Extended-Spectrum Beta-Lactamase Escherichia coli Diabetic Foot Osteomyelitis Causing Sausage Toe Deformity: Successful Therapy with Ertapenem in the Outpatient Setting.

BACKGROUND Diabetic foot osteomyelitis is a high-morbidity and debilitating complication of diabetic foot ulcers that contributes to significantly worse quality of life in the affected population and higher cost of healthcare services. One of the clinical presentations of diabetic foot osteomyelitis is the 'sausage' toe deformity, which affects the phalanges (local soft tissue infection and underlying bony changes). This deformity is highly suggestive of the presence of osteomyelitis. Unfortunately, during recent years, the emergence of antibiotic-resistant bacteria have created great difficulties in choosing appropriate empirical antibiotics for the treatment of diabetic foot infections. Multidrug-resistant pathogens have been strongly related to higher morbidity and mortality compared with infections caused by their antibiotic-susceptible counterparts. CASE REPORT We describe a case of a 74-year-old woman with long-standing insulin-treated type 2 diabetes, who experienced extended-spectrum beta-lactamase-producing Escherichia coli infection that caused diabetic foot osteomyelitis with 'sausage' deformity in her second right toe. She was successfully treated with surgical debridement combined with the administration of ertapenem in the outpatient setting, completing, in total, a 6-week course of antibiotic therapy. CONCLUSIONS 'Sausage' toe deformity is one of the clinical presentations of diabetic foot osteomyelitis, and should be an alarming sign in everyday clinical practice. Ertapenem is an excellent option for the treatment of diabetic foot infections caused by extended-spectrum beta-lactamase E. coli in the outpatient setting. Early diagnosis and proper therapeutic approach are of great importance to reduce the risk of amputations, overall mortality, total cost, and the surge of antimicrobial resistance in the community.

Successful Outpatient Treatment of Severe Diabetic-Foot Myositis and Osteomyelitis Caused by Extensively Drug-Resistant Enterococcus faecalis with Teicoplanin plus Rifampicin: A Case Report.

BACKGROUND Foot ulcers are high-morbidity and debilitating complications of diabetes mellitus, and carry significantly increased rates of associated major amputations. They contribute to significantly worse quality of life. Osteomyelitis is a frequent complication of diabetic foot ulcers, since bacteria can contiguously spread from soft tissues to the bone, involving the cortex first and then the bone marrow. Unfortunately, clinically unsuspected osteomyelitis is frequent in persisting diabetic foot ulcers. It is associated with limb amputations and increased mortality. CASE REPORT We describe a 76-year-old man with long-standing insulin-treated type 2 diabetes, who experienced extensively drug-resistant Enterococcus faecalis diabetic foot myositis and osteomyelitis associated with sepsis. He was successfully treated with surgical debridement combined with the administration of teicoplanin plus rifampicin in the outpatient setting, completing, in total, a twelve-week course of antibiotic therapy. CONCLUSIONS Clinically unsuspected osteomyelitis in patients with persisting diabetic foot ulcers has been associated with infections from highly resistant bacteria. Early and accurate diagnosis of diabetic foot osteomyelitis, as well as proper therapeutic approach (antimicrobial and surgical), is of great importance to reduce the risk of minor and major amputations, septic shock leading to multiple organ failure, and overall mortality.

GLP-1 receptor agonists, SGLT-2 inhibitors, and obstructive sleep apnoea: can new allies face an old enemy?

Obstructive sleep apnoea (OSA) is the most common form of abnormal sleep pattern (ASP). It is characterized by narrowing of the upper airways (complete or partial) during sleep. Although continuous positive airway pressure is recognized as the gold standard treatment of OSA, unfortunately treatment adherence is often suboptimal and does not address the pathophysiological mechanisms governing its pathogenesis. Weight gain is an important risk factor for the development and worsening of OSA both in adults and in children. Meaningful and sustained weight reduction using lifestyle modifications alone remains difficult and challenging. Novel therapeutic strategies are vital because currently there are no approved pharmacological therapies. This paper explores thoroughly both preclinical and clinical studies that investigated the possible role of GLP-1 receptor agonists and SGLT-2 inhibitors in individuals with ASP and especially OSA. It also discusses their future role in order to ameliorate the global burden of OSA.

SGLT2 inhibitors, intrarenal hypoxia and the diabetic kidney: insights into pathophysiological concepts and current evidence.

Approximately 20-40% of all diabetic patients experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). A large body of evidence suggests that renal hypoxia is one of the main forces that drives diabetic kidney disease, both in its early and advanced stages. It promotes inflammation, generation of intrarenal collagen, capillary rarefaction and eventually accumulation of extracellular matrix that destroys normal renal architecture. SGLT2 inhibitors are unquestionably a practice-changing drug class and a valuable weapon for patients with type 2 diabetes and chronic kidney disease. They have achieved several beneficial kidney effects after targeting multiple and interrelated signaling pathways, including renal hypoxia, independent of their antihyperglycemic activities. This manuscript discusses the pathophysiological concepts that underly their possible effects on modulating renal hypoxia. It also comprehensively investigates both preclinical and clinical studies that explored the possible role of SGLT2 inhibitors in this setting, so as to achieve long-term renoprotective benefits.

Pioglitazone in diabetic kidney disease: forgotten but not gone.

Diabetic kidney disease (DKD) is described in approximately 20-40% of all diabetic patients and is associated with significant cardiovascular and all-cause mortality. The involvement of multiple metabolic, haemodynamic, inflammatory, and tubular pathways in the pathophysiology of DKD generates the need for multitargeted treatment approaches to improve its development at all levels and delay or even reverse its progression. Thiazolidinediones are potent exogenous agonists of PPAR-γ, which augment the effects of insulin on its cellular targets, mainly at the level of adipose tissue. Pioglitazone, currently the main thiazolidinedione in clinical practice, has achieved significant improvements of albuminuria in patients with type 2 diabetes. It can also interfere with most cellular pathways involved in the development and evolution of DKD. This paper explores the pathophysiological mechanisms governing its possible nephroprotective activity during a diabetic state. It also discusses its future role to ameliorate the global burden of DKD.

GLP-1 receptor agonists, polycystic ovary syndrome and reproductive dysfunction: Current research and future horizons.

Polycystic ovary syndrome (PCOS) is a disorder that involves several organ systems and cellular pathways. It is strongly influenced by environmental and epigenetic factors. The principal goal of all therapeutic approaches to individuals with reproductive abnormalities is the treatment of subfertility or the regulation of menstruation when pregnancy is not desired. Obesity is closely related to insulin resistance (IR) and subsequent hyperinsulinemia, which aggravate hyperandrogenism and impair early follicle development. Weight loss is of vital importance for overweight/obese individuals with anovulatory infertility. The GLP-1R agonists have achieved remarkable weight reduction and abdominal fat loss in patients with type 2 diabetes (T2D), as well as in overweight/obese individuals and individuals with prediabetes. They have also been shown to promote lower fasting insulin levels and insulin resistance markers. These beneficial effects have been suggested to be particularly helpful in women with PCOS, while their possible role in the hypothalamic-pituitary-gonadal axis is under intense research. This review analyzes the current evidence for GLP-1R agonists, focusing on their effects on ovarian morphology, menstrual dysfunction and fertility outcomes. It also discusses their future role in achieving targeted therapeutic approaches.

Bacteroides fragilis Bacteremia Complicated by Spondylodiscitis, Spinal Epidural Abscess, and Sepsis: A Case Report.

BACKGROUND Pyogenic spondylitis comprises several clinical entities, including native vertebral osteomyelitis, septic discitis, pyogenic spondylodiscitis, and epidural abscess. The lumbar spine is most often infected, followed by the thoracic and cervical areas. It mainly develops (i) after spine surgery; (ii) from history of blunt trauma to the spinal column; (iii) from infections in adjacent structures (such as soft tissues); (iv) from iatrogenic inoculation after invasive procedures (such as lumbar puncture); and (v) from hematogenous bacterial spread to the vertebra (mainly through the venous route). Any delay in diagnosis and treatment can lead to significant spinal cord injury, permanent neurological damage, septicemia, and death. CASE REPORT We describe a 63-year-old man with no significant past medical history who presented with fever and an altered level of consciousness. Significant thoracic spine pain was also reported during the last 3 months. The final diagnosis was vertebral spondylodiscitis, contiguous spinal epidural abscess, and sepsis due to Bacteroides fragilis bacteremia. Clinical recovery was achieved after surgical decompressive therapy with abscess drainage combined with appropriate antibiotic therapy for 12 weeks. The primary focus of the infection was not clarified, despite all the investigations that were performed. CONCLUSIONS Spondylodiscitis, spinal epidural abscess, and sepsis as complications of Bacteroides fragilis bacteremia are rare in a patient without any previously known predisposing conditions and without an obvious primary focus. Early diagnosis and proper treatment of anaerobic spondylodiscitis, especially if epidural abscess and sepsis are present, are of great importance to reduce mortality and avoid long-term complications.

Pioglitazone, Bladder Cancer, and the Presumption of Innocence.

BACKGROUND: Thiazolidinediones are potent exogenous agonists of PPAR-γ that augment the effects of insulin to its cellular targets, mainly at the level of adipose tissue. Pioglitazone, the main thiazolidinedione in clinical practice, has shown cardiovascular and renal benefits in patients with type 2 diabetes, durable reduction of glycated hemoglobulin levels, important improvements of several components of the metabolic syndrome, and beneficial effects of non-alcoholic fatty liver disease. OBJECTIVE: Despite all of its established advantages, the controversy for an increased risk of developing bladder cancer, combined with the advent of newer drug classes that achieved major cardiorenal effects, have significantly limited its use spreading a persistent shadow of doubt for its future role. METHODS: Pubmed, Google, and Scope databases have been thoroughly searched, and relevant studies were selected. RESULTS: This paper thoroughly explores both in vitro and in vivo (animal models and humans) studies that investigated the possible association of pioglitazone with bladder cancer. CONCLUSION: Currently, the association of pioglitazone with bladder cancer cannot be based on solid evidence. This evidence cannot justify its low clinical administration, especially in the present era of individualised treatment strategies. Definite clarification of this issue is imperative and urgently anticipated from future high quality and rigorous pharmacoepidemiologic research, keeping in mind its unique mechanism of action and its significant pleiotropic effects.

Empagliflozin therapy and insulin resistance-associated disorders: effects and promises beyond a diabetic state.

Empagliflozin is a SGLT2 inhibitor that has shown remarkable cardiovascular and renal activities in patients with type 2 diabetes (T2D). Preclinical and clinical studies of empagliflozin in T2D population have demonstrated significant improvements in body weight, waist circumference, insulin sensitivity, and blood pressure - effects beyond its antihyperglycaemic control. Moreover, several studies suggested that this drug possesses significant anti-inflammatory and antioxidative stress properties. This paper explores extensively the main preclinical and clinical evidence of empagliflozin administration in insulin resistance-related disorders beyond a diabetic state. It also discusses its future perspectives, as a therapeutic approach, in this high cardiovascular-risk population.

Spontaneous Rupture of a Bicuspid Aortic Valve in a Middle-Aged Weightlifter.

We describe a 58-year-old Caucasian male weightlifter who presented with acute shortness of breath after finishing his extensive exercise routine. Acute aortic valve regurgitation, due to spontaneous rupture of a bicuspid aortic valve, was diagnosed. Urgent surgical intervention was carried out, during which the bicuspid aortic valve was resected and replaced with an On-X bileaflet mechanical valve. The patient remains asymptomatic and is treated with warfarin, being in excellent physical condition 4 years after aortic valve replacement. LEARNING POINTS: Spontaneous rupture of a bicuspid aortic valve, after heavy weightlifting, is a very rare cause of acute aortic valve regurgitation.Echocardiography is of vital importance to distinguish the reason for this medical emergency from other possible causes.Prompt diagnosis and surgical treatment can achieve excellent long-term results.

Retroperitoneal ganglioneuroma causing chronic lower back and leg pain in an 80-year-old man: A case report.

INTRODUCTION: and importance: Retroperitoneal ganglioneuromas that cause lower back and leg pain are extremely rare and are often misdiagnosed. Surgical resection has excellent prognosis in long-term survival. CASE PRESENTATION: We present an 80-year-old man with two-year worsening left lower back and leg pain. He was treated as presumed lumbar spine spondylosis with several courses of physical therapy together with medical treatment. An abdomen CT scan disclosed a tumour in the left retrorenal space. The tumour was resected and the histopathologic examination suggested a completely excised retroperitoneal ganglioneuroma. During one-year follow-up the patient is free of pain without any local recurrence. CLINICAL DISCUSSION: Retroperitoneal ganglioneuromas are rare benign tumors that originate from neural crest-derived cells of the paravertebral sympathetic plexus and sometimes from the adrenal medulla. They are usually asymptomatic and discovered on routine clinical examination or on autopsy. Occasionally they may show symptoms due to local pressure effect or rarely they are hormonally active and present with adrenergic symptoms. Complete resection of the tumor is important in order establish the final diagnosis and alleviate symptoms from pressure effects. CONCLUSION: This case highlights the need for great vigilance among physicians in order to consider any possible retroperitoneal pathology when indicated in the differential diagnosis of lower back and leg pain, before establishing other more common diagnosis, especially in the older population.

