foot disease and to evidence on excess mortality observed in people with diabetes admitted to hospitals.