Novel telomerase reverse transcriptase gene mutation in a family with aplastic anaemia.

Telomerase Reverse Transcriptase (TERT) encodes the telomerase reverse transcriptase enzyme and is the most frequently mutated gene in patients with telomeropathies. Heterozygous variants impair telomerase activity by haploinsufficiency and pathogenic variants are associated with bone marrow failure syndrome and predisposition to acute myeloid leukaemia. Owing to their rarity, telomeropathies are often unrecognised and misdiagnosed. Herein, we report a novel TERT gene variant, c.2605G > A p.(Asp869Asn) in a family with hereditary aplastic anaemia. This report emphasises the importance of routine deep genetic screening for rare TERT variants in patients with a family history of cytopenia or aplastic anaemia, which could identify clinically inapparent telomere disorders.

THE EFFECTS OF ENDOCRINE DISRUPTORS ON FEMALE GONADAL AXIS: AN UPDATE.

Endocrine disruptors (EDs) are considered to have an impact on the function of reproductive axis at different levels as well on reproductive organs in both sexes. Complexity of female reproductive system influenced with various stressors including EDs lead to morphological and functional alterations. This is resulting in modulation of neuroendocrine regulation with consequent developmental irregularities and derangements, causative infertility, endometriosis as well as premature ovarian insufficiency or polycystic ovary syndrome. A number of experimental clues was obtained on female animal models using various EDs such as synthetic estrogens and phytoestrogens, neurotransmitters, pesticides or various chemicals. These substances lead towards consequent derangement of the neuroendocrine control of reproduction from early phases of reproductive development towards different phases of adult reproductive period. This text will address some novel insights into the effects of EDs on neuroendocrine regulation of gonadal axis, effects on ovaries as well on endometrium during implantation period.

The effect of metformin and myoinositol on metabolic outcomes in women with polycystic ovary syndrome: role of body mass and adiponectin in a randomized controlled trial.

PURPOSE: To compare the effects of insulin sensitizers metformin (MET) and myo-inositol (MI) on adiponectin levels and metabolic characteristics in women with polycystic ovary syndrome (PCOS) with respect to their body mass index (BMI). METHODS: In this open label, parallel randomized clinical trial, 66 women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of adiponectin, hormonal and metabolic laboratory outcomes and clinical assessment of BMI, body composition and Ferriman-Gallwey score (FG score) were evaluated before and after treatment. RESULTS: After the 6-month intervention, comparison between MET and MI in time to treatment analysis showed no significant differences between the two treatments for all analyzed parameters. Only borderline significantly lower AUC glucose was found in the MET group in comparison to the MI group (p = 0.071). The main effect of treatment was shown for glucose concentration at 120 min OGTT (p = 0.032) and testosterone (p = 0.002). The main effect of time was shown for body mass (p = 0.004), waist circumference (p < 0.001), BMI (p = 0.003), body fat mass (p = 0.001), adiponectin (p = 0.020), fasting glucose (p = 0.001), testosterone (p = 0.015), SHBG (p = 0.013), 17OH progesterone (p = 0.008), LH (p = 0.004) and estradiol (p = 0.014). CONCLUSION: Our study showed similar effects of MET and MI on BMI, body composition, hormonal profile, metabolism of glucose and insulin, and adiponectin level. The two insulin sensitizers, MET and MI, were useful in reducing BMI and improving body composition without significant differences between the two treatments in PCOS women. TRIAL REGISTRATION: ISRCTN13199265. Trial registration date: 14.04.2021. (ISRCTN Registry), retrospectively registered.

THE EFFECT OF MYOINOSITOL AND METFORMIN ON CARDIOVASCULAR RISK FACTORS IN WOMEN WITH POLYCYSTIC OVARY SYNDROME: A RANDOMIZED CONTROLLED TRIAL.

