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Rayaz A Malik - Top 30 Publications

Greater corneal nerve loss at the inferior whorl is related to the presence of diabetic neuropathy and painful diabetic neuropathy.

We assessed whether a measure of more distal corneal nerve fibre loss at the inferior whorl(IW) region is better than proximal measures of central corneal nerve damage in relation to the diagnosis of diabetic peripheral neuropathy(DPN), painful DPN and quality of life(QoL). Participants underwent detailed assessment of neuropathy, QoL using the SF36 questionnaire, pain visual analogue score(VAS), and corneal confocal microscopy(CCM). Corneal nerve fibre density (CNFD), branch density (CNBD) and length (CNFL) at the central cornea and inferior whorl length (IWL) and average(ANFL) and total(TNFL) nerve fibre length were compared in patients with and without DPN and between patients with and without painful DPN and in relation to QoL. All CCM parameters were significantly reduced, but IWL was reduced ~three-fold greater than CNFL in patients with and without DPN compared to controls. IWL(p = 0.001), ANFL(p = 0.01) and TNFL(p = 0.02) were significantly lower in patients with painful compared to painless DPN. The VAS score correlated with IWL(r = -0.36, P = 0.004), ANFL(r = -0.32, P = 0.01) and TNFL(r = -0.32, P = 0.01) and QoL correlated with CNFL(r = 0.35, P = 0.01) and IWL(r = 0.4, P = 0.004). Corneal nerve fibre damage is more prominent at the IW, lower in patients with painful compared to painless neuropathy and relates to their QoL. IWL may provide additional clinical utility for CCM in patients with DPN.

Improvement in Neuropathy Specific Quality of Life in Patients with Diabetes after Vitamin D Supplementation.

To assess the effect of vitamin D supplementation on neuropathy specific quality of life (NeuroQoL) in patients with painful diabetic neuropathy.

Corneal confocal microscopy detects severe small fibre neuropathy in diabetes patients with charcot neuroarthropathy.

The aim of this study was to identify the extent of small fibre neuropathy in patients with Charcot neuroarthropathy (CN).

Hypercholesterolaemia - practical information for non-specialists.

Hypercholesterolaemia is amongst the most common conditions encountered in the medical profession. It remains one of the key modifiable cardiovascular risk factors and there have been recent advances in the risk stratification methods and treatment options available. In this review, we provide a background into hypercholesterolaemia for non-specialists and consider the merits of the different risk assessment tools available. We also provide detailed considerations as to: i) when to start treatment, ii) what targets to aim for and iii) the role of low density lipoprotein cholesterol.

The H-Reflex as a Biomarker for Spinal Disinhibition in Painful Diabetic Neuropathy.

Neuropathic pain may arise from multiple mechanisms and locations. Efficacy of current treatments for painful diabetic neuropathy is limited to an unpredictable subset of patients, possibly reflecting diversity of pain generator mechanisms, and there is a lack of targeted treatments for individual patients. This review summarizes preclinical evidence supporting a role for spinal disinhibition in painful diabetic neuropathy, the physiology and pharmacology of rate-dependent depression (RDD) of the spinal H-reflex and the translational potential of using RDD as a biomarker of spinally mediated pain.

Corneal and Retinal Neuronal Degeneration in Early Stages of Diabetic Retinopathy.

To examine the neuronal structural integrity of cornea and retina as markers for neuronal degeneration in nonproliferative diabetic retinopathy (NPDR).

Effect of Roux-en-Y Bariatric Surgery on Lipoproteins, Insulin Resistance, and Systemic and Vascular Inflammation in Obesity and Diabetes.

Obesity is a major modifiable risk factor for cardiovascular disease. Bariatric surgery is considered to be the most effective treatment option for weight reduction in obese patients with and without type 2 diabetes (T2DM).

Circulating microparticles in acute diabetic Charcot foot exhibit a high content of inflammatory cytokines, and support monocyte-to-osteoclast cell induction.

