Sanjeev Kumar Gupta

Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection

The aim of the present research was to study the prevalence and severity of vitamin D deficiency in patients with diabetic foot infection. Patients were enrolled in two groups: diabetic patients with foot infection (n 125) as cases and diabetic patients without the infection as controls (n 164). Serum 25-hydroxyvitamin D (25(OH)D) was measured by RIA. Data were presented as means and standard deviations unless otherwise indicated and were analysed by SPSS. Results revealed that 25(OH)D (nmol/l) was significantly lower (40·25 (sd 38·35) v. 50·75 (sd 33·00); P < 0·001) in cases than in controls. Vitamin D inadequacy (25(OH)D < 75 nmol/l) was equally common in cases and controls (OR 1·45, 95 % CI 0·8, 3·0; P = 0·32), but cases had a greater risk of vitamin D deficiency (25(OH)D < 50 nmol/l) than controls (OR 1·8, 95 % CI 1·1, 3·0; P = 0·02). Risk of severe vitamin D deficiency (25(OH)D < 25 nmol/l) was significantly higher in cases than in controls (OR 4·0, 95 % CI 2·4, 6·9; P < 0·0001). Age, duration of diabetes and HbA1c were significantly higher in cases than in controls and therefore adjusted to nullify the effect of these variables, if any, on study outcome. The study concluded that vitamin D deficiency was more prevalent and severe in patients with diabetic foot infection. This study opens up the issue of recognising severe vitamin D deficiency (< 25 nmol/l) as a possible risk factor for diabetic foot infections and the need for vitamin D supplementation in such patients for a better clinical outcome. This could be substantiated by similar data from future studies.

A Functional Single Nucleotide Polymorphism -1562C>T in the Matrix Metalloproteinase-9 Promoter Is Associated With Type 2 Diabetes and Diabetic Foot Ulcers

Impaired neovascularization is the hallmark of type 2 diabetes, which results in various macro- and microvascular complications and the development of foot ulcerations later in life. Matrix metalloproteinases (MMPs) are the key enzymes which influence matrix remodeling. Here, we aim to investigate that whether single nucleotide polymorphism (SNP -1562C>T) (rs3918242) in the promoter region of MMP-9 gene, which alters the transcriptional activity of MMP-9 is associated with type 2 diabetes and diabetic foot ulcers (DFUs). This case–control study was composed of 730 individuals, out of which 463 patients were with type 2 diabetes mellitus (T2DM) and 267 were nondiabetic healthy controls (non-DM controls). T2DM patients were subclassified as 149 cases without any secondary complications (T2DMNSC), 110 with DFUs, 204 T2DM patients having one or the other secondary complications. Genotyping for -1562C>T SNP in MMP-9 gene was done by polymerase chain reaction–restriction fragment length polymorphism method and sequencing. SNP -1562C>T of MMP-9 gene showed a significant association with T2DM and DFU. The allele distribution differed significantly between patients and normal control group (odds ratio = 1.82, P = .00005, 95% confidence interval = 1.36-2.42 for T2DM vs control and odds ratio = 2.112, P = .00048, 95% confidence interval = 1.38-3.126 for DFU vs control) indicating strong association of SNP -1562C>T of MMP-9 gene with T2DM and DFU in an Indian population. SNP -1562C>T in the promoter of the MMP-9 gene results in increased expression at the level of the transcription. To the best of our knowledge, this is the first report that suggests that SNP -1562C>T in the promoter of the MMP-9 gene is associated with T2DM and DFU. An increased MMP-9 production from high expressing T allele may promote matrix degradation.