CONTEXT: Cardiovascular risk is increased in women with polycystic ovary syndrome (PCOS). Do insulin sensitizing agents such as metformin (MET) and myoinositol (MI) ameliorate biomarkers of cardiovascular risk? OBJECTIVE: To compare the effects of MET and MI on blood pressure, lipid profile and high sensitive C-reactive protein (hs-CRP) in women with PCOS in respect to their body mass index (BMI). DESIGN: Open label, parallel randomized, single center study. SUBJECTS AND METHODS: Sixty six women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of hormones, lipid profile, oxidized LDL (ox-LDL), hs-CRP, blood pressure measurement and clinical assessment of BMI, waist circumference (WC) and Ferriman Gallwey score (FG score) were performed before and after treatment. RESULTS: Thirty patients in each group completed the trial. Compared with MET, MI significantly decreased diastolic blood pressure (DBP) (p=0.036) and significantly increased serum hs-CRP (p=0.043). No differences between groups in total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, ox-LDL and triglycerides were reported after 6 months. Treatment with MI reduced BMI (p=0.037), WC (p=0.005), DBP (p=0.021) and TC (p=0.008). During MET treatment a significant decrease in BMI (p=0.005), WC (p=0.004), FG score (p=0.001), testosterone (p=0.013) and free androgen index (FAI) (p=0.006) was observed. CONCLUSIONS: Our study showed an advantage of MI in reduction of DBP and TC thus predicting favorable metabolic and cardiovascular outcomes in PCOS women. MET more effectively decrease indices of hyperandrogenism.

ENDOCRINE DISRUPTING CHEMICALS AND OBESITY: THE EVOLVING STORY OF OBESOGENS.

Increase in obesity pandemic all over the world consequently leads to the investigation of possible causes. In addition to the traditional explanation using the so-called caloric model, the field of endocrine disruptors (EDs), especially subgroup called obesogens, offered more light on the pathogenetic mechanisms involved. After the Second World War a correlation between an increased production of exogenous pollutants and actual obesity epidemic was suggested. "Obesogen hypothesis" implies that molecules called obesogens inadequately stimulate the development of adipose cells and lipid accumulation in existing adipose cells, as well as change metabolic balance or hormonal control of appetite and satiety, leading to an increase in body fat mass. The list of obesogens includes some industrial chemicals, biocides, pharmaceuticals, pollutants, and smoke. EDs from the group of obesogens may exert their effects by the impairment in the programming development of adipocytes, by an increase in energetic depot in the adipose tissue, and by influencing neuroendocrine control of appetite and satiety. Increased scientific evidence on obesogens and their mechanisms of action may help to prevent obesity and mitigate deleterious effects of the environment on human life and development. New translational studies are needed to explain the possible mechanism proposed.

A rare case report of autoimmune haemolytic anemia in a female child due to a Donath-Landsteiner antibody.

Paroxysmal cold hemoglobinuria is a rare form of autoimmune hemolytic anemia caused by the Donath-Landsteiner autoantibody. The condition is characterized by the presence of an IgG biphasic hemolysin with specificity to the P blood group antigen. The antibody biphasic action may be demonstrated in the Donath-Landsteiner test. While paroxysmal cold hemoglobinuria can be manifested at any age, it typically appears in children following a viral upper respiratory syndrome or immunization, though rarely. This report describes a 23-months old girl presented with 5 days history of fever, erythrocytopenia, leukocytosis and occurrence of dark urine. On admission, the physical examination showed pallor, no scleral icterus, a mild hyperemic throat and no hepatosplenomegaly. The investigations revealed severe anemia with hemoglobin of 44g/L, increased reticulocyte count (10.67%), elevated lactate dehydrogenase (2603IU/L), decreased serum haptoglobin (0.159g/L), normal G6PD. Direct antiglobulin test was positive with C3d and C3c complement components only. Direct and indirect Donath-Landsteiner tests were positive. The girl was treated with a intravenous immunoglobulin infusion and Cefotaxime. She received transfusion of red blood cells, crossmatched, although P antigen untyped. Despite this in vitro serological incompatibility she had a hemoglobin increase. The patient was discharged in stable condition on the seventh day following admission. Paroxysmal cold hemoglobinuria is a hemolytic anemia for which a specific diagnostic test is available. Timely recognition of the disease by pediatricians is crucial as well as the highly skilled hospital blood bank staff performing Donath-Landsteiner testing.

Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease.

BACKGROUND: Blocking of lymphocyte trafficking to bile ducts is a potential mechanism to alter the disease course of patients with primary sclerosing cholangitis (PSC). AIM: To describe the effect of the α4 ß7 integrin antibody, vedolizumab, on liver biochemistry and disease activity in patients with PSC and inflammatory bowel disease (IBD). METHODS: This is a retrospective multi-centre study of adult patients with a diagnosis of both IBD and PSC. The primary outcome was change in serum alkaline phosphatase level at weeks 14 and 30. Secondary outcomes included changes in other liver biochemistries and in clinical outcomes for the bowel disease. A safety analysis for adverse events was performed. RESULTS: Thirty-four patients (16 Crohn's disease, 18 ulcerative colitis) were included. Nine (26%) had a history of liver transplant. Median follow-up on vedolizumab was 9 months (IQR: 7-16). There was no overall change in serum alkaline phosphatase level with vedolizumab therapy (median 268 [IQR: 105-551] IU/L at baseline versus 249 [IQR: 183-634] IU/L, P = 0.99 at week 30). No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30. Clinical remission was achieved at week 30 in 55% of Crohn's disease and 29% of ulcerative colitis patients. Seven (21%) patients ceased vedolizumab; six patients stopped therapy due to persistent IBD activity and one for worsening of liver biochemistries. CONCLUSION: Vedolizumab treatment in patients with PSC and IBD did not improve liver biochemistry but was associated with improvement in bowel disease and a favourable safety profile.

Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies.

We assessed the risks of immune-related adverse events with anticytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and antiprogrammed death 1 (PD1) therapies by meta-analysis. Twenty-one studies including 11,144 patients were found. Anti-CTLA4 therapy was associated with a significantly higher risk of overall immune-related adverse events: diarrhea, immune-related colitis, pruritus, and rash compared to control therapies (relative risk (RR) = 2.43, 2.10, 11.39, 3.88, 3.87, 95% confidence interval (CI) = 1.77-3.34, 1.52-2.45, 6.30-20.59, 2.37-6.37, 2.39-6.27, P < 0.001 for all outcomes). Anti-PD1 therapy was associated with a significantly higher risk of pruritus (RR = 4.01, 95% CI = 1.97 to 8.17, P < 0.001); however, it did not increase the risks of other adverse events. Anti-CTLA4 and anti-PD1 therapies have distinct features of immune-related adverse events. The results of our study would aid the surveillance and management of immune-related adverse events in patients receiving these therapies.

Systematic review with meta-analysis: the efficacy and safety of CT-P13, a biosimilar of anti-tumour necrosis factor-α agent (infliximab), in inflammatory bowel diseases.

