Clinical Evaluation of Morphology Discrimination: An Algorithm for Rhythm Discrimination in Cardioverter Defibrillators

The aim of this study was to test the new morphology discrimination diagnostic algorithm for ICDs that differentiates supraventricular tachycardias (SVTs) from VTs by analysis of ventricular depolarization complexes morphology. Twenty-five patients implanted with a St. Jude Ventritex single chamber ICD were studied during electrophysiological evaluation at predischarge and were followed for 7 +/- 4 months. Sensitivity and specificity for VT detection and overall diagnostic accuracy of the morphology discrimination algorithm were calculated on 326 detected events. At electrophysiological evaluation, the algorithm was tested during 67 episodes of right atrial pacing, during 119 episodes of RV pacing (at basal interventricular septum and RV apex) and during 27 episodes of sustained AF: specificity was 98%, sensitivity was 66%, and diagnostic accuracy was 80%. All episodes of AF were correctly diagnosed as SVT. Exclusion of detections related to pacing at the basal interventricular septum, resulted in a specificity of 98%, a sensitivity of 85%, and a diagnostic accuracy of 93%. During follow-up, evaluation of the morphology discrimination algorithm on 113 spontaneous episodes (31 VTs, 31 AF, 7 SVTs, and 44 sinus tachycardias) exhibited a specificity of 89%, a sensitivity of 100%, and a diagnostic accuracy of 92%. In conclusion, the morphology discrimination algorithm exhibits a high specificity in discriminating VTs from SVTs, although with a corresponding reduction in sensitivity. The preliminary experience on spontaneous episodes is promising. To correct for the reduction in sensitivity, it is advisable to use this algorithm in parallel with other algorithms for rhythm discrimination (sudden onset, stability) coupled with extended high rate.     

Synthetic Tyr-phospho and non-hydrolyzable phosphonopeptides as PTKs and TC-PTP inhibitors*

Tyrosine-specific protein kinases and phosphatases are important signal transducing enzymes in normal cellular growth and differentiation and have been implicated in the etiology of a number of human neoplastic processes. In order to develop agents which inhibit the function of these two classes of enzymes by interfering with the binding of their substrates, we synthesized analogs derived from the peptide EDNEYTA. This sequence reproduces the main autophosphorylation site of Src tyrosine kinases. In this work we report the synthesis, by classical solution methods, of the phosphotyrosyl peptide ED-NEYpTA as well as of three analogs in which the phosphotyrosine is replaced by a phosphinotyrosine and by two unnatural, non-hydrolyzable amino acids 4-phosphonomethyl-l -phenylalanine and 4-phosphono-l -phenylalanine. The Src peptide and its derivatives were tested as inhibitors of three non-receptor tyrosine kinases (Lyn, belonging to the Src family, CSK and PTK-IIB) and a non-receptor protein tyrosine phosphatase obtained from human T-cell (TC-PTP). The biomimetic analogues, which do not significantly affect the activity of CSK, PTK-IIB and TC-PTP, act:is efficient inhibitors on Lyn, influencing both the exogenous phosphorylation and, especially, its autophosphorylation. In particular, the Pphe derivative may provide a basis for the design of a class of inhibitors specific for Lyn and possibly Src tyrosine kinases, capable of being used in vivo and in vitro conditions. © Munksgaard 1995.     

Paroxysmal Bundle Branch Block of Supraventricular Origin: A Possible Source of Misdiagnosis in Detecting Ventricular Tachycardia Using Time Domain Analyses of Intraventricular Electrograms

Current implantable antitachycardia devices use several methods for differentiating sinus rhythm (SR) from supraventricular tachycardia (SVT) or ventricular tachycardia (VT). These methods include sustained high rate, the rate of onset, changes in cycle length, and sudden onset. Additional methods for detecting VT include techniques based upon ventricular electrogram morphology. The morphological approach is based on the assumption that the direction of cardiac activation, as sensed by a bipolar electrode in the ventricle, is different when the patient is in SR as compared to VT. Whether paroxysmal bundle branch block of supraventricular origin (BBB) can be differentiated from VT has not been determined. In this study, we compared the morphology of the ventricular electrogram during sinus rhythm with a normal QRS (SRNIQRS) or SVT with a normal QRS (SVTNIQRS) with the morphologies of BBB and VT in 30 patients undergoing cardiac electrophysiology studies. Changes in ventricular electrogram morphology were determined using three previously proposed time domain methods for VT detection: Correlation Waveform Analysis (CWA), Area of Difference (AD), and Amplitude Distribution Analysis (ADA). CWA, AD, and ADA distinguished VT from SRNIQRS or SVTNIQRS in 16/17 (94%), 14/17 (82%), and 12/17 (71%) patients, and BBB from SRNIQRS or SVTNIQRS in 15/15 (100%), 13/15 (87%), and 6/15 (40%) patients, respectively. However, the ranges of values during BBB using these methods overlapped with ranges of values during VT in all cases for CWA, AD, and ADA. Hence, BBB may be a source of misdiagnosis in detecting VT when these time domain methods are used for ventricular electrogram analysis.     

Biobanking in the digital pathology era

Digital Pathology is becoming more and more important to achieve the goal of precision medicine. Advances in whole-slide imaging, software integration, and the accessibility of storage solutions have changed the pathologists’ clinical practice, not only in terms of laboratory workflow but also for diagnosis and biomarkers analysis. In parallel with the pathology setting advancement, translational medicine is approaching the unprecedented opportunities unrevealed by artificial intelligence (AI). Indeed, the increased usage of biobanks’ datasets in research provided new challenges for AI applications, such as advanced algorithms, and computer-aided techniques. In this scenario, machine learning-based approaches are being propose in order to improve biobanks from biospecimens collection repositories to computational datasets. To date, evidence on how to implement digital biobanks in translational medicine is still lacking. This viewpoint article summarizes the currently available literature that supports the biobanks’ role in the digital pathology era, and to provide possible practical applications of digital biobanks.     