Wound healing research: a perspective from India

W and particularly chronic wounds are major concerns for the patient and clinician alike; chronic wounds affect a large number of patients and seriously reduce their quality of life. Current estimates indicate that nearly 6 million people suffer from chronic wounds worldwide. There are very few Indian studies on the epidemiology of chronic wounds. In one study, the prevalence of chronic wounds in the community was reported as 4.5 per 1000 population whereas that of acute wounds was nearly doubled at 10.5 per 1000 population. The causes for chronic wounds are many, including such systemic conditions as diabetes mellitus, atherosclerosis, tuberculosis, and leprosy. Other major causes include venous ulcers, pressure sores, and trauma vasculitis. Such conditions as tuberculosis and leprosy, which are uncommon in Western societies, are often encountered in India. However, diabetic foot ulcers are an extremely common clinical condition encountered in Varanasi, India, similar to that seen in the Western population. In the above-referenced study, inadequate and inappropriate treatment of acute wounds was the commonest cause of chronic wounds. The practice of walking and working barefoot especially in the agricultural fields also contributed as causes. This unequivocally underscores the importance of conceptualizing and implementing quality wound care programs at the community level. Needless to say, these programs imply a multidisciplinary approach composed of a dedicated group of wound care health personnel including wound care nurses. In India, the problem of chronic wounds is compounded by other demographic factors such as low literacy rates, poor access to health care, lack of adequate manpower, and inadequate health infrastructure. The other major area of concern for wound care physicians is a limited knowledge of the physiological processes involved in wound healing. The field of wound healing and tissue regeneration represents a tremendously diverse area of clinical and scientific activity encompassing the most basic of wound care therapies to the most advanced analysis of cellular regulatory mechanisms. Chronic wounds, burns, and scars are complex, they have many causes, and they affect patients in many different ways. As a result, they can only be understood using a broad range of scientific and medical disciplines. Chronic wounds afflict a very large number of patients and seriously reduce their quality of life. Why some wounds heal in a reasonable time frame whereas others do not is something that we still do not understand despite the almost limitless scientific advances in the past few decades. The physiology of wound healing should be a major area of focus for ongoing scientific research. At present, there is a multitude of therapeutic approaches for the management of chronic wounds. Many of these are driven by industry, and the actual benefits of these treatment protocols are yet to be published. In the past, not much attention was devoted to chronic wounds, as the federal governments, the private sector, and the medical community were slow to focus on this growing health care problem. But with the rising elderly population and the increasing incidence of diabetes, the care of these wounds is fast becoming a billion-dollar business. Treatments that exist today, however, are often expensive and often not reimbursed through medical insurance. Current efforts in woundhealing research are directed toward developing new methods for promoting wound closure to be used alongside the traditional approaches of debridement and infection control. The most important of these innovations includes the use of skin substitutes and biomolecules that stimulate skin repair. Future research may identify targets for newer therapies. The Wound Management Research Team should be a multidisciplinary team composed of laboratory scientists as well as medical and clinical specialists. The development of a new therapy by the research team would involve various considerations such as the efficacy of the product, its side effects, the health economics, marketing of strategies, and above all the cost-benefit analysis. It is thus imperative that the research team must develop a network of contacts and collaborations with academic

An introduction of Tertiary Peritonitis.

Intraperitoneal infection known as peritonitis is a major killer in the practice of clinical surgery. Tertiary peritonitis (TP) may be defined as intra-abdominal infection that persists or recurs ³48 h following successful and adequate surgical source control. A planned or on-demand relaparotomy after an initial operation is probably most frequent way to diagnose TP, but is a late event to occur. Hence it is desirable to have timely and nonoperative diagnosis of TP after the initial operation and subsequent initiation of an appropriate therapy to reduce the complications and to improve the outcome.

Increased expression of TLR9 associated with pro-inflammatory S100A8 and IL-8 in diabetic wounds could lead to unresolved inflammation in type 2 diabetes mellitus (T2DM) cases with impaired wound healing

BACKGROUND Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which causes a chain of abrupt biochemical and physiological changes. Immune dys-regulation is the hallmark of T2DM that could contribute to prolonged inflammation causing transformation of wounds into non-healing chronic ulcers. Toll like receptor -9 (TLR9) is a major receptor involved in innate immune regulation. TLR9 activation induces release of pro-inflammatory molecules like S100A8 and interleukin-8 (IL-8) by myeloid cells causing migration of myeloid cells to the site of inflammation. We hypothesized that pro-inflammatory S100A8 and IL-8 proteins could cause persistent inflammation in chronic wounds like diabetic foot ulcer (DFU) and may contribute to impaired wound healing in T2DM patients. MATERIALS AND METHODS Expression of TLR9 and its downstream effector molecules S100A8, and IL-8 were analyzed in chronic diabetic wound and non-diabetic control wound tissue samples by semiquantitative reverse transcriptase - polymerase chain reaction (RT-PCR), quantitative RT-PCR, western blot and immunofluorescence. CD11b(+)CD33(+) myeloid cells were analyzed by flow cytometry. RESULTS TLR9 message and protein were higher in diabetic wounds compared to control wounds (p=0.03, t=2.21 for TLR9 mRNA; p=<0.001, t=4.21 for TLR9 protein). TLR9 down-stream effector molecules S100A8 and IL-8 were also increased in diabetic wounds (p=0.003, t=3.1 for S100A8 mRNA; p=0.04, t=2.04 for IL-8). CD11b(+) CD33(+) myeloid cells were decreased in T2DM as compared to non-diabetic controls (p=0.001, t=3.6). DFU subjects had higher levels of CD11b(+) CD33(+) myeloid cells as compared to non-DFU T2DM control (p=0.003, t=2.8). Infection in the wound microenvironment could be the cause of increase in CD11b(+)CD33(+) myeloid cells in DFU (p=0.03, t=2.5). CONCLUSION The up-regulation of myeloid cell-derived pro-inflammatory molecules S100A8 and IL-8 in combination with lower levels of CD11b(+) CD33(+) myeloid cells may cause the impairment of wound healing in T2DM subjects leading to chronic ulcers.