BACKGROUND: Biosimilars of anti-tumour necrosis factor (TNF)-α agents have now become clinically available for the treatment of inflammatory bowel diseases (IBD). AIM: To perform a systematic review and meta-analysis to evaluate the efficacy and safety of biosimilars of anti-TNF-α agents in patients with IBD. METHODS: Electronic databases were searched. The outcomes were the pooled rates of clinical response or remission, sustained clinical response or remission, and adverse events in patients with IBD induced with or switched to biosimilars of anti-TNF-α agents. RESULTS: Eleven observational studies reporting outcomes in 829 patients treated with biosimilar of infliximab (CT-P13) were identified. The pooled rates of clinical response among Crohn's disease (CD) and ulcerative colitis (UC) at 8-14 weeks were 0.79 (95% confidence interval (CI) = 0.65-0.88) and 0.74 (95% CI = 0.65-0.82), respectively, and at 24-30 weeks were 0.77 (95% CI = 0.63-0.86) and 0.77 (95% CI = 0.67-0.85) respectively. Adverse events were rare (CD, 0.08 (95% CI = 0.02-0.26); UC, 0.08 (95% CI = 0.03-0.17)). The pooled rates of sustained clinical response among CD and UC after switching from infliximab to CT-P13 at 30-32 weeks were 0.85 (95% CI = 0.71-0.93) and 0.96 (95% CI = 0.58-1.00), respectively, and at 48-63 weeks were 0.75 (95% CI = 0.44-0.92) and 0.83 (95% CI = 0.19-0.99) respectively. Adverse events were rare (CD, 0.10, 95% CI = 0.02-0.31; UC, 0.22, 95% CI = 0.04-0.63). CONCLUSIONS: CT-P13 was associated with excellent clinical efficacy and safety profile, supporting its use in the treatment of IBD.

The effect of parathyroidectomy on insulin sensitivity in patients with primary hyperparathyroidism - an never ending story?

Previous studies demonstrated insulin resistance and increased prevalence of impaired glucose tolerance and type 2 diabetes mellitus in patients with primary hyperparathyroidism (PHPT). The effect of curative parathyroidectomy on insulin sensitivity was associated with conflicting results depending on which method for measuring the insulin sensitivity has been used. There was no improvement using HOMA and QUICKI while minimal model demonstrated significant improvement in insulin sensitivity. The aim of our study was to evaluate the insulin sensitivity before and after parathyroidectomy in patients with PHPT using a euglycemic clamp. 44 patients with PHPT and 11 age and body mass index matched healthy controls participated in study protocol. Before surgery M values and HOMA IR suggest insulin resistance in patients with PHPT. There was no difference in M index (3.74±1.89 vs. 4.62±2.27, p>0.05), HOMA IR (2.94±1.39 vs. 3.29±0.81, p>0.05), AUC glucose (863.0±261.3 vs. 842.3±165.5, p>0.05), AUC insulin (7068.7±4159.0 vs. 7229.6±2581.7, p>0.05), ISI (4.73±2.77 vs. 4.25±2.94, p>0.05) and AIR (47.89±32.05 vs. 38.96±21.20, p>0.05) between patients with PHPT and HC. There was significant improvement in insulin sensitivity after parathyroidectomy but both preoperative and postoperative M values were not significantly different in comparison to HC. There were no significant changes in HOMA IR, AUC glucose, AUC insulin, ISI and AIR before and after therapy. In conclusion, we observed significant improvement in insulin sensitivity after parathyroidectomy in patients with PHPT. There was no difference in parameters of insulin secretion before and after parathyroidectomy in patients with PHPT.

Growth hormone replacement normalizes impaired fibrinolysis: new insights into endothelial dysfunction in patients with hypopituitarism and growth hormone deficiency.

BACKGROUND: Cardiovascular morbidity in adult patients with growth hormone deficiency (GHD) and hypopituitarism is increased. Clustering of cardiovascular risk factors leading to endothelial dysfunction and impaired fibrinolysis has also been reported and may account for progression to overt vascular changes in these patients. However, effect of long lasting GH replacement therapy on fibrinolytic capacity in GH deficient patients has not been investigated so far. OBJECTIVE: To investigate fibrinolysis before and after challenge with venous occlusion in GHD patients with hypopituitarism before and during one year of growth hormone replacement. DESIGN: Hospital based, interventional, prospective study. INVESTIGATED SUBJECTS: Twenty one patient with GHD and fourteen healthy control subjects matched for age, sex and body mass index (BMI). METHODS: Anthropometric, metabolic and fibrinolytic parameters were measured at the start and after three, six and twelve months of treatment with human recombinant GH. RESULTS: At baseline GHD patients had significantly impaired fibrinolysis compared to healthy persons. During treatment with GH, significant changes were observed in insulin like growth factor 1(IGF-1) [from baseline 6.9(2.4-13.5) to 22.0(9.0-33.0) nmol/l after one month of treatment; p<0.01] and fibrinolysis. Improvement in fibrinolysis was mostly attributed to improvement of stimulated endothelial tissue plasminogen activator (t-PA) release in response to venous occlusion [from baseline 1.1(0.4-2.6) to 1.9(0.5-8.8) after one year of treatment; p<0.01]. CONCLUSION: Growth hormone replacement therapy has favorable effects on t-PA release from endothelium and net fibrinolytic capacity in GHD adults, which may contribute to decrease their risk of vascular complications.

