Which dyskinesia scale best detects treatment response?

Numerous scales assess dyskinesia in Parkinson's disease (PD), variably focusing on anatomical distribution, phenomenology, time, severity, and disability. No study has compared these scales and their relative ability to detect change related to an established treatment. We conducted a randomized placebo‐controlled trial of amantadine, assessing dyskinesia at baseline and at 4 and 8 weeks using the following scales: Unified Dyskinesia Rating Scale (UDysRS), Lang‐Fahn Activities of Daily Living Dyskinesia Rating Scale (LF), 26‐Item Parkinson's Disease Dyskinesia scale (PDD‐26), patient diaries, modified Abnormal Involuntary Movements Scale (AIMS), Rush Dyskinesia Rating Scale (RDRS), dyskinesia items from the Movement Disorder Society–sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), and Clinical Global Impression (severity and change: CGI‐S, CGI‐C). Scale order was randomized at each visit, but raters were aware of each scale as it was administered. Sensitivity to treatment was assessed using effect size. Sixty‐one randomized dyskinetic PD subjects (31 amantadine, 30 placebo) completed the study. Four of the 8 scales (CGI‐C, LF, PDD‐26, and UDysRS) detected a significant treatment. The UDysRS Total Score showed the highest effect size (η² = 0.138) for detecting treatment‐related change, with all other scales having effect sizes < 0.1. No scale was resistant to placebo effects. This study resolves 2 major issues useful for future testing of new antidyskinesia treatments: among tested scales, the UDysRS, having both subjective and objective dyskinesia ratings, is superior for detecting treatment effects; and the magnitude of the UDysRS effect size from amantadine sets a clear standard for comparison for new agents. © 2012 Movement Disorder Society     

Correction to: Community Participation Comparison Between Adults on the Autism Spectrum and Adults in the General Population

Journal of Autism and Developmental Disorders - A correction to this paper has been published: https://doi.org/10.1007/s10803-021-05108-3     

Impact of parity on ewe vaginal mechanical properties relative to the nonhuman primate and rodent

Introduction and hypothesis

Parity is the leading risk factor for the development of pelvic organ prolapse. To assess the impact of pregnancy and delivery on vaginal tissue, researchers commonly use nonhuman primate (NHP) and rodent models. The purpose of this study was to evaluate the ewe as an alternative model by investigating the impact of parity on the ewe vaginal mechanical properties and collagen structure.

Methods

Mechanical properties of 15 nulliparous and parous ewe vaginas were determined via uniaxial tensile tests. Collagen content was determined by hydroxyproline assay and collagen fiber thickness was analyzed using picrosirius red staining. Outcome measures were compared using Independent samples t or Mann–Whitney U tests. ANOVA (Gabriel’s pairwise post-hoc test) or the Welch Alternative for the F-ratio (Games Howell post-hoc test) was used to compare data with previously published NHP and rodent data.

Results

Vaginal tissue from the nulliparous ewe had a higher tangent modulus and tensile strength compared with the parous ewe (p?<?0.025). The parous ewe vagina elongated 42 % more than the nulliparous ewe vagina (p?=?0.015). No significant differences were observed in collagen structure among ewe vaginas. The tangent modulus of the nulliparous ewe vagina was not different from that of the NHP or rodent (p?=?0.290). Additionally, the tangent moduli of the parous ewe and NHP vaginas did not differ (p?=?0.773).

Conclusions

Parity has a negative impact on the mechanical properties of the ewe vagina, as also observed in the NHP. The ewe may serve as an alternative model for studying parity and ultimately prolapse development.

     

Pannexin‐1 and P2X7‐Receptor Are Required for Apoptotic Osteocytes in Fatigued Bone to Trigger RANKL Production in Neighboring Bystander Osteocytes

Osteocyte apoptosis is required to induce intracortical bone remodeling after microdamage in animal models, but how apoptotic osteocytes signal neighboring “bystander” cells to initiate the remodeling process is unknown. Apoptosis has been shown to open pannexin‐1 (Panx1) channels to release adenosine diphosphate (ATP) as a “find‐me” signal for phagocytic cells. To address whether apoptotic osteocytes use this signaling mechanism, we adapted the rat ulnar fatigue‐loading model to reproducibly introduce microdamage into mouse cortical bone and measured subsequent changes in osteocyte apoptosis, receptor activator of NF‐κB ligand (RANKL) expression and osteoclastic bone resorption in wild‐type (WT; C57Bl/6) mice and in mice genetically deficient in Panx1 (Panx1KO). Mouse ulnar loading produced linear microcracks comparable in number and location to the rat model. WT mice showed increased osteocyte apoptosis and RANKL expression at microdamage sites at 3 days after loading and increased intracortical remodeling and endocortical tunneling at day 14. With fatigue, Panx1KO mice exhibited levels of microdamage and osteocyte apoptosis identical to WT mice. However, they did not upregulate RANKL in bystander osteocytes or initiate resorption. Panx1 interacts with P2X₇R in ATP release; thus, we examined P2X₇R‐deficient mice and WT mice treated with P2X₇R antagonist Brilliant Blue G (BBG) to test the possible role of ATP as a find‐me signal. P2X₇RKO mice failed to upregulate RANKL in osteocytes or induce resorption despite normally elevated osteocyte apoptosis after fatigue loading. Similarly, treatment of fatigued C57Bl/6 mice with BBG mimicked behavior of both Panx1KO and P2X₇RKO mice; BBG had no effect on osteocyte apoptosis in fatigued bone but completely prevented increases in bystander osteocyte RANKL expression and attenuated activation of resorption by more than 50%. These results indicate that activation of Panx1 and P2X₇R are required for apoptotic osteocytes in fatigued bone to trigger RANKL production in neighboring bystander osteocytes and implicate ATP as an essential signal mediating this process. © 2016 American Society for Bone and Mineral Research.     

Extraintestinal pathogenic Escherichia coli survives within neutrophils

Extracellular pathogenic Escherichia coli (ExPEC) strains are common causes of a variety of clinical syndromes, including urinary tract infections, abdominal infections, nosocomial pneumonia, neonatal meningitis, and sepsis. ExPEC strains are extracellular bacterial pathogens; therefore, the innate immune response (e.g., professional phagocytes) plays a crucial role in the host defense against them. Studies using the model ExPEC strain CP9 demonstrated that it is relatively resistant to neutrophil-mediated bactericidal activity. Although this could be due to resistance to phagocytosis, the ability of CP9 to survive the intracellular killing mechanisms of neutrophils is another possibility. Using a variation of the intracellular invasion assay, we studied the survival of CP9 within peripheral blood-derived human neutrophils. Our results indicated that CP9 did survive within human neutrophils, but we were unable to demonstrate that intracellular replication occurred. This finding was not unique to CP9, since when a conservative assessment of survival was used, four of six additional ExPEC strains, but not an E. coli laboratory strain, were also capable of survival within neutrophils. Initial studies in which we began to decipher the mechanisms by which CP9 is able to successfully survive intracellular neutrophil-mediated bactericidal activity demonstrated that CP9 was at least partially susceptible to the neutrophil oxidative burst. Therefore, absolute resistance to the oxidative burst is not a mechanism by which ExPEC survives within neutrophils. In addition, electron microscopy studies showed that CP9 appeared to be present in phagosomes within neutrophils. Therefore, avoidance of phagosomal uptake or subsequent escape from the phagosome does not appear to be a mechanism that contributes to CP9's survival. These findings suggest that survival of ExPEC within neutrophils may be an important virulence mechanism.     

Growing from Our Roots: Strategies for Developing Culturally Grounded Health Promotion Interventions in American Indian,Alaska Native,and Native Hawaiian Communities

Given the paucity of empirically based health promotion interventions designed by and for American Indian, Alaska Native, and Native Hawaiian (i.e., Native) communities, researchers and partnering communities have had to rely on the adaptation of evidence-based interventions (EBIs) designed for non-Native populations, a decidedly sub-optimal approach. Native communities have called for development of Indigenous health promotion programs in which their cultural worldviews and protocols are prioritized in the design, development, testing, and implementation. There is limited information regarding how Native communities and scholars have successfully collaborated to design and implement culturally based prevention efforts “from the ground up.” Drawing on five diverse community-based Native health intervention studies, we describe strategies for designing and implementing culturally grounded models of health promotion developed in partnership with Native communities. Additionally, we highlight indigenist worldviews and protocols that undergird Native health interventions with an emphasis on the incorporation of (1) original instructions, (2) relational restoration, (3) narrative-[em]bodied transformation, and (4) indigenist community-based participatory research (ICBPR) processes. Finally, we demonstrate how culturally grounded interventions can improve population health when they prioritize local Indigenous knowledge and health-positive messages for individual to multi-level community interventions.