Mitochondrial Dysfunction and Mitophagy in Parkinson's Disease: From Mechanism to Therapy.

Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson's disease (PD) for over 30 years. Despite this, the role of mitochondrial dysfunction as an initiator, propagator, or bystander remains undetermined. The discovery of the role of the PD familial genes PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN) in mediating mitochondrial degradation (mitophagy) reaffirmed the importance of this process in PD aetiology. Recently, progress has been made in understanding the upstream and downstream regulators of canonical PINK1/parkin-mediated mitophagy, alongside noncanonical PINK1/parkin mitophagy, in response to mitochondrial damage. Progress has also been made in understanding the role of PD-associated genes, such as SNCA, LRRK2, and CHCHD2, in mitochondrial dysfunction and their overlap with sporadic PD (sPD), opening opportunities for therapeutically targeting mitochondria in PD.

Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models.

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of Parkinson's disease (PD). The LRRK2 PD-associated mutations LRRK2G2019S and LRRK2R1441C, located in the kinase domain and in the ROC-COR domain, respectively, have been demonstrated to impair mitochondrial function. Here, we sought to further our understanding of mitochondrial health and mitophagy by integrating data from LRRK2R1441C rat primary cortical and human induced pluripotent stem cell-derived dopamine (iPSC-DA) neuronal cultures as models of PD. We found that LRRK2R1441C neurons exhibit decreased mitochondrial membrane potential, impaired mitochondrial function and decreased basal mitophagy levels. Mitochondrial morphology was altered in LRRK2R1441C iPSC-DA but not in cortical neuronal cultures or aged striatal tissue, indicating a cell-type-specific phenotype. Additionally, LRRK2R1441C but not LRRK2G2019S neurons demonstrated decreased levels of the mitophagy marker pS65Ub in response to mitochondrial damage, which could disrupt degradation of damaged mitochondria. This impaired mitophagy activation and mitochondrial function were not corrected by the LRRK2 inhibitor MLi-2 in LRRK2R1441C iPSC-DA neuronal cultures. Furthermore, we demonstrate LRRK2 interaction with MIRO1, a protein necessary to stabilize and to anchor mitochondria for transport, occurs at mitochondria, in a genotype-independent manner. Despite this, we found that degradation of MIRO1 was impaired in LRRK2R1441C cultures upon induced mitochondrial damage, suggesting a divergent mechanism from the LRRK2G2019S mutation.

Effects of ghrelin on food caching behaviour and body composition in black-capped chickadees (Poecile atricapillus).

Several metabolic hormones signal an organism's energy balance to the brain and modulate feeding behaviours accordingly. These metabolic signals may also regulate other behaviour related to energy balance, such as food caching or hoarding. Ghrelin is one such hormone, but it appears to exert different effects on appetite and fat levels in birds and mammals. Ghrelin treatment inhibits food intake and decreases fat stores in some bird species, but these effects may differ between acylated and unacylated (des-acyl) forms of ghrelin. The effect of ghrelin on food caching in birds has been examined in only one study, that found both leptin and unacylated ghrelin reduced food caching and mass gain in coal tits (Periparus ater). We expanded on this to test how both forms of ghrelin affect food caching and body composition in black-capped chickadees (Poecile atricapillus). We injected each bird with acylated ghrelin, unacylated ghrelin, and a saline control and then measured food caching every 20 min for two hours post-injection. We also measured body mass fat levels the day before, and after treatment using quantitative magnetic resonance (QMR). Contrary to prior work, we found no effects of either form of ghrelin on food caching, or body or fat mass. Future work is required to determine if the difference between our results and those of the prior study stems from species differences in response to ghrelin and/or in the motivation to cache food, or ghrelin effects being modulated by energy reserves.

Transcriptomics Provide Insights into Early Responses to Sucrose Signaling in Lupinus albus, a Model Plant for Adaptations to Phosphorus and Iron Deficiency.