Necrotizing Soft Tissue Infections: Surgeon's Prospective

Necrotizing soft tissue infections (NSTIs) are fulminant infections of any layer of the soft tissue compartment associated with widespread necrosis and systemic toxicity. Delay in diagnosing and treating these infections increases the risk of mortality. Early and aggressive surgical debridement with support for the failing organs significantly improves the survival. Although there are different forms of NSTIs like Fourniers gangrene or clostridial myonecrosis, the most important fact is that they share common pathophysiology and principles of treatment. The current paper summarizes the pathophysiology, clinical features, the diagnostic workup required and the treatment principles to manage these cases.

Secretase inhibitors for the treatment of Alzheimer's disease: Long road ahead

Alzheimers disease (AD) is a neurodegenerative disease, characterized by progressive loss of memory which is associated with other cognitive deficits. The two protein structures in the brain i.e. neurofibrillary tangles and senile plaques are considered to hamper the normal cognitive activity of the brain. There are various therapeutic interpolations under investigation to thwart and treat AD. Secretases inhibitors are important agents that inhibit the development of senile plaques. β-secretase (BACE) inhibitors are in lime light for the drug development of AD. BACE initiates the production of Aβ, so its inhibition provides a valid target for the AD. BACE inhibitors viz. LY2811376, LY2886721, E2609 are in different phases of clinical trials. However, chemical study of MK8931 was discontinued due to lack of chances of finding a positive clinical effect. AREAS COVERED The review incorporates exhaustive literature reports on secretase inhibitors, γ-secretase modulators (GSMs) and α-secretase enhancers. The recent studies on the natural products as GSMs have also been included.

Association of Variant rs7903146 (C/T) Single Nucleotide Polymorphism of TCF7L2 Gene With Impairment in Wound Healing Among North Indian Type 2 Diabetes Population A Case–Control Study

The variants of transcription factor 7-like 2 (TCF7L2) gene have been shown to be associated with type 2 diabetes mellitus (T2DM) and its several secondary complications. Here, we aimed to examine the possible role of one of the common variant of this gene, rs7903146 (C/T), with impairment of wound healing in cases with T2DM. A total of 750 individuals, including 322 patients with T2DM and 120 patients with diabetic foot ulcers (DFUs) and 308 controls, were analyzed for rs7903146 variant of the TCF7L2 gene. Genotyping was done by polymerase chain reaction–restriction fragment length polymorphism. For rs7903146 variant, TT genotype frequency in patients with DFU was 10.8% and in controls was 5.2%. Risk genotype (TT) frequencies showed statistically significant difference between the DFU patients versus non-DM control group (odds ratio = 2.44, P = .037, 95% confidence interval = 1.05-5.64) compared with nonrisk genotype (CC + CT). In the present study, a positive significant association between DFU and the TT genotype of rs7903146 (C/T) variant of TCF7L2 gene was found.

Leg ulcers in the tropics.

Leg ulcers are an important clinical condition and are often difficult to treat. The treatment has to continue for long periods, and the associated morbidity leads to significant loss of work. The successful treatment of leg ulcers or chronic wounds depends upon accurate diagnosis and treatment of the underlying cause. In Western societies, most leg ulcers are due to venous insufficiency, arterial disease, neuropathy (usually diabetic), or some combination of these factors. In tropical countries, however, there have been no large series of leg ulcers reported. The prevalence of leg ulcers and etiology are unknown. In this article, a short review is presented of the etiology and management of lower extremity ulcers as seen in the tropical countries.

Decreased expression of heat shock proteins may lead to compromised wound healing in type 2 diabetes mellitus patients

BACKGROUND Heat shock proteins (HSPs) are inducible stress proteins expressed in cells exposed to stress. HSPs promote wound healing by recruitment of dermal fibroblasts to the site of injury and bring about protein homeostasis. Diabetic wounds are hard to heal and inadequate HSPs may be important contributors in the etiology of diabetic foot ulcers (DFU). OBJECTIVE To analyze the differential expression of HSPs and their downstream molecules in human diabetic wounds compared to control wounds. METHODS Expressional levels of HSP27, HSP47 and HSP70 and their downstream molecules like TLR4, p38-MAPK were seen in biopsies from 101 human diabetic wounds compared to 8 control subjects without diabetes using RT-PCR, western blot and immunohistochemistry. RESULTS Our study suggested a significant down regulation of HSP70, HSP47 and HSP27 (p value=<0.001 for HSP70; p value=0.007 for HSP47; p value=0.007 for HSP27) in DFU along with their downstream molecules TLR4 and p38-MAPK (p value=0.006 for p38-MAPK; p value=0.02 for TLR4). HSP70 levels were significantly lower in male subjects and their levels increased significantly with the grades of wound on Wagners scale. Infection status of the wounds was found to be significantly associated with the increased levels of HSP70 and HSP27 in infected diabetic wounds. CONCLUSIONS Our study demonstrates that the down regulation of HSPs in diabetic wounds is associated with wound healing impairment in T2DM subjects.