Treatment of thalassaemia: a review of the new approaches on transfusion safety and the novel therapeutics

Lifetime red cell concentrate (RCC) transfusions still account for significant iron overload‐related morbidity and mortality despite chelation therapy in thalassaemia. The cumulative risk of transfusion‐transmitted infections is substantial for thalassaemia patients. Pathogen reduction technologies for RCC may imply a proactive approach against new/re‐emerging pathogens and may be an ultimate safeguard for transfusion safety in the developing countries. Red cell alloimmunization may become a significant clinical challenge in thalassaemia. The availability of high‐throughput molecular blood group antigen typing in the donors may allow perfect match transfusion, beyond ABO‐D and CEK antigen‐matched transfusions. Allogeneic stem cell transplantation (A‐SCT) is the only available curative therapy in thalassaemia, but carries a substantial risk of serious adverse events and mortality. Gene addition therapy for correction of the α‐globin chain imbalance overcomes the problems of donor availability and immunological complications of A‐SCT. Gene editing by either gene disruption or correction emerged as a potential alternative to gene addition therapy in beta‐thalassaemia. A new era of novel therapeutics targeting α/β imbalance, ineffective erythropoiesis or iron dysregulation is unfolding in thalassaemia management, and a number of those now have agents in preclinical and clinical development. Hydroxyurea (HU) may improve globin chain imbalance and be beneficial for reducing or omitting transfusion requirement. Ruxolitinib has allowed steady decrease in spleen volume that may serve for avoiding splenectomy in beta‐thalassaemia. Luspatercept may restore normal erythroid differentiation and improve anaemia. Hepcidin mimetics or TMPRSS6 inhibitors may modulate ineffective erythropoiesis by iron restriction and improve anaemia and organ iron loading.     

How do gastric carcinoma classification systems relate to mucin expression patterns? An immunohistochemical analysis in a series of advanced gastric carcinomas

Gastric carcinoma classifications differ in their value for distinguishing tumors according to their morphological pattern, functional properties, and biological significance. In this study we evaluated which of three established classification systems is best correlated with the expression patterns of certain mucins. A total of 160 gastric carcinomas from Turkey and Germany were screened immunohistochemically for the expression of MUC1, MUC2, MUC5AC, and MUC6, and the results were related to the different tumor categories in Lauren's, Carneiro's, and Goseki's classifications. It was found that in all three classifications carcinomas belonging to the gland-forming category most commonly expressed MUC1: 78% of Goseki's grade I carcinomas, 81.1% of Lauren's intestinal type carcinomas, and 82.8% of Carneiro's glandular type. MUC2 was expressed in all Goseki grade II carcinomas, which comprise the mucinous type, while it was not significantly associated with any of the other classifications. MUC5AC was found in all Goseki grade IV carcinomas, i.e., signet ring cell carcinomas. It was also significantly associated with Carneiro's mixed type and isolated cell type carcinomas, while there was no correlation with any of Lauren's types. MUC6 failed to show a relationship with any of the categories of the various classifications. We conclude that Goseki's classification is best correlated with MUC expression patterns because it distinguishes clearly between MUC1-positive gland-forming carcinomas, MUC2-positive mucinous ones, and MUC5AC-positive signet ring cell carcinomas. It is likely that each of these gastric carcinoma types has its own carcinogenesis.     

Corrigendum

Corrigendum

Corrigendum     

A cluster of nosocomial Klebsiella oxytoca bloodstream infections in a university hospital.