Phosphorus (P) and iron (Fe) deficiency are major limiting factors for plant productivity worldwide. White lupin (Lupinus albus L.) has become a model plant for understanding plant adaptations to P and Fe deficiency, because of its ability to form cluster roots, bottle-brush-like root structures play an important role in the uptake of P and Fe from soil. However, little is known about the signaling pathways involved in sensing and responding to P and Fe deficiency. Sucrose, sent in increased concentrations from the shoot to the root, has been identified as a long-distance signal of both P and Fe deficiency. To unravel the responses to sucrose as a signal, we performed Oxford Nanopore cDNA sequencing of white lupin roots treated with sucrose for 10, 15, or 20 min compared to untreated controls. We identified a set of 17 genes, including 2 bHLH transcription factors, that were up-regulated at all three time points of sucrose treatment. GO (gene ontology) analysis revealed enrichment of auxin and gibberellin responses as early as 10 min after sucrose addition, as well as the emerging of ethylene responses at 20 min of sucrose treatment, indicating a sequential involvement of these hormones in plant responses to sucrose.

Does cardiovascular preparticipation screening cause psychological distress in athletes? A systematic review.

OBJECTIVE: To evaluate the psychological implications of cardiovascular preparticipation screening (PPS) in athletes. DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE, PubMed, CINAHL, SPORTDiscus, APA PsycInfo, Cochrane Library and grey literature sources. STUDY ELIGIBILITY CRITERIA: Observational and experimental studies assessing a population of athletes who participated in a cardiovascular PPS protocol, where psychological outcomes before, during and/or after PPS were reported. METHODS: Results of included studies were synthesised by consolidating similar study-reported measures for key psychological outcomes before, during and/or after screening. Summary measures (medians, ranges) were computed across studies for each psychological outcome. RESULTS: A total of eight studies were included in this review (median sample size: 479). Study cohorts consisted of high school, collegiate, professional and recreational athletes (medians: 59% male, 20.5 years). Most athletes reported positive reactions to screening and would recommend it to others (range 88%-100%, five studies). Increased psychological distress was mainly reported among athletes detected with pathological cardiac conditions and true-positive screening results. In comparison, athletes with false-positive screening results still reported an increased feeling of safety while participating in sport and were satisfied with PPS. A universal conclusion across all studies was that most athletes did not experience psychological distress before, during or after PPS, regardless of the screening modality used or accuracy of results. CONCLUSION: Psychological distress associated with PPS in athletes is rare and limited to athletes with true-positive findings. To mitigate downstream consequences in athletes who experience psychological distress, appropriate interventions and resources should be accessible prior to the screening procedure. PROSPERO REGISTRATION NUMBER: CRD42021272887.

Comparative evaluation of an electrocardiogram workflow model for athletic cardiovascular screening: Primary care network versus sports cardiology interpretation.

BACKGROUND: Electrocardiogram (ECG) testing in pre-participation screening (PPS) remains controversial due to its cost, resource dependency, and the potential for inaccurate interpretations. At most centres, ECGs are conducted internally by providers trained in athletic ECG interpretation. Outsourcing ECG requisitions to an athlete's primary care network (PCN) may reduce institutional demands. This study compared PCN-conducted athletic ECG interpretation to expert sports cardiology interpretation. METHODS: This was a retrospective, single-centre chart-review study of all athletes who underwent cardiovascular PPS between 2017 and 2021. All athletes submitted an ECG with their screening package, which was conducted and interpreted within their PCN. All ECGs were reinterpreted by a sports cardiologist using the International Criteria (IC) for electrocardiographic interpretation in athletes. Overall, positive, and negative percent agreement were used to compare PCN-conducted ECG interpretation with IC interpretation. RESULTS: A total of 740 athletes submitted a screening package with a valid ECG (mean age: 18.5 years, 39.6% female). PCN-conducted ECGs were interpreted by 181 unique physicians. Among 41 (5.5%) PCN-conducted ECGs that were initially interpreted as abnormal, only 5 (0.7%) were classified as abnormal according to the IC. All PCN-conducted ECGs reported as normal were also classified as normal according to the IC. The overall agreement between PCN-conducted and IC ECG interpretation was 95.1% (positive percent agreement: 100%, negative percent agreement: 95.1%). CONCLUSIONS: Normal PCN-conducted athletic ECGs are interpreted with high agreement to the IC. Majority of PCN-conducted ECGs interpreted as abnormal are indeed normal as per the IC. These findings suggest that a PPS workflow model that outsources ECG requisitions to a PCN may be a reliable approach to PPS, all while reducing screening-related institutional costs and resource requirements.

