Wide QRS-complex tachycardia with variable VA-conduction: what is the mechanism?

We describe the case of a 16-year-old woman with a surgically corrected tetralogy of Fallot presenting with recurrent wide-QRS-complex tachycardia. The tachycardia could be induced and terminated with ventricular stimulation only. QRS morphology during sinus rhythm and tachycardia was identical and variable VA-conduction was observed. Mapping of the tachycardia showed that variations of HH intervals preceded VV intervals. Therefore, a mechanism involving re-entry within the bundle branches was suggested. However, detailed mapping showed cranial to caudal depolarization of the His bundle, leading to the diagnosis of atrioventricular node re-entrant tachycardia. The tachycardia was abolished by radiofrequency catheter ablation of the slow AV nodal pathway. We conclude that variable VA conduction can occur in patients with atrioventricular node re-entrant tachycardia. The atrial tissue is not always an integral part of the re-entrant circuit.     

Using diffusion tensor imaging and mixed-effects models to investigate primary and secondary white matter degeneration in Alzheimer's disease and mild cognitive impairment

White matter (WM) degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI) may be a key indicator of early damage in AD. Here, we analyzed WM diffusion tensor data using Tract-Based Spatial Statistics in conjunction with mixed-effects models. Four indices of diffusion were assessed in 61 healthy control, 19 non-amnestic MCIs, 14 amnestic MCIs, and 9 AD patients. The aim of the study was to use advanced mixed-effects models to investigate the retrogenesis hypothesis of AD, which suggests that tracts that are late to myelinate in ontogenetic development are the earliest to be affected in AD. Our results show that a number of late-myelinating pathways, including the parahippocampal region and the inferior longitudinal fasciculus, were predominantly affected by changes in WM volume. Conversely, early-myelinating pathways were found to be affected by a combination of both WM and gray matter (GM) atrophy. A model of the entire WM structure of the brain returned GM models for two indices of diffusion, suggesting that more complex regional landscapes of diffusion lie hidden beneath a global analysis of the entire brain. Our results warn against an explanation of white matter damage that points simply to one of two mechanisms: secondary degeneration or direct damage of myelin. We suggest that tracts may be affected by both mechanisms, with the balance depending on whether tracts are early or late-myelinating. A greater understanding of the pattern of WM changes in AD may prove useful for the early detection of AD.     

Pathogenesis of Necrotizing Enterocolitis: Modeling the Innate Immune Response

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants. The pathophysiology is likely secondary to innate immune responses to intestinal microbiota by the premature infant''s intestinal tract, leading to inflammation and injury. This review provides an updated summary of the components of the innate immune system involved in NEC pathogenesis. In addition, we evaluate the animal models that have been used to study NEC with regard to the involvement of innate immune factors and histopathological changes as compared to those seen in infants with NEC. Finally, we discuss new approaches to studying NEC, including mathematical models of intestinal injury and the use of humanized mice.Necrotizing enterocolitis (NEC) is a disorder characterized by intestinal necrosis in premature infants that results in significant morbidity and mortality.¹ Approximately 7% of infants with a birth weight between 500 and 1500 g develop NEC.¹ The pathogenesis is characterized by intestinal inflammation that can progress to systemic infection/inflammation, multiorgan failure, and death. The bowel is distended and hemorrhagic on gross inspection. On microscopic examination, signs of inflammation, mucosal edema, epithelial regeneration, bacterial overgrowth, submucosal gas bubbles, and ischemic transmural necrosis are seen (Figure 1, A–E).²Open in a separate windowFigure 1Examples of the various grades of morphological damage in hematoxylin and eosin–stained specimens. A–E: Representative samples of premature infants with necrotizing enterocolitis. A: Age-matched control from patient with jejunal atresia. B: Mild injury with hemorrhagic necrosis of mucosa and loss of villus tip architecture. C: Progressive injury with inflammatory infiltration of muscularis with complete villus destruction. D: Severe muscular and epithelial damage with complete loss of mucosa. E: Perforation with transmural necrosis with complete loss of epithelial and muscular architecture. F–J: Representative samples from intestinal injury secondary to gavage feeding in the setting of hypothermia and hypoxia in neonatal rats. F: Intact morphology, grade 0. G: Sloughing of villus tips, grade 1. H: Mid-villus necrosis, grade 2. I: Loss of villi, grade 3. J: Complete destruction of the mucosa, grade 4. Insets in F–J show higher magnified portions of the same sections, corresponding to the boxed regions. K–O: Representative images of tissue injury secondary to 60 minutes of intestinal ischemia and 90 minutes of reperfusion in 2-week-old mice. K: Sham-operated mice (no ischemia). L: Villus tip necrosis. M: Mid-villus necrosis. N: Loss of villus architecture. O: Complete loss of mucosal architecture. F–J, reprinted with permission from Nature Publishing Group.²⁸ Scale bars = 50 μm (A–E, K–O). Original magnification, ×20 (A–O, main images, and F–J, insets).Currently the pathogenesis of NEC is believed to have multifactorial causes, including intestinal immaturity and microbial dysbiosis. Intestinal immaturity leads to a compromised intestinal epithelial barrier, an underdeveloped immune defense, and altered vascular development and tone. The compromised epithelial barrier and underdeveloped immune system, when exposed to luminal microbiota that have been shaped by formula feedings, antibiotic exposure, and Cesarean delivery, can lead to intestinal inflammation and sepsis. Despite therapeutic success in animal model systems, there are relatively few therapeutic strategies that have allowed for significantly improved outcomes in infants with NEC. Two hurdles that persist are our incomplete understanding of the developing immune system in premature infants and our inability to adequately replicate these complex factors in animal models.^3,4 This review summarizes the complex intestinal immune system in premature infants and details what is known about the involvement of innate immune factors in NEC, both in animal models and in human disease.     

