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The incidence of cardiovascular disease is substantially increased in patients with type 1 diabetes compared to the general population. Robust evidence from the randomized Diabetes Control and Complications Trial (DCCT) and the long-term epidemiologic surveillance of its participants suggest that tight glycemic control by means of intensive insulin treatment is efficacious both in primary and secondary prevention of cardiovascular disease. New antidiabetic agents with proven cardiorenal benefit in patients with type 2 diabetes, such as Glucagen-Like Polypeptide-1 Receptor Agonists (GLP-1RA) and Sodium-Glucose co-Transporter-2 Inhibitors (SGLT-2inh), have been tested as adjunctive to insulin treatment in a few clinical trials in patients with type 1 diabetes. Despite their favorable effect on risk factors for atherosclerotic disease, such as body weight and blood pressure, the lack of evidence for a direct effect on cardiovascular outcomes and an increased risk for serious adverse events, such as diabetic ketoacidosis, limit their use in patients with type 1 diabetes. New metrics of glycemia, alterations in diabetes classification and precision medicine may contribute in an individualized approach of cardiovascular risk prevention in patients with diabetes.

Metformin has been for many years the first-line pharmaceutic treatment for most patients with type 2 diabetes. However, new classes of antidiabetic agents with proven cardiorenal benefits beyond glycemic control challenge metformin’s predominance. The hypoglycemic effect of metformin is mediated in liver by inhibiting gluconeogenesis and improving insulin sensitivity and in intestines by reducing glucose absorption, increasing incretins and altering intestinal microbiome. After decades of use metformin has been proved to be one of the most potent, safe and cost-effective medications for the treatment of type 2 diabetes. Several other pleiotropic actions of metformin in inflammation pathways suggest a potential cardioprotective role. This hypothesis has been tested in a few randomized trials and in more observational studies and metanalyses with controversial results. Given the lack of robust evidence for the cardioprotective effect of metformin compared to the newer antidiabetic agents, current treatment algorithms are under scrutiny. Ongoing randomized clinical trials comparing metformin to placebo are expected to elucidate the effect of metformin on specific cardiovascular and renal outcomes.

Platelet microparticles (PMPs), which are microvesicles shed from platelets, participate in inflammation, vascular homeostasis, and thrombosis. PMPs are increased in obese women with polycystic ovary syndrome (PCOS). Agents that modulate hormonal aspects of PCOS could affect the levels of PMPs. The aim of the present study was to evaluate the effects of oral contraceptives (OCPs), antiandrogen, and metformin use for 6 and 12 months on PMPs in normal-weight women with PCOS. Forty-five women with PCOS and 13 healthy women were recruited. Biochemical, hormonal, and clinical parameters were recorded. Women with PCOS received treatment with OCPs, OCPs+antiandrogens, or metformin, depending on their main complaint or clinical/biochemical findings. PMPs were measured at baseline and after 6 and 12 months. At baseline, patients with PCOS had higher levels of PMPs than controls (p = 0.017), which increased after 6-month treatment with OCPs (p = 0.006). Subsequently, they decreased after 12-month treatment (p = 0.046). Metformin had no effect on PMP levels. In conclusion, PMP levels are increased in PCOS and further increase with OCP use. This effect could possibly contribute to the increased risk of venous thromboembolism associated with OCP use. However, further studies are needed to elucidate the exact role of PMPs in PCOS.

Background Several treatments are available to reduce the risk of fragility fractures associated with osteoporosis. The choice of treatment requires knowledge of patients’ values and preferences. The aim of the present study was to summarize what is known about the values and preferences relevant to the management of osteoporosis in women. Methods We conducted a comprehensive search of several databases for studies reported in any language that had included women who had already started or were about to start any pharmacological therapy for osteoporosis. Pairs of reviewers independently selected the studies and extracted the data. The results were synthesized narratively. Results We included 26 studies reporting on 15,348 women (mean age, 66 years). The women considered the effectiveness and adverse events equally, followed by the convenience of taking the drug and its effect on daily routine (less frequent dosing was preferred, the oral route was preferred, and the injectable route was preferred over oral if given less frequently). The treatment cost and duration were less important factors for decision making. Fear of breast cancer and fear of resuming uterine bleeding were common reasons for not choosing estrogen therapy. Calcium and vitamin D were viewed as safe and natural. Across the studies, the preferences were not affected by age, previous drug exposure, or employment status. Conclusions Women starting osteoporosis medications value effectiveness and side effects equally and prefer medications given less frequently. Injectable drugs appear acceptable if given less frequently. More research on patient values and preferences is needed to guide decision making in osteoporosis.

Background Beta-blockers are used for prophylaxis of variceal bleeding. Our aim was to assess the efficacy and safety of carvedilol for primary or secondary prevention of variceal bleeding in patients with cirrhosis. Methods We searched Medline, Embase, CENTRAL and gray literature sources for randomized controlled trials (RCTs) comparing carvedilol with placebo or any active intervention. We synthesized data using random effects models. We summarized the strength of evidence using GRADE criteria. Results We included 13 trials with 1598 patients. Carvedilol was as efficacious as endoscopic variceal ligation (EVL) (4 RCTs, risk ratio [RR] 0.74, 95% confidence interval [CI] 0.37-1.49) or propranolol (3 RCTs, RR 0.76, 95%CI 0.27-2.14) for primary prevention of variceal bleeding. Likewise, carvedilol was as efficacious as EVL (3 RCTs, RR 1.10, 95%CI 0.75-1.61), non-selective beta-blockers (NSBBs) plus isosorbide-5-mononitrate (2 RCTs, RR 1.02, 95%CI 0.70-1.51) or propranolol (2 RCTs, RR 0.39, 95%CI 0.15-1.03) for secondary prevention of variceal bleeding. Carvedilol was associated with lower all-cause mortality compared to EVL (3 RCTs, RR 0.51, 95%CI 0.33-0.79). There was no difference in any other efficacy outcome. Finally, there were no significant differences in the safety profiles compared with EVL and NSBBs. Our confidence in the effect estimates for all outcomes was very low. Conclusion Carvedilol is as efficacious and safe as standard-of-care interventions for the primary and secondary prevention of variceal bleeding.

