Toxicity of Atorvastatin on Pancreas Mitochondria: A Justification for Increased Risk of Diabetes Mellitus

Statins (including atorvastatin) are a widely used class of drugs, and like all medications, they have a potential for adverse effects. Recently, it has been shown that statins also exert side effects on the pancreas. In vitro studies have suggested that this class of drugs induced a reduction in insulin secretion. Also, the use of statins is associated with a raised risk of diabetes mellitus (DM), but the mechanisms underlying statin‐induced diabetes are poorly known. Literature data indicate that several statins are able to induce apoptosis signalling. This study was designed to examine the mechanism of atorvastatin on mitochondria obtained from rat pancreas. In our study, mitochondria were obtained from the pancreas and then exposed to atorvastatin and vehicle to investigate probable toxic effects. The results showed that atorvastatin (25, 50, 75, 100 and 125 μM) increased reactive oxygen species (ROS) production, mitochondrial swelling, collapse of mitochondrial membrane potential and cytochrome c release, the orchestrating factor for mitochondria‐mediated apoptosis signalling. Atorvastatin also reduced the ATP levels. These results propose that the toxicity of atorvastatin on pancreas mitochondria is a key point for drug‐induced apoptotic cell loss in the pancreas and therefore a justification for increased risk of DM.     

A comparative study on clinical pathology changes in experimentally infected sheep with active and arrested larvae of Haemonchus contortus

Hypobiosis is the larval arrest of parasites and is an adaptation to host and environmental conditions. This study was conducted to compare clinicopathological changes in sheep experimentally infected with fresh and arrested larvae of Haemonchus contortus. Twenty-eight apparently healthy 6-month-old Shal lambs, whose stool samples were eggs per gram (EPG) negative, were divided into four groups: A, B, C and D. Groups A and D received fresh larvae and placebo, respectively. Treatment groups (B and C) were infected by arrested larvae obtained under different conditions such as humidity (B, 70%; C, 40–50%), temperature (B, 8–10°C; C, 35–37°C) and light intensity (B, low; C, high). Clinical signs were monitored until day?60, haematological examination [hematocrit (Hct), haemoglobin (Hb), red blood cells (RBC), mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), white blood cells (WBC) and differential cell count] and biochemical examination (Ca, Mg, P, total Pro, Alb, Globulins and Alb/Glob ratio) were performed on the first day and 2?months after infection with the larvae. In addition to the faecal egg count, the number of larvae and adult worms were determined in abomasal contents. The mean number of adult worms and faecal egg count in group A were significantly higher than in other groups (p?<?0.01). The proportion of arrested larvae and percentage of hypobiosis in group B differed significantly from other groups (p?<?0.05). The body weights of group A, B and C were significantly different compared with group D (p?<?0.01). No difference in weight gain was observed between the treatment groups B and C. Considerable reduction in RBC, Hb and PCV were observed in the different treatment groups, but these reductions were highly significant in group A (p?<?0.05) while MCV, MCH and MCHC did not show any change. The comparison of total WBC and differential cell count between groups indicated the presence of eosinophilia in group A (p?<?0.0005). Serum protein, albumin and calcium concentration decreased only in group A (p?<?0.01).     

Autophagy: The multi‐purpose bridge in viral infections and host cells

Autophagy signaling pathway is involved in cellular homeostasis, developmental processes, cellular stress responses, and immune pathways. The aim of this review is to summarize the relationship between autophagy and viruses. It is not possible to be fully comprehensive, or to provide a complete “overview of all viruses”. In this review, we will focus on the interaction of autophagy and viruses and survey how human viruses exploit multiple steps in the autophagy pathway to help viral propagation and escape immune response. We discuss the role that macroautophagy plays in cells infected with hepatitis C virus, hepatitis B virus, rotavirus gastroenteritis, immune cells infected with human immunodeficiency virus, and viral respiratory tract infections both influenza virus and coronavirus.     

Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects

Objectives: Impairment in early B-cell development can cause a predominantly antibody deficiency with severe depletion of peripheral B-cells. Mutations in the gene encoding for Bruton’s-tyrosine-kinase (BTK) and the components of the pre-B-cell receptor complex or downstream signaling molecules have been related to this defect in patients with agammaglobulinemia.

Methods: Iranian patients with congenital agammaglobulinemia were included and the correlation between disease-causing mutations and parameters such as clinical and immunologic phenotypes were evaluated in available patients.

Results: Out of 87 patients, a molecular investigation was performed on 51 patients leading to identification of 39 cases with BTK (1 novel mutation), 5 cases of µ-heavy chain (3 novel mutations) and 1 case of Igα-deficiencies.

Conclusion: Although there is no comprehensive correlation between type of responsible BTK mutation and severity of clinical phenotype, our data suggest that BTK-deficient and autosomal recessive agammaglobulinemia patients differ significantly regarding clinical/immunologic characteristics.     

Novel <Emphasis Type="Italic">UBR1</Emphasis> gene mutation in a patient with typical phenotype of Johanson–Blizzard syndrome

Johanson–Blizzard syndrome is a rare autosomal recessive disorder, characterized by exocrine pancreatic deficiency and a wide range of other abnormalities. We present here an infant with failure to thrive, exocrine pancreatic deficiency, short stature and developmental delay, cutis aplasia on the scalp, aplasia of alae nasi, hypospadias, hypothyroidism, myxomatous mitral valve, and patent ductus arteriosus. Molecular studies revealed a novel homozygous nonsense mutation in exon 38 of the UBR1 gene, which confirmed the diagnosis of Johanson–Blizzard syndrome. It should be acknowledged that the combination of exocrine pancreatic insufficiency and nasal wing hypo-aplasia is pathognomonic for this syndrome. Prompt diagnosis and exact monitoring of the patients with JBS are required to avoid further complications.     

No evidence for association of the ENPP1 (PC-1) K121Q variant with risk of type 2 diabetes in a Japanese population

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1, also known as PC-1) inhibits insulin signal transduction pathway(s). Previous studies have demonstrated the K121Q variant of the ENPP1 gene to have a significant functional role in determining susceptibility to insulin resistance and type 2 diabetes (T2D). To assess whether the K121Q variant has any impact on T2D in Japanese, we undertook an extensive case-control association study using a total of 911 unrelated Japanese T2D patients and 876 control subjects. No significant difference was observed in either genotype distribution (P=0.95) or allele frequency (P=0.83) between T2D and control groups. Notably, the frequency of the ancestral Q121 allele, which is also present in other primates, was quite high in African-Americans, and showed a marked ethnic variation (77.3% in African-Americans, 16.7% in European Americans, 10.5% in Japanese and 4.2% in Han Chinese). Consequently, the pairwise F_ST value (a classic measure of genetic distance between pairs of population) showed highly significant differentiations between African-American and non-African-American populations (F_ST>0.3). Our results indicated that the K121Q variant of the ENPP1 gene has very little, if any, impact on T2D susceptibility in Japanese, but may play a role in the inter-ethnic variability in insulin resistance and T2D.An erratum to this article can be found at     

Symptoms of body dysmorphic disorder among people presenting for cosmetic dental treatment: a comparative study of cosmetic dental patients and a general population sample

Abstract – Objectives: To determine appearance concerns of patients presenting for cosmetic treatment. Methods: This cross‐sectional comparative study included consecutive patients of six different cosmetic clinics (n = 170), and a sample of the general population (n = 878). A study‐specific self‐report questionnaire was administered to document demographic and appearance concerns. Presence of body dysmorphic disorder (BDD) was assessed based on DSM‐IV criteria. Results: Cosmetic dental patients did not differ from the reference sample with regard to happiness and satisfaction as regards their appearance. However, differences were found with regard to frequency of previous general cosmetic (16.5% versus 5.9%) and cosmetic dental (47.9% versus 24.8%) procedures. Furthermore, a significantly higher proportion of the cosmetic dental patients sufficed for the two key screening criteria of BDD (9.5% versus 5.5%), and for the full diagnostic screening of BDD (4.2% versus 1.5%) compared with the respondents of the reference group. Conclusions: The results suggest that symptoms of BDD are relatively common among patients attending cosmetic clinics. It is important to assess the long‐term effects of comprehensive cosmetic procedures, particularly in patients with disproportionate appearance concerns.     

Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels

Abstract. Erythropoietin is protective against cardiac ischemia, but the underlying mechanisms are unknown. We determined whether erythropoietin (0.5 – 10.0 U/ml) confers acute cardioprotection in infant rabbit hearts and the contribution of protein kinases, nitric oxide synthase and potassium channels to the underlying mechanism. Hearts from normoxic infant New Zealand White rabbits (n=8/group) were isolated and perfused in the Langendorff mode. Biventricular function was recorded under steady-state conditions prior to 30 min global no-flow ischemia and 35 min reperfusion. Administration of erythropoietin for 15 min immediately prior to ischemia resulted in a concentration-dependent increase in recovery of left and right ventricular developed pressure in rabbit hearts following myocardial ischemia and reperfusion. The optimal concentration of erythropoietin that afforded maximum recovery of developed pressure was manifest at 1.0 U/ml. Erythropoietin (1.0 U/ml) treatment resulted in phosphorylation of PKC, p38 MAP kinase and p42/44 MAP kinase. The cardioprotective effects of erythropoietin were abolished by the protein kinase inhibitors SB203580 (p38 MAP kinase), PD98059 (p42/44 MAP kinase) and chelerythrine (PKC) as well as the potassium channel blockers glibenclamide, HMR 1098, 5-HD and Paxilline. Nitrite and nitrate release from hearts before (2.3 ± 0.9 nmol/min/g) and after (2.4 ± 1.9 nmol/min/g) 15 min treatment with erythropoietin (1.0 U/ml) were not different. L-NAME and L-NMA did not block the cardioprotective effect of erythropoietin. We conclude the rapid activation of potassium channels and protein kinases by erythropoietin represents an important new mechanism for increasing cardioprotection.This work was supported in part by grants HL54075, HL66334 and HL65203 to JEB and HL61417 and HL71214 to KAP from the National Institutes of Health.     

The effect of ciprofloxacin on cyclophosphamide pharmacokinetics in patients with non-Hodgkin lymphoma

Cyclophosphamide (CPA) is widely used in chemotherapy. The CPA is a prodrug that requires metabolic transformation to generate the active metabolite, 4-hydroxy-CPA (4-OH-CPA). Ciprofloxacin (CF) is a fluoroquinolone antibiotic with a broad spectrum that is commonly used in treatment of a variety of infections. It has been reported that prophylactic administration of CF during CPA conditioning was a high-risk factor for relapse in patients undergoing allogeneic bone marrow transplantation. In the present study we investigated the pharmacokinetics of CPA and 4-OH-CPA in eight non-Hodgkin lymphoma (NHL) patients treated with CPA together with or without CF. Clearance and distribution volumes of CPA were significantly (P < 0.01) lower (4.7 L/h and 42.3 L, respectively) when patients were treated with CF prior to CPA compared to that observed when the patients did not receive CF (5.9 L/h and 48.1 L, respectively). No change in the elimination half-life was observed. The CF administration prior to CPA has resulted in significantly (P < 0.01) lower exposure to 4-OH-CPA as expressed as area under the plasma concentration curve (AUC). The metabolic ratio AUC(4-OH-CPA)/AUC(CPA) was lower in all patients treated with CF prior to CPA compared to that observed when patients received CPA only (P = 0.008). Our study showed that CF administration alters CPA kinetics in patients with NHL. Other antibiotics than these contain fluoroquinolones should be used during CPA therapy.