Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia

Despite the excellent efficacy of imatinib in chronic myeloid leukemia (CML), the response in patients is heterogeneous, which may in part be caused by pharmacogenetic variability. Imatinib has been reported to be a substrate of the P-glycoprotein pump. In the current study, we focused on the ABCB1 (MDR1) genotype. We analyzed the 3 most relevant single nucleotide polymorphisms of MDR1 in 90 CML patients treated with imatinib. Among the patients homozygous for allele 1236T, 85% achieved a major molecular response versus 47.7% for the other genotypes (P = .003). For the 2677G>T/A polymorphism, the presence of G allele was associated with worse response (77.8%, TT/TA; vs 47.1%, GG/GA/GT; P = .018). Patients with 1236TT genotype had higher imatinib concentrations. One of the haplotypes (1236C-2677G-3435C) was statistically linked to less frequent major molecular response (70% vs 44.6%; P = .021). Hence, we demonstrated the usefulness of these single nucleotide polymorphisms in the identification of CML who may or may not respond optimally to imatinib.     

Protein-losing enteropathy in Crohn's disease

Protein-losing enteropathy (PLE) is a rare but severe complication of Crohn's disease (CD) and hypoalbuminemia can be one of the presenting symptoms of this illness. The diagnosis of PLE can only be made after exclusion of malnutrition and liver or kidney failure. Significant intestinal leakage can be caused by mucosal injury, increased lymphatic pressure or dilated lymphatics and has been reported in a large number of diseases. The protein-losing can be diagnosed by assessing the excretion of different radiolabeled macromolecules in the faeces or by the clearance of alpha-1-antitrypsine in stools. The primary approach should be the optimization of the nutritional status. Medical treatment of the underlying disease is primordial. In other cases surgical resection of the most affected areas is inevitable. We report a case of a 21-year-old male with a 4 year history of CD, who developed significant hypoproteinemia with pitting oedema, initially in the absence of any other sign of severe disease activity. A "Cr-chloride albumin excretion confirmed our hypothesis of protein-losing enteropathy. Because of sub-obstruction signs some months later, a laparotomy was performed which revealed a severely affected loop with dilatation of the proximal jejunum. Interestingly, multiple large lymph nodes and dilated lymphatics were seen. A partial jejunal resection was performed for stricturing Crohn's disease. Histology showed severe mesenteric granulomatosis, dilated lymph vessels and granulomatous vasculitis. After the resection our patient improved without further albumin infusions and the oedema resolved.     

Gene polymorphisms of the renin-angiotensin system and early development of hypertension

BACKGROUND: A case-control association study was conducted to investigate a possible involvement of polymorphisms of three renin-angiotensin system genes: ACE (I/D and T-3892C), AGT (M235T and T174M), and AT1R (A1166C) in the early development of hypertension. METHODS: One hundred nineteen hypertensive and 125 normotensive participants aged 18 to 40 years were selected from a broader sample representative of the general population of Croatia. The selection criteria for hypertensive cases were systolic blood pressure (BP) higher than 140 mm Hg or diastolic BP higher than 90 mm Hg and a history of hypertension according to patient interview. RESULTS: Among the polymorphisms investigated, only those located on the ACE gene were associated with hypertension. For ACE I/D, the odds ratio for hypertension of DD versus II homozygote individuals was 2.50 (95% confidence interval [CI] 1.19-5.25) and for ACE T-3892C, the odds ratio of CC versus TT individuals was 2.32 (95% CI 1.05-5.10). Both polymorphisms of the ACE gene were in tight linkage disequilibrium. Of the investigated risk factors for hypertension, only body mass index (BMI) showed an influence on the early development of hypertension, acting independently of the ACE polymorphism. Their additive effect gives rise to 86% of hypertensives in subjects having both the DD genotype and BMI >or=30 kg/m(2). CONCLUSIONS: The present study provides evidence of the association of the ACE gene polymorphisms and premature hypertension. In addition, BMI proved to be another important predictor of the disorder acting independently of the ACE gene.     

