Identification and functional characterization of imatinib‐sensitive DTD1‐PDGFRB and CCDC88C‐PDGFRB fusion genes in eosinophilia‐associated myeloid/lymphoid neoplasms

Eosinophilia‐associated myeloid neoplasms with rearrangement of chromosome bands 5q31‐33 are frequently associated with PDGFRB fusion genes, which are exquisitely sensitive to treatment with imatinib. In search for novel fusion partners of PDGFRB, we analyzed three cases with translocation t(5;20)(q33;p11), t(5;14)(q33;q32), and t(5;17;14)(q33;q11;q32) by 5′‐rapid amplification of cDNA ends polymerase chain reaction (5′‐RACE‐PCR) and DNA‐based long‐distance inverse PCR (LDI‐PCR) with primers derived from PDGFRB. LDI‐PCR revealed a fusion between CCDC88C exon 25 and PDGFRB exon 11 in the case with t(5;17;14)(q33;q11;q32) while 5′‐RACE‐PCR identified fusions between CCDC88C exon 10 and PDGFRB exon 12 and between DTD1 exon 4 and PDGFRB exon 12 in the cases with t(5;14)(q33;q32) and t(5;20)(q33;p11), respectively. The PDGFRB tyrosine‐kinase domain is predicted to be retained in all three fusion proteins. The partner proteins contained coiled‐coil domains or other domains, which putatively lead to constitutive activation of the PDGFRB fusion protein. In vitro functional analyses confirmed transforming activity and imatinib‐sensitivity of the fusion proteins. All three patients achieved rapid and durable complete hematologic remissions on imatinib. © 2014 Wiley Periodicals, Inc.     

BRUGADA SYNDROME

Brugada syndrome is a rare cardiac arrhythmia characterized by electrocardiographic right bundle branch block and persistent ST-segment elevation in the right precordial leads. It is associated with ventricular fibrillation and a high risk for sudden cardiac death, predominantly in younger males with structurally normal hearts. Patients can remain asymptomatic, and electrocardiographic patterns can occur both spontaneously or after pharmacological induction. So far, several pathogenic genes have been identified as associated with the disease, but SCN5A is the most prevalent one. Two consensus reports to define the diagnostic criteria, risk stratification, and management of patients have been published in the last few years. This brief review focuses on the recent clinical diagnosis, genetic basis, and advances in pharmacological treatment of Brugada syndrome.     

Comparative effects of sevoflurane and propofol based general anaesthesia for elective surgery on memory

Introduction

Unconscious processing of words during general anaesthesia has been suggested. We used the process dissociation procedure (PDP) to test memory performance during sevoflurane and propofol anaesthesia in relation to hypnotic depth.

Material and methods

One hundred participants anaesthetised for elective surgery (50 with propofol and 50 with sevoflurane) and 50 non-anaesthetized listened to a list of words. The bispectral index (BIS) of the anaesthetised patients was recorded. Within 36 h after word presentation, memory was assessed using a word stem completion task, based on Buchner''s model applied on the PDP.

Results

There was evidence of memory for words presented during light (BIS 61-80) (p = 0.001) and adequate (BIS 41-60) (p = 0.008) but not deep anaesthesia (BIS 21-40) (p = 0.09). The PDP showed a significant implicit but not explicit memory contribution (mean total explicit memory scores: 0.04 ±0.07 in all BIS categories; mean implicit memory scores: 0.01 ±0.04, 0.1 ±0.08, and 0.05 ±0.09 at BIS = 21-40, 41-60, and 61-80, respectively). There was a statistically significant difference between the mean implicit memory score (I) of the propofol and sevoflurane group in the BIS category 41-60 in general (p = 0.016), and after incision (I_A.I.) (p = 0.005) in particular, with propofol depressing I more than sevoflurane in both cases. Memory performance of nonanaesthetized participants was better, with a higher contribution of explicit and a comparable contribution of implicit memory.

Conclusions

During general anaesthesia, implicit memory persists even in adequate hypnotic states. Sevoflurane affects the implicit memory of adequately anaesthetised subjects less than propofol.     

Implementation of HIV early infant diagnosis and HIV type 1 RNA viral load determination on dried blood spots in Cameroon: challenges and propositions

The testing of dried blood spots (DBSs) for human immunodeficiency type 1 (HIV-1) proviral DNA by PCR is a technology that has proven to be particularly valuable in diagnosing exposed infants. We implemented this technology for HIV-1 early infant diagnosis (EID) and HIV-1 RNA viral load determination in infants born of HIV-1-seropositive mothers from remote areas in Cameroon. The samples were collected between December 2007 and September 2010. Fourteen thousand seven hundred and sixty-three (14,763) DBS samples from infants born of HIV-positive mothers in 108 sites nationwide were tested for HIV. Of these, 1452 were positive on first PCR analyses (PCR1), giving an overall infection rate of 12.30%. We received only 475 DBS specimen for a second PCR testing (PCR2); out of these, 145 were positive. The median HIV-1 RNA viral load for 169 infant DBS samples tested was 6.85 log copies/ml, with values ranging from 3.37 to 8 log copies/ml. The determination of the viral load on the same DBS as that used for PCR1 allowed us to bypass the PCR2. The viral load values were high and tend to decrease with age but with a weak slope. The high values of viral load among these infants call for early and effective administration of antiretroviral therapy (ART). The findings from this study indicate that the use of DBS provides a powerful tool for perinatal screening programs, improvement on the testing algorithm, and follow-up during treatment, and thus should be scaled up to the entire nation.     

A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births

Haemoglobinopathies are the most common hereditary disorders in Greece. Although there is a successful national prevention program, established 35 years ago, there is lack of an official registry and collection of epidemiological data for haemoglobinopathies. This paper reports the results of the first National Registry for Haemoglobinopathies in Greece (NRHG), recently organized by the Greek Society of Haematology. NRHG records all patients affected by thalassaemia major (TM), thalassaemia intermedia (TI), "H" Haemoglobinopathy (HH) and sickle cell disease (SCD). Moreover, data about the annual rate of new affected births along with deaths, between 2000 and 2010, are reported. A total of 4,506 patients are registered all over the country while the number of affected newborns was significantly decreased during the last 3 years. Main causes for still having affected births are: (1) lack of medical care due to financial reasons or low educational level; (2) unawareness of time limitations for prenatal diagnosis (PD); due either to obstetricians' malpractice or to delayed demand of medical care of couples at risk; and (3) religious, social or bioethical reasons. Cardiac and liver disorders consist main causes for deaths while life expectancy of patients lengthened after 2005 (p < 0.01). The NRHG of patients affected by haemoglobinopathies in Greece provides useful data about the haemoglobinopathies in the Greek population and confirms the efficacy of the National Thalassaemia Prevention Program on impressively decreasing the incidence of TM and sickle cell syndromes.     

Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis

Thrombomodulin is a cell surface-expressed glycoprotein that serves as a cofactor for thrombin-mediated activation of protein C (PC), an event further amplified by the endothelial cell PC receptor. The PC pathway is a major anticoagulant mechanism that downregulates thrombin formation and hedges thrombus formation. The objectives of this review were to review recent findings regarding thrombomodulin structure, its involvement in the regulation of hemostasis and further discuss the implication, if any, of the genetic polymorphisms in the thrombomodulin gene in the risk of development of thrombosis. We performed a literature search by using electronic bibliographic databases. Although the direct evaluation of risk situations associated with thrombomodulin mutations/polymorphisms could be of clinical significance, it appears that mutations that affect the function of thrombomodulin are rarely associated with venous thromboembolism. However, several polymorphisms are reported to be associated with increased risk for arterial thrombosis. Additionally studies on knock out mice as well studies on humans bearing rare mutations suggest that thrombomodulin dysfunction may be implicated in the pathogenesis of myocardial infraction.     

Single-catheter radiofrequency ablation of a permanent junctional reciprocating tachycardia in a premature neonate

A 34-week premature neonate presented with drug-refractory permanent junctional incessant tachycardia and haemodynamic compromise. The patient underwent successful radiofrequency catheter ablation using a single-catheter approach. The child remains in sinus rhythm, without pharmacological treatment, 2 years after the procedure.