Effects of alternate fasting or very low calorie diet and low calorie diet on metabolic syndrome in severely obese patients.

BACKGROUND AND AIM: Weight loss improves the metabolic syndrome (MetS) features and related clinical abnormalities in obese subjects. The aim of this study was to assess the effects of a non-surgical therapeutic program on the MetS in severely obese patients. PATIENTS AND METHODS: Sixty-four extremely obese patients were involved in the therapeutic program, which consisted of two alternating phases: the three-week therapeutic fasting or semi-fasting in hospital conditions and the low calorie diet with dosed physical activity in outpatient conditions. At the baseline we measured: anthropometric parameters, blood pressure and lipid profile. Subjects underwent an oral glucose tolerance test and insulin resistance/sensitivity was evaluated by the homeostasis model assessment and the oral glucose insulin sensitivity. After weight reduction by at least 10%, all mentioned assessments were repeated. RESULTS: None of the patients had significant adverse effects. Forty-one patients aged 43.0±11.5 years completed the study. The mean weight loss was 27 kg or 18% of the initial weight (p<0.01), which was followed by a significant decrease of the insulin resistance, the overall prevalence of MetS (32%) and all MetS parameters, without the significant change in high-density lipoprotein. This weight loss pogram substantially improves the MetS in extremely obese patients. CONCLUSION: The tailored alternating either fasting or semi- fasting should be considered as an optional approach to manage extreme obesity and related metabolic abnormality.

Diagnosis of Fanconi's Anemia by Diepoxybutane Analysis in Children from Serbia.

The high sensitivity of Fanconi's anemia (FA) cells to drug induced DNA interstrand crosslinks (ICL) such as diepoxybutane (DEB) was used as a part of FA screening in the children with clinical suspicion of FA. The study considered a total of 66 children with the hematological and/or congenital phenotypic symptoms reminiscent of FA. Blood samples from patients with clinical suspicion of FA and controls were collected for chromosome fragility evaluation by the DEB test. According to the results of DEB test, the patients were divided into two subgroups: FA displaying typical DEB sensitive cellular response and non FA. In this study, 10 out of 66 patients were found to have a FA cellular phenotype. The percentage of DEB-induced aberrant cells was increased more than 26 times in FA patients (range 22.00-82.00% with a mean of 48.32%) when compared to non FA patients (range 0.00-12.00% with a mean of 1.84%). The number of DEB-induced breaks/cells was more than 68 times higher in FA patients (range 0.26-4.39 with a mean of 1.37 breaks/cell) when compared to non FA patients (range 0.00-0.20 with a mean of 0.02 breaks/cell). The spontaneous chromosome fragility values in FA patients were overlapping those in non FA patients. Our results indicate that the DEB sensitivity test is the most reliable in vitro method for verification of the FA cellular phenotype.

The structure of sterile cytoplasm types within a maize genebank collection.

