Mechanisms, screening modalities and treatment options for individuals with non-alcoholic fatty liver disease and type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum of disease ranging from excessive accumulation of fat within the liver (simple steatosis), inflammation (non-alcoholic steatohepatitis) through to fibrosis, cirrhosis and end-stage liver disease. There is also an increased risk of hepatocellular carcinoma. The principal risk factor for NAFLD is overweight or obesity, along with type 2 diabetes, and NAFLD itself is also a risk factor for incident type 2 diabetes. Overweight/obesity is synergistic with alcohol consumption in causing progressive and insidious liver damage. Recent consensus advocates a change in nomenclature from NAFLD to 'metabolic associated fatty liver disease' (MAFLD), reflective of the associated metabolic abnormalities (insulin resistance/type 2 diabetes and metabolic syndrome components). Additional extra-hepatic manifestations of NAFLD include cardiovascular disease, chronic kidney disease and certain cancers. Unlike other micro- and macrovascular complications of type 2 diabetes, systematic screening or surveillance protocols have not been widely adopted in routine diabetes care to assess for presence/severity of NAFLD. Various screening tools are available (non-invasive tests and biochemical indices) combined with imaging techniques (e.g. transient elastography) to detect steatosis and more importantly advanced fibrosis/cirrhosis to facilitate appropriate surveillance. Liver biopsy may be sometimes necessary. Treatment options for type 2 diabetes, including lifestyle interventions (dietary change and physical activity), glucose-lowering therapies and metabolic surgery, can modulate hepatic steatosis and to a lesser extent fibrosis. Awareness of the impact of liver disease on the choice of glucose-lowering medications in individuals with type 2 diabetes is also critical.

Mirogabalin besylate in the treatment of neuropathic pain.

Neuropathic pain (NeP) is a global cause of suffering and debilitation leading to significant morbidity and reduced quality of life. New treatments are needed to address the growing prevalence of NeP and its impact on sleep, mood and functionality. Mirogabalin besylate (mirogabalin, Tarlige) is a gabapentinoid therapy developed by Daiichi Sankyo which is approved in Japan for the treatment of postherpetic neuralgia and painful diabetic peripheral neuropathy. Mirogabalin has a potent pain-modulating effect with a unique high affinity and prolonged dissociation rate for the a2delta-1 subunit of voltage-gated calcium (Ca2+) channels (VGCCs) on the dorsal root ganglion resulting in more sustained analgesia compared with traditional gabapentinoids. Additionally, mirogabalin has a superior adverse events (AEs) profile due to a rapid dissociation from the a2delta-2 subunit of VGCCs potentially implicated in central nervous system-specific AEs. The most common AEs for mirogabalin are dizziness (approximately 8-16%), somnolence (approximately 6-24%) and headache (approximately 6-14%), with a lower incidence of constipation, nausea, diarrhea, vomiting, edema, fatigue and weight gain. Postmarketing studies are required to evaluate its analgesic durability and efficacy when combined with other antineuropathic agents such as tricyclics, duloxetine and tramadol/tapentadol.

Diabetic peripheral neuropathy in people with type 2 diabetes: too little too late.

Diabetic peripheral neuropathy in people with type 2 diabetes is poorly managed because of its insidious onset, delayed diagnosis and more complex aetiology resulting from the contribution of not only hyperglycaemia, but also ageing, hyperlipidaemia, hypertension and obesity. Because there is no US Food and Drug Adminstration-approved disease-modifying therapy for diabetic peripheral neuropathy, the key to ameliorating it in type 2 diabetes has to be through earlier diagnosis and timely multi-factorial risk factor reduction. The management of painful diabetic peripheral neuropathy also requires a detailed appraisal of the choice of therapy, taking into account efficacy, patient wishes, comorbidities, side effect profile and potential for abuse.

Latent autoimmune diabetes of adulthood (LADA) is associated with small fibre neuropathy.

AIM: To assess if latent autoimmune diabetes of adulthood (LADA) is associated with small fibre neuropathy. METHODS: Participants with LADA (n=31), Type 2 diabetes (n=31) and healthy control participants without diabetes (n=31) underwent a detailed assessment of neurologic deficits, quantitative sensory testing, electrophysiology, skin biopsy and corneal confocal microscopy. RESULTS: The groups were matched for age (healthy control without diabetes: 53.5±9.1 vs. Type 2 diabetes: 58.0±6.5 vs. LADA: 53.2±11.6 years), duration of diabetes (Type 2 diabetes: 10.0±8.3 vs. LADA: 11.0±9.1 years) and blood pressure. However, BMI (P=0.01) and triglycerides (P=0.0008) were lower and HbA1c (P=0.0005), total cholesterol (P=0.01) and HDL (P=0.002) were higher in participants with LADA compared with Type 2 diabetes. Peroneal motor nerve conduction velocity (P=0.04) and sural sensory nerve conduction velocity (P=0.008) were lower in participants with latent autoimmune diabetes in adults compared with Type 2 diabetes. Intra-epidermal nerve fibre density (P=0.008), corneal nerve fibre density (P=0.003) and corneal nerve branch density (P=0.006) were significantly lower in participants with LADA compared with Type 2 diabetes. There were no significant differences in the other neuropathy parameters. CONCLUSIONS: Despite comparable age and duration of diabetes, participants with LADA demonstrate more severe neuropathy and particularly small fibre neuropathy, compared with participants with Type 2 diabetes.

Harvesting visible light with MoO3 nanorods modified by Fe(iii) nanoclusters for effective photocatalytic degradation of organic pollutants.

The photocatalytic performance of MoO3 is limited due to its weak visible light absorption ability and quick recombination of charge carriers. In the present work, we report the facile synthesis of Fe(iii)-grafted MoO3 nanorods using a hydrothermal method followed by an impregnation technique with the aim of enhancing the light harvesting ability and photocatalytic efficiency of MoO3. The prepared samples were characterized through the standard analytical techniques of XRD, SEM-EDS, TEM, XPS, UV-Vis-DRS, FT-IR, TG-DTA and PL spectrophotometry. XPS and TEM analyses reveal that Fe(iii) ions are successfully grafted onto the surface of the MoO3 nanorod with intimate interfacial contact. The photocatalytic performances of the prepared samples were investigated by studying the degradation of methylene blue (MB), rhodamine B (RhB) and 4-nitrophenol (4-NP) under visible light irradiation. The surface-modified MoO3 with Fe(iii) ions showed excellent photocatalytic activity towards the degradation of the above-mentioned pollutants, where Fe(iii) ions act as effective cocatalytic sites to produce hydroxyl radicals through multi-electron reduction of oxygen molecules. The improved photocatalytic activity could be ascribed to the effective separation of charge carriers and efficient production of hydroxyl radicals via the rapid capture of electrons by Fe(iii) through a well-known photoinduced interfacial charge transfer mechanism. Based on scavenger analysis study, a mechanism for the enhanced photocatalytic activity has been discussed and proposed. The concept of surface grafting onto large bandgap semiconductors with ubiquitous elements opens up a new avenue for the development of visible-light-responsive photocatalysts with excellent photocatalytic activity.

NerveCheck: An inexpensive quantitative sensory testing device for patients with diabetic neuropathy.

AIMS: Sensory neuropathy is central to the development of painful neuropathy, and foot ulceration in patients with diabetes. Currently, available QST devices take considerable time to perform and are expensive. NerveCheck is the first inexpensive ($500), portable QST device to perform both vibration and thermal testing and hence evaluate diabetic peripheral neuropathy (DPN). This study was undertaken to establish the reproducibility and diagnostic validity of NerveCheck for detecting neuropathy. METHODS: 130 subjects (28 with DPN, 46 without DPN and 56 control subjects) underwent QST assessment with NerveCheck; vibration perception and thermal testing. DPN was defined according to the Toronto criteria. RESULTS: NerveCheck's intra correlation coefficient for vibration, cold and warm sensation testing was 0.79 (95% LOA: -4.20 to 6.60), 0.86 (95% LOA: -1.38 to 2.72) and 0.71 (95% LOA: -2.36 to 3.83), respectively. The diagnostic accuracy (AUC) for vibration, cold and warm sensation testing was 86% (SE: 0.038, 95% CI 0.79-0.94), 79% (SE: 0.058, 95% CI 0.68-0.91) and 72% (SE: 0.058, 95% CI 0.60-0.83), respectively. CONCLUSIONS: This study shows that NerveCheck has good reproducibility and comparable diagnostic accuracy to established QST equipment for the diagnosis of DPN.

Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement.