Background Osteoporosis and osteopenia are associated with increased fracture incidence in postmenopausal women. We aimed to determine the comparative effectiveness of various available pharmacological therapies. Methods We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus for randomized controlled trials that enrolled postmenopausal women with primary osteoporosis and evaluated the risk of hip, vertebral, or nonvertebral fractures. A network meta-analysis was conducted using the multivariate random effects method. Results We included 107 trials (193,987 postmenopausal women; mean age, 66 years; 55% white; median follow-up, 28 months). A significant reduction in hip fractures was observed with romosozumab, alendronate, zoledronate, risedronate, denosumab, estrogen with progesterone, and calcium in combination with vitamin D. A significant reduction in nonvertebral fractures was observed with abaloparatide, romosozumab, denosumab, teriparatide, alendronate, risedronate, zoledronate, lasofoxifene, tibolone, estrogen with progesterone, and vitamin D. A significant reduction in vertebral fractures was observed with abaloparatide, teriparatide, parathyroid hormone 1-84, romosozumab, strontium ranelate, denosumab, zoledronate, risedronate, alendronate, ibandronate, raloxifene, bazedoxifene, lasofoxifene, estrogen with progesterone, tibolone, and calcitonin. Teriparatide, abaloparatide, denosumab, and romosozumab were associated with the highest relative risk reductions, whereas ibandronate and selective estrogen receptor modulators had lower efficacy. The evidence for the treatment of fractures with vitamin D and calcium remains limited despite numerous large trials. Conclusions This network meta-analysis provides comparative effective estimates for the various available treatments to reduce the risk of fragility fractures in postmenopausal women.

Background We performed a systematic review and network meta-analysis to compare probiotics to current therapies in the induction and maintenance of remission in ulcerative colitis (UC). Methods We systematically searched Medline, Embase, CENTRAL up to November 2018. We included randomised controlled trials (RCTs) in patients with mild to moderate UC that compared probiotics, sulfasalazine, mesalamine (low dose Results Forty-eight trials (probiotics 6 trials) of induction therapy and 30 trials (probiotics 6 trials) of maintenance therapy were included in the analysis. In studies with probiotics concomitant treatment, mainly mesalamine, were allowed. At induction, probiotics were not superior to placebo (OR 1.43; 95%CI 0.84–2.42) and they were inferior to combined oral and topical mesalamine therapy (OR 0.28; 95%CI 0.12–0.66) and combined mesalamine and beclomethasone therapy (OR 0.27; 95%CI 0.09–0.83). On SUCRA analysis, combination therapies (SUCRA 0.92 and 0.93) were ranked the highest followed by balsalazide (SUCRA 0.71), budesonide ΜΜΧ (SUCRA 0.68), standard dose mesalamine (SUCRA 0.52), beclomethasone (SUCRA 0.50), olsalazine (SUCRA 0.41), probiotics (SUCRA 0.29), low dose mesalamine (SUCRA 0.26) and sulfasalazine (SUCRA 0.23) in terms of inducing remission. Probiotics were well tolerated. At maintenance, probiotics (OR 0.35; 95%CI 0.19–0.62) and their combination with mesalamine (OR 0.38; 95%CI 0.15–0.99) had lower rate of relapse compared with placebo, but there were no differences when compared with other treatments. On SUCRA analysis, probiotics either alone or combined with mesalamine had comparable SUCRA values to standard dose mesalamine (SUCRA 0.59) and sulfasalazine (SUCRA 0.68). The combination of oral and rectal mesalamine was superior to placebo (OR 0.10; 95%CI 0.04–0.26) and all other treatments and it was ranked highest (SUCRA 0.99). Probiotics were ranked the best tolerated option in terms of discontinuation due to adverse events (SUCRA 0.80). Conclusion Probiotics are well tolerated but they are not effective in inducing remission in active UC. They may be effective when added to mesalamine therapy in preventing relapse of quiescent UC, but large, well-designed RCTs are needed.

Background The aim of the study was to assess the efficacy and safety of tofacitinib and its impact on quality of life in patients with moderate-to-severe ulcerative colitis. Methods We conducted a systematic review and meta-analysis of randomized controlled trials comparing tofacitinib with placebo or any active comparator. We searched Medline, Embase, the Cochrane Library and gray literature for articles published up to May 2017. We synthesized data using a fixed-effect model. We conducted subgroup analysis based on prior exposure to anti-tumor necrosis factor (TNF). We summarized the strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results We included three trials with 1220 participants. Compared with placebo, tofacitinib was effective in inducing clinical remission (odds ratio [OR] 3.84, 95% confidence interval [CI] 2.29-6.44, I2: 41%, GRADE: moderate), clinical response (OR 2.95, 95%CI 2.21-3.95, I2: 0%, GRADE: high), mucosal healing (OR 2.70, 95%CI 1.81-4.03, I2: 0%, GRADE: high). Tofacitinib was effective in both anti-TNF-naive and -experienced patients. Tofacitinib had a favorable effect on quality of life. There were no significant differences in the safety profile in terms of the incidence of any or serious adverse events compared to placebo. The risk for infections was increased (OR 1.51, 95%CI 1.05-2.19, I2: 0%, GRADE: moderate), but the incidence of serious infections did not differ between tofacitinib and placebo. Conclusion In patients with moderate-to-severe ulcerative colitis, short-term treatment with tofacitinib is effective for induction of remission and improvement of quality of life.

Background Myofasciitis is a rare disease of the muscles and its fascia, which is most common in adults and is very rarely found in children. Aim Description of a case of myositis-peritonitis(fasciitis) in a 4 year old female toddler and arise the awareness of the hospital and general paediatrician for the clinical presentation of this rare disease. Method-material-case description In November of 2016 a 4 year old toddler of greek origin from the state of Magnesia, Greece, was admitted to the emergency department of our hospital. The toddler presented claudication 12 hours prior to the admission and symptoms of upper and lower respiratory tract infection with cough from several days. At the admission the toddler presented claudication, limitation of the active and passive motility of both hips, especially the right, limited motility of the truncus and limbs, swelling of right cheek and right temple. Imaging studies revealed swelling of the soft tissues around the right hip joint and swelling of multiple intra-parotid and neck lymph nodes. The blood examination at the admission revealed leukocytosis, mild increase of the indicators of inflammation, of creatine phosphokinase (CPK) and increased coagulation time. Because of the clinical picture of the patient intravenous antibiotics were givenB(ceftriaxone and clindamycin).The differential diagnosis included myositis, fasciitis, septic arthritis of right hip joint and invasive general microbe infection. Results Because of the rapid deterioration of the clinical and laboratory picture in the next 12 hours (further increase of CPK, indicators of inflammation) the toddler was transferred to a tertiary Hospital of Athens. The imaging studies revealed a consolidation of the basis of the right lung and mild consolidation behind the heart. The MRI revealed swelling and inflammation of the majority of the muscles of the haunches, the thighs (especially the right), swelling of the subcutaneous tissue of both haunches and its fascias. The clinical and imaging picture was compatible with myofasciitis. The general status of the patient was improved and the antibiotic therapy was continued for 14 days in total. The metabolic and rheumatologic results are still pending. Conclusions The data in literature for myofasiitis are not enough but we believe that it is localised histological inflammation that may be caused by a previous immunisation with alluminium adjuvants contained vaccines, rather than a primary inflammatory muscle disease. The histological hallmark of myofasciitis is the infiltration of the muscle and its fascia by macrophage cells. The symptoms include joint pain, muscle weakness, fatigue, fever and pain on the palpation of the muscles.

Bckground Hemophagocytic syndrome (HS) is an hyperinflammatory syndrome caused by severe hypercytokinemia with excessive activation of macrophages and lymphocytes. HS can be primary, or secondary, as a response to infection, malignacy or autoimmune disease. Aim The description of a case of HS as the first manifection of systemic lupus erythematosus diagnosed at our paediatric department. and arise the awareness of the hospital and general paediatrician for the clinical and laboratory presentation of this rare disease. Method A nine year girl was admitted, due to fever and fatigue. During her hospitalisation, she developed anaemia and leukocytopenia, elevated liver enzymes and renal function worsening (Urea: 59 mg/dl, microscopic hematuria, albuminuria). Prolonged fever, splenomegaly, bicytopenia, hyperferritinemia (Fer: 38 450 ng/ml) and hypertriglyceridemia (TRGs: 468 mg/dl) put the suspicion of HS diagnosis. Immunology tests revealed the presence of positive anti-nuclear antibodies and low C3 and C4 levels. She was transferred to a tetriary paediatric hospital for further investigation and treatment. Results At the tertiary paediatric hospital, secondary hemophagocytic syndrome was confirmed -hemophagocytosis was found at a bone marrow puncture-biopsy that was performed- and Systemic Lupus Erythematosus proved to be the primary cause. The duration of hospitalisation was 15 days, and the treatment included methylprednisone, ivig, hydroxychlroroquine and cyclophosphamide. Conclusion Hemophagocytic syndrome is a rare life threatening entity, that should be taken into concideration when prolonged fever is investigated. Being connected to bad prognosis and risk of permanent tissue damage, prompt diagnosis and treatment are required.

Background and aims Neonatal infections (NI) among newborn during the neonatal period, may be contracted by transplacental transfer in utero, in the birth canal during delivery (perinatal), or by other means after birth. It is a retrospective recording of early and late NI of neonates hospitalised in pre-NICU during 2015–2016. Methods Recording of the cases of NI according to the ICD-10 system and excel editing. Results 118 cases of NI have been collected, 61 (2015), 57 (2016), 38 females (33, 3%) and 80 males (67, 7%), in total. The neonates were referred from the OBGyn Department of Achillopouleio General Hospital(61,8%), the delivery room of the same hospital(24,5%), OBGyn Department of private hospitals(5,9%), paediatric private practice(6,7%) and 1 baby was born on board. 47,5%(56) had normal-labour and 52, 5%(62) cesarian-section. The amniotic fluid was dirty in 16%(19) and clear in 84% (99). The day of admission in the hospital was on the 1st, 2nd, 3rd and >4th day of life( 57%(67), 21%(25), 4%(5), 7%(8) and 11%(13), respectively). Blood cultures were done on all the babies on admission (positive with S. Epidermidis(0,85%). Other body fluid cultures included: Urine culture (22,8%), culture of faeces(1,69%), and orbital fluid(1,69%) with negative results. 11% (13) had lumbar puncture (0,84% positive for S. saprophyticus). 32,2%(38) neonates with TORCH investigation( 0,84% was positive for HSV). The clinical features on admission were lethargy 8,47%(10), feeding problems 16,9%(20), vomiting 9,3%(11), grunting 14,4%(17), tremor 3,38%(4), jaundice 16,9%(20), respiratory distress 9,3%(11), pallor 22%(26), apnea 13,5%(16), bloody faeces 0,85%(1), bradycardia 2,5%(3), hypoglycemia 0,85%(1), acrocyanosis 3,38%(4) and skin problems 2,5%(3). Lab results showed elevated CRP (>10):42,3% (50) and elevated WBC (>20000):31,3%(37), respectively. The drug treatment provided was: Ampicilline-Amicacine for 3 days (11,4%), 5 days(43,2%) and the rest different duration and combination of drug treatment. Conclusion The Department of Paediatrics personnel treated successfully the cases of NI, despite the absence of a neonatologist. Only 3 cases per year needed reference to tertiary hospital for further management. The admission criteria followed NICE guidelines.