Maize Research Institute (MRI) gene bank maintains a collection of 6000 maize accessions. Within this collection over 100 sources of cytoplasmic male sterility (CMS) were found in field trials, i.e. more than 2% of the total accession numbers. These sources are distributed among Yugoslav open-pollinated varieties (4.56% of them contain CMS), as well as introduced heterozygous genotypes and inbred lines. In order to identify cytoplasm types the gene-bank sources of CMS were screened using a PCR assay with specific primers for C, T and S cytoplasms. Predominant cytoplasmic male sterility type among the analyzed accessions was CMS-S. Results were inconclusive for three accessions, i.e. different results for the progenies of two ears per accession were obtained. For another two accessions a new PCR product profile was identified, consisting of one band characteristic for CMS-S and one unspecific for any of the three CMS types. The PCR approach enabled a simple, fast and reliable large scale screening of maize cytoplasm among MRI gene bank accessions, significantly reducing time for cytoplasm characterizations compared to classical method of testing with restorers for each known type of CMS.

Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women.

OBJECTIVE: To compare the concentrations of cytokines belonging to Th17 axis (interleukin (IL)-17 and IL-23) and Th1 axis (IL-12 and interferon (IFN)-gamma) in obese and lean women, and to investigate their relationships with the proinflammatory adipokine leptin, proinflammatory cytokine macrophage migration inhibitory factor (MIF) and anthropometric and metabolic parameters of obesity. DESIGN: Cross-sectional study. SUBJECTS: Twenty-six obese women (age 20-52 years, body mass index (BMI): 30-48 kg/m(2)) and 20 healthy lean women (age 23-46 years, BMI: 18-25 kg/m(2)). MEASUREMENTS: Plasma levels of cytokines and leptin, BMI, waist circumference (WC) and insulin resistance index HOMA (homeostatic model assessment). RESULTS: Blood concentrations of IL-17, IL-23, MIF and leptin, but not IL-12 or IFN-gamma, were higher in obese compared with lean women (P=0.002, 0.046, 0.006 and 0.002, respectively). There was a positive correlation between IL-17 and IL-23 (r(s)=0.530), which was at the border of statistical significance (P=0.065). Neither IL-17 nor IL-23 correlated with leptin or MIF, and there was no association between IL-17 and IL-23 levels with BMI, WC or HOMA index. CONCLUSION: Interleukin-23/IL-17 axis is stimulated in obese women independently of the increase in abdominal fat, insulin resistance, leptin and MIF levels.

Ssr analysis for genetic structure and diversity determination of maize local populations from former Yugoslavia territories.

A collection of 2178 local populations from ex-Yugoslavia territories is maintained in Maize Research Institute (MRI) gene bank. These populations were characterized mainly by morphological markers. In this work 21 local populations belonging to seven different agro-ecological groups have been subjected to SSR analysis using a DNA-pooling strategy. The objective of this work was to develop genetic fingerprints for characterization, identification and classification of the populations, as well as for estimation of their genetic diversity. Also, a DNA-pooling strategy was employed with the aim to certify if it could be applied for population analysis with SSR markers. Statistical analysis of 25 informative SSR primers revealing 224 alleles (bands) showed that the average within-population mean number of alleles was 2.55, the average values for total and within-population diversity were 0.784 and 0.502, respectively and G(ST) value was 0.360. Genetic distance values calculated using Modified Rogers' Distance were in the range from 0.35 to 0.60. The silver staining method of DNA used for bulked samples showed some weakness that could be overcome with a more sensitive staining method. Nevertheless, the results in this work indicate that the SSR analysis of bulks could be used for characterizing a large number of populations in gene banks.

Total ghrelin levels during acute insulin infusion in patients with polycystic ovary syndrome.

