LOCAL USE OF GRANULOCYTE-MACROPHAGES COLONY STIMULATING FACTOR IN TREATMENT OF CHRONIC DIABETIC NEUROPATHIC ULCER (CASE REVIEW).

One of the main causes of amputations in patients with Diabetes Mellitus patients is a chronic diabetic foot ulcer. The authors present a clinical case and discussion of a successful use of Granulocyte-Macrophages Colony Stimulating Factor (GM-CSF) treatment for the promotion of healing of a chronic diabetic foot ulcer. A 65 year-old woman was admitted to the Diabetes Center with complaints of a deep non-healing chronic foot ulcer for the last 18 months. At the examination a 5 cm ulcer on the plantar surface of the right foot was revealed. The patient had a 15-year history of Diabetes Mellitus type 2, complicated by neuropathy (peripheral and autonomic), retinopathy, nephropathy and Charcot joints in both legs and the right 4th toe had been amputation. She also had a history of heart failure. Healing of the ulcer could not be achieved with prior administered treatment. The decision was made to use GM-CSF treatment option in the area of the ulcer. Patient received local intradermal injections of GM-CSF (400 mcg twice a week) into the ulcerated foot for the duration of two months. The ulcer healed completely after one year of treatment with GM-CSF. Osteomyelitis was ruled out by scintigraphy. The patient did not develop any clinical side-effects or peripheral blood cell count abnormalities to the treatment. GM-CSF is a safe and effective treatment for chronic non-healing diabetic foot ulcers.

Anemia and stroke: Where do we stand?

Anemia seems to have a clear relationship with cerebrovascular events (CVEs), as there is a direct connection between central nervous system, blood supply, and tissue oxygen delivery. Anemia is considered a hyperkinetic state which disturbs endothelial adhesion molecule genes that may lead to thrombus formation. Furthermore, blood flow augmentation and turbulence may result in the migration of this thrombus, thus producing artery-to-artery embolism. It is for this reason that anemia is characterized as "the fifth cardiovascular risk factor." Anemia is consistently present in patients with acute stroke, ranging from 15% to 29%, while the mortality rate was significantly higher in patients suffering from anemia at the time of admission. Different types of anemia (sickle cell disease, beta thalassemia, iron deficiency anemia [IDA]) have been associated with increased cardiovascular and CVE risk. The relation between hemoglobin level and stroke would require further investigation. Unfortunately, treatment of anemia in cardiovascular and cerebrovascular disease still lacks clear targets and specific therapy has not developed. However, packed red blood cell transfusion is generally reserved for therapy in patients with CVEs. What is more, treatment of IDA prevents thrombosis and the occurrence of stroke; although iron levels should be checked, chronic administration favors thrombosis. Regarding erythropoietin (EPO), as there is lack of studies in anemic stroke patients, it would be desirable to utilize both neuroprotective and hematopoietic properties of EPO in anemic stroke patients. This review aims to clarify the poorly investigated and defined issues concerning the relation of anemia and CVEs.

Is management of hyperglycaemia in acute phase stroke still a dilemma?

INTRODUCTION: Close monitoring of blood glucose levels during the immediate post-acute stroke phase is of great clinical value, as there is evidence that the risk of neurological deterioration is associated with both hyper- and hypoglycaemia. The aim of this review paper is to summarise the evidence on post-stroke blood glucose management and its impact on clinical outcomes, during the early post-acute stage. FINDINGS: Post-stroke hyperglycaemia has been associated with increased cerebral oedema, haemorrhagic transformation, lower likelihood of recanalisation and deteriorating neurological state. Thus, hyperglycaemia during an acute stroke may result in poorer clinical outcomes, infarct progression, poor functional recovery and increased mortality rates. Although hypoglycaemia may also lead to poorer outcomes via further brain injury, it can be readily reversed by glucose administration. In most patients, the goal of regular treatment is euglycaemia and for acute-stroke patients, a reasonable approach is to target control of glucose level at 100-150 mg/dL. CONCLUSION: Both hypoglycaemia and hyperglycaemia may lead to further brain injury and clinical deterioration; that is the reason these conditions should be avoided after stroke. Yet, when correcting hyperglycaemia, great care should be taken not to switch the patient into hypoglycaemia, and subsequently aggressive insulin administration treatment should be avoided. Early identification and prompt management of hyperglycaemia, especially in acute ischaemic stroke, is recommended. Although the appropriate level of blood glucose during acute stroke is still debated, a reasonable approach is to keep the patient in a mildly hyperglycaemic state, rather than risking hypoglycaemia, using continuous glucose monitoring.

Hypercalcemia and multiple osteolytic lesions in an adult patient with relapsed pre-B acute lymphoblastic leukemia: a case report.

