Intra-His bundle blocks (102 cases).

Some intra-His bundle (intra-HB) blocks escape the routine exploration of the His bundle and are confused with supra- or infrahisian blocks. We believe that a more accurate exploration (recording of His bundle activity successively at the proximal end and the distal end of the His bundle, dynamic tests and drug injection) is needed to detect some concealed cases, mostly paroxysmal intra-HB blocks. In this series of 102 cases of intra-HB blocks, 20% had no criteria of AV block on the surface electrocardiogram, and only 4% had an intact conduction pattern (normal PR interval and normal QRS complexes.) A first degree intra-HB block was found in 35% (15 cases with a normal PR interval), a second degree intra-HB block in 23% and a thired degree intra-HB block in 42% of the cases (unidirectional in 4 cases). Of the 43% having an isolated intra-HB block, most were elderly women with a chronic third degree AV block.     

Peer Reviewed: Mortality of Urban Aboriginal Adults in Canada, 1991–2001

Objective

To compare mortality patterns for urban Aboriginal adults with those of urban non-Aboriginal adults.

Methods

Using the 1991–2001 Canadian census mortality follow-up study, our study tracked mortality to December 31, 2001, among a 15% sample of adults, including 16 300 Aboriginal and 2 062 700 non-Aboriginal persons residing in urban areas on June 4, 1991. The Aboriginal population was defined by ethnic origin (ancestry), Registered Indian status and/or membership in an Indian band or First Nation, since the 1991 census did not collect information on Aboriginal identity.

Results

Compared to urban non-Aboriginal men and women, remaining life expectancy at age 25 years was 4.7 years and 6.5 years shorter for urban Aboriginal men and women, respectively. Mortality rate ratios for urban Aboriginal men and women were particularly elevated for alcohol-related deaths, motor vehicle accidents and infectious diseases, including HIV/AIDS. For most causes of death, urban Aboriginal adults had higher mortality rates compared to other urban residents. Socio-economic status played an important role in explaining these disparities.

Conclusion

Results from this study help fill a data gap on mortality information of urban Aboriginal people of Canada.

Keywords

Aboriginal people, First Nations, Métis, Inuit, North American Indians, age-standardized mortality rates, mortality rate, life expectancy     

IL-7 Is the Limiting Homeostatic Factor that Constrains Homeostatic Proliferation of CD8+ T Cells after Allogeneic Stem Cell Transplantation and Graft-versus-Host Disease

Immune reconstitution after allogeneic hematopoietic stem cell transplantation relies primarily on homeostatic proliferation (HP) of mature T lymphocytes, but this process is typically impaired during graft-versus-host disease (GVHD). We previously showed that low IL-7 levels combined with lack of dendritic cell (DC) regeneration constrain CD4⁺ T cell HP during GVHD. However, it is not clear whether these alterations to the peripheral CD4⁺ T cell niche also contribute to impair CD8⁺ T cell regeneration during GVHD. We found that IL-7 therapy was sufficient for restoring CD8⁺ T cell HP in GVHD hosts while forcing DC regeneration with Flt3-L had only a modest effect on CD8⁺ T cell HP in IL-7 treated mice. Using bone marrow chimeras, we showed that HP of naïve CD8⁺ T cells is primarily regulated by MHC class I on radio-resistant stromal cells, yet optimal recovery of CD8⁺ T cell counts still requires expression of MHC class I on both radio-resistant and radio-sensitive hematopoietic cells. Thus, IL-7 level is the primary limiting factor that constrains naïve CD8⁺ T cell HP during GVHD, and accessibility of MHC class I on stromal cells explains how IL-7 therapy, as a single agent, can induce robust CD8 ⁺ T cell HP in the absence of DCs.     

Sulfatase‐mediated manipulation of the astrocyte‐Schwann cell interface

Schwann cell (SC) transplantation following spinal cord injury (SCI) may have therapeutic potential. Functional recovery is limited however, due to poor SC interactions with host astrocytes and the induction of astrogliosis. Olfactory ensheathing cells (OECs) are closely related to SCs, but intermix more readily with astrocytes in culture and induce less astrogliosis. We previously demonstrated that OECs express higher levels of sulfatases, enzymes that remove 6‐O‐sulfate groups from heparan sulphate proteoglycans, than SCs and that RNAi knockdown of sulfatase prevented OEC‐astrocyte mixing in vitro. As human OECs are difficult to culture in large numbers we have genetically engineered SCs using lentiviral vectors to express sulfatase 1 and 2 (SC‐S1S2) and assessed their ability to interact with astrocytes. We demonstrate that SC‐S1S2s have increased integrin‐dependent motility in the presence of astrocytes via modulation of NRG and FGF receptor‐linked PI3K/AKT intracellular signaling and do not form boundaries with astrocytes in culture. SC‐astrocyte mixing is dependent on local NRG concentration and we propose that sulfatase enzymes influence the bioavailability of NRG ligand and thus influence SC behavior. We further demonstrate that injection of sulfatase expressing SCs into spinal cord white matter results in less glial reactivity than control SC injections comparable to that of OEC injections. Our data indicate that sulfatase‐mediated modification of the extracellular matrix can influence glial interactions with astrocytes, and that SCs engineered to express sulfatase may be more OEC‐like in character. This approach may be beneficial for cell transplant‐mediated spinal cord repair. GLIA 2016 GLIA 2017;65:19–33     

Management and outcome challenges in newborns with gastroschisis: A 6-year retrospective French study

Objective: To identify the gestational age (GA) at which risk of mortality and severe outcome was minimized comparing preterm delivery and expectant management.