Controversial data were reported concerning fasting ghrelin (decreased, normal or elevated) in polycystic ovary syndrome (PCOS). The aim of our study was to clarify ghrelin levels in non-obese, overweight, and obese PCOS patients; to investigate the effect of acute insulin infusion on ghrelin in PCOS as a chronic insulin-resistant state, with and without the impact of obesity, and to examine ghrelin-androgen interaction. In that order, we evaluated 1) ghrelin levels among 8 nonobese patients with PCOS [body mass index (BMI): 20.52+/-1.31 kg/m2], 8 overweight and obese patients with PCOS (BMI: 34.36+/-6.53 kg/m2) and their respective controls, 2) ghrelin suppression during euglycemic hyperinsulinemic clamp, and 3) ghrelin-androgen interrelationship. After overnight fast, 2-h euglycemic hyperinsulinemic clamp, was performed in all investigated women. Fasting ghrelin was significantly lower in non-obese PCOS than in controls (64.74+/-25.69 vs 108.36+/-52.60; p<0.05) as well as in overweight and obese PCOS in comparison with controls (38.71+/-14.18 vs 98.77+/-40.49; p<0.05). Insulin infusion significantly suppressed ghrelin in all subgroups of investigated women. Analysis of variance for repeatable measures confirmed that there was no significant difference in pattern of response between PCOS and controls. In conclusion, women with PCOS had lower fasting ghrelin and decreased insulin sensitivity independently of their BMI, compared to the controls. In addition, there were no differences between fasting ghrelin levels among non-obese, overweight, and obese women with PCOS. During euglycemic hyperinsulinemic clamp, ghrelin decreased in all studied groups to a similar extent, implying that, compared to chronic hyperinsulinemia, acute hyperinsulinemia reduces ghrelin levels independently of the degree of insulin resistance.

Effect of biphasic insulin aspart on glucose and lipid control in patients with Type 2 diabetes mellitus.

OBJECTIVE: This study examined the efficacy and safety of biphasic insulin aspart 30 (BIAsp 30) monotherapy in insulin-naive patients with Type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: In this 12-week, open-labelled, uncontrolled, clinical-experience study involving 71 patients with secondary oral antidiabetic agent failure, patients received BIAsp 30 after discontinuing oral antidiabetic drugs (OADs). Glucose and lipid concentrations, hypoglycaemic episodes and adverse events were assessed before and after treatment. Patient data were categorised according to previous OADs into the biguanides (BI) plus sulfonylureas/meglitinides (SU/MEG) and SU-only groups. RESULTS: After treatment, glucose and lipid control was significantly improved in both groups, with a greater improvement in the SU-only group. Mean glycated haemoglobin, fasting blood glucose and postprandial blood glucose excursion improved by 2.15 +/- 1.24%, 3.70 +/- 3.18 mmol/l and 1.26 +/- 2.65 mmol/l in the BI plus SU/MEG group, and by 3.09 +/- 1.62%, 6.11 +/- 5.02 mmol/l and 2.06 +/- 2.33 mmol/l in the SU-only group, respectively. Mean high-density lipoprotein cholesterol and triglycerides improved by 0.09 +/- 0.18 mmol/l and 0.94 +/- 1.17 mmol/l in the BI plus SU/MEG group and by 0.09 +/- 0.18 mmol/l and 1.04 +/- 2.72 mmol/l in the SU-only group, respectively. No major hypoglycaemic episodes or serious treatment-related adverse events were reported. CONCLUSIONS: Our study showed that BIAsp 30 treatment safely improved glucose and lipid control in insulin-naive patients with Type 2 diabetes poorly controlled on BI plus SU/MEG and SU-only. Key limitations were the lack of a comparator group and the short study duration.

Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis.

The present study reports for the first time a dual antiglioma effect of the well-known antidiabetic drug metformin. In low-density cultures of the C6 rat glioma cell line, metformin blocked the cell cycle progression in G(0)/G(1) phase without inducing significant cell death. In confluent C6 cultures, on the other hand, metformin caused massive induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation, mitochondrial depolarization and oxidative stress. Metformin-triggered apoptosis was completely prevented by agents that block mitochondrial permeability transition (cyclosporin A) and oxygen radical production (N-acetylcisteine), while the inhibitors of JNK activation (SP600125) or glycolysis (sodium fluoride, iodoacetate) provided partial protection. The antiglioma effect of metformin was reduced by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and was mimicked by the AMPK agonist AICAR. Similar effects were observed in the human glioma cell line U251, while rat primary astrocytes were completely resistant to the antiproliferative and proapoptotic action of metformin.