Paroxysmal regular supraventricular tachycardia: the diagnostic accuracy of the transesophageal ventriculo-atrial interval

Objective: To establish the diagnostic accuracy of the transesophageal ventriculo‐atrial (VA) interval in patients with paroxysmal supraventricular tachycardia (PSVT) and normal baseline electrocardiogram (ECG). Methods: The transesophageal VA interval during tachycardia was recorded in 318 patients (age 45 ± 17 years, 58% female) with PSVT and a normal surface ECG between attacks. Subsequently, all patients underwent an ablation procedure establishing the correct tachycardia diagnosis. Results: AV nodal reentrant tachycardia (AVNRT), AV reentrant tachycardia through a concealed accessory pathway (AVRT), and ectopic atrial tachycardia (EAT) were found in 213, 95, and 10 cases, respectively. Receiver operating characteristic curve analysis identified an optimal cutoff for a binary categorization of AVNRT versus AVRT/EAT at ≤80 ms (area under the curve 0.891). Owing to a biphasic distribution, AVNRT was very likely at VA intervals ≤90 ms with a sensitivity, specificity, and positive predictive value (PPV) of 87%, 91%, and 95%. In the range 91–160 ms the corresponding values for AVRT were 88%, 95%, and 88% (90%, 99%, and 98% in male patients). In the small group with VA intervals >160 ms (n = 29), the diagnosis was less clear (PPV of 67% for AVNRT). Conclusions: In patients with sudden onset regular tachycardia and a normal ECG during sinus rhythm, a transesophageal VA interval of ≤80 ms has the highest diagnostic accuracy to diagnose AVNRT versus AVRT/EAT. Overall, the biphasic distribution of VA intervals suggests considering AVNRT at 90 ms and below and AVRT between 91 and 160 ms (in particular in male patients) while the diagnosis is vague at VA intervals above 160 ms. Ann Noninvasive Electrocardiol 2011;16(4):327–335     

Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression

The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and poorly understood. Some mothers of children with ASD have autoantibodies that react to fetal brain proteins, raising the possibility that a subset of ASD cases may be associated with a maternal antibody response during gestation. The mechanism by which the maternal immune system breaks tolerance has not been addressed. We hypothesized that the mechanism may involve decreased expression of the MET receptor tyrosine kinase, an ASD risk gene that also serves as a key negative regulator of immune responsiveness. In a sample of 365 mothers, including 202 mothers of children with ASD, the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P=0.003). To determine the mechanism of this genetic association, we measured MET protein and cytokine production in freshly prepared peripheral blood mononuclear cells from 76 mothers of ASD and typically developing children. The MET rs1858830 C allele was significantly associated with MET protein expression (P=0.025). Moreover, decreased expression of the regulatory cytokine IL-10 was associated with both the MET gene C allele (P=0.001) and reduced MET protein levels (P=0.002). These results indicate genetic distinction among mothers who produce ASD-associated antibodies to fetal brain proteins, and suggest a potential mechanism for how a genetically determined decrease in MET protein production may lead to a reduction in immune regulation.     

Autoantibodies to cerebellum in children with autism associate with behavior

Autism is a heterogeneous disorder with a poorly understood biological basis. Some children with autism harbor plasma autoantibodies that target brain proteins. Similarly, some mothers of children with autism produce antibodies specific to autism that target pairs of fetal brain proteins at 37/73 and 39/73 kDa. We explored the relationship between the presence of brain-specific autoantibodies and several behavioral characteristics of autism in 277 children with an autism spectrum disorder and 189 typically developing age-matched controls. Further, we used maternal autoantibody data to investigate potential familial relationships for the production of brain-directed autoantibodies. We demonstrated by Western blot that autoantibodies specific for a 45 kDa cerebellar protein in children were associated with a diagnosis of autism (p = 0.017) while autoantibodies directed towards a 62 kDa protein were associated with the broader diagnosis of autism spectrum disorder (ASD) (p = 0.043). Children with such autoantibodies had lower adaptive (p = 0.0008) and cognitive function (p = 0.005), as well as increased aberrant behaviors (p < 0.05) compared to children without these antibodies. No correlation was noted for those mothers with the most specific pattern of anti-fetal brain autoantibodies and children with the autoantibodies to either the 45 or 62 kDa bands. Collectively, these data suggest that antibodies towards brain proteins in children are associated with lower adaptive and cognitive function as well as core behaviors associated with autism. It is unclear whether these antibodies have direct pathologic significance, or if they are merely a response to previous injury. Future studies are needed to determine the identities of the protein targets and explore their significance in autism.     

Behavioral Correlates of Maternal Antibody Status Among Children with Autism

Autism spectrum disorders (ASDs) affect approximately 1 in 110 children in the United States. This report profiles fetal-brain reactive autoantibodies of a large cohort of mothers of children with autism and controls, yielding significant associations between the presence of IgG reactivity to fetal brain proteins at 37 and 73 kDa and a childhood diagnosis of full autism (p = 0.0005), which also correlated with lower expressive language scores (p = 0.005). Additionally, we report on reactivity to proteins at 39 and 73 kDa, which correlated with the broader diagnosis of ASD (p = 0.0007) and increased irritability on the Aberrant Behavioral Checklist (p = 0.05). This study provides evidence of multiple patterns of reactivity to fetal brain proteins by maternal antibodies associated with ASD and specific childhood behavioral outcomes.     

Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei

Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei , Trypanosoma brucei gambiense , and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC(50) = 47 nM) and T. b. rhodesiense (IC(50) = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug target.