A review of the coracoclavicular joint: Description, etiology, and clinical significance.

The coracoclavicular joint (CCJ) is a synovial joint that forms between the conoid tubercle of the clavicle and the coracoid process of the scapula in approximately 2.5% of the population. The number of bilateral to unilateral cases is almost equal. The number of right-sided and left-sided cases is also almost equal. It is found in both males and females but most often in male adults. Very few cases have been identified in juveniles. Found in populations all over the world, the highest frequencies of CCJ are in Asia. The etiology is unknown but it is most likely caused by metaplastic change of the trapezoid and surrounding tissue due to compression and friction of the coracoacromial ligament between the clavicle and coracoid process. Typically asymptomatic, but if so, the most common complaint is anterior should pain exacerbated by extreme abduction. Successful treatment includes steroid injection and surgical excision.

REST Protects Dopaminergic Neurons from Mitochondrial and α-Synuclein Oligomer Pathology in an Alpha Synuclein Overexpressing BAC-Transgenic Mouse Model.

Alpha-synuclein pathology is associated with dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's patients. Working across human and mouse models, we investigated mechanisms by which the accumulation of soluble α-synuclein oligomers leads to neurodegeneration. Biochemical analysis of the midbrain of α-synuclein overexpressing BAC-transgenic male and female mice revealed age- and region-dependent mitochondrial dysfunction and accumulation of damaged proteins downstream of the RE1 Silencing Transcription Factor (REST). Vulnerable SN dopaminergic neurons displayed low REST levels compared with neighboring protected SN GABAergic neurons, which correlated with the accumulation of α-synuclein oligomers and disrupted mitochondrial morphology. Consistent with a protective role, REST levels were reduced in patient induced pluripotent stem cell-derived dopaminergic neurons carrying the SNCA-Triplication mutation, which accumulated α-synuclein oligomers and mitochondrial damage, and displayed REST target gene dysregulation. Furthermore, CRISPR-mediated REST KO induced mitochondrial dysfunction and impaired mitophagy in vitro Conversely, REST overexpression attenuated mitochondrial toxicity and mitochondrial morphology disruption through the transcription factor PGC-1α. Finally, decreased α-synuclein oligomer accumulation and mitochondrial dysfunction in mice correlated with nuclear REST and PGC-1α in protected SN GABAergic neurons compared with vulnerable dopaminergic neurons. Our findings show that increased levels of α-synuclein oligomers cause dopaminergic neuronal-specific dysfunction through mitochondrial toxicity, which can be attenuated by REST in an early model of Parkinsonian pathology. These findings highlight REST as a mediator of dopaminergic vulnerability in PD.SIGNIFICANCE STATEMENT Understanding early Parkinsonian pathophysiology through studies of advanced preclinical models is fundamental to the translation of disease-modifying therapies. Here we show disease-relevant levels of α-synuclein expression in mice leads to accumulation of α-synuclein oligomers in the absence of overt aggregation, and mitochondrial dysfunction in dopaminergic neurons lacking the RE1 Silencing Transcription Factor. Our findings identify the mechanism of action of RE1 Silencing Transcription Factor and PGC-1α as mediators of dopaminergic vulnerability in α-synuclein BAC-transgenic mice and induced pluripotent stem cell-derived dopaminergic cultures, highlighting their potential as therapeutic targets.

Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo.

A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes.

PI3Kδ inhibition prevents IL33, ILC2s and inflammatory eosinophils in persistent airway inflammation.

BACKGROUND: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group 2 innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. RESULTS: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. CONCLUSIONS: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.

Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants.

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 µg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.

Improving inferences about private land conservation by accounting for incomplete reporting.