BACKGROUND: Hypercalcemia and severe osteolytic lesions are rare complications of acute lymphoblastic leukemia (ALL) in childhood, and those cases share similar clinical features. Similarly, hypercalcemia is a rare feature in adult ALL. Here, we report an uncommon case of an adult patient with relapsed precursor B ALL (pre-B ALL) who developed multiple osteolytic lesions and hypercalcemia. CASE DESCRIPTION: A 24-year-old male patient, diagnosed with pre-B ALL, was admitted in our hospital due to severe lumbar pain. After reviewing laboratory, radiological and clinical findings, the patient was diagnosed as having relapse of a mixed phenotype acute leukemia, according to bone marrow aspiration (9% blasts) and cytogenetic analysis, with multiple osteolytic lesions in all lumbar vertebrae, sacrum and ilium and severe hypercalcemia (13.3 mg/dL). Thus, FLAG-IDA rescue therapy and hydration plus furosemide, corticoids and bisphosphonates were administered. Despite initial amelioration, his hematological condition deteriorated and he died due to severe sepsis as a result of severe immunosuppression. CONCLUSION: Two possible mechanisms have been suggested for hypercalcemia in hematological malignancy, either the leukemic infiltration or the paraneoplastic production of a variety of humoral factors and proinflammatory cytokines. However, hypercalcemia and severe osteolytic lesions are rare features in ALL adult patients and their combination may be indicator of poor prognosis. Hippokratia 2015, 19 (1): 78-81.

Simultaneous manifestation of pleural effusion and acute renal failure associated with dasatinib: a case report.

WHAT IS KNOWN AND OBJECTIVE: Dasatinib is a novel second-generation inhibitor of multiple tyrosine kinases, indicated for the treatment for Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy. Although dasatinib is a potent, efficacious and generally well-tolerated drug, patients are also subject to various adverse effects. The most common pulmonary-related side effect is pleural effusion (PE). Renal failure has been reported rarely as a side effect of dasatinib treatment. We report the first case of a patient with imatinib-resistant CML who developed PE and acute renal failure (ARF) simultaneously, after being placed on dasatinib therapy. CASE SUMMARY: We report a 58-year-old female dasatinib-treated patient with Ph+ chronic phase CML who was admitted to our hospital due to persisted dyspnoea and fever. After reviewing the laboratory and clinical findings, we determined our patient as having simultaneously ARF and PE related to dasatinib therapy. Dasatinib was discontinued, and after 10 days of treatment with ampicillin-sulbactam, allopurinol, amlodipine, furosemide and methylprednisolone, she was discharged home effusion free and with ameliorated renal function. WHAT IS NEW AND CONCLUSION: PE is the most common extra-haematological toxicity observed during dasatinib treatment whose pathogenesis is still unclear. A possible role of cytokines, such as platelet-derived growth factor receptor (PDGFR)-ß and vascular endothelial growth factor (VEGF), in causing endothelial permeability has been suggested. The aetiology of renal failure is also unclear in these patients, but two different possible mechanisms have been suggested such as tumour lysis syndrome and toxic tubular damage. In conclusion, here we describe the first case of simultaneous manifestation of PE and ARF associated with dasatinib. Thus, in patients treated with tyrosine kinase inhibitors, especially those with predisposing nephrological or haematological factors, serum creatinine levels should be monitored routinely.

Hypovitaminosis D and peripheral arterial disease: emerging link beyond cardiovascular risk factors.

Vitamin D has received increasing interest for its beneficial effect on health. Beyond its conventional role in bone metabolism, emerging evidence suggests a possible link between low vitamin D levels and cardiovascular disease (CVD), including peripheral arterial disease (PAD), and cardiovascular risk factors. Vitamin D interacts either directly with the vascular tree or indirectly through its association with cardiovascular risk factors, but the exact mechanism remains controversial. This review outlines the association between hypovitaminosis D and PAD. Both entities are quite prevalent in the general population and, therefore, their potential association might have important clinical implications. Whether vitamin D deficiency represents a novel risk factor for PAD/CVD, and whether vitamin D supplementation would reduce the burden of CVD still remains to be answered. Until then, vitamin D intake is not recommended for PAD/CVD prevention. Outdoor physical activity, coupled with adequate but safe sun exposure, is a healthy lifestyle practice suggested for the prevention of both PAD and hypovitaminosis D.

Adipokines and stroke: a review of the literature.

Stroke represents one of the most important menaces to public health. A number of modifiable and non-modifiable risk factors have been identified and studied in detail; among those, obesity, the new world epidemic, seems to be one of the most important in terms of prevention. The discovery of the secretory role of the adipose tissue and of adipokines has opened new fields of research. A number of studies have been published on their relation to cardiovascular risk and the potential of using them as prevention markers. In the present review the physiology of leptin, adiponectin and resistin is described and their role in the pathogenesis of stroke is examined.

Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Study results.

Chronic kidney disease (CKD) is a global health problem associated with considerable morbidity and mortality and despite advances in the treatment of end stage renal disease (ESRD) mechanisms to prevent and delay its progression are still being sought. The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in many of the pathophysiologic changes that lead to progression of renal disease. Traditionally RAAS was considered as an endocrine system and its principal role was to maintain blood pressure (BP). In recent years local RAAS has been described to operate independently from systemic and local angiotensin II (AngII) in the kidney to contribute in hypertension and kidney damage. The benefits of strict BP control in slowing kidney disease progression have been demonstrated in several clinical trials and the question whether specific agents like angiotensin converting enzyme antagonists (ACEIs) and angiotensin receptor blockers (ARBs) provide renoprotective benefits beyond BP lowering is to be answered. Several studies support these agents reduce proteinuria and protect renal function, whereas the opposite is stated by others. According to guidelines, their use is recommended as first line agents in diabetic renal disease and non diabetic renal disease with albuminuria, whereas there is no data to support the same in non diabetic nonalbuminuric renal disease. Dual blockage of RAAS with the combination of ACEIs and ARBs could offer an alternative in strict RAAS blockade, but studies up to now can not prove its safety and the combination is not recommended until ongoing trials will provide new and unarguable results.

Adipogenesis and osteoblastogenesis: trans-differentiation in the pathophysiology of bone disorders.

Mesechymal stem cells as pluripotent cells are involved in the differentiation of adipocytes under regulation of genes and transcription factors. The plasticity observed between adipocytes and osteoblasts differentiation is the basis of transdifferentiation, observed in both experimental and clinical level. This review analyzes not only the adipose tissue as an endocrine organ but also the underlying mechanism of trans-differentiation between adipocytes and osteoblasts. Fat and bone tissue interaction is altered by activation or silencing of genes, signaling molecules and transcription factors. Disorders of this interaction include ectopic ossification syndromes and other bone disorders like osteoporosis and multiple myeloma. Further research will reveal the instinct mechanisms of this imbalance in the pathophysiology of many metabolic disorders such as diabetes mellitus, atherogenesis e.t.c.

Effects of buflomedil on skin blood flow in patients with type 2 diabetes mellitus without overt micro- or macroangiopathy.

AIM: The aim of this study was to assess the effects of buflomedil on the peripheral microcirculation in patients with type 2 diabetes mellitus (T2DM) without overt micro- or macroangiopathy. METHODS: Twenty-three patients with T2DM were randomly assigned to receive buflomedil 600 mg/day for six months (N.=12) or no medication (N.=11). Skin blood flow in the lower limbs was assessed at baseline and after 3 and 6 months using Laser Doppler. We measured the following laser Doppler parameters: volume, flow and velocity. RESULTS: In patients treated with buflomedil, there was a significant increase in volume (P=0.039) and a trend for an increase in both flow and velocity (P=0.097 for both parameters). In contrast, significant decreases in volume and flow were observed in the control group (P=0.045 and P=0.027, respectively) whereas velocity did not change (P=0.150). CONCLUSION: In conclusion, buflomedil appears to have a beneficial effect on the peripheral microcirculation in patients with T2DM.

Role of phytosterols in lipid-lowering: current perspectives.

The cholesterol-lowering effect of plant sterols was first discovered in the early 1950s. However, it is only recently that plant sterols have become clinically important, when advances in food-technology have made it possible to combine sterols with a variety of food products including margarines, yogurts, fruit juices and cereal bars. We review the clinical trial evidence of lipid-lowering efficacy of plant sterols and discuss their implications in routine clinical practice. To generate the evidence we searched the Pubmed database for English language literature, using relevant keywords and medical subject heading (MeSH) terms, and extracted the findings from recently published studies and meta-analyses on this topic. Our findings suggest that the short-term use of food supplements rich in plant sterols is a safe and effective strategy; to maximize the benefits of dietary and lifestyle therapy, either with or without statin therapy, among majority of dyslipidemic patients with need for additional lipid-lowering.

Breastfeeding and diabetes.

