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AbstractBackground and purposePerry disease (or Perry syndrome) is an autosomal dominant neurodegenerative disorder characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, weight loss and distinct TDP‐43 pathology. It is caused by mutations of the DCTN1 gene encoding an essential component of axonal transport. The objectives were to provide the current state of knowledge on clinical, pathological and genetic aspects of Perry disease, as well as practical suggestions for the management of the disease.MethodsData on new patients from New Zealand, Poland and Colombia were collected, including autopsy report. Also all of the published papers since the original work by Perry in 1975 were gathered and analyzed.ResultsParkinsonism was symmetrical, progressed rapidly and was poorly responsive to L‐Dopa; nonetheless, a trial with high doses of L‐Dopa is warranted. Depression was severe, associated with suicidal ideations, and benefited from antidepressants and L‐Dopa. Respiratory symptoms were the leading cause of death, and artificial ventilation or a diaphragm pacemaker prolonged survival. Weight loss occurred in most patients and was of multifactorial etiology. Autonomic dysfunction was frequent but underdiagnosed. There was a clinical overlap with other neurodegenerative disorders. An autopsy showed distinctive pallidonigral degeneration with TDP‐43 pathology. Genetic testing provided evidence of a common founder for two families. There was striking phenotypic variability in DCTN1‐related disorders. It is hypothesized that oligogenic or polygenic inheritance is at play.ConclusionsPerry disease and other DCTN1‐related diseases are increasingly diagnosed worldwide. Relatively effective symptomatic treatments are available. Further studies are needed to pave the way toward curative/gene therapy.

AimsOrthopaedic and reconstructive surgeons are faced with large defects after the resection of malignant tumours of the sacrum. Spinopelvic reconstruction is advocated for resections above the level of the S1 neural foramina or involving the sacroiliac joint. Fixation may be augmented with either free vascularized fibular flaps (FVFs) or allograft fibular struts (AFSs) in a cathedral style. However, there are no studies comparing these reconstructive techniques.MethodsWe reviewed 44 patients (23 female, 21 male) with a mean age of 40 years (SD 17), who underwent en bloc sacrectomy for a malignant tumour of the sacrum with a reconstruction using a total (n = 20), subtotal (n = 2), or hemicathedral (n = 25) technique. The reconstructions were supplemented with a FVF in 25 patients (57%) and an AFS in 19 patients (43%). The mean length of the strut graft was 13 cm (SD 4). The mean follow-up was seven years (SD 5).ResultsThere was no difference in the mean age, sex, length of graft, size of the tumour, or the proportion of patients with a history of treatment with radiotherapy in the two groups. Reconstruction using an AFS was associated with nonunion (odds ratio 7.464 (95% confidence interval (CI) 1.77 to 31.36); p = 0.007) and a significantly longer mean time to union (12 months (SD 3) vs eight (SD 3); p = 0.001) compared with a reconstruction using a FVF. Revision for a pseudoarthrosis was more likely to occur in the AFS group compared with the FVF group (hazard ratio 3.84 (95% CI 0.74 to 19.80); p = 0.109); however, this was not significant. Following the procedure, 32 patients (78%) were mobile with a mean Musculoskeletal Tumor Society Score 93 of 52% (SD 24%). There was a significantly higher mean score in patients reconstructed with a FVF compared with an AFS (62% vs 42%; p = 0.003).ConclusionSupplementation of spinopelvic reconstruction with a FVF was associated with a shorter time to union and a trend towards a reduced risk of hardware failure secondary to nonunion compared with reconstruction using an AFS. Spinopelvic fixation supplemented with a FVF is our preferred technique for reconstruction following resection of a sacral tumour. Cite this article: Bone Joint J 2021;103-B(8):1414–1420.

Thyroid disease is a very common condition that influences the entire human body, including cognitive function and mental health. As a result, thyroid disease has been associated with multiple neuropsychiatric conditions. However, the relationship between thyroid dysfunction and suicide is still controversial. We conducted a systematic review and meta-analysis to describe the association of thyroid function with suicidal behavior in adults. We searched four data bases (MEDLINE, EMBASE, PsycINFO, and Scopus) from their inception to 20 July 2018. Studies that reported mean values and standard deviation (SD) of thyroid hormone levels [Thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3)] in patients with suicidal behavior compared with controls were included in this meta-analysis. The abstracts and papers retrieved with our search strategies were reviewed independently and in duplicate by four reviewers for assessment of inclusion criteria and data extraction, as well as for evaluation of risk of bias. Random-effects models were used in this meta-analysis to establish the mean difference on thyroid function tests between groups. Overall, 2278 articles were identified, and 13 studies met the inclusion criteria. These studies involved 2807 participants, including 826 participants identified with suicidal behavior. We found that patients with suicide behavior had lower levels of FT3 (−0.20 pg/mL; p = 0.02) and TT4 (−0.23 µg/dL; p = 0.045) compared to controls. We found no differences in either TSH, FT4, or TT3 levels among groups. With our search strategy, we did not identify studies with a comparison of overt/subclinical thyroid disease prevalence between patients with and without suicide behavior. The studies included in this meta-analysis had a low-to-moderate risk of bias. In the available literature, the evidence regarding the association of thyroid disorders and suicidal behavior is limited. We found that patients with suicidal behavior have significantly lower mean FT3 and TT4 levels when compared to patients without suicidal behavior. The clinical implications and pathophysiologic mechanisms of these differences remain unknown and further research is needed.