Private lands provide key habitat for imperiled species and are core components of function protectected area networks; yet, their incorporation into national and regional conservation planning has been challenging. Identifying locations where private landowners are likely to participate in conservation initiatives can help avoid conflict and clarify trade-offs between ecological benefits and sociopolitical costs. Empirical, spatially explicit assessment of the factors associated with conservation on private land is an emerging tool for identifying future conservation opportunities. However, most data on private land conservation are voluntarily reported and incomplete, which complicates these assessments. We used a novel application of occupancy models to analyze the occurrence of conservation easements on private land. We compared multiple formulations of occupancy models with a logistic regression model to predict the locations of conservation easements based on a spatially explicit social-ecological systems framework. We combined a simulation experiment with a case study of easement data in Idaho and Montana (United States) to illustrate the utility of the occupancy framework for modeling conservation on private land. Occupancy models that explicitly accounted for variation in reporting produced estimates of predictors that were substantially less biased than estimates produced by logistic regression under all simulated conditions. Occupancy models produced estimates for the 6 predictors we evaluated in our case study that were larger in magnitude, but less certain than those produced by logistic regression. These results suggest that occupancy models result in qualitatively different inferences regarding the effects of predictors on conservation easement occurrence than logistic regression and highlight the importance of integrating variable and incomplete reporting of participation in empirical analysis of conservation initiatives. Failure to do so can lead to emphasizing the wrong social, institutional, and environmental factors that enable conservation and underestimating conservation opportunities in landscapes where social norms or institutional constraints inhibit reporting.

La incorporación de las tierras privadas a la planeación de la conservación regional y nacional ha sido un reto a pesar de su importancia como hábitat para especies en peligro y como componentes nucleares de las redes funcionales de áreas protegidas. La identificación de las localidades en donde sea probable que los propietarios privados participen en las iniciativas de conservación puede ayudar a evitar conflictos costosos y a aclarar las compensaciones entre los beneficios ecológicos y los costos sociopolíticos. La evaluación empírica y espacialmente explícita de los factores asociados con la conservación en tierras privadas es una herramienta emergente usada para la identificación de oportunidades de conservación en el futuro. Sin embargo, la mayoría de los datos sobre la conservación en tierras privadas es reportada voluntariamente y está incompleta, lo cual complica realizar estas evaluaciones. Usamos una aplicación novedosa de los modelos de ocupación para analizar la presencia de la mitigación por conservación en tierras privadas. Comparamos diferentes formulaciones de los modelos de ocupación con un modelo de regresión logística para predecir las localidades de la mitigación por conservación con base en un marco de trabajo de un sistema socioecológico espacialmente explícito. Combinamos un experimento de simulación con un estudio de caso sobre datos de mitigación en Idaho y Montana (Estados Unidos) para ilustrar la utilidad del marco de trabajo de ocupación para el modelado de la conservación en tierras privadas. Los modelos de ocupación que consideraron explícitamente la variación en los reportes produjeron estimados de los predictores que estuvieron sustancialmente menos sesgados que los estimados producidos por la regresión logística bajo todas las condiciones simuladas. Los modelos de ocupación produjeron estimaciones para seis predictores que evaluamos en nuestro estudio de caso, los cuales fueron mayores en magnitud pero menos certeros que aquellos producidos por la regresión logística. Estos resultados sugieren que los modelos de ocupación tienen como resultado inferencias cualitativamente diferentes a la regresión logística con respecto a los efectos de los predictores sobre la presencia de mitigación por conservación y resaltan la importancia de la integración de los reportes variables e incompletos sobre la participación dentro del análisis empírico de las iniciativas de conservación. Si se falla en lo anterior se puede terminar enfatizando el factor social, institucional y ambiental equivocado que permite la conservación, además de subestimar las oportunidades de conservación en paisajes en donde las normas sociales o las restricciones institucionales inhiben el reporte de datos.

Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration.

Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied-the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.

Ecological and sociopolitical assessment of congressional and presidential designation of federal protected areas.

Protected areas are one of the most effective means by which biodiversity is conserved, but are often criticized for either neglecting the importance of local communities or sacrificing conservation objectives for political expedience. In the United States, federal protected areas can be designated via a democratic legislation process or via executive action, which allows for comparison of the ecological and sociopolitical context of these top-down and bottom-up processes. We compared protected areas resulting from congressional designation vs. presidential designation with respect to their ecological context (using measures of biodiversity and climate refugial potential) and sociopolitical context (using measures of local support for conservation and reliance on natural resource-based industries). We found minimal differences between these designation modes for both ecological and sociopolitical variables. These results suggest that presidentially designated protected areas tend to be no more burdensome to local communities and no less valuable for ecological conservation than more widely accepted federal protected areas such as national parks, and they provide new evidence to inform the current debate over national monuments.

Assessment of the Conservation Measures Partnership's effort to improve conservation outcomes through adaptive management.

