Our results provide the first demonstration, to our knowledge, of a risk-conferring genetic modifier in a large LQTS cohort. Subject to confirmation in additional cohorts, we suggest that the NOS1AP tag SNP genotype may provide an additional clinical dimension, which helps assess risk and choice of therapeutic strategies in LQTS.

Bartonella henselae is the major etiological agent of cat scratch disease in humans. Cats act as the natural reservoir of B. henselae and can transmit the infection to humans by a bite or scratch. The prevalence of B. henselae in cat populations was evaluated by serological and bacteriological tests. A total of 769 stray cats from three urban and three rural areas in northern Italy were sampled between January 1999 and December 2000. The positive and the negative predictive values of serological tests with respect to bacteremic status were evaluated. Tests of a total of 140 cats (18%) resulted in detection of bacteremia. A total of 540 cats were tested by serology; 207 (38%) were seropositive. Of the 531 cats tested by both methods, the results for 65 (12.2%) showed both bacteremia detection and seropositivity. The molecular typing of the isolates showed that 20.6% of bacteremic cats were infected with B. henselae type I strain, 61.1% were infected with B. henselae type II, and 18.3% were coinfected with both. A statistically significant difference in antibody and bacteremia prevalences among geographical areas was detected. Statistical analysis showed no association between characteristics such as seroprevalencebacteremic status, sex, general health status, and the presence of ectoparasites. The negative predictive value of serological test was 84.7%, and the positive predictive value was 31.8%. Receiving operator characteristic analysis of the data showed that serological tests had a low predictive value in relation to the bacteremic status of a cat; in surveys aimed at assessing the real risk of B. henselae infection in a human population, therefore, we suggest the use of blood culture as the reference test. Nevertheless, both blood culture assays and serological tests for Bartonella infection should be performed for a complete evaluation of the health status of cats.Although cat scratch disease (CSD) was recognized in 1930 and first reported in 1950 by Debrè et al. (8), the etiological agent was identified only in 1992 when Bartonella henselae was definitely associated with CSD in humans (23,24). Several years later, another Bartonella species, B. clarridgeiae, was identified as a causative agent of CSD in humans (20,21). Cats act as a natural reservoir of the bacteria and can transmit Bartonella to humans by a scratch or bite. Bartonella infection in cats is usually not characterized by clinical manifestations, but infected cats can remain bacteremic for long periods, thus playing a major role as a reservoir for the bacteria (5, 19). The cat flea, Ctenocephalides felis felis, plays an important role in cat-to-cat transmission of the infection (7,10,18). A similar role may also be played by ticks (Ixodes pacificus) (4).Epidemiological studies worldwide have shown a high level of variability of Bartonella seroprevalence in cats. Seroprevalence levels ranging from 1 to 8.5% in Germany and Switzerland (1,12,15) and up to 56% in The Netherlands (2) and 81% in California (6) have been found. In Europe, the highes...

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmo-genic cardiac disease predisposing affected individuals to sudden cardiac death (SCD). Methods and Results: Here we provide data on the largest CPVT population thus far described. The study population consisted of 177 patients (64% female) of 93 families. All 93 probands (pbs) were screened for RYR2 mutations: 54 (58%) pbs carried a heterozygous RYR2 mutation, 1 pb a compound heterozygous RYR2 mutation and 3 pbs a homozygous (1), compound heterozygous (1) or heterozygous (1) CASQ2 mutation. One KCNJ2 mutation (T305I) was detected in a total of 15 pbs. In family members, another 40 RYR2 mutation carriers were identified. Only 29 of 95 gene carriers were phenotypically silent, therefore the penetrance of a RYR2 mutation was 69%. Of note, female sex was predominant among CPVT probands without a RYR2 mutation. Before the initiation of any treatment related to CPVT, 77 of 93 (83%) pbs experienced a cardiac e vent. Mean age of first event was 12±9 years. Neither sex nor the presence/absence of a RYR2 mutation was associated with a higher risk of developing events or with a younger age at onset of symptoms. Before therapy, 70% and 40% of 177 patients remained free of cardiac arrest and SCD before therapy by age 20 and 40 years, respectively. A history of juvenile SCD (<40 yrs) was present in 36% of families: the mean age of the lethal event was 18±9 yrs. One-hundred CPVT patients were initiated on β-blockers. On top, 41 patients were implanted with an ICD. During a mean follow-up time of 4.5±3 years, 28% of patients experienced a syncope (n=11), cardiac arrest (n=5) or appropriate ICD shock (n=12). Neither sex nor genotype was associated with a worse response to therapy. Conclusions: In this largest CPVT population reported so far, the presence/absence of a RYR2 mutation wasn’t associated with different clinical characteristics or response to therapy as compared to non-mutation carriers. CPVT remains a highly malignant disease with only a moderate response to β-blockers.

Background : Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic or bidirectional ventricular tachycardia (BVT). Andersen-Tawil syndrome (ATS1), which are mainly caused by KCNJ2 mutations, phenocopies CPVT and may manifest the typical adrenergically mediated BVT. The purpose of this study was assess whether patients (pts) lacking periodic paralysis typical of ATS1 and diagnosed as CPVT because of BVT carry KCNJ2 mutations. Methods and Results : Mutational analysis of KCNJ2 was performed in 23 RyR2 and CASQ2 genotype-negative CPVT pts with normal QT interval. Two novel missense mutations (S220I and T305I) were identified. Mutations were absent in >400 reference alleles. Both of the pts present exercise or isoproterenol induced BVT, baseline ECG with prominent U wave and mild facial abnormalities. In vitro characterization showed that no current is detectable when S220I and T305I mutants clones are expressed; on the contrary co-expression of WT and mutant KCNJ2 to mimic heterozygosis present in patients, caused significant dominant negative effect (see figure ). Confocal laser microscopy revealed normal sarcolemmal localization of the mutant channels and of the heterozygous channels. Conclusions : KCNJ2 mutation with loss of function are present in a minority of pts with clinical diagnosis of CPVT. Given the limited number of CPVT pts with KCNJ2 mutations it is impossible to determine whether their prognosis is identical to that of RyR2 and CASQ2 related CPVT. Screening of KCNJ2 should be considered in CPVT pts without mutations in RyR2 and CASQ2 genes.