Insulin degludec in pregestational diabetes: evidence and perspectives.

Pregestational diabetes is described when a woman with diabetes before the onset of pregnancy becomes pregnant and consequently she is vulnerable to higher risk for adverse outcomes in the embryo/foetus. Strict glycaemic control, with minimal glucose variability, starting from before conception and maintained throughout pregnancy decreases significantly adverse foetal and maternal outcomes; maternal hypoglycaemic episodes are the major barrier in achieving this goal. Insulin degludec is an ultralong-acting analogue, which has half-life of over 25 h and full duration of effect of more than 42 h, reaching a steady-state serum concentration after 2-3 days of its administration. It promotes flat, steady, peakless and predictable insulin concentrations, with minor intra-individual and inter-individual variability. It also exerts a low mitogenic/metabolic potency ratio. This review examines thoroughly all current evidence of the administration of insulin degludec in pregestational diabetes as well as its future role in this population.

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.

Insulin Resistance, Hyperinsulinemia and Atherosclerosis: Insights into Pathophysiological Aspects and Future Therapeutic Prospects.

Insulin resistance describes the lack of activity of a known quantity of insulin (exogenous or endogenous) to promote the uptake of glucose and its utilization in an individual, as much as it does in metabolically normal individuals. On the cellular level, it suggests insufficient power of the insulin pathway (from the insulin receptor downstream to its final substrates) that is essential for multiple mitogenic and metabolic aspects of cellular homeostasis. Atherosclerosis is a slow, complex, and multifactorial pathobiological process in medium to large arteries and involves several tissues and cell types (immune, vascular, and metabolic cells). Inflammatory responses and immunoregulation are key players in its development and progression. This paper examines the possible pathophysiological mechanisms that govern the connection of insulin resistance, hyperinsulinemia, and the closely associated cardiometabolic syndrome with atherosclerosis, after exploring thoroughly both in vitro and in vivo (preclinical and clinical) evidence. It also discusses the importance of visualizing and developing novel therapeutic strategies and targets for treatment, to face this metabolic state through its genesis.

Musculoskeletal Pain and Right Leg Paresthesia Revealed as Large Ovarian Mucinous Cystadenoma: A Case Report.

BACKGROUND Epithelial neoplasms are the most common and heterogenous group of ovarian tumors. Approximately 10-15% are primary ovarian mucinous neoplasms. Almost 80% of these consist of benign mucinous neoplasms, while the rest are borderline neoplasms, non-invasive (intraepithelial and intraglandular) carcinomas, and invasive carcinomas. Small ovarian cystadenomas are generally asymptomatic and are mainly found incidentally during an ultrasound examination for another gynecologic disorder. As their size increases, nonspecific symptoms and clinical signs develop as a result of mass effect to adjacent structures or because of tumor torsion. The main clinical symptoms are abdominal and/or pelvic pain, fullness, and discomfort. Large cystadenomas have also been associated with nausea and vomiting, urinary problems, persistent cough, back pain, metrorrhagia, and feminization. CASE REPORT We report a case of a 31-year-old woman with a body mass index of 39 who presented with increasing sacrococcygeal pain and right leg paresthesia over a 2-year period. She was treated for possible musculoskeletal and spine problems. She was finally diagnosed with a large right ovarian mucinous cystadenoma expanding in the sacrococcygeal region. She was successfully treated with complete excision of the tumor and achieved complete remission of all her symptoms. CONCLUSIONS Large ovarian mucinous cystadenomas, which develop in the sacrococcygeal region, can lead to symptoms that mimic musculoskeletal and spine problems. Early diagnosis is of great importance towards the goal of implementing proper therapeutic approaches and achieve complete remission of all clinical symptoms.

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.

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.

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.

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.

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.

Targeted therapy for gastrointestinal stromal tumors: current status and future perspectives.

Gastrointestinal stromal tumors (GISTs) present 80% of gastrointestinal tract mesenchymal tumors, with systemic chemotherapy and radiotherapy being unable to improve survival of patients with advanced disease. The identification of activating mutations in either KIT cell surface growth factor receptor or platelet-derived growth factor receptor alpha, which lead to ligand-independent signal transduction, paved the way for the development of novel agents that selectively inhibit key molecular events in disease pathogenesis. The development of imatinib mesylate in the treatment of metastatic GIST represents a therapeutic breakthrough in molecularly targeted strategies, which crucially improved patients' prognosis while its usefulness in adjuvant and neoadjuvant setting is under study. Sunitinib malate is available in the second-line setting, with ongoing studies evaluating its role in an earlier disease stage, while other targets are under intense investigation in order to enrich the therapeutical armamentarium for this disease. GIST phenotype seems to be an essential indicator of treatment response; thus, obtaining genotype information of each patient may be critical in order to tailor individualized treatment strategies and achieve maximal therapeutic results.

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.

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.

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.

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.

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.

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.

Serological diagnosis of Chlamydophila pneumoniae infection in Greek COPD patients by microimmunofluorescence and ELISA.

BACKGROUND: The possible role of Chlamydophila pneumoniae infection in episodes of acute exacerbation of COPD (AECOPD) was described in 4-34% of COPD patients, but never in Greece. The possible association of chronic C. pneumoniae infection with disease severity is under study, with a diversity of results reported. MATERIAL/METHODS: Seventy-five Greek patients with AECOPD were tested for serum C. pneumoniae antibodies using the microimmunofluorescence (MIF) test and ELISA during the first day of their hospitalization and 30 days after enrollment. Serological diagnosis of acute and past C. pneumoniae infection was determined and the sensitivities, specificities, and predictive values of both methods were evaluated. Chronic C. pneumoniae infection was also estimated in both the patient group and a control group. RESULTS: Seven patients (9.3%) had serological evidence of acute C. pneumoniae infection. Although ELISA and MIF produced equal results for the diagnosis of acute C. pneumoniae infection, the sensitivity and negative predictive value of ELISA for the diagnosis of past C. pneumoniae infection was low when MIF was used as the gold-standard method. Chronic C. pneumoniae infection was more common in COPD patients than in the control group and was even more common in patients with FEV(1)<50%. CONCLUSIONS: Acute C. pneumoniae infection is associated with AECOPD in Greece. ELISA may currently be a valuable diagnostic tool for the diagnosis of acute C. pneumoniae infection, but not for the diagnosis of past infection. The possible role of chronic C. pneumoniae infection in COPD progression needs further investigation.