Sympathetic innervation improves the contractile performance of neonatal cardiac ventricular myocytes in culture

We propose that sympathetic innervation could contribute to the improvement in cardiac contractility that normally occurs during neonatal life because these processes are developmentally coincident. Effects of sympathetic innervation were studied in primary cultures of isolated, not previously innervated ventricular cardiomyocytes from neonatal rats. Innervation was produced by addition of autologous neurons from the thoracolumbar sympathetic ganglia, and amplitude and frequency of myocyte contraction were measured by on-line video motion analysis. Sympathetic innervation significantly (P less than 0.0001) increased amplitude of contraction (by 34 +/- 8%) and decreased contraction frequency (by 36 +/- 3%). The effect of innervation on myocyte contractility was not attenuated by adrenoceptor blockade (10(-6) M propranolol and 10(-6) M phentolamine), but could be reproduced using medium conditioned by cocultures of neurons and myocytes. Sympathetic innervation improves the contractility of isolated cardiomyocytes, indicating that autonomic innervation contributes to maturation of cardiac function.     

Ventricular arrhythmias and cardiac hemodynamics in patients with myocardial infarction. Comparison of the acute and post-hospitalization phases

Sixty-six patients with myocardial infarction (MI) were studied during the acute hospital phase and during the six months after hospital discharge. The clinical characteristics, location of infarction, and data from right heart catheterization were studied in an attempt to determine what factors were associated with ventricular rhythm disturbance.Those patients with serious ventricular arrhythmias (SVA) in the acute phase of infarction were found to have a significantly greater degree of myocardial dysfunction as measured by pulmonary artery and pulmonary wedge pressure than patients with more normal rhythm (p<.05). Clinical classification of patients and location of infarction were not helpful in predicting SVA during the acute infarction period.Knowledge of hemodynamic data, presence of SVA and clinical characteristics in the acute infarction period were of no value in predicting the occurrence of SVA after hospital discharge. Patients having had an acute diaphragmatic infarction were found to have a higher incidence of SVA after hospital discharge.     

Dynamic tracking of human hematopoietic stem cell engraftment using in vivo bioluminescence imaging

The standard approach to assess hematopoietic stem cell (HSC) engraftment in experimental bone marrow transplantation models relies on detection of donor hematopoietic cells in host bone marrow following death; this approach provides data from only a single time point after transplantation for each animal. In vivo bioluminescence imaging was therefore explored as a method to gain a dynamic, longitudinal profile of human HSC engraftment in a living xenogeneic model. Luciferase expression using a lentiviral vector allowed detection of distinctly different patterns of engraftment kinetics from human CD34+ and CD34+CD38- populations in the marrow NOD/SCID/beta 2mnull mice. Imaging showed an early peak (day 13) of engraftment from CD34+ cells followed by a rapid decline in signal. Engraftment from the more primitive CD34+CD38- population was relatively delayed but by day 36 increased to significantly higher levels than those from CD34+ cells (P <.05). Signal intensity from CD34+CD38-engrafted mice continued to increase during more than 100 days of analysis. Flow cytometry analysis of bone marrow from mice after death demonstrated that levels of 1% donor cell engraftment could be readily detected by bioluminescence imaging; higher engraftment levels corresponded to higher image signal intensity. In vivo bioluminescence imaging provides a novel method to track the dynamics of engraftment of human HSC and progenitors in vivo.     

A double‐blind,placebo‐controlled phase II study of the efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer,in sickle cell disease

This placebo‐controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), a fetal globin gene‐inducing short‐chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12–55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β⁰ thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK‐1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1–1.6%) with HQK‐1001 and 0.2% (95% CI: ?0.7–1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK‐1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK‐1001 and 1.7 with placebo. The most common adverse events in the HQK‐1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK‐1001 at this dose and schedule are not recommended in SCD. Intermittent HQK‐1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation. Am. J. Hematol. 89:709–713, 2014. © 2014 Wiley Periodicals, Inc.     

It's costly punishment,not altruistic: Low midfrontal theta and state anger predict punishment

Punishment in economic games has been interpreted as “altruistic.” However, it was shown that punishment is related to trait anger instead of trait altruism in a third-party dictator game if compensation is also available. Here, we investigated the influence of state anger on punishment and compensation in the third-party dictator game. Therefore, we used movie sequences for emotional priming, including the target states anger, happy, and neutral. We measured the Feedback-Related Negativity (FRN) and midfrontal theta band activation, to investigate an electro-cortical correlate of the processing of fair and unfair offers. Also, we assessed single-trial FRN and midfrontal theta band activation as a predictor for punishment and compensation. We found that punishment was linked to state anger. Midfrontal theta band activation, which has previously been linked to altruistic acts and cognitive control, predicted less punishment. Additionally, trait anger led to enhanced FRN for unfair offers. This led to the interpretation that the FRN depicts the evaluation of fairness, while midfrontal theta band activation captures an aspect of cognitive control and altruistic motivation. We conclude that we need to redefine “altruistic punishment” into “costly punishment,” as no direct link of altruism and punishment is given. Additionally, midfrontal theta band activation complements the FRN and offers additional insights into complex responses and decision processes, especially as a single trial predictor.      