Spontaneous and catheter-induced secondary coronary artery dissection: a single-centre experience

6497 consecutive patients who underwent coronary angiography in our institution in a three-year period were analysed. Spontaneous coronary artery dissection was noted in five, and unexpected dissection secondary to coronary arteriography in three patients. All patients with spontaneous dissection presented clinically as myocardial infarction. Three patients (two of them with spontaneous dissection) underwent urgent coronary artery bypass grafting. Percutaneous coronary intervention was successful in two patients with spontaneous and in one with unexpected secondary dissection. One patient with spontaneous and one with secondary dissection were treated medically after failed intervention. In conclusion, spontaneous coronary artery dissection is rare, but not exceptional. Its true incidence might have been underestimated before the advent of coronary interventions in acute myocardial infarction. Survival of all our patients, in contrast to earlier reports on mortality rates up to 50%, may be attributed to the benefits of modern surgery and interventional cardiology.     

IL-20 is an arteriogenic cytokine that remodels collateral networks and improves functions of ischemic hind limbs

Successful therapeutic angiogenesis for the treatment of ischemic disorders relies on selection of optimal proangiogenic or arteriogenic agents that are able to promote establishment of functional collateral networks. Here, we show that IL-20, a pleiotropic inflammatory cytokine, displays an imperative effect on vascular remodeling. Stimulation of both large and microvascular endothelial cells with IL-20 leads to activation of receptor-dependent multiple intracellular signaling components, including increased phosphorylation levels of JAK2/STAT5, Erk1/2, and Akt; activation of small GTP-binding proteins Rac and Rho; and intracellular release of calcium. Surprisingly, IL-20 significantly promotes endothelial cell tube formation without affecting their proliferation and motility. These findings suggest that the vascular function of IL-20 involves endothelial cell organization, vessel maturation, and remodeling. Consistent with this notion, delivery of IL-20 to the ischemic muscle tissue significantly improves arteriogenesis and blood perfusion in a rat hind-limb model. Our findings provide mechanistic insights on vascular functions of IL-20 and define therapeutic implication of this cytokine for the treatment of ischemic disorders.     

Clostridium difficile binary toxin CDT

Binary toxin (CDT) is frequently observed in Clostridium difficile strains associated with increased severity of C. difficile infection (CDI). CDT belongs to the family of binary ADP-ribosylating toxins consisting of two separate toxin components: CDTa, the enzymatic ADP-ribosyltransferase which modifies actin, and CDTb which binds to host cells and translocates CDTa into the cytosol. CDTb is activated by serine proteases and binds to lipolysis stimulated lipoprotein receptor. ADP-ribosylation induces depolymerization of the actin cytoskeleton. Toxin-induced actin depolymerization also produces microtubule-based membrane protrusions which form a network on epithelial cells and increase bacterial adherence. Multiple clinical studies indicate an association between binary toxin genes in C. difficile and increased 30-d CDI mortality independent of PCR ribotype. Further studies including measures of binary toxin in stool, analyses of CDI mortality caused by CDT-producing strains, and examination of the relationship of CDT expression to TcdA and TcdB toxin variants and PCR ribotypes are needed.     

Cutoff levels of 17-alpha-hydroxyprogesterone in neonatal screening for congenital adrenal hyperplasia should be based on gestational age rather than on birth weight

OBJECTIVE: In newborn screening programs for congenital adrenal hyperplasia, 17-alpha-hydroxyprogesterone (17OHP) cutoff levels are based on birth weight (BW) or on gestational age (GA). We investigated which approach would result in the greatest specificity and sensitivity. STUDY DESIGN: For the determination of 17OHP, a neonatal 17OHP assay was used in filter paper blood of 9492 newborns. The relationships between 17OHP and BW and between 17OHP and GA were studied by regression analysis. Reference curves with a specificity of 99.95% were constructed with the method that summarizes the distribution by three smoothed curves representing the skewness (L curve), the median (M curve), and the coefficient of variation (S curve). Median cutoff levels for BW and for GA according to the 99.95% reference curves were calculated. RESULTS: Regression analysis showed that GA is a better predictor of 17OHP than BW (R(2) was 50.6 vs. 35.8%, respectively). At a specificity of 99.95%, the calculated median 17OHP cutoff level was lower for GA [12.6 microg/liter (38 nmol/liter)] than for BW [17.6 microg/liter (54 nmol/liter)], thus leading to a greater sensitivity. CONCLUSION: This study demonstrates that GA is a better predictor of 17OHP in newborns and will result in greater specificity than BW despite the fact that the determination of GA might be less reliable than BW.     