BACKGROUND: On February 19, 2003, four patients (patients 1-4) in the neurology ward underwent cranial magnetic resonance angiography (MRA) and developed fever within 1 hour afterward. Klebsiella oxytoca was isolated from blood cultures of patients 1 through 3. OBJECTIVE: To identify the source of this cluster of nosocomial K. oxytoca bloodstream infections. DESIGN: Outbreak investigation. SETTING: A 1,000-bed university hospital. METHODS: The infection control team reviewed patient charts and interviewed nursing staff about the preparation and administration of parenteral fluids. The procedure of cranial MRA was observed. Arbitrarily primed polymerase chain reaction (AP-PCR) was performed to show the clonal relationship among these three strains. RESULTS: AP-PCR revealed that three K. oxytoca isolates had the same molecular profile. Cranial MRA was found to be the only common source among these patients. During MRA, before injection of the contrast medium, normal saline solution was infused to check the functioning of the intravenous catheter. Use of the solution for multiple patients was routine, but the access diaphragm of the bottle was not cleansed. The bottle of normal saline solution used on February 19 had already been discarded and the culture sample taken from the solution on the day of observation was sterile. CONCLUSIONS: We speculate that normal saline solution became contaminated during manipulation and that successive uses might have been responsible for this cluster. Poor aseptic techniques employed during successive uses appear to be the most likely route of contamination. Use of parenteral solutions for multiple patients was discontinued.     

The interaction of the diltiazem with oral and intravenous cyclosporine in rats.

This study investigated the effect of diltiazem on the bioavailability of oral and intravenous cyclosporine (CsA) in rats. While control rats received normal saline, experimental groups received 60 or 90 mg/kg diltiazem orally for 3 days. Each group divided into 2 equal groups that received a single oral dose or i.v. injection of CsA. Pharmacokinetic parameters were analyzed by nonparametric analysis of variance. Pretreatment with 60 or 90 mg/kg diltiazem decreased the area under the blood CsA concentration-time curve (AUC) of oral CsA compared to control group (54.5% and 65.5% for AUC(0-24), 57.6% and 62.2% for AUC(0-infinity), respectively, p<0.05). Mean CsA maximum concentration (Cmax) decreased from 0.4 +/- 0.1 microg/ml to 0.1 +/- 0.0 microg/mL in rats pretreated with 90 mg/kg diltiazem (p<0.05). The absolute bioavailability after oral administration (F(p.o.)) in the 60 or 90 mg/kg diltiazem groups were lower than the control group (9.6% and 8.5% versus 22.6%). Pretreatment with 90 mg/kg but not 60 mg/kg of diltiazem increased the AUC(0-infinity), elimination half-life (t1/2) of intravenous CsA (116.0%, 219.2%, respectively, p<0.05) and decreased the intravenous CsA clearence (CL(i.v.)) (62.9%, p<0.05). Diltiazem decreased the bioavailability of oral CsA, while it increased the bioavailability of intravenous CsA. One must consider this interaction when administering oral or intravenous CsA concomitantly with diltiazem.     

MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

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Resveratrol Triggers Apoptosis Through Regulating Ceramide Metabolizing Genes in Human K562 Chronic Myeloid Leukemia Cells

Cancer is a major worldwide health problem and one of the leading causes of death either in developed or developing countries. Plant extracts and derivatives have always been used for various disease treatments and many anticancer agents issued from plants and vegetables are clinically recognized and used all over the world. Lycium europaeum (Solanaceae) also called “wolfberry” was known since ancient times in the Mediterranean area as a medicinal plant and used in several traditional remedies. The Lycium species capacity of reducing the incidence of cancer and also of halting or reserving the growth of cancer was reported by traditional healers. In this study, the antiproliferative capacity, protective properties, and antioxidant activity of the hydro-alcoholic fruit extract of Lycium europaeum were investigated. Results showed that Lycium extract exhibits the ability to reduce cancer cell viability, inhibits proliferation, and induces apoptosis in A549 human lung cancer cells and PC12 rat adrenal medulla cancer cells, in a concentration- and time-dependent manner. Cytotoxic effect on normal rat cerebellum granule cells was assessed to be nonsignificant. Results also showed that Lycium fruit extract protected lipids, proteins, and DNA against oxidative stress damages induced by H₂O₂ via scavenging reactive oxygen species.