The mitochondrial ubiquitin (Ub) kinase PINK1 and the cytosolic E3 Ub ligase PRKN (Parkin) together mediate the selective degradation of damaged mitochondria via the autophagy‐lysosome system (mitophagy). Complete loss of either gene function results in failure of this mitochondrial quality control and thus accumulation of damaged organelles. While homozygous or compound heterozygous mutations in PINK1 or PRKN are the most common causes of early‐onset Parkinson's disease (PD), the contribution of heterozygous variants to PD is debated. However, recently we identified a partial dominant‐negative effect of a heterozygous PINK1 missense mutations that is associated with a significant increased risk and an earlier onset compared to late‐onset, sporadic PD. This underscores that not all missense mutations are alike and suggests critical threshold functions of this stress‐activated, neuroprotective pathway. Here, we analyzed the underlying mechanisms in greater detail and found that the pathogenic PINK1 mutant, which can dimerize with wild‐type PINK1 protein, is aberrantly auto‐phosphorylated, impacting its enzymatic activity towards the substrates Ub and PRKN. Phosphorylation of both PINK1 targets however, is critical for PRKN recruitment as well as efficient labeling of mitochondria with phosphorylated poly‐Ub chains that serve as the mitophagy tag. In addition to cells from PD patients, we confirmed the altered phosphorylation pattern of mutant PINK1 under endogenous conditions in isogenic CRISPR/Cas9 genome engineered cells. Excitingly, while studying the pathogenic mechanisms in detail with a structure‐function approach, we identified a novel PINK1 variant that exerts even greater kinase activity than wild type PINK1. Our results further suggest that this hyperactive form of PINK1 likely modulates substrate receptivity thereby resulting in enhanced kinase activity and greater mitophagy rates. Going forward, it will be interesting to study if enhanced PINK1 signaling translates into greater neuroprotection. An in‐depth understanding of the regulation and enzyme functions of PINK1 may provide a rationale for a structure‐function based drug design in the future. Support or Funding Information This work was partially supported by funding from the Mayo Clinic Foundation, the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [R01#NS085070] and the Michael J. Fox Foundation for Parkinson's Research to W.S. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Self‐replicating, self‐calcifying nanosized particles (NPs) can be isolated from mammalian blood and calcified human tissue. Intravenous injection of these biologic NPs into rabbits accelerates occlusion of endothelium‐denuded carotid arteries. Since platelet activation is an initiating step in arterial repair, experiments were designed to determine if biologic NPs alter platelet functions. Platelet rich plasma was prepared from human citrate anti‐coagulated blood. Platelet aggregation (light transmission) and ATP secretion were monitored in response to sTRAP (10 μM) prior to and following incubation with either control solution, biologic NPs (50, 150, 500 NTUs) or hydroxyapatite (HA). NPs increased light transmission and ATP secretion when added immediately to the platelet solution. Both rate and maximal aggregation induced by sTRAP were reduced in the presence of NPs. NPs increased stimulated release of ATP at moderate doses but only after 15 minutes of incubation. HA crystals reduced rather than augmented ATP secretion. These results suggest that NPs cause a shape change in platelets and formation of microaggregates under basal conditions. NPs selectively augment agonist‐stimulated ATP secretion in a dose and time dependent fashion. Therefore, NP activation of platelets could contribute to the increased vascular response to injury in vivo.

Heterogeneous, phospholipid‐rich sub‐micron vesicles (“microvesicles”) shed by activated vascular and blood cells may reflect or influence the coagulant propensity of blood. To determine how the anticoagulant used to collect the blood affects microvesicle (Mv) recovery and characteristics, blood was collected from laboratory volunteers and participants of the Kronos Early Estrogen Prevention Study (KEEPS) into tubes containing either sodium citrate, EDTA or hirudin plus tick anticoagulant peptide (H&T). Microvesicles prepared by double centrifugation were analyzed by flow cytometry to define size and surface markers. There were 2–3 times the number of platelet‐derived (CD61 positive) Mv in preparations from citrate and H&T plasma, relative to numbers in EDTA plasmas. Procoagulant activity of Mv was determined by surface phosphatidylserine (PS) expression using annexin‐V‐fluorescein. Annexin‐V (PS) positive Mv did not differ, but total (PS positive and negative) Mv was 2 fold lower from EDTA plasma compared to citrate and H&T. These results suggest that anticoagulation of blood itself alters microvesicle characteristics. Therefore, standardization and specification of the anticoagulant is warranted to identify potential contribution of microvesicles to cardiovascular pathophysiology. Funded by, NIH HL78638, Kronos Research Institute and Mayo Foundation.

Estrogen receptor beta (βER) is present in platelets but little is known about how βER contributes to platelet physiology. Platelet mitochondrial function and circulating platelