Kinetics of leukocyte sequestration in the lungs of acutely septic primates: a study using 111In-labeled autologous leukocytes

To further clarify the role of leukocytes in the pathogenesis of ARDS, we studied the localization and kinetics of leukocyte migration using 111In-labeled autologous white cell scans (111In wbc scans) in four primates made acutely septic with infusions of Escherichia coli. Whole body images were obtained with a gamma camera and were acquired on computer every 15 min beginning immediately after the E. coli infusion. Simultaneous measurements of C5a and peripheral blood leukocyte count were also obtained. Within 5 min of initiating sepsis, three major events occurred: complement activation as measured by the production of C5a, a profound fall in peripheral leukocyte count, and a significant increase in the sequestration of leukocytes in the lungs. The pulmonary sequestration reached a peak at 15 min with a mean of 152% of baseline activity. This sequestration consisted of a population that was predominantly neutrophils. Damage to the pulmonary capillary endothelium was demonstrated by an increase in extravascular lung water. The results support a role for neutrophils and complement as mediators in the pathogenesis of ARDS.     

Dental abnormalities in individuals with pathogenic germline variation in DICER1

Pathogenic germline variation in the microRNA processing gene DICER1 gives rise to an autosomal dominant, tumor‐predisposition disorder. Conditional deletion of Dicer1 in murine dental epithelium shows that it controls tooth patterning, size, number, and shape. The human dental phenotype of people with germline pathogenic variation in DICER1 is unknown. DICER1‐carriers (n = 57) and family controls (n = 55) were evaluated at the NIH Clinical Center dental clinic as part of a comprehensive medical evaluation. Digital panoramic radiographs, bite‐wing radiographs, and oral photographs were collected. A single observer, blind to DICER1 status, reviewed the dental records and determined the presence or absence of 11 dental characteristics as described in the clinic notes, radiographs, or oral photographs. Subjective phenotypes were reviewed on radiographs by two examiners (blind to DICER1 status) for the presence or absence of the dental characteristics to reduce inconsistencies. By simple association, bulbous crown, periodontitis, and taurodontism were all significant (p < .05). Logistic regression with chi‐square maximum likelihood estimates showed that bulbous crown and periodontitis remained significant. Recognition of these phenotypes may aid identification of individuals and families at risk for DICER1‐associated neoplasms. These findings may also guide dental care for individuals with germline DICER1 pathogenic variation.     

The Influence of Body Dissatisfaction on Set Shifting Ability

Set shifting, or the ability to shift back and forth between multiple tasks or mental sets, has been shown to be impaired in individuals with eating disorders. The purpose of this study was to experimentally examine set shifting among acutely body dissatisfied women. Participants included 146 undergraduate women selected for self-reported high or low body shame. Each participant was randomized to one of three still-image induction groups: body dissatisfaction, negative affect, or neutral affect. Immediately following the induction, participants were administered the Wisconsin Card Sorting Test (WCST) to assess set shifting. A 2 (high vs. low body shame) × 3 (induction group condition) ANOVA was conducted on the total number of WCST perseverative errors. The results suggest that for women who feel relatively satisfied with their bodies, thin ideal or negative affective images do not impact set shifting performance. However, for women who experience body shame, acute body dissatisfaction and negative affect may impact executive functioning as demonstrated by set shifting performance. In other words, women who endorse body shame may have difficulty shifting set during moments of increased negative affect, regardless of the general or body-specific nature of the negative affect.     

Patient Engagement in Neurological Clinical Trials Design: A Conference Summary

Objectives

The conference objectives included educating patients and advocates about clinical trials, educating the clinical research community about patient perspectives on participating in clinical trial design, and identifying strategies to increase participation in clinical trial design for neurological disorders.

Design

Observations were noted during a 1‐day conference attended by patients, patient advocates, clinical trial staff, and investigators. The conference offered didactic sessions, small, and large group discussions.

Participants

Conference participants were patients, patient advocates, clinical trial staff, students, and investigators interested in engaging patients in clinical trial design for neurological disorders.

Measures

Conference participants were asked to consider lessons learned that could increase patient engagement in clinical trial design.

Results

We found that there is growing interest in including patients in the design of clinical trials for neurological disorders. Several themes emerged on how to move forward: networking; the multifaceted roles of advocates in research; training and education; creating patient–researcher partnerships; and clinical trials regulation issues.

Conclusions

The conference provided a forum for dialogue regarding stakeholder engagement in the design of clinical trials for neurological disorders. This experience provides a template for replication and dissemination of this conference and informs next steps to accelerate the pathway from dialogue to action.     