A systematic review of the evidence for Canada's Physical Activity Guidelines for Adults

This systematic review examines critically the scientific basis for Canada's Physical Activity Guide for Healthy Active Living for adults. Particular reference is given to the dose-response relationship between physical activity and premature all-cause mortality and seven chronic diseases (cardiovascular disease, stroke, hypertension, colon cancer, breast cancer, type 2 diabetes (diabetes mellitus) and osteoporosis). The strength of the relationship between physical activity and specific health outcomes is evaluated critically. Literature was obtained through searching electronic databases (e.g., MEDLINE, EMBASE), cross-referencing, and through the authors' knowledge of the area. For inclusion in our systematic review articles must have at least 3 levels of physical activity and the concomitant risk for each chronic disease. The quality of included studies was appraised using a modified Downs and Black tool. Through this search we identified a total of 254 articles that met the eligibility criteria related to premature all-cause mortality (N = 70), cardiovascular disease (N = 49), stroke (N = 25), hypertension (N = 12), colon cancer (N = 33), breast cancer (N = 43), type 2 diabetes (N = 20), and osteoporosis (N = 2). Overall, the current literature supports clearly the dose-response relationship between physical activity and the seven chronic conditions identified. Moreover, higher levels of physical activity reduce the risk for premature all-cause mortality. The current Canadian guidelines appear to be appropriate to reduce the risk for the seven chronic conditions identified above and all-cause mortality.     

Human epidermal growth factor receptor 2 oncoprotein expression in breast cancer patients from central Anatolia, Turkey

Aim:   Human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis and the frequency of HER2 positivity in breast cancer patients varies among different regions of the world. We studied HER2 expression in Turkish breast cancer patients.
Methods:   HER 2 expression was evaluated immunohistochemically in 107 breast cancer patients. HER2 expression was reported as negative or positive (3+) according to cellular membrane staining characteristics. The frequency of HER2 overexpression, distribution according to clinical characteristics, effect on survival and effect of chemotherapy on survival in relation to HER2 overexpression was evaluated.
Results:   The median age of patients was 49 years (range 27–76). HER2 was 3+ in 34 patients (31.8%). There was no significant difference in age, menopausal status, histopathology, lymph node involvement, stage and estrogen and/or progesterone receptor positivity in relation to HER2 expression. Forty-three patients (40.2%) relapsed and 21 patients (19.6%) died during the follow-up period. There was no significant difference in the relapse rate, distribution of relapse sites and death rate in relation to HER2 expression. The 3- and 5-year disease free survival rates were 67.1 and 40.5%, and the overall survival rates were 87.5 and 66.1%, respectively. Survival rate and calculated survival time were relatively shorter in HER2 3+ patients than in non-HER2 3+ patients, but these differences were not statistically significant. HER2 status did not affect survival period according to chemotherapy group.
Conclusion:   Immunohistochemistry findings of HER2 expression in Turkish breast cancer patients were similar to those found in the published reports. A shorter survival period was observed in HER2 3+ patients, but the difference was not statistically significant.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.      

肾脏占位性病变的超声造影特点

目的探讨不同类型肾脏占位病变的超声造影特点。方法对照病理诊断结果分析76例肾脏占位病变Sono Vue超声造影特征。结果肾恶性肿瘤62例,良性肿瘤14例。肾恶性肿瘤超声造影剂的充盈和消退呈多样性,以同步增强和快增强多见,造影剂的快速消退和缓慢消退之间无明显差别,差异无统计学意义(P>0.05)。恶性肿瘤典型的表现是整个病灶弥漫增强,轮廓边界清晰,呈"亮球"征(95.2%),并多有假包膜(87.1%)。肾错构瘤表现为无假包膜的不均匀增强,而肾囊肿始终无增强。结论超声造影有助于肾占位病变的鉴别诊断和预后判断。     

LWMH与VKA对DVT患者院外抗凝效益-风险对比

【目的】通过对经住院治疗后下肢深静脉血栓形成(deep venous thrombosis,DVT)患者院外分别继续应用低分子肝素(low molecule weight heparin,LMWH)或维生素K拮抗剂(vitamin K antagonists,VKA)的效益-风险比的对比研究,探讨较为有效、安全、简便的抗凝方案。【方法】将2008年12月-2011年3月符合纳入标准的患者随机分为A组(应用低分子肝素钙)和B组(应用华法林),并随访6个月,期间通过定期监测凝血功能及血小板计数,调整用药方案;每2个月做1次全面随访,包括有无出血、肝素诱导的血小板减少和复发事件的发生。【结果】两组均取得有效的抗凝效果,并且A组副作用发生率在各监测点明显低于B组(P<0.05),随访中发现两组DVT复发率无差异(P>0.05),但随着抗凝时间延长,两组患者出血发生率增加。在DVT复发患者中,髂股深静脉血栓形成者复发率最高,其次是股静脉、腘静脉。患者对应用A治疗方案的依从性较高。【结论】DVT患者院外继续应用LWMH抗凝效果可靠,用药安全性高,副作用较小,操作及监测简单,与应用VKA相比效益-风险比较高。