Background and aims Neonatal infections (NI) among newborn during the neonatal period, may be contracted by transplacental transfer in utero, in the birth canal during delivery (perinatal), or by other means after birth. It is a retrospective recording of early and late NI of neonates hospitalised in pre-NICU during 2015–2016. Methods Recording of the cases of NI according to the ICD-10 system and excel editing. Results 118 cases of NI have been collected, 61 (2015), 57 (2016), 38 females (33, 3%) and 80 males (67, 7%), in total. The neonates were referred from the OBGyn Department of Achillopouleio General Hospital(61,8%), the delivery room of the same hospital(24,5%), OBGyn Department of private hospitals(5,9%), paediatric private practice(6,7%) and 1 baby was born on board. 47,5%(56) had normal-labour and 52, 5%(62) cesarian-section. The amniotic fluid was dirty in 16%(19) and clear in 84% (99). The day of admission in the hospital was on the 1 st , 2 nd , 3 rd and >4 th day of life( 57%(67), 21%(25), 4%(5), 7%(8) and 11%(13), respectively). Blood cultures were done on all the babies on admission (positive with S. Epidermidis(0,85%). Other body fluid cultures included: Urine culture (22,8%), culture of faeces(1,69%), and orbital fluid(1,69%) with negative results. 11% (13) had lumbar puncture (0,84% positive for S. saprophyticus). 32,2%(38) neonates with TORCH investigation( 0,84% was positive for HSV). The clinical features on admission were lethargy 8,47%(10), feeding problems 16,9%(20), vomiting 9,3%(11), grunting 14,4%(17), tremor 3,38%(4), jaundice 16,9%(20), respiratory distress 9,3%(11), pallor 22%(26), apnea 13,5%(16), bloody faeces 0,85%(1), bradycardia 2,5%(3), hypoglycemia 0,85%(1), acrocyanosis 3,38%(4) and skin problems 2,5%(3). Lab results showed elevated CRP (>10):42,3% (50) and elevated WBC (>20000):31,3%(37), respectively. The drug treatment provided was: Ampicilline-Amicacine for 3 days (11,4%), 5 days(43,2%) and the rest different duration and combination of drug treatment. Conclusion The Department of Paediatrics personnel treated successfully the cases of NI, despite the absence of a neonatologist. Only 3 cases per year needed reference to tertiary hospital for further management. The admission criteria followed NICE guidelines.

Background Hemophagocytic syndrome (HS) is an hyperinflammatory syndrome caused by severe hypercytokinemia with excessive activation of macrophages and lymphocytes. HS can be primary, or secondary, as a response to infection, malignacy or autoimmune disease. Aim The description of a case of HS as the first manifection of systemic lupus erythematosus diagnosed at our paediatric department. and arise the awareness of the hospital and general paediatrician for the clinical and laboratory presentation of this rare disease. Method/material A nine year girl was admitted, due to fever and fatigue. During her hospitalisation, she developed anaemia and leukocytopenia, elevated liver enzymes and renal function worsening (Urea: 59 mg/dl, microscopic hematuria, albuminuria). Prolonged fever, splenomegaly, bicytopenia, hyperferritinemia (Fer: 38 450 ng/ml) and hypertriglyceridemia (TRGs: 468 mg/dl) put the suspicion of HS diagnosis. Immunology tests revealed the presence of positive anti-nuclear antibodies and low C3 and C4 levels. She was transferred to a tetriary paediatric hospital for further investigation and treatment. Results At the tertiary paediatric hospital, secondary hemophagocytic syndrome was confirmed -hemophagocytosis was found at a bone marrow puncture-biopsy that was performed- and Systemic Lupus Erythematosus proved to be the primary cause. The duration of hospitalisation was 15 days, and the treatment included methylprednisone, ivig, hydroxychlroroquine and cyclophosphamide. Conclusion Hemophagocytic syndrome is a rare life threatening entity, that should be taken into concideration when prolonged fever is investigated. Being connected to bad prognosis and risk of permanent tissue damage, prompt diagnosis and treatment are required.