Catalysis leads to posttranslational inactivation of the type 1 deiodinase and alters its conformation

Previously, it was shown that the type 1 deiodinase (D1) is subject to substrate-dependent inactivation that is blocked by pretreatment with the inhibitor of D1 catalysis, propylthiouracil (PTU). Using HepG2 cells with endogenous D1 activity, we found that while considerable D1-mediated catalysis of reverse tri-iodothyronine (rT(3)) is observed in intact cells, there was a significant loss of D1 activity in sonicates assayed from the same cells in parallel. This rT(3)-mediated loss of D1 activity occurs despite no change in D1 mRNA levels and is blocked by PTU treatment, suggesting a requirement for catalysis. Endogenous D1 activity in sonicates was inactivated in a dose-dependent manner in HepG2 cells, with a ～50% decrease after 10?nM rT(3) treatment. Inactivation of D1 was rapid, occurring after only half an hour of rT(3) treatment. D1 expressed in HEK293 cells was inactivated by rT(3) in a similar manner. (75)Se labeling of the D1 selenoprotein indicated that after 4?h rT(3)-mediated inactivation of D1 occurs without a corresponding decrease in D1 protein levels, though rT(3) treatment causes a loss of D1 protein after 8-24?h. Bioluminescence resonance energy transfer studies indicate that rT(3) exposure increases energy transfer between the D1 homodimer subunits, and this was lost when the active site of D1 was mutated to alanine, suggesting that a post-catalytic structural change in the D1 homodimer could cause enzyme inactivation. Thus, both D1 and type 2 deiodinase are subject to catalysis-induced loss of activity although their inactivation occurs via very different mechanisms.     

Polyarteritis nodosa presenting with clinical and radiologic features suggestive of polymyositis

We report a patient who presented with clinical and MRI findings suggestive of polymyositis but, in whom, muscle biopsy disclosed a strikingly different diagnosis. A 65-year-old woman presented with 3-week history of bilateral proximal muscle pain and weakness. Laboratory investigations showed markedly elevated inflammatory markers and mildly elevated muscle enzymes. MRI scans of lower limbs showed features suggestive of polymyositis. However, muscle biopsy showed features of a polyarteritis-type vasculitis affecting an intramuscular blood vessel. Our reports highlight the critical role of muscle biopsy in establishing the correct diagnosis in patients with suspected myositis.     

Anxiety, Appearance Contingent Self-Worth, and Appearance Conversations with Friends in Relation to Disordered Eating: Examining Moderator Models

This study examined whether anxiety, combined with a focus on appearance, would identify individuals most likely to exhibit eating pathology, conceptualized as safety behaviors/avoidance strategies. In particular, we examined appearance contingent self-worth and appearance conversations with friends as possible moderators of the anxiety-disordered eating relation. Participants were 441 women attending a Southeastern university who completed an online survey. Results indicated that those with the three-way combination of high anxiety, high appearance contingent self-worth, and frequent appearance conversations exhibited the most frequent binge eating. While no significant three-way interactions emerged for broad eating pathology and dietary restraint, in both models it was the anxiety × appearance contingent self-worth interaction that accounted for unique variance in these eating patterns. Results provide researchers and clinicians with a better understanding of who experiences various types of disordered eating in association with anxiety and possible points of intervention.     

Perspectives of patients with cystic fibrosis on preventive counseling and transition to adult care

The purpose of this study was to investigate how adolescents and adults with cystic fibrosis (CF) view preventive counseling and their transition to adult-centered care within a children's hospital. Thirty-two patients >/=16 years old diagnosed with CF were recruited from a pediatric tertiary care setting. During face-to-face interviews, patients were asked 27 structured questions and completed a 30-item self-administered questionnaire on preventive counseling by healthcare providers and on transition issues. The median age of patients was 25.5 years (range, 16-43 years); 69% of patients identified a pulmonologist as their "main doctor," even though 78% had a primary care provider. Participants felt that 13-16 years of age was the best time for them to begin spending time alone with their main doctor. Less than half of the participants recalled receiving preventive counseling during the previous 12 months, and more patients wanted to discuss issues than actually did. Qualitative data emphasized the importance of independence in making decisions in healthcare and establishing relationships with providers, and many patients did not desire to transfer care to an adult hospital. Participants identified adult-focused services such as inpatient rooms, discussion groups, work options, and social service support that would enhance care. In conclusion, the majority of adolescent/young adult patients with CF receiving care in a pediatric institution reported satisfaction with their healthcare. However, patients identified preventive issues that they desired to be more regularly addressed, starting in early adolescence, and changes in the delivery of services to enhance transition to adult-oriented care. This study underscored the understanding of the integration of transition planning into the facilitation of healthcare decision-making by the adolescent in issues of self-care, sexuality, education, and finances. Future initiatives to enhance the care of patients with CF should provide training of pulmonologists in preventive care and increased attention to helping patients utilize appropriate primary-care services during the adult years. In addition, prospective studies are needed to compare outcomes of CF patients who have transitioned and transferred to adult hospitals and those transitioning to adult-oriented services in a pediatric institution.     

Complex regional pain syndrome: the case for spinal cord stimulation (a brief review)

Complex regional pain syndrome is a disabling disorder with an unknown mechanism which is extremely resistant to conventional pharmaceutical and therapeutic therapies. In this paper we present the underlying theories of this disorder. We present spinal cord stimulation as an alternative to conventional interventions in the management of this disabling condition spinal cord stimulation significantly improves pain, reduces narcotic intake and improves activity levels and overall quality of life. There is now a significant body of evidence to support the utilization of spinal cord stimulation in the management of complex regional pain syndrome.