Significance of papillary muscle abnormalities identified by cardiovascular magnetic resonance in hypertrophic cardiomyopathy

Increased thickness of the left ventricular (LV) wall is the predominant feature of the hypertrophic cardiomyopathy (HC) phenotype. The structural characteristics of the LV papillary muscles (PMs) have received little attention. In this study, cardiovascular magnetic resonance (CMR) was used to characterize PM morphology in a large HC population. Cine and delayed enhancement (DE) CMR images were obtained in 201 patients with HC and 43 control subjects. PM number and mass index were greater in patients with HC compared with controls (2.5 vs 2.1, p <0.001, and 6 +/- 2 vs 3 +/- 2 g/m(2), p <0.001, respectively), including 109 (54%) with PM mass > or =7 g/m(2) (> or =2 SDs above the mean for controls). Greater LV wall mass index was associated with more substantial PM mass (r = 0.09, p <0.001). Furthermore, 12 patients with HC (19%) had normal LV mass with localized wall thickness but increased PM mass. In patients with HC with LV outflow obstruction at rest, PMs were positioned closer to the ventricular septum (displaced anteriorly: 58% vs 42% for subjects without obstruction, p = 0.02), with more marked hypertrophy (9 +/- 5 vs 6 +/- 4 g/m(2), p <0.001). Preoperative CMR identified 3 patients with accessory, anteriorly displaced PMs judged to contribute to outflow obstruction, which were resected during septal myectomy. DE of the PMs was identified in 13 patients with HC (6%), including 3 with DE confined to PMs. In conclusion, CMR demonstrates LV PMs to be part of the cardiomyopathic process in HC, with increases in number and mass, and not uncommonly associated with remodeling with DE. The identification of accessory PMs may be useful in planning preoperative strategy.     

The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat

It has been proposed that increases in tissue cyclic adenosine monophosphate during ischemia may be responsible for the induction of arrhythmias that occur during the early minutes of ischemia. We have tested this hypothesis using the isolated perfused rat heart with coronary artery occlusion for 30 minutes. In control hearts, after a transient small rise, cyclic adenosine monophosphate content remained close to its preischemic value (3.0 +/- 0.1 nM/g dry weight) throughout the period of occlusion. Eight percent (1/12) of the hearts fibrillated. Ninety-two percent (11/12) of the hearts exhibited ventricular tachycardia, and the mean total number of premature ventricular complexes was 528 +/- 121. Inclusion of epinephrine (1.0 microM) in the perfusion fluid elevated cyclic adenosine monophosphate prior to coronary occlusion (to 10.7 +/- 0.6 nM/g dry weight) and also throughout the ischemic period. It also increased arrhythmias such that 83% (20/24) of hearts fibrillated, 100% exhibited ventricular tachycardia, and the mean number of premature ventricular complexes increased to 747 +/- 86. Inclusion of forskolin (0.2 microM), which stimulates adenyl cyclase independently of the beta-receptor, increased cyclic adenosine monophosphate content to a greater extent than epinephrine, to 14.1 +/- 0.9 nM/g dry weight before the onset of ischemia and to 8.2 +/- 0.4 nM/g dry weight after 30 minutes of ischemia. Despite the large increase in cyclic adenosine monophosphate, there was no increase in rhythm disturbances which were less than those seen in controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise refractoriness after histamine inhalation in asthmatic subjects

Both exercise and histamine inhalation cause bronchoconstriction in asthmatic subjects. Repeated challenges with both stimuli cause less bronchoconstriction. Exercise refractoriness and histamine tachyphylaxis may occur through release of inhibitory mediators in the airways. The purpose of this study was to determine whether prior challenge with exercise or histamine reduced the subsequent bronchoconstriction to the opposite challenge. Eight asthmatic subjects with exercise bronchoconstriction were studied on 4 study days. On each study day, two consecutive tests were separated by 1 h as follows: on Day 1, two exercise challenges; on Day 2, two histamine inhalation tests; on Days 3 and 4, a histamine test was followed by an exercise challenge or an exercise challenge was followed by a histamine test. On Day 1, the mean fall in the FEV1 after the initial exercise challenge was 22.13% (SD, 7.12%); after the second exercise challenge, 1 h later, it was 11.13% (SD, 10.69%) (p less than 0.005). On Day 2, the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) was 1.68 mg/ml (%SD, 2.02) for the first test and 2.68 mg/ml (%SD, 1.99) for the second test 1 h later (p less than 0.005). However, after exercise bronchoconstriction, the histamine PC20 was 1.88 mg/ml (%SD, 2.03), not different from the control value (p less than 0.5). In contrast, the fall in FEV1 after exercise after prior inhalation of histamine was 15.63% (SD, 10.0%) compared with 23.13% (SD, 8.6%) on the control day (p less than 0.005). Therefore, inhibitory mediators released during histamine inhalation can cause exercise refractoriness; however, the converse is not true.     

A Thrombus Susceptibility Comparison of Two Pulsatile Penn State 50?cc Left Ventricular Assist Device Designs

Left ventricular assist devices (LVADs) have proven successful as bridge to transplant devices for patients awaiting donor organs. While survival rates continue to increase, destination therapy remains hindered by thrombus formation within the device. Research has shown that thrombosis is correlated to the fluid dynamics within the device and may be a result of sustained shear rates below 500?s^?1 on the polyurethane blood sac used in the Penn State pulsatile LVAD. Particle image velocimetry is used to compare flow within two 50?cc LVAD designs to assess fluid patterns and quantify wall shear rates in regions known from in vivo studies to be susceptible to thrombus formation. The two designs differ in their front face geometry. The V-1 model has an outward-facing ??dome?? whereas the face of the V-2 model is flat. A thrombus susceptibility metric, which uses measured wall shear rates and exposure times, was applied to objectively compare pump designs over the entire cardiac cycle. For each design, there are regions where wall shear rates remained below 500?s^?1 for the entire cardiac cycle resulting in high thrombus susceptibility potential. Results of this study indicate that the V-2 device had an overall lower propensity for thrombus formation in the current region of interest.     

MUSHROOM BODY INFLUENCE ON LOCOMOTOR ACTIVITY AND CIRCADIAN RHYTHMS IN DROSOPHILA MELANOGASTER

Whether or not mechanisms underlying circadian locomotor rhythms and learning are related anatomically through the mushroom bodies (MBs) was investigated by monitoring behavioral rhythmicity in flies with MB lesions induced by chemical ablation and by mutations in five different genes. All flies tested were later examined histologically to assess (1) MB neuroanatomy, and (2) the condition of the putative pacemaker cells -- the ventral Lateral Neurons (LN v s) and their terminals that project to the vicinity of the MB calyces. All groups of flies had normal rhythms except for mushroom body miniature ( mbm ; only in a wild-type Berlin genetic background) and mushroom body defect ( mud ). MB ablation had no effect on the gender-specific differences in the rhythmic activity profile that are typical of wild-type flies. However, ablated males had a slightly longer period than untreated males and were more active under constant dark conditions. LN v s and their arborization patterns appeared normal in MB-ablated and in most mutant flies. Activity defects of mbm flies were attributed to genetic background rather than to the mutation alone. Misrouted LN v projections and ～14% arrhythmia of mud flies were uncorrelated and attributed to pleiotropy rather than to specific effects of MB lesions. Our results imply that MBs are not involved in circadian activity rhythms but that they do have an inhibitory effect on activity levels of male flies.     

Perceptions of Families of Individuals with Autism Spectrum Disorder during the COVID-19 Crisis

Caring for an individual with autism spectrum disorder (ASD) in ideal circumstances can be stressful, and the Coronavirus disease (COVID-19) pandemic created a high degree of disruption to life and stress to families living with an individual with ASD. We conducted an online survey of families in Michigan that revealed higher levels of stress in caregivers of younger individuals with ASD and those with greater severity of ASD symptoms. Stress around therapeutic service disruption, finances, and illness predominated and greater stress was reported for caregivers of individuals receiving greater intensity of services pre-COVID-19. Respondents voiced concerns about receiving respite care during COVID-19, and those expressing interest in respite also reported greater symptom severity in the person with ASD.

     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.     

Reduced tidal volume increases 'air hunger' at fixed PCO2 in ventilated quadriplegics.

The act of breathing diminishes the discomfort associated with hypercapnia and breath-holding. To investigate the mechanisms involved in this effect, we studied the effect of tidal volume (VT) on CO2-evoked air hunger in 5 high-level quadriplegic subjects whose ventilatory capacity was negligible, and who lacked sensory information from the chest wall. Subjects were ventilated at constant frequency with a hyperoxic gas mixture, and end-tidal PCO2 was maintained at a constant but elevated level. VT was varied between the subjects' normal VT and a smaller VT. Subjects used a category scale to rate their respiratory discomfort or 'air hunger' at 30-40 sec intervals. In 4 of 5 subjects there was a strong inverse relationship between breath size and air hunger ratings. The quality of the sensation associated with reduced VT was nearly identical to that previously experienced with CO2 alone. We conclude that afferent information from the lungs and upper airways is sufficient to modify the sensation of air hunger.     

Paraflagellar rod protein-specific CD8+ cytotoxic T lymphocytes target Trypanosoma cruzi-infected host cells

Our previous studies show that in mice immunized with the paraflagellar rod (PFR) proteins of Trypanosoma cruzi protective immunity against this protozoan parasite requires MHC class I-restricted T cell function. To determine whether PFR-specific CD8+ T cell subsets are generated during T. cruzi infection, potential CTL targets in the PFR proteins were identified by scanning the amino acid sequences of the four PFR proteins for regions of 8-10 amino acids that conform to predicted MHC class I H-2b binding motifs. A subset of the peptide sequences identified were synthesized and tested as target antigen in 51Cr-release assays with effector cells from chronically infected T. cruzi mice. Short-term cytotoxic T lymphocyte (CTL) lines specific for two of the peptides, PFR-1(164-171) and PFR-3(123-130), showed high levels of lytic activity against peptide-pulsed target cells, secreted interferon (IFN)-gamma in response to parasite-infected target cells, and were found to be CD8+, CD4-, CD3+, TCRalphabeta+ cells of the Tc1 subset. Challenge of PFR immunized CD8-/- and perforin-deficient (PKO) mice confirmed that while CD8+ cells are required for survival of T. cruzi challenge infection, perforin activity is not required. Furthermore, while lytic activity of PFR-specific CD8+ T cell lines derived from PKO mice was severely impaired, the IFN-gamma levels secreted by CTLs from PKO mice were equivalent to that of normal mice, suggesting that the critical role played by CD8+ T cells in immunity to the parasite may be secretion of type 1 cytokines rather than lysis of parasite infected host cells.