Introduction Neutropenia is the decrease of neutrophil count in the blood. It is classified as mild, when the Absolute Neutrophil Count (ANC) is 1000–1500 cells/µL, or Aim Incidence and causes of neutropenia in hospitalised children in our Paediatric Clinic during the year 2016. Methods All the hospitalised children from 01-01-2016 to 31-12-2016 were screened for the presence of neutropenia during their hospitalisation. The type of neutropenia, the causes and the other blood cells counts were recorded for every neutropenic child. Results Among 784 children hospitalised during 2016, 35 were found to be neutropenic (4,46%). None of these children had known neutropenia in their history. Viral infections were the first cause of neutropenia, with the second cause (14%) being the use of antimicrobial drugs. The majority of neutropenias were mild to moderate (83%), whereas 6 children presented with severe neutropenia. Among them, three patients were diagnosed with viral infections, two had autoimmune diseases and the other remained undiagnosed. A percentage of 8,5% had also reduction in other blood cells. Conclusion The most common form of neutropenia in hospitalised children is mild-moderate neutropenia of viral aetiology, which resolves itself. However, major systematic diseases should always be excluded.

Background Myofasciitis is a rare disease of the muscles and its fascia, which is most common in adults and is very rarely found in children. Aim Description of a case of myositis-peritonitis(fasciitis) in a 4 year old female toddler and arise the awareness of the hospital and general paediatrician for the clinical presentation of this rare disease. Method-material-case description In November of 2016 a 4 year old toddler of greek origin from the state of Magnesia, Greece, was admitted to the emergency department of our hospital. The toddler presented claudication 12 hours prior to the admission and symptoms of upper and lower respiratory tract infection with cough from several days. At the admission the toddler presented claudication, limitation of the active and passive motility of both hips, especially the right, limited motility of the truncus and limbs, swelling of right cheek and right temple. Imaging studies revealed swelling of the soft tissues around the right hip joint and swelling of multiple intra-parotid and neck lymph nodes. The blood examination at the admission revealed leukocytosis, mild increase of the indicators of inflammation, of creatine phosphokinase (CPK) and increased coagulation time. Because of the clinical picture of the patient intravenous antibiotics were givenB(ceftriaxone and clindamycin).The differential diagnosis included myositis, fasciitis, septic arthritis of right hip joint and invasive general microbe infection. Results Because of the rapid deterioration of the clinical and laboratory picture in the next 12 hours (further increase of CPK, indicators of inflammation) the toddler was transferred to a tertiary Hospital of Athens. The imaging studies revealed a consolidation of the basis of the right lung and mild consolidation behind the heart. The MRI revealed swelling and inflammation of the majority of the muscles of the haunches, the thighs (especially the right), swelling of the subcutaneous tissue of both haunches and its fascias. The clinical and imaging picture was compatible with myofasciitis. The general status of the patient was improved and the antibiotic therapy was continued for 14 days in total. The metabolic and rheumatologic results are still pending. Conclusions The data in literature for myofasiitis are not enough but we believe that it is localised histological inflammation that may be caused by a previous immunisation with alluminium adjuvants contained vaccines, rather than a primary inflammatory muscle disease. The histological hallmark of myofasciitis is the infiltration of the muscle and its fascia by macrophage cells. The symptoms include joint pain, muscle weakness, fatigue, fever and pain on the palpation of the muscles.

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs. Purpose To assess the efficacy and safety of SGLT2 inhibitors in adults with type 2 diabetes. Data sources MEDLINE, EMBASE, and the Cochrane Library from inception through April 2013 without language restrictions; regulatory authorities' reports; and gray literature. Study selection Randomized trials comparing SGLT2 inhibitors with placebo or other medication for type 2 diabetes. Data extraction Three reviewers extracted or checked data for study characteristics, outcomes of interest, and risk of bias, and 3 reviewers summarized strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Data synthesis Sodium-glucose cotransporter 2 inhibitors were compared with placebo in 45 studies (n = 11 232) and with active comparators in 13 studies (n = 5175). They had a favorable effect on hemoglobin A1c level (mean difference vs. placebo, -0.66% [95% CI, -0.73% to -0.58%]; mean difference vs. active comparators, -0.06% [CI, -0.18% to 0.05%]). Sensitivity analyses incorporating unpublished data showed similar effect estimates. Compared with other agents, SGLT2 inhibitors reduced body weight (mean difference, -1.80 kg [CI, -3.50 to -0.11 kg]) and systolic blood pressure (mean difference, -4.45 mm Hg [CI, -5.73 to -3.18 mm Hg]). Urinary and genital tract infections were more common with SGLT2 inhibitors (odds ratios, 1.42 [CI, 1.06 to 1.90] and 5.06 [CI, 3.44 to 7.45], respectively). Hypoglycemic risk was similar to that of other agents. Results for cardiovascular outcomes and death were inconclusive. An imbalance in incidence of bladder and breast cancer was noted with dapagliflozin compared with control. Limitation Most trials were rated as high risk of bias because of missing data and last-observation-carried-forward methods. Conclusion Sodium-glucose cotransporter 2 inhibitors may improve short-term outcomes in adults with type 2 diabetes, but effects on long-term outcomes and safety are unclear. Primary funding source None.

Acute pancreatitis is rare in pregnancy but it is associated with increased incidence of maternal and fetal mortality. It should be considered in the differential diagnosis of upper quadrant abdominal pain with or without nausea and vomiting. The commonest identified causes of acute pancreatitis in pregnancy are gallstones, alcohol and hypertriglyceridemia. The main laboratory finding is increased amylase activity. Appropriate investigations include ultrasound of the right upper quadrant and measurement of serum triglycerides and ionized calcium. Management of gallstone pancreatitis is controversial, although laparoscopic cholecystectomy and endoscopic retrograde cholangiopancreatography (ERCP) are often used and may be associated with lower complication rates. In hypertriglyceridemia-induced acute pancreatitis ω-3 fatty acids and even therapeutic plasma exchange can be used. We also discuss preventive measures.