Conservation practice has demonstrated an increasing desire for accountability of actions, particularly with respect to effectiveness, efficiency, and impact to clearly identified objectives. This has been accompanied by increased attention to achieving adaptive management. In 2002, practitioners representing several prominent conservation nongovernmental organizations (NGOs) launched a community of practice called the Conservation Measures Partnership (CMP). The partnership CMP has worked to establish standards of conservation practice to improve accountability of conservation actions through adaptive management. The focal organizing framework for CMP has been the Open Standards for the Practice of Conservation (OS). We evaluated, through an online survey and personal interviews, the first decade of CMP and the OS. The CMP has garnered a positive reputation among agencies, NGOs, and funders and has succeeded in developing a large user base of the OS. However, CMP has not fully achieved its goal of making the OS standard operating procedure for the largest NGOs (e.g., The Nature Conservancy, World Wildlife Fund), despite it being widely used within these organizations. This lack of institutionalization is attributable to multiple causes, including an increase in the number of partially overlapping decision-support frameworks and challenges achieving full-cycle adaptive management. Users strongly believed the OS fosters better conservation practice and highly valued the OS for improving their practice. A primary objective of the OS is to assist practitioners to achieve full-cycle adaptive management to better integrate learning into improving the effectiveness and efficiency of actions. However, most practitioners had not yet achieved cycle completion for their projects. To improve the effectiveness of CMP, OS, and conservation practice in general, we recommend collaborative efforts among the proponents of multiple decision-support frameworks to foster strong institutional adoption of a common set of adaptive-management standards for conservation accountability.

Feasibility of Administering High-Dose (131) I-MIBG Therapy to Children with High-Risk Neuroblastoma Without Lead-Lined Rooms.

BACKGROUND: Although (131) I-metaiodobenzylguanidine ((131) I-MIBG) therapy is increasingly used for children with high-risk neuroblastoma, a paucity of lead-lined rooms limits its wider use. We implemented radiation safety procedures to comply with New York City Department of Health and Mental Hygiene regulations for therapeutic radioisotopes and administered (131) I-MIBG using rolling lead shields. PROCEDURE: Patients received 0.67 GBq (18 mCi)/kg/dose (131) I-MIBG on an IRB-approved protocol (NCT00107289). Radiation safety procedures included private room with installation of rolling lead shields to maintain area dose rates ≤0.02 mSv/hr outside the room, patient isolation until dose rate <0.07 mSv/hr at 1 m, and retention of a urinary catheter with collection of urine in lead boxes. Parents were permitted in the patient's room behind lead shields, trained in radiation safety principles, and given real-time radiation monitors. RESULTS: Records on 16 (131) I-MIBG infusions among 10 patients (age 2-11 years) were reviewed. Mean ± standard deviation (131) I-MIBG administered was 17.67 ± 11.14 (range: 6.11-40.59) GBq. Mean maximum dose rates outside treatment rooms were 0.013 ± 0.008 mSv/hr. Median time-to-discharge was 3 days post-(131) I-MIBG. Exposure of medical staff and parents was below regulatory limits. Cumulative whole-body dose received by the physician, nurse, and radiation safety officer during treatment was 0.098 ± 0.058, 0.056 ± 0.045, 0.055 ± 0.050 mSv, respectively. Cumulative exposure to parents was 0.978 ± 0.579 mSv. Estimated annual radiation exposure for inpatient nurses was 0.096 ± 0.034 mSv/nurse. Thyroid bioassay scans on all medical personnel showed less than detectable activity. Contamination surveys were <200 dpm/100 cm(2) . CONCLUSIONS: The use of rolling lead shields and implementation of specific radiation safety procedures allows administration of high-dose (131) I-MIBG and may broaden its use without dedicated lead-lined rooms.

Sturgeon osteocalcin shares structural features with matrix Gla protein: evolutionary relationship and functional implications.