OBJECTIVES: To explore phenotypic differences between individuals with sporadic inclusion body myositis (sIBM) who are seropositive for the NT5c1A antibody compared with those who are seronegative. METHODS: Cross-sectional clinical, serological and functional analysis in 25 consecutive participants with sIBM. RESULTS: All participants met criteria for clinically defined or probable sIBM. 18 of 25 participants with sIBM (72%) were seropositive for the NT5c1A antibody. No differences between median age and duration of illness between the two groups were seen. Females have higher odds of being seropositive (OR=2.30). Participants with seropositive sIBM took significantly longer to get up and stand (p=0.012). There were no significant differences between the two groups in terms of distance covered on a 6 min walk. Seropositive participants were more likely to require assistive devices such as a walker or wheelchair for mobility (OR=23.00; p=0.007). A number of secondary (exploratory) outcomes were assessed. NT5c1A seropositive sIBM cases had lower total Medical Research Council (MRC) sum score and MRC sum score on the right (p=0.03 and 0.02, respectively). Participants with the NT5c1A antibody were significantly more likely to have symptoms of dysphagia (OR=10.67; p=0.03) and reduced forced vital capacity (p=0.005). Facial weakness occurred in 50% of seropositive participants while it was only seen in 14% of seronegative participants. CONCLUSIONS: Even though the small sample size limits definite conclusions, our cross-sectional study showed seropositivity to the NT5c1A antibody is associated with greater motor and functional disability in sIBM. The study also suggests more prominent bulbar, facial and respiratory involvement in individuals positive for NT5c1A antibodies.

Burning through the pain: treatments for diabetic neuropathy.

The rise in the global burden of diabetes is spurring an increase in the prevalence of its complications. Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, with multiple clinical manifestations. The most common is a symmetrical length-dependent dysfunction and damage of peripheral nerves. The management of DPN rests on three tenets: intensive glycaemic control, even though the evidence of benefit is questionable in people with type 2 diabetes; pathogenetic therapies; and symptomatic treatment. A number of pathogenetic treatments have been evaluated in phase III clinical trials, including α-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage) and aldose-reductase inhibitors (reduce flux through the polyol pathway), protein kinase C inhibitors (prevent hyperglycaemia-induced activation of protein kinase C), nerve growth factors (stimulate nerve regeneration) and Actovegin® (improves tissue glucose and oxygen uptake). However, none have gained US Food and Drug Administration or European Medicines Agency (EMA) approval, questioning the validity of current trial designs and the endpoints deployed to define efficacy. For painful diabetic neuropathy, clinical guidelines recommend: atypical analgesics for pain relief, including duloxetine and amitriptyline; the γ-aminobutyric acid analogues gabapentin and pregabalin; opioids, including Tapentadol; and topical agents such as lidocaine and capsaicin. No single effective treatment exists for painful DPN, highlighting a growing need for studies to evaluate more potent and targeted drugs, as well as combinations. A number of novel potential candidates, including erythropoietin analogues and angiotensin II type 2 receptor anatagonists are currently being evaluated in phase II clinical trials.

The diagnostic accuracy of Neuropad for assessing large and small fibre diabetic neuropathy.

AIMS: Neuropad is a simple visual indicator test, with moderate diagnostic performance for diabetic peripheral neuropathy. As it assesses sweating, which is a measure of cholinergic small nerve fibre function, we compared its diagnostic performance against established measures of both large and, more specifically, small fibre damage in patients with diabetes. METHODS: One hundred and twenty-seven participants (89 without diabetic peripheral neuropathy and 38 with) aged 57 ± 9.7 years underwent assessment with Neuropad, large nerve fibre assessments: Neuropathy Disability Score, vibration perception threshold, peroneal motor nerve conduction velocity; small nerve fibre assessments: neuropathy symptoms (Diabetic Neuropathy Symptoms score) corneal nerve fibre length and warm perception threshold. RESULTS: Neuropad has a high sensitivity but moderate specificity against large fibre neuropathy assessments: Neuropathy Disability Score (> 2) 70% and 50%, vibration perception threshold (> 14 V) 83% and 53%, and peroneal motor nerve conduction velocity (< 42 m/s) 81% and 54%, respectively. However, the diagnostic accuracy of Neuropad was significantly improved against corneal nerve fibre length (< 14 mm/mm2) with a sensitivity and specificity of 83% and 80%, respectively. Furthermore, the area under the curve for corneal nerve fibre length (85%) was significantly greater than with the Neuropathy Disability Score (66%, P = 0.01) and peroneal motor nerve conduction velocity (70%, P = 0.03). For neuropathic symptoms, sensitivity was 78% and specificity was 60%. CONCLUSIONS: The data show the improved diagnostic performance of Neuropad against corneal nerve fibre length. This study underlines the importance of Neuropad as a practical diagnostic test for small fibre neuropathy in patients with diabetes.

Diabetes, Obesity and Atrial Fibrillation: Epidemiology, Mechanisms and Interventions.