Evaluation of magnetic resonance imaging issues for implantable microfabricated magnetic actuators

The mechanical robustness of microfabricated torsional magnetic actuators in withstanding the strong static fields (7 T) and time-varying field gradients (17 T/m) produced by an MR system was studied in this investigation. The static and dynamic mechanical characteristics of 30 devices were quantitatively measured before and after exposure to both strong uniform and non-uniform magnetic fields. The results showed no statistically significant change in both the static and dynamic mechanical performance, which mitigate concerns about the mechanical stability of these devices in association with MR systems under the conditions used for this assessment. The MR-induced heating was also measured in a 3-T/128-MHz MR system. The results showed a minimal increase (1.6 °C) in temperature due to the presence of the magnetic microactuator array. Finally, the size of the MR-image artifacts created by the magnetic microdevices were quantified. The signal loss caused by the devices was approximately four times greater than the size of the device.     

Rhombencephalosynapsis as a cause of aqueductal stenosis: an under-recognized association in hydrocephalic children

Background

Rhombencephalosynapsis is a rare genetic aberration characterized by variable vermian hypoplasia/aplasia in conjunction with united cerebellar hemispheres. Genetic defects in the isthmic organizer at the mesencephalic–metencephalic junction are presumably responsible for the associated aqueductal stenosis.

Objective

We performed a retrospective review of 20 children with rhombencephalosynapsis to evaluate for and emphasize the association of aqueductal stenosis and hydrocephalus.

Materials and methods

We retrospectively reviewed the MR and CT images of 20 children (0–11 years old) with rhombencephalosynapsis encountered at two academic children’s hospitals. Rhombencephalosynapsis spectrum severity was graded based on pre-existing literature. We analyzed examinations for ventriculomegaly and degree of aqueductal stenosis. The collicular distances were measured from the collicular apices. Imaging studies were also analyzed for malformations of cortical and cerebellar development.

Results

Thirteen of the 20 children (65%) with rhombencephalosynapsis presented with clinical or imaging evidence of hydrocephalus and aqueductal stenosis, principally involving the caudal cerebral aqueduct. All children with aqueductal stenosis had collicular fusion. All six children with complete rhombencephalosynapsis had aqueductal stenosis. The cerebral aqueduct varied from normal to stenotic in children with incomplete rhombencephalosynapsis. Corpus callosum dysgenesis was present in four children.

Conclusion

Aqueductal stenosis in the setting of rhombencephalosynapsis is an under-recognized cause of noncommunicating hydrocephalus. Our findings support the hypothesis that a defect involving the common gene(s) responsible for the differentiation and development of both the roof plate and midline cerebellar primordium at the mesencephalon/first rhombomere junction may be responsible for the association of aqueductal stenosis and rhombencephalosynapsis.     

X-linked mental retardation with thin habitus,osteoporosis, and kyphoscoliosis: Linkage to Xp21.3-p22.12

We reevaluated a family previously described as having nonspecific X-linked mental retardation (XLMR) by Snyder and Robinson [1969: Clin Pediatr 8:669–674] (MIM 309583). Clinical and DNA studies were conducted on 17 relatives, including 6 males with mild-to-moderate mental retardation, 3 carrier females, and 8 normal males. In contrast to the normal appearance and minimal clinical findings reported 22 years ago, affected males were found to have a characteristic set of clinical findings. These developed gradually over the first 2 decades, and included thin body build with diminished muscle mass, osteoporosis and kyphoscoliosis, slight facial asymmetry with a prominent lower lip, nasal speech, high narrow or cleft palate, and long great toes. Carrier females were clinically normal. Multipoint linkage analysis indicated linkage to markers distal to the 3′ end of DMD (DXS41 and DXS989), with a maximal lod score of 4.7. On the basis of these findings, this entity is redefined as XLMR syndrome. © 1996 Wiley-Liss, Inc.     

Synthesis and characterization of substituted benzoylhydrazones of naloxone

Naloxone benzoylhydrazone (NalBzoH) has proved a valuable tool in the investigation of opioid receptor subtypes. In the present study, we have examined a series of derivatives of NalBzoH in which substitutions have been made on the benzoyl ring. Overall, we see dramatic effects on the binding affinities of derivatives against the various opioid receptor subtypes. Although the range of affinities against the mu receptors is quite modest, ranges of the others vary almost 30-fold for kappa₃, 50-fold for kappa₁ and 100-fold for delta and kappa₂ binding. Few substituted derivatives display greater affinity than NalBzoH for any of the receptors, except for delta sites where several derivatives have affinities almost tenfold greater than NalBzoH. Along with the wide variations in affinity, the compounds also appear to exhibit widely divergent activities in traditional biosasays. © 1996 Wiley-Liss, Inc.