The present review outlines the role of breastfeeding in diabetes. In the mother, breastfeeding has been suggested to reduce the incidence of type 2 diabetes mellitus, the metabolic syndrome and cardiovascular disease. Moreover, it appears to reduce the risk of premenopausal breast cancer and ovarian cancer. In the neonate and infant, among other benefits, lactation confers protection from future both type 1 and type 2 diabetes. Whether lactation protects women with gestational diabetes mellitus and their offspring from future T2DM remains to be answered. Importantly, for diabetic mothers, antidiabetic treatment itself may affect breastfeeding. There is not enough data to allow the use of oral hypoglycaemic agents. Therefore, insulin currently remains the optimal antidiabetic treatment during lactation. In conclusion, breastfeeding could be considered a modifiable risk factor for the development of diabetes and even a potential protective lifestyle measure from future cardio-metabolic and malignant diseases. Therefore, health care professionals should encourage both women with and without diabetes to breastfeed their children.

Amiodarone: pharmacological profile, animal-model experimental data and clinical use. How important is the vasodilating effect?

Amiodarone, the major representative of class III antiarrhythmic agents, is widely used in the treatment of ventricular and hyperventricular arrhythmias, being specifically useful in the therapy of patients suffering from life threatening ventricular arrhythmias. The combination of antianginal and antiarrthythmic actions of amiodarone is an extremely significant advantage regarding the treatment of patients with chronic atherosclerotic cardiopathy, as heart rate disorders are frequently fatal in coronary heart disease and, reversely, a high percentage of cardiac arrhythmias are caused by coronary heart disease. Since 1980s, several experimental in vitro and in vivo data, as well as clinical studies, regarding both systematic and coronary circulation, support the vasodilative effects of amiodarone. We have previously showed that amiodarone in vitro exerts a vasodilator effect in isolated vessel tissue, mainly via the activation of intracellular calcium binding mechanisms, a fact that differentiates this agent from other coronary vasodilative drugs, such as calcium channel blockers, that affect extracellular calcium ions entrance. Thus, the vasodilative, antianginal and antiarrhythmic actions of amiodarone may be further enhanced by the simultaneous supplementation of calcium channel blockers via synergistic mechanisms, supporting the clinical use of such drug combinations. Finally, as amiodarone and noradrenaline have been reported to exert antagonistic actions, the application of amiodarone is particularly indicated in pathologic conditions characterized by the stimulation of sympathetic nervous system (sympathicotonia).

Initiative for a new diabetes therapeutic approach in a Mediterranean country: the INDEED study.

AIM: To assess the efficacy of a strategy to improve vascular risk management in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a pilot best practice implementation enhancement programme that enrolled 578 patients with T2DM. A baseline visit was followed by a concerted effort from previously trained physicians to improve adherence to lifestyle advice and optimise drug treatment for all vascular risk factors. The patients were followed-up for 6 months. The UKPDS risk engine was used to estimate vascular risk in patients without established coronary heart disease (CHD) (n = 279). RESULTS: There was an improvement in compliance to lifestyle measures and increased prescription of evidence-based medication. In patients without established CHD there was a 37% reduction in estimated risk for CHD, 44% for fatal CHD, 10% for stroke and 25% for fatal stroke (p < or = 0.003 for all comparisons vs. baseline). There was also a substantial increase in the proportion of patients with established CHD who achieved their vascular risk factor targets. CONCLUSIONS: This is the first study to increase the adherence to multiple interventions in patients with T2DM in both primary care and hospital settings. Education of physicians and patients, distribution of guidelines/brochures, and the completion of a one-page form, motivated both physicians and patients to achieve multiple vascular risk factor goals.

Standardized arrangement for a guideline-driven treatment of the metabolic syndrome: the SAGE-METS study.

AIM: To substantially increase awareness, treatment and effective control of the metabolic syndrome (MetS) and its components. SUBJECTS AND METHODS: This is a pilot best practice implementation enhancement programme to reduce the estimated cardiovascular disease (CVD) risk in 628 MetS patients with or without diabetes or CVD by improving quality of care. A baseline visit was followed by action to improve adherence to lifestyle advice and drug treatment for CVD risk factors by physicians specifically trained to implement guidelines. Finally, after 6 months, a single-page form was completed, showing if patients were at CVD risk factor target. If not, there was an analysis of the reason why. RESULTS: The programme was effective in improving utilization of evidence-based treatment in 628 MetS patients. There was a substantially greater patient perception of MetS, an enhancement in compliance with lifestyle advice and increased prescription of evidence-based medication, leading to a 48% (p < 0.0001) improvement in estimated CVD risk. There was a substantial increase in the number of subjects on target for specific CVD risk factors. CONCLUSIONS: This is the first study to increase adherence to multiple interventions for all MetS components on an outpatient basis, in both primary care and teaching hospital settings. Physician and patient education, distribution of printed guidelines and brochures, and completion of a single-page form motivated both physicians and patients to achieve multiple CVD risk factor guideline goals. The absence of a control group is a limitation of this study. Further work is also needed to establish if the improvements observed are sustained on a long-term basis.