Single center study of 53 consecutive patients with pituitary stalk lesions

Background

The etiological spectrum of pituitary stalk lesions (PSL) is wide and yet specific compared to the other diseases of the sellar and suprasellar region. Because of the pituitary stalk’s (PS) critical location and role, biopsies of these lesions are rarely performed, and their underlying pathology is often a conundrum for clinicians. A pituitary MRI in association with a clinical context can facilitate their diagnosis.

Aim

To present the various causes of PSL—their clinical, hormonal, histopathological, and MRI characteristics in order to gain better insight into this pathology.

Method

A retrospective observational study consisting of 53 consecutive patients with PSL of the mean age 32?±?4.2 years (range 6–67), conducted at the Department for Neuroendocrinology, Clinical Center of Serbia 2010–2018.

Results

Congenital malformations were the most common cause of PSL in 25 of 53 patients (47.1%), followed by inflammatory (9/53; 16.9%) and neoplastic lesions (9/53; 16.9%). The exact cause of PSL was established in 31 (58.4%) patients, of whom 23 were with congenital PS abnormalities and 8 with histopathology of PSL (7 neoplastic and 1 Langerhans Cell Hystiocytosis). A probable diagnosis of PSL was stated in 12 patients (22.6%): 6 with lymphocytic panhypophysitis, while Rathke cleft cyst, tuberculosis, dissemination of malignancy in PS were each diagnosed in 2 patients. In 10 patients (18.8%), the etiology of PSL remained unknown.

Conclusion

Due to the inability of establishing an exact diagnosis, the management and prognosis of PSL are difficult in many patients. By presenting a wide array of causes implicated in this condition, we believe that our study can aid clinicians in the challenging cases of this pathology.

     

Dynamic left ventricular outflow tract obstruction in senile cardiac amyloidosis.

Dynamic left ventricular outflow tract (LVOT) obstruction is classically seen in hypertrophic obstructive cardiomyopathy (HOCM). This can also be seen in cardiac amyloidosis. We describe a rare case of senile systemic amyloidosis with dynamic LVOT obstruction and concomitant three vessel coronary artery disease presenting with clinical and echocardiographic findings similar to those seen in HOCM. We also highlight the importance of distinguishing the sub-types of amyloidosis so that the appropriate therapy can be offered to patients with cardiac involvement, including coronary artery bypass grafting and septal myotomy/myectomy to relieve LVOT obstruction in the more benign forms of cardiac amyloidosis.     

Nano Zero Valent Iron (nZVI) as an Amendment for Phytostabilization of Highly Multi-PTE Contaminated Soil

In recent years, a lot of attention has been given to searching for new additives which will effectively facilitate the process of immobilizing contaminants in the soil. This work considers the role of the enhanced nano zero valent iron (nZVI) strategy in the phytostabilization of soil contaminated with potentially toxic elements (PTEs). The experiment was carried out on soil that was highly contaminated with PTEs derived from areas in which metal waste had been stored for many years. The plants used comprised a mixture of grasses—Lolium perenne L. and Festuca rubra L. To determine the effect of the nZVI on the content of PTEs in soil and plants, the samples were analyzed using flame atomic absorption spectrometry (FAAS). The addition of nZVI significantly increased average plant biomass (38%), the contents of Cu (above 2-fold), Ni (44%), Cd (29%), Pb (68%), Zn (44%), and Cr (above 2-fold) in the roots as well as the soil pH. The addition of nZVI, on the other hand, was most effective in reducing the Zn content of soil when compared to the control series. Based on the investigations conducted, the application of nZVI to soil highly contaminated with PTEs is potentially beneficial for the restoration of polluted lands.