Circulating microparticles (MPs) are major mediators in cardiovascular complications of type 2 diabetes (T2D); however, their contribution to Charcot foot (CF) disease is not known. Here, we purified and assessed the origin, concentration and content of circulating MPs from 33 individuals: 11 with T2D and acute CF, 11 T2D patients with equivalent neuropathy and 11 non-diabetic controls. First, we demonstrated that there were no differences in the distribution of MPs of endothelial, platelet origin among the 3 groups. However, MPs from leukocytes and monocytes origin were increased in CF patients. Moreover, we demonstrated that monocytes-derived MPs originated more frequently from intermediate and non-classical monocytes in CF patients. Five cytokines (G-CSF, GM-CSF, IL-1-ra, IL-2 and IL-16) were significantly increased in MPs from acute CF patients. Applying ingenuity pathways analysis, we found that those cytokines interacted well and induced the activation of pathways that are involved in osteoclast formation. Further, we treated THP-1 monocytes and monocytes sorted from healthy patients with CF-derived MPs during their differentiation into osteoclasts, which increased their differentiation into multinucleated osteoclast-like cells. Altogether, our study suggests that circulating MPs in CF disease have a high content of inflammatory cytokines and could increase osteoclast differentiation in vitro.

Ophthalmic and clinical factors that predict four-year development and worsening of diabetic retinopathy in type 1 diabetes.

To investigate the role of ophthalmic imaging markers - namely retinal thickness measures and corneal nerve morphology - in predicting four-year development and worsening of diabetic retinopathy (DR) in type 1 diabetes (T1DM).

Effects of procalcitonin-guided treatment on antibiotic use and need for mechanical ventilation in patients with acute asthma exacerbation: Meta-analysis of randomized controlled trials.

The primary outcome was to determine whether serum procalcitonin-guided antibiotic therapy can reduce antibiotic exposure in patients with an acute exacerbation of asthma presenting to the primary care facility or emergency department, or during hospital admission. The secondary outcome was the need for mechanical ventilation.

Corneal Confocal Microscopy Detects Corneal Nerve Damage in Patients Admitted With Acute Ischemic Stroke.

Corneal confocal microscopy can identify corneal nerve damage in patients with peripheral and central neurodegeneration. However, the use of corneal confocal microscopy in patients presenting with acute ischemic stroke is unknown.

CIDP and other inflammatory neuropathies in diabetes - diagnosis and management.

Distal symmetric polyneuropathy (DSPN) is the most common neuropathy to occur in diabetes mellitus. However, patients with diabetes can also develop inflammatory neuropathies, the most common and most treatable of which is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Whether diabetes is a risk factor for CIDP remains under debate. Early studies suggested that patients with diabetes were at increased risk of CIDP, but epidemiological studies failed to confirm the association, and subsequent data have re-opened the debate. Inadequate interpretation of investigations and differentials between CIDP and other neuropathies that can occur in diabetes, such as DSPN, diabetic radiculoplexus neuropathies and vasculitic multiple mononeuropathy, might mean that CIDP is under-recognized. Despite a response rate of >80% to first-line therapies for CIDP in patients with or without diabetes, those with diabetes often present with greater disability owing to late referral and axonal pathology attributed to DSPN. The increasing worldwide prevalence of diabetes creates an urgent need to improve identification of potentially treatable neuropathies, such as CIDP. In this Review, we consider the features of CIDP in patients with diabetes, and discuss how these features can be used to differentiate the condition from other neuropathies. We also review the management options for CIDP and other inflammatory neuropathies in patients with diabetes.

Diabetic Neuropathy and Gait: A Review.

Diabetic peripheral neuropathy (DPN) is a major sequela of diabetes mellitus and may have a detrimental effect on the gait of people with this complication. DPN causes a disruption in the body's sensorimotor system and is believed to affect up to 50% of patients with diabetes mellitus, dependent on the duration of diabetes. It has a major effect on morbidity and mortality. The peripheral nervous system controls the complex series of events in gait through somatic and autonomic functions, careful balancing of eccentric and concentric muscle contractions and a reliance on the sensory information received from the plantar surface. In this literature review focussing on kinetics, kinematics and posture during gait in DPN patients, we have identified an intimate link between DPN and abnormalities in gait and demonstrated an increased risk in falls for older patients with diabetes. As such, we have identified a need for further research on the role of gait abnormalities in the development of diabetic foot ulceration and subsequent amputations.

Presence of Peripheral Neuropathy Is Associated With Progressive Thinning of Retinal Nerve Fiber Layer in Type 1 Diabetes.