Importance of the field: The sodium/hydrogen exchanger-1 (NHE-1/SLC9A1) is a ubiquitous plasma membrane protein whose main role is maintenance of intracellular pH and volume. NHE-1 plays a role in atherogenesis; however, its clinical relevance has not yet been established.Areas covered in this review: We herein review the contribution of NHE-1 in atherogenesis (namely its effect on endothelial cells, monocytes, smooth muscle cells and platelets).What the reader will gain: Studies have shown that NHE is involved in atherogenesis-related properties of isolated monocytes. We also consider the relationship between NHE-1 and vascular risk factors such as obesity, diabetes mellitus, hypertension, dyslipidemia and inflammation.Take home message: Even though clinical trials with certain NHE-1 inhibitors have had discouraging results, NHE-1 cannot be excluded as a potential future therapeutic target for the prevention and/or treatment of atherosclerosis.

Background: Sodium/hydrogen exchanger-1 (NHE-1) contributes to maintaining intracellular pH (pHi). We assessed the effect of glucose, insulin, leptin and adrenaline on NHE-1 activity in human monocytes in vitro. These cells play a role in atherogenesis and disturbances in the hormones evaluated are associated with obesity and diabetes. Methods and Results: Monocytes were isolated from 16 healthy obese and 10 lean healthy subjects. NHE-1 activity was estimated by measuring pHi with a fluorescent dye. pHi was assessed pre- and post-incubation with glucose, insulin, leptin and adrenaline. Experiments were repeated after adding a NHE-1 inhibitor (cariporide) or an inhibitor of protein kinase C (PKC), nitric oxide synthase (NOS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, phosphoinositide 3-kinases (PI3K) or actin polymerization. Within the whole study population, glucose enhanced NHE-1 activity by a processes involving PKC, NOS, PI3K and actin polymerization (p = 0.0006 to 0.01). Insulin-mediated activation of NHE-1 (p = Conclusions: Selective inhibition of NHE-1 in monocytes could become a target for drug action in atherosclerotic vascular disease.

Ezetimibe, an inhibitor of cholesterol intestinal absorption, is a lipid lowering agent with potential pleiotropic actions. Ezetimibe in combination with a statin is effective in decreasing low density lipoprotein cholesterol (LDL-C), lowering triglyceride and raising high density lipoprotein cholesterol levels. Ezetimibe plus statin achieve LDL-C targets in a greater proportion of patients than statin monotherapy. Ezetimibe also seems to improve renal function, insulin resistance and inflammatory markers. These actions are useful in patients with diabetes. Ezetimibe is a well-tolerated and effective (in terms of achieving LDL-C targets) option in patients with hyperlipidemia with or without diabetes. This editorial will discuss several properties of ezetimibe, with special reference to diabetes.

We assessed the effect of epinephrine on human monocytes. Monocytes were isolated from 16 healthy obese and 10 lean healthy subjects. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Obese subjects were subdivided into 2 sub-groups, insulin sensitive (IS) and insulin resistant (IR). Monocyte properties [attachment to laminin 1, migration through laminin 1, oxidized-low density lipoprotein (oxLDL) phagocytosis] were assessed pre- and post-stimulation in vitro with epinephrine. Experiments were repeated after incubation with a Na+/H + exchanger-1 inhibitor (NHE-1) (cariporide). Epinephrine increased monocyte attachment to laminin in lean and obese IR subjects through involvement of NHE-1, PKC, NO synthase, NADPH oxidase and actin polymerization. In contrast, epinephrine did not affect monocyte migration. Epinephrine increased oxLDL phagocytosis in all groups studied. Incubation with cariporide attenuated oxLDL phagocytosis. Epinephrine induces monocyte dysfunction which may be atherogenic.

Monocytes and oxidative stress are central in atherosclerosis. Monocyte attachment to laminin-1 derived from either healthy volunteers or patients with diabetes mellitus type II has been evaluated by three different assays: the myeloperoxidase assay, Hemacolor kit, and crystal violet staining. Monocytes derived from diabetic patients showed an increased ability to attach to native laminin-1 as compared with controls. In addition, monocytes derived from both healthy donors and diabetics attached at a higher degree to laminin-1 carbonylated by methylglyoxal in comparison with the native molecule. The results indicate an increased interaction between monocytes and laminin-1 in the case that the protein is carbonylated.

The oxidative modification of proteins has been shown to play a major role in a number of pathological processes. One such modification is the addition of the carbonyl groups to the amino acid residue in proteins. For the measurement of the carbonyl groups in low concentration protein samples, we have modified the ELISA (enzyme-linked immunosorbent assay) method that was developed by Buss et al. [Buss, I. H; Chan, T. P.; Sluis, K. B.; Domigan, N. M.; Winterbourn, C. C. Protein carbonyl measurement by a sensitive ELISA method. Free Radic. Biol. Med. 23:361–366; 1997 [14] ]. In the modified method, protein samples diluted in phosphate-buffered saline were adsorbed to wells of an ELISA plate and then reacted with dinitrophenylhydrazine (DNPH). The protein-conjugated DNPH was probed by a commercial anti-DNPH antibody, and then a second antibody conjugated with horseradish peroxidase was added for quantification. The method was calibrated using oxidized albumin, and required only 5 μg protein. This obviated the need to concentrate protein in experimental and clinical samples with low amounts of protein. In addition the effect of TCA on carbonyl measurement is eliminated. The standard curve was linear in the range of 0–3.36 nmol carbonyls/mg protein, which is the range within which clinical samples fell. The results correlated well with the colorimetric carbonyl assay. The method was used to analyze the amount of protein carbonyl in aqueous humor and diluted plasma samples.

Aim To assess the efficacy and safety of the novel sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin compared with placebo or other antidiabetic agents in patients with type 2 diabetes. Methods We conducted a systematic review and meta-analysis of randomized controlled trials. We searched Medline, Embase and the Cochrane Library through December 2013 and grey literature. Two reviewers working independently extracted relevant data and carried out risk-of-bias assessments. We synthesized results using random-effects models and computed weighted mean differences (WMDs) and odds ratios (ORs). Results We included 10 studies with 6203 participants. Compared with placebo, mean changes in haemoglobin A1c were −0.62% [95% confidence interval (CI) −0.68 to −0.57%] for empagliflozin 10 mg and −0.66% (−0.76 to −0.57%) for empagliflozin 25 mg. Empagliflozin 25 mg daily had glycaemic efficacy similar to metformin or sitagliptin (WMD −0.11%; 95% CI −0.25 to 0.03%), without increasing risk for hypoglycaemia. It was also associated with body weight loss (WMD −1.84; 95% CI −2.30 to −1.38 kg vs. placebo) and had a favourable effect on blood pressure. Incidence of hypoglycaemia with empagliflozin was similar to placebo (OR 1.10; 95% CI 0.87 to 1.39); nevertheless we noted an increased risk for genital tract infections (OR 3.31; 95% CI 1.55 to 7.09). Findings were similar for the 10-mg dosing regimen. Conclusions Empagliflozin effectively lowers blood glucose and provides additional clinical benefits including body weight and blood pressure reduction. Ongoing trials will elucidate the long-term safety and effect of empagliflozin on cardiovascular outcomes.

We report a case of a bone marrow aspiration and trephine biopsy (BMATB) associated haematoma in an 85-years old male without any predisposing risk factors. Six days after BMATB, he suffered from a massive thigh and buttock haematoma and a fall in haematocrit. It is important to know that BMATB can have complications aiding early recognition and therapy.

We assessed the effect of glucose and insulin on human monocytes. Monocytes were isolated from 16 healthy obese and 10 lean healthy participants. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Obese participants were subdivided into 2 subgroups: insulin sensitive (IS) and insulin resistant (IR). Monocyte oxidized low-density lipoprotein (oxLDL) phagocytosis was assessed pre and poststimulation in vitro with glucose or insulin. Experiments were repeated after incubation with a Na+/H+ exchanger-1 inhibitor ([NHE-1]; cariporide) or rosiglitazone. Glucose increased oxLDL phagocytosis in all groups studied (at 1 or 3 hours incubation; P = .037-.002). Insulin increased oxLDL phagocytosis in all groups studied after 1-hour incubation (P = .027-.015) but not at 3 hours. Incubation with cariporide attenuated oxLDL phagocytosis except in the obese IS group. Rosiglitazone eliminated glucose- and insulin-induced increase in oxLDL phagocytosis in all studied groups. Glucose and insulin induce oxLDL phagocytosis.

Obesity is a rapidly expanding epidemic in Western societies, with rates of more than 30% across Europe, and it is associated with an increased risk of metabolic disturbances. Previous reports have documented an association of reduced physical activity and abstinence from the traditional Mediterranean diet (MD) with increased mortality rate and prevalence of obesity in a population of Greek subjects.The aim of the present study was to evaluate and analyze the dietary habits in a population of Greek overweight and obese subjects and to investigate the potential associations between those patterns and the prevalence of metabolic syndrome components.The study recruited 226 consecutive adult (30 men, 169 women) overweight or obese (body mass index25 kg/m(2)) individuals attending the Metabolic Diseases Unit. Medical history, dietary history, and anthropometric parameters were recorded during the first visit. Fasting blood samples were collected for biochemistry assaying.According to the nutrient intake history and Mediterranean Diet Scale (MDS), participants were divided into 3 groups: those adhering to the MD and those not following the MD, who were further subdivided into the high-carbohydrate (HC) and high-fat (HF) diet groups according to the source of maximum energy intake. Adherence to the MD was associated with a lower prevalence of metabolic syndrome (27.3%, 69.2%, and 60.4% in MD, HC, and HF respectively, p = 0.006), lower low-density lipoprotein cholesterol (p = 0.009, MD vs. HF), and lower postchallenge glucose values (p = 0.028, MD vs. HF).Adherence to the MD seems to be declining among Greek overweight and obese subjects, a phenomenon that is associated with an increase in the prevalence of the metabolic syndrome.

To investigate the relationship between MKKS gene variations, obesity-related traits and features of the metabolic syndrome (MS) in the Greek population. Genotype and haplotype analysis was carried out for six known MKKS gene polymorphisms (534C>T, 985+16T>G, 985+33C>G, 986−29A>T, 1161+58A>G and 1595G>T) in 220 obese subjects (body mass index ⩾30 kg/m2) and 330 non-obese controls. Genotype frequencies of the 985+16T>G, 986−29A>T and 1595G>T SNPs were significantly different between obese and non-obese individuals (P=0.0016, 0.0196 and 0.0069, respectively). Obese carriers of the risk alleles of the above three polymorphisms had a significantly increased prevalence of arterial hypertension. Furthermore, obese carriers of the G allele for the 985+16T>G polymorphism had an increased prevalence of type 2 diabetes mellitus and of MS component traits. A new polymorphism was detected, namely a C to T substitution at position 1129 (1129C>T or N377N). Frequency of the T allele for the 1129C>T polymorphism was significantly higher in control individuals than in obese subjects (P=0.0253). Haplotype TGTGT was more prevalent in obese than in controls (P=0.0002) and was associated with increased prevalence of the MS in obese subjects (P