Amplification and overexpression of the ABCC3 (MRP3) gene in primary breast cancer

The ATP-binding cassette (ABC) of active transporters comprises a group of proteins that which facilitate efflux of anticancer drugs from cancer cells. We focused on the gene amplification and protein expression of ABCC3 (also known as MRP3) in breast cancer cell lines and clinical tumor samples. Fluorescence and chromogenic in situ hybridization, using an ABCC3-specific probe, was used to analyze 11 breast cancer cell lines and 112 clinical tumor samples. The results of ABCC3 were correlated with the amplification status of HER2 and topoisomerase II alpha (TOP2A), which are located close to ABCC3 at 17q12-q21. Immunohistochemistry was used to assess ABCC3 protein overexpression. Of the cell lines studied 6 HER2-positive lines and 1 HER2-negative line exhibited amplification of ABCC3. In the HER-2-negative clinical tumor samples, only 4/55 (7.3%) exhibited ABCC3 amplification. In the HER2-positive tumors, ABCC3 was amplified in 16/57 tumors (28.1%, P=0.0059). TOP2A did not exhibit any consistent coamplification pattern. ABCC3 (MRP3) protein overexpression was more common in tumors with gene amplification (P=0.069). In silico analysis of 804 breast cancers with matched gene expression and copy number microarray data revealed significant differences ABCC3 across the molecular subtypes. Specifically, increased ABCC3 mRNA and gene copy numbers were most prominent in HER2 amplified and/or HER2-enriched classified tumors. Moreover, differential ABCC3 mRNA levels were found within the HER-2 amplified subset when stratified by the estrogen receptor status. We conclude that ABCC3 is frequently amplified and overexpressed in HER2-positive breast cancer, and something that warrants further studies correlating the results with therapeutic outcome.     

Artemether and tribendimidine lack activity in experimental treatment of Paragonimus westermani in the dog

Artemether and tribendimidine are active against several trematode species, but no data are available regarding the lung fluke Paragonimus westermani. We infected six dogs with 100 P. westermani metacercariae each. At day 103 post-infection, four dogs were treated orally for 3 days with either artemether (total dose, 66.7 and 75 mg/kg) or tribendimidine (total dose, 100 mg/kg). The remaining dogs were left untreated and served as control. Sixteen days after the final dosing, dogs were killed, and P. westermani flukes were recovered from the lungs and counted. Neither artemether nor tribendimidine showed activity against P. westermani at this dose regimen in dogs.     

Respiratory viral infections during the 2009–2010 winter season in Central England, UK: incidence and patterns of multiple virus co-infections

Acute viral respiratory infections are the most common infections in humans. Co-infection with different respiratory viruses is well documented but not necessarily well understood. The aim of this study was to utilise laboratory data from the winter season following the 2009 influenza A(H1N1) outbreak to investigate rates of respiratory virus co-infections, virus prevalence in different age groups and temporal variations in virus detection. The Health Protection Agency Public Health Laboratory (HPA PHL) Birmingham, UK, routinely uses polymerase chain reaction (PCR) to detect common respiratory viruses. The results from specimens received for respiratory virus investigations from late September 2009 to April 2010 were analysed. A total of 4,821 specimen results were analysed. Of these, 323 (13.2?%) had co-detections of two viruses, 22 (0.9?%) had three viruses and four (0.2?%) had four viruses. Reciprocal patterns of positive or negative associations between different virus pairs were found. Statistical analysis confirmed the significance of negative associations between influenza A and human metapneumovirus (HMPV), and influenza A and rhinovirus. Positive associations between parainfluenza with rhinovirus, rhinovirus with respiratory syncytial virus (RSV) and adenovirus with rhinovirus, parainfluenza and RSV were also significant. Age and temporal distributions of the different viruses were typical. This study found that the co-detection of different respiratory viruses is not random and most associations are reciprocal, either positively or negatively. The pandemic strain of influenza A(H1N1) was notable in that it was the least likely to be co-detected with another respiratory virus.     

Prevalence and mother-to-infant transmission of hepatitis viruses B, C, and E in Southern Tanzania.

Hepatitis B and C markers were tested in 980 pregnant women, in the infants born to infected mothers, and in a random sample of 42 and 50, respectively, children born to uninfected mothers in Tanzania. Sixty-two women (6.3%) were positive for HBsAg and 15 (24%) were HBeAg-seropositive. Anti-HCV was detected in 49 women (5%), 15 (31%) of whom had detectable viremia. HCV RNA serum levels were low and only genotype 4 was identified. Sixty-six women (6.7%) were positive for anti-HIV, six of whom were coinfected with HBV and one with HCV. Anti-HEV was negative in the 180 women tested. At 8 months of age, HBsAg was detected in 8% and 2% of children born to HBV-infected and noninfected mothers, respectively (P = 0.2). Corresponding figures at 18 months of age were 31% and 21% (P = 0.3). When tested at 2 months of age, HCV RNA was not detected in any of the 43 children born to anti-HCV-positive mothers nor in any of 50 children born to anti-HCV-negative mothers. At 18 months, only one child, born to an anti-HCV-positive mother, had detectable HCV RNA. None of the infants born to women with HIV coinfection were infected with hepatitis viruses. This study suggests that exposure to HEV does not occur in southern Tanzania. The prevalence of current HBV infection in pregnant women from rural Tanzania is lower than in other sub-Saharan areas. In early childhood, HBV infection appears to occur by horizontal rather than maternofilial mechanisms of transmission. The prevalence of HCV infection is similar to that in other African countries. The results of this study show for the first time in Africa that mother-to-infant transmission does not play a significant role in the acquisition of HCV infection.