Reduced retinal nerve fiber layer (RNFL) thickness has been demonstrated in patients with diabetic peripheral neuropathy (DPN) in cross-sectional studies. This prospective study defines longitudinal alterations to the RNFL thickness in individuals with type 1 diabetes without (DPN-ve) and with (DPN+ve) DPN and in relation to risk factors for nerve damage.

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy.

The progression and pathophysiology of neuropathy in impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) is poorly understood, especially in relation to autophagy. This study was designed to assess whether the presence of autophagy-related structures was associated with sural nerve fiber pathology, and to investigate if endoneurial capillary pathology could predict the development of T2DM and neuropathy.

Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities.

To assess the effect of applying a protocol for image selection and the number of images required for adequate quantification of corneal nerve pathology using in vivo corneal confocal microscopy (IVCCM).

Corneal Confocal Microscopy: An Imaging Endpoint for Axonal Degeneration in Multiple Sclerosis.

To evaluate whether corneal confocal microscopy (CCM) detects axonal degeneration and whether this is associated with retinal nerve fiber degeneration and clinical disability in patients with multiple sclerosis (MS).

Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy.

Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible technique that quantifies small nerve fibres. We have compared the diagnostic capability of CCM against a range of established measures of nerve damage in patients with diabetic neuropathy.

Optical coherence tomography predicts 4-year incident diabetic neuropathy.

To examine the capability of optical coherence tomography-derived retinal thickness measures in detecting 4-year incident diabetic peripheral neuropathy (DPN).

Use of Corneal Confocal Microscopy to Evaluate Small Nerve Fibers in Patients With Human Immunodeficiency Virus.

Objective quantification of small fiber neuropathy in patients with human immunodeficiency virus (HIV)-associated sensory neuropathy (HIV-SN) is difficult but needed for diagnosis and monitoring. In vivo corneal confocal microscopy (IVCCM) can quantify small fiber damage.

Use of Corneal Confocal Microscopy to Detect Corneal Nerve Loss and Increased Dendritic Cells in Patients With Multiple Sclerosis.

Multiple sclerosis (MS) is characterized by demyelination, axonal degeneration, and inflammation. Corneal confocal microscopy has been used to identify axonal degeneration in several peripheral neuropathies.

Corneal confocal microscopy best identifies the development and progression of neuropathy in patients with type 1 diabetes.

A sub-set of 38 individuals with type 1 diabetes that fulfilled a strict criterion of "normal" classification for all 7 measures of neuropathy at baseline, were identified and followed. Corneal nerve morphology, as captured with corneal confocal microscopy demonstrated the greatest, and most sustained degeneration over a 4 year period.

Perceptions of Painful Diabetic Peripheral Neuropathy in South-East Asia: Results from Patient and Physician Surveys.

There are no data on physician-patient communication in painful diabetic peripheral neuropathy (pDPN) in the Asia-Pacific region. The objective of this study was to examine patient and physician perceptions of pDPN and clinical practice behaviors in five countries in South-East Asia. Primary care physicians and practitioners, endocrinologists, diabetologists, and patients with pDPN completed separate surveys on pDPN diagnosis, impact, management, and physician-patient interactions in Hong Kong, Malaysia, the Philippines, Taiwan, and Thailand. Data were obtained from 100 physicians and 100 patients in each country. The majority of physicians (range across countries, 30-85%) were primary care physicians and practitioners. Patients were mostly aged 18-55 years and had been diagnosed with diabetes for >5 years. Physicians believed pDPN had a greater impact on quality of life than did patients (ranges 83-92% and 39-72%, respectively), but patients believed pDPN had a greater impact on items such as sleep, anxiety, depression, and work than physicians. Physicians considered the diagnosis and treatment of pDPN a low priority, which may be reflected in the generally low incidence of screening (range 12-65%) and a lack of awareness of pDPN. Barriers to treatment included patients' lack of awareness of pDPN. Both physicians and patients agreed that pain scales and local language descriptions were the most useful tools in helping to describe patients' pain. Most patients were monitored upon diagnosis of pDPN (range 55-97%), but patients reported a shorter duration of monitoring compared with physicians. Both physicians and patients agreed that it was patients who initiated conversations on pDPN. Physicians most commonly referred to guidelines from the American Diabetes Association or local guidelines for the management of pDPN. This study highlights important differences between physician and patient perceptions of pDPN, which may impact on its diagnosis and treatment. For a chronic and debilitating complication like pDPN, the physician-patient dialogue is central to maximizing patient outcomes. Strategies, including education of both groups, need to be developed to improve communication.

Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain.

Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43+) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT]).

Abnormal Remodeling of Subcutaneous Small Arteries Is Associated With Early Diastolic Impairment in Metabolic Syndrome.

Small artery pathophysiology is frequently invoked as a cause of obesity-related diastolic heart failure. However, evidence to support this hypothesis is scant, particularly in humans.

Small-fibre neuropathy in men with type 1 diabetes and erectile dysfunction: a cross-sectional study.

The aim of this study was to identify the contribution of small- and large-fibre neuropathy to erectile dysfunction in men with type 1 diabetes mellitus.

Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy.

Impaired rate-dependent depression (RDD) of the Hoffman reflex is associated with reduced dorsal spinal cord potassium chloride cotransporter expression and impaired spinal γ-aminobutyric acid type A receptor function, indicative of spinal inhibitory dysfunction. We have investigated the pathogenesis of impaired RDD in diabetic rodents exhibiting features of painful neuropathy and the translational potential of this marker of spinal inhibitory dysfunction in human painful diabetic neuropathy. Impaired RDD and allodynia were present in type 1 and type 2 diabetic rats but not in rats with type 1 diabetes receiving insulin supplementation that did not restore normoglycemia. Impaired RDD in diabetic rats was rapidly normalized by spinal delivery of duloxetine acting via 5-hydroxytryptamine type 2A receptors and temporally coincident with the alleviation of allodynia. Deficits in RDD and corneal nerve density were demonstrated in patients with painful diabetic neuropathy compared with healthy control subjects and patients with painless diabetic neuropathy. Spinal inhibitory dysfunction and peripheral small fiber pathology may contribute to the clinical phenotype in painful diabetic neuropathy. Deficits in RDD may help identify patients with spinally mediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.

Effects of panretinal laser photocoagulation on the corneal nerve plexus and retinal nerve fiber layer in retinal vein occlusion.

To determine the effects of panretinal photocoagulation (PRP) on corneal sub-basal nerve plexus (SBNP) and peripapillary retinal nerve fiber layer (RNFL) thickness in patients with unilateral central retinal vein occlusion (CRVO) who had previously undergone PRP treatment.

Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy.

Oxaliplatin, an organoplatinum compound, is used in the treatment of colorectal cancer, but its clinical use can be limited due to the development of peripheral neuropathy. Whilst mitochondrial dysfunction has been implicated as a major pathomechanism for oxaliplatin-induced neurotoxicity, the prevention of autophagy may also aggravate neuronal cell death. Melatonin, a well-known mitoprotectant and autophagy inducer, was used to examine its neuroprotective role in oxaliplatin-induced peripheral neuropathy (OIPN). Melatonin prevented the loss of mitochondrial membrane potential (Ψm) and promoted neuritogenesis in oxaliplatin-challenged neuro-2a cells. It did not interfere with the cytotoxic activity of oxaliplatin in human colon cancer cell line, HT-29. Melatonin treatment significantly alleviated oxaliplatin-induced pain behavior and neuropathic deficits in rats. It also ameliorated nitro-oxidative stress mediated by oxaliplatin, thus prevented nitrosylation of proteins and loss of antioxidant enzymes, and therefore, it improved mitochondrial electron transport chain function and maintained cellular bioenergetics by improving the ATP levels. The protective effects of melatonin were attributed to preventing oxaliplatin-induced neuronal apoptosis by increasing the autophagy pathway (via LC3A/3B) in peripheral nerves and dorsal root ganglion (DRG). Hence, it preserved the epidermal nerve fiber density in oxaliplatin-induced neuropathic rats. Taken together, we provide detailed molecular mechanisms for the neuroprotective effect of melatonin and suggest it has translational potential for oxaliplatin-induced neuropathy.

Assessment of Corneal Sensation, Innervation and Retinal Nerve Fiber Layer in Patients Treated with Multiple Intravitreal Ranibizumab Injections.

To evaluate the effects of repeated intravitreal ranibizumab injections on corneal sensitivity, corneal sub-basal nerve plexus (SBNP) and peripapillary retinal nerve fiber layer (RNFL) thickness in patients with neovascular age-related macular degeneration (AMD).