Body mass index (BMI) is a powerful predictor of death, type 2 diabetes (T2DM) and cardiovascular (CV) morbidity and mortality. Over the last few decades, we have witnessed a global rise in adult obesity of epidemic proportions. Similarly, there has been a parallel increase in the incidence of atrial fibrillation (AF), itself a significant cause of cardiovascular morbidity and mortality. This may be partly attributable to advances in the treatment of coronary heart disease (CHD) and heart failure (HF) improving life expectancy, however, epidemiological studies have demonstrated an independent association between obesity, diabetes and AF, suggesting possible common pathophysiological mechanisms and risk factors. Indeed, cardiac remodeling, haemodynamic alterations, autonomic dysfunction, and diastolic dysfunction have been reported in obese and diabetic cohorts. Moreover, diabetic cardiomyopathy is characterized by an adverse structural and functional cardiac phenotype, which may predispose to the development of AF. In this review, we discuss the pathophysiological and mechanistic relationships between obesity, diabetes and AF, and some of the challenges posed in the management of this high-risk group of individuals.

Obesity, diabetes and atrial fibrillation; epidemiology, mechanisms and interventions.

The last few decades have witnessed a global rise in adult obesity of epidemic proportions. The potential impact of this is emphasized when one considers that body mass index (BMI) is a powerful predictor of death, type 2 diabetes (T2DM) and cardiovascular (CV) morbidity and mortality [1, 2]. Similarly we have witnessed a parallel rise in the incidence of atrial fibrillation (AF), the commonest sustained cardiac arrhythmia, which is also a significant cause of cardiovascular morbidity and mortality. Part of this increase is attributable to advances in the treatment of coronary heart disease (CHD) and heart failure (HF) improving life expectancy and consequently the prevalence of AF. However, epidemiological studies have demonstrated an independent association between obesity and AF, possibly reflecting common pathophysiology and risk factors for both conditions. Indeed, weight gain and obesity are associated with structural and functional changes of the cardiovascular system including left atrial and ventricular remodeling, haemodynamic alterations, autonomic dysfunction, and diastolic dysfunction. Moreover, diabetic cardiomyopathy is characterized by an adverse structural and functional cardiac phenotype which may predispose to the development of AF [3]. In this review, we discuss the pathophysiological and mechanistic relationships between obesity, diabetes and AF, and the challenges posed in the management of this high-risk group of individuals.

Survey of palliative care concepts among medical students in India.

BACKGROUND: Students must develop a "tension for change" before new material is learned. Therefore, a needs assessment generally precedes curriculum change in order to identify what the target population thinks they already know about a subject. Undergraduate medical education in India is a 4(1/2) -year course. This is followed by a 1-year internship before the new physician can practice independently. AIM: To assess the level of awareness in palliative care concepts among final-year students at Kasturba Medical College, Manipal, India. MATERIALS AND METHODS: One hundred eleven final-year students participated in a survey study 6 months before graduation. The data were collected after the survey and the responses were analyzed. RESULTS: The reported theoretical knowledge of palliative care concepts was better than the level of confidence in performing practical aspects of palliative care. CONCLUSION: Before this survey, we hypothesized that medical students in India would have low levels of self-reported understanding of palliative care and its components. In contrast, they reported a high level of understanding of palliative care but very little understanding and confidence in performing the associated skills. From this, we conclude that these medical students are ready for instruction in the practical skills of palliative care.

Survey of palliative care concepts among medical interns in India.

BACKGROUND: Medical knowledge, if theoretical, will fade away if not reinforced especially if not clinically implemented. We conducted a survey study amongst interns to assess awareness and confidence of common palliative care issues. Undergraduate medical education in India is a 4(1/2) -year course. This is followed by a 1-year internship before the new physician can practice independently. AIM: To compare the level of awareness in palliative care concepts among interns to that of final-year medical students at Kasturba Medical College, Manipal, India. MATERIALS AND METHODS: Forty-four interns participated in a survey study. The data were collected after the survey and the responses were analyzed. We compared these data with those obtained from conducting the same survey among medical students. RESULTS: The reported theoretical knowledge of palliative care concepts was better than the level of confidence in performing practical aspects of palliative care. The interns, overall, did not out-perform the students. CONCLUSION: Before this survey, we hypothesized that interns in India would have low levels of self-reported understanding of palliative care and its components. We were hoping to see an improvement in knowledge and confidence with training. In contrast, there was not much of an improvement but rather a decline in some areas. From this, we conclude that when medical students become interns, they need reinforcement of knowledge and more hands-on experience.