Empagliflozin and the Diabetic Kidney: Pathophysiological Concepts and Future Challenges.

Chronic kidney disease is a serious co-morbidity of patients with diabetes, which amplifies the global burden of this disease, affects the quality of their life, and significantly increases both morbidity and mortality. Therefore, there is a high unmet clinical need to develop therapeutic strategies in order to prevent, delay, or even reverse its evolution. EMPA-REG OUTCOME trial has fundamentally changed the therapeutic landscape of patients with type 2 diabetes and signified a new era in which treatment approaches should be tailored based on end-organ protection and patient comorbidities rather than focusing only on their antihyperglycemic effects. This paper discusses the seminal EMPA-REG OUTCOME trial, focusing on its renal outcomes, and explores extensively the possible pathophysiological mechanisms governing the nephroprotective activity of empagliflozin both in in vitro and in vivo (animal models and humans) studies during a diabetic state. It also discusses the safety of empagliflozin therapy and its future role in order to ameliorate the global burden of CKD both in patients with and without diabetes.

Liraglutide: New Perspectives for the Treatment of Polycystic Ovary Syndrome.

Polycystic ovary syndrome is a complex and heterogenous disorder involving multiple organ systems and different molecular pathways. It is tightly associated with obesity and especially abdominal obesity. As body weight reduction is the main modifiable risk factor for polycystic ovary syndrome, therapeutic approaches in overweight or obese women with polycystic ovary syndrome have been developed. Liraglutide is a glucagon-like peptide-1 receptor agonist that promotes sustained weight loss, as well as abdominal fat reduction, in individuals with obesity, prediabetes, and type 2 diabetes mellitus. The majority of current clinical studies have demonstrated that liraglutide therapy achieved significant reductions in body weight, body mass index, and abdominal circumference in overweight and obese women with polycystic ovary syndrome. Liraglutide therapy promoted significant improvements in free testosterone and sex hormone-binding globulin levels in some studies. Important metabolic and hormonal improvements were also reported after the combination of liraglutide with metformin. Increased menstrual frequency, as well as potential positive effects in reproduction, were described. However, the small number of participants, short duration, and low daily liraglutide dose are some of the main limitations of these studies. Larger and longer, multi-centred, double-blind, placebo-controlled trials of liraglutide monotherapy or combination therapy, with prolonged post-interventional monitoring, are crucially anticipated. Metabolic, hormonal, and reproductive primary outcomes should be uniformly addressed, to tailor future targeted treatment approaches, according to the patient phenotype and needs. This will improve long-term therapeutic outcomes in this population.

Liraglutide Therapy in a Prediabetic State: Rethinking the Evidence.

BACKGROUND: Prediabetes is defined as a state of glucose metabolism between normal glucose tolerance and type 2 diabetes. Continuous ß-cell failure and death are the reasons for the evolution from normal glucose tolerance to prediabetes and finally type 2 diabetes. INTRODUCTION: The necessity of new therapeutic approaches in order to prevent or delay the development of type 2 diabetes is obligatory. Liraglutide, a long-acting GLP-1 receptor agonist, has 97% homology for native GLP-1. Identification of the trophic and antiapoptotic properties of liraglutide in preclinical studies, together with evidence of sustained ß-cell function longevity during its administration in type 2 diabetes individuals, indicated its earliest possible administration during this disease, or even before its development, so as to postpone or delay its onset. METHODS: Pubmed and Google databases have been thoroughly searched and relevant studies were selected. RESULTS: This paper explores the current evidence of liraglutide administration both in humans and animal models with prediabetes. Also, it investigates the safety profile of liraglutide treatment and its future role to postpone or delay the evolution of type 2 diabetes. CONCLUSION: Liralgutide remains a valuable tool in our therapeutic armamentarium for individuals who are overweight or obese and have prediabetes. Future well designed studies will give valuable information that will help clinicians to stratify individuals who will derive the most benefit from this agent, achieving targeted therapeutic strategies.

Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns.

The prevalence of type 2 diabetes (T2D) is rapidly increasing. This is strongly related to the contemporary lifestyle changes that have resulted in increased rates of overweight individuals and obesity. Central (intra-abdominal) obesity is observed in the majority of patients with T2D. It is associated with insulin resistance, mainly at the level of skeletal muscle, adipose tissue and liver. The discovery of macrophage infiltration in the abdominal adipose tissue and the unbalanced production of adipocyte cytokines (adipokines) was an essential step towards novel research perspectives for a better understanding of the molecular mechanisms governing the development of insulin resistance. Furthermore, in an obese state, the increased cellular uptake of non-esterified fatty acids is exacerbated without any subsequent ß-oxidation. This in turn contributes to the accumulation of intermediate lipid metabolites that cause defects in the insulin signaling pathway. This paper examines the possible cellular mechanisms that connect central obesity with defects in the insulin pathway. It discusses the discrepancies observed from studies organized in cell cultures, animal models and humans. Finally, it emphasizes the need for therapeutic strategies in order to achieve weight reduction in overweight and obese patients with T2D.

Incretin-based therapies in prediabetes: Current evidence and future perspectives.

The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless ß-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on ß-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater ß-cell mass and function are preserved and the possibility of ß-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on ß-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.

Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit.

The prevalence of type 2 diabetes is evolving globally at an alarming rate. This fact is mainly the result of our global lifestyle "modernization" that has resulted in overweight and obesity. Dysfunction of peroxisome proliferator activated receptor-gamma (PPAR-gamma) has been implicated in the development of insulin resistance, while a reduce expression of many PPAR-gamma regulated genes has been observed in an obese diabetic state. Thiazolidinediones (TZDs) are potent exogenous agonists of PPAR-gamma, which augment the effects of insulin to its cellular targets and mainly at the level of adipose tissue. Preclinical and clinical studies have demonstrated that apart from their glucose-lowering activity, these drugs also regulate the production of inflammatory mediators by cells that play a pivotal role in the pathogenesis of atherosclerosis. This paper summarizes the evolving changes observed in an enlarged adipose tissue and examines the activity of TZDs in their main cellular targets. It also discusses whether these cellular pleiotropic effects can result in a clinically meaningful outcome, in terms of cardiovascular benefit, in this population.

Polymorphisms of the NRAMP1 gene: distribution and susceptibility to the development of pulmonary tuberculosis in the Greek population.

BACKGROUND: Ample evidence suggests that host genetic factors affect human susceptibility to tuberculosis. The natural resistance-associated macrophage protein 1 (NRAMP1) gene seems to play a role in the pathophysiology of a number of intracellular infections, including mycobacteria. A case-control study was conducted in the Greek population to determine whether NRAMP1 polymorphisms affect the susceptibility to development of overt pulmonary tuberculosis. MATERIAL/METHODS: NRAMP1 polymorphisms (3'UTR, D543N, INT4) were evaluated among 142 patients with culture-positive pulmonary tuberculosis and 144 ethnically matched healthy controls having latent M. tuberculosis infection. Patients with human immunodeficiency virus infection were excluded. RESULTS: Out of the 3 NRAMP1 polymorphisms, a trend of increased incidence of INT4 polymorphism was found in the patients' group compared to the control group. A lack of association was observed between the 2 groups as far as the other 2 polymorphisms (D543N, 3'UTR) are concerned. INT4-CC homozygotes were found to have a higher risk to develop pulmonary tuberculosis compared to GG homozygotes (p=0.022). An increased incidence G/TGTG/C genotype combination was found in the patients' group as compared to controls. G/TGTG/C genotype combination was associated with a 36% higher risk of developing pulmonary tuberculosis (p=0.004) compared to the baseline expression of G/TGTG/G combination. CONCLUSIONS: INT4-NRAMP1 polymorphism may have a role in the development of culture-positive pulmonary tuberculosis after an initial M. tuberculosis latent infection. The possible role of INT4-NRAMP1 polymorphism in the development of active pulmonary tuberculosis needs further investigation.