OBJECTIVE To assess insulin sensitivity in young adult normoglycemic beta-thalassaemia major patients. METHODS We measured insulin sensitivity with the euglycemic insulin clamp in 10 young adult (mean age 24.85 +/- 2.45 yrs) normoglycemic beta-thalassaemia major patients and 10 sex- & age-matched controls. Liver iron accumulation was assessed by magnetic resonance imaging (MRI). RESULTS Glucose infusion rate (M) required to maintain euglycemia was significantly reduced in thalassaemic patients compared to controls (261.5 +/- 63.5 mg/m2 x min vs. 355.6 +/- 35.3 mg/m2 x min, P = 0.008). Consequently, significantly reduced in the thalassaemic group were also tissue sensitivity to insulin (M/I(s-s)) and glucose metabolic clearance rate (M/G(s-s)). There was significant negative correlation between ferritin levels and glucose infusion rate (r = -0.918 P = 0.004). No significant correlations were observed between age, body mass index, daily transfusional iron accumulation, liver iron content and any of the euglycemic clamp parameters. Fasting insulin levels were significantly increased in patients with beta-thalassaemia major compared to controls (P = 0.01), and had significant negative correlation to MRI-derived liver iron content (r = -0.733, P = 0.03). CONCLUSIONS Our data indicate that reduced insulin sensitivity resulting in hyperinsulinaemia precedes the manifestation of glucose intolerance in patients with beta-thalassaemia major. Insulin resistance seems to correlate with increased serum ferritin levels.

Objectives: The application of a novel assay for the direct measurement of prooxidant–antioxidant balance (PAB) in type II diabetes and the evaluation of antioxidant therapy. Design and methods: The assay is based on 3,3′,5,5′-tetramethylbenzidine and its cation, used as a redox indicator participating in two simultaneous reactions. PAB was determined in the sera of healthy volunteers and type II diabetes patients. The results were compared with clinical and biological parameters, protein oxidation markers, as well as the results of antioxidant and prooxidant assays. PAB, after administration of vitamins C and E for 1 day, 1 month and 2 months was also determined. Results: Increased PAB was found in the patients' group and correlated with parameters involved in diabetic complications, protein oxidation markers, antioxidant and prooxidant assays. One day after vitamin administration, a significant shift of PAB towards antioxidants was observed. PAB remained unchanged after 1 month and changed marginally in favor of prooxidants in the second month of the therapy. Conclusions: These results indicate that the measurement of PAB may be useful to identify and follow-up patients who need antioxidant therapy.

Background & Aims Guidelines advocate use of magnetic resonance imaging (MRI) to estimate concentrations of iron in liver, to identify patients with iron overload, and to guide titration of chelation therapy. However, this recommendation was not based on a systematic synthesis and analysis of the evidence for MRI's diagnostic accuracy. Methods We conducted a systematic review and meta-analysis to investigate the diagnostic accuracy of MRI in identifying liver iron overload in patients with hereditary hemochromatosis, hemoglobinopathy, or myelodysplastic syndrome; liver biopsy analysis was used as the reference standard. We searched MEDLINE and EMBASE databases, the Cochrane Library, and gray literature, and computed summary receiver operating curves by fitting hierarchical models. We assessed methodologic quality using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Results Our final analysis included 20 studies (819 patients, total). Sensitivity and specificity values varied greatly, ranging from 0.00 to 1.00 and from 0.50 to 1.00, respectively. Because of substantial heterogeneity and variable positivity thresholds, we calculated only summary receiver operating curves (and summary estimate points for studies that used the same MRI sequences). T2 spin echo and T2* gradient-recalled echo MRI sequences accurately identified patients without liver iron overload (liver iron concentration > 7 mg Fe/g dry liver weight) (negative likelihood ratios, 0.10 and 0.05 respectively). However, these MRI sequences are less accurate in establishing a definite diagnosis of liver iron overload (positive likelihood ratio, 8.85 and 4.86, respectively). Conclusions Based on a meta-analysis, measurements of liver iron concentration by MRI may be accurate enough to rule out iron overload, but not to definitely identify patients with this condition. Most studies did not use explicit and prespecified MRI thresholds for iron overload, therefore some patients may have been diagnosed inaccurately with this condition. More studies are needed of standardized MRI protocols and to determine the effects of MRI surveillance on the development of chronic liver disease and patient survival.

Ruggenenti et al. (1) report the effect of adding ezetimibe to simvastatin in patients with type 2 diabetes. Some additional comments could be of interest. The serum HDL cholesterol was significantly lower after adding …

Non-dipping is a common pattern of arterial hypertension and it is associated with increased cardiovascular risk. Use of ambulatory blood pressure monitoring, as suggested in recent guidelines, could further increase its prevalence among subjects with hypertension. In this review we discuss assessment, relevance and associated factors. Non-dipping could be addressed through chronotherapy, the use of specific classes of anti-hypertensives, such as renin-angiotensin blockers, or modification of associated factors. However, more data are needed in order to comprehensively estimate factors associated with non-dipping and how they could be modified.

Magnesium depletion in clinical practice is mainly related to loop diuretics and thiazides. Among patients treated with diuretics more than 1/3 exhibit hypomagnesa. Arrhythmias and sudden death attributed to magnesium depletion could be prevented by Mg administration. Magnesium deficiency in experimental animals promotes atherosclerotic lesions whereas this ion is involved in various stages of myocardial damage after experimental coronary artery occlusion. In humans magnesium administration in the first 24 hours of myocardial infarction was related to beneficial effects in first year mortality rate. Nevertheless more evidence from clinical investigation is needed for permanent conclutions.