Osteocalcin (OC) and matrix Gla protein (MGP) are considered evolutionarily related because they share key structural features, although they have been described to exert different functions. In this work, we report the identification and characterization of both OC and MGP from the Adriatic sturgeon, a ray-finned fish characterized by a slow evolution and the retention of many ancestral features. Sturgeon MGP shows a primary structure, post-translation modifications, and patterns of mRNA/protein distribution and accumulation typical of known MGPs, and it contains seven possible Gla residues that would make the sturgeon protein the most γ-carboxylated among known MGPs. In contrast, sturgeon OC was found to present a hybrid structure. Indeed, although exhibiting protein domains typical of known OCs, it also contains structural features usually found in MGPs (e.g. a putative phosphorylated propeptide). Moreover, patterns of OC gene expression and protein accumulation overlap with those reported for MGP; OC was detected in bone cells and mineralized structures but also in soft and cartilaginous tissues. We propose that, in a context of a reduced rate of evolution, sturgeon OC has retained structural features of the ancestral protein that emerged millions of years ago from the duplication of an ancient MGP gene and may exhibit intermediate functional features.

Teleost fish osteocalcin 1 and 2 share the ability to bind the calcium mineral phase.

The occurrence of a second osteocalcin (OC2) has been reported in teleost fish, where it coexists with OC1 in some species. While it has been proposed that OC2 gene originated from OC1 through the fish whole-genome duplication event, little information is available on its molecular function and physiological role. The present study brings biological data supporting the presence of OC2 in the mineral phase of teleost fish bone and its association with the mineral phase together with OC1. The occurrence of OC2 forms with different levels of phosphorylation or γ-carboxylation, and with amino acid substitutions was observed. Comparative analysis of mature peptide sequences revealed the high conservation existing between OC1 and OC2, in particular within the core γ-carboxyglutamic acid domain, and suggests that both protein forms may have the same function, i.e., binding of calcium ions or hydroxyapatite crystals.

Phase I pharmacokinetic and biodistribution study with escalating doses of ²²³Ra-dichloride in men with castration-resistant metastatic prostate cancer.

PURPOSE: ²²³Ra-Dichloride (²²³Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent. METHODS: Ten patients received either 50, 100, or 200 kBq of ²²³Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed. RESULTS: Pharmacokinetic studies showed rapid clearance of ²²³Ra from the vasculature, with a median of 14% (range 9-34%), 2% (range 1.6-3.9%), and 0.5% (range 0.4-1.0%) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52% of administered ²²³Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4% of administered ²²³Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients. CONCLUSION: ²²³Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.

The direct anterior approach for conversion to total hip arthroplasty after acetabular fixation is safe and effective.

INTRODUCTION: Total Hip Arthroplasty (THA) after prior acetabular fracture repair is known to be demanding as studies have shown inferior implant survival rates and higher infection rates for these procedures. The direct anterior (DA) approach might help mitigate some of these risks by utilizing a new surgical tissue plane. However, potential criticisms of the DA approach for these surgeries include the inability to access previous acetabular implants or heterotopic ossification (HO) if they were to inhibit implant placement. The goals of this study are to analyze the efficacy of the DA approach for conversion to hip arthroplasty surgery after previous acetabular fixation. METHODS: After reviewing all records at our institution using current procedural terminology codes, we isolated patients with previous acetabular repair who underwent conversion to THA through the DA approach. Patient records were reviewed, and patients were contacted to obtain Harris Hip Scores. RESULTS: 23 patients (16 males and 7 females) were found with a mean follow-up time of 46 months (range 16-156 months). The mean age was 50 (range 28 - 83) and mean BMI was 28.5 (range 15.2 - 39.2). The average blood loss was 400 ml (range 200 - 900). The average operative time was 140 min (range 85-200 min). In 7 cases (32%) implants were encountered during acetabular reaming but the implants were either removed entirely or removed partially with a burr so that the acetabular cup could be positioned within acceptable parameters. In 2 cases pre-operative HO was encountered and was resected. The average Harris Hip Score at final follow-up was 92 (range 75 - 100). There were no deep infections and no neurovascular injuries encountered. 2 patients (9%) underwent revision surgery for aseptic femoral stem loosening. There was 1 anterior dislocation (4.5%) at 3 days post-operatively that was successfully treated with closed reduction and maintenance of hip precautions. Otherwise, the remaining 19 (86%) patients went on to uncomplicated recovery. CONCLUSION: This is the largest known cohort analyzing the DA approach for conversion to hip arthroplasty after previous acetabular fixation. Overall, we demonstrate that the DAA is safe for conversion THA after acetabular fixation.