Methods: Retrospective study performed between 2009 and 2014 of newborns with gastroschisis in three large French level III neonatal intensive care units. Each department followed two distinct strategies: elective delivery at 35 weeks’ GA and a delayed approach.

Results: We included 69 gastroschisis cases. The lengths of stay lasting more than 60 days were significantly greater in the planned delivery group than in the expectant approach group (18/30 (60%) vs. 8/39 (20.5%), p?=?0.001). Gastroschisis cases receiving antenatal corticoids during the last two weeks of gestation required significantly less surgeries during their initial stay (p?=?0.003) as well as shorter parenteral feedings (p?=?0.002). A multivariate logistic regression showed that a GA of less than 36 weeks’ GA was is a pejorative factor for a stay above 60 days, regardless of whether it was a simple or complex gastroschisis, (OR=?3.8; p?=?0.021). A complex gastroschisis was a risk factor for significantly longer parenteral feedings, regardless of the center where patient is treated (Beta = ?0.3, p?=?0.035).

Conclusions: Future research should focus on decisions about delivery timing by incorporating risk of neonatal morbidity.     

Novel PRKAR1A gene mutations in Carney Complex

Carney complex is a syndrome that may include cardiac and mucocutaneous myxomas, spotting skin pigmentation, and endocrine lesions. Many patients with Carney complex have been shown to have a stop codon mutation in the PRKAR1A gene in the 17q22-24 region. Here we present the case of a 57 year-old man with multiple skin lesions and cardiac myxomas. Histology of the skin lesions showed lentigenous melanocytic hyperplasia and cutaneous myxomas, confirming the diagnosis of Carney complex. Lesional and control normal tissue from the patient were identified and sequenced for the PRKAR1A gene. A germline missense mutation was identified at exon 1A. This is the first report of this mutation, and one of the few reported missense mutation associated with Carney complex. This finding strengthens the argument that there are alternative ways in which the protein kinase A 1-alpha subunit plays a role in tumorigenesis     

Association of smoking with risk of multiple sclerosis: a population-based study

Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have shown an association between smoking and MS risk. Here, in a population-based Canadian cohort, we investigate the relationship between personal and maternal smoking exposure and the risk of MS. Using the longitudinal Canadian database, 3,157 MS cases and 756 spouse controls were administered questionnaires on active and passive smoking history. Mothers of cases and controls were also asked about their smoking exposure during pregnancy. The MS cases were more likely to have smoked than spouse controls (odds ratio 1.32, 95 % confidence interval 1.10–1.60, p = 0.003). This association was driven by an excess of ever-smokers in male MS cases. No association was seen with maternal active or passive smoking exposure during pregnancy. Ever-smoking is associated with increased MS risk in males. Further work is needed to understand the mechanism underlying this association.     

Myocardial distribution of cardioplegia administered by antegrade and retrograde routes to ischemic myocardium

Objective

To study the distribution of a cardioplegic solution delivered by antegrade and retrograde routes to ischemic myocardium. Retrograde administration has been suggested to improve protection of the ischemic myocardium. However, there are insufficient data on perfusion of ischemic and necrotic zones by the retrograde route.

Design

A laboratory study in dogs.

Method

In 12 dogs, 500 mL of hyperkalemic crystalloid cardioplegia containing 0.5 mCi of thallium-201 was injected antegradely or retrogradely through the coronary sinus after 3 hours of occlusion and 2 hours of reperfusion of the left anterior descending coronary artery. Myocardial distribution of the cardioplegic solution was measured by computer planimetry in the normally perfused zone, in the ischemic area and in the necrotic zone.

Results

The mean (and standard deviation) area at risk of ischemia (% of the left ventricle) delimited by Evans blue perfusion was smaller in dogs receiving a retrograde injection than in those receiving an antegrade injection (34% [3%] v. 42% [4%], p = 0.15). The infarct size (% of the area at risk indicated by triphenyltetrazolium dye) averaged 25% (11%) and 20% (7%) respectively (p = 0.36). The ratio of thallium-201 activity in ischemic to normal myocardium averaged 76% (13%) in the retrograde and 89 (12%) in the antegrade groups (p = 0.75). The ratio of thallium activity of infarct to normal myocardium averaged 56% (8%) in the retrograde group and 93% (19%) in the antegrade group (p = 0.18). Large areas of hypoactivity in the left ventricular myocardium were noted on scintigraphic imaging in all dogs that received retrograde perfusion.

Conclusions

The retrograde injection of cardioplegia through the coronary sinus does not improve the distribution of cardioplegic solution in the acutely ischemic myocardial area nor in the zone of acute infarction in the dog. Because some cells may remain viable in the border zone and into the necrotic area, retrograde cardioplegia may result in suboptimal protection and incomplete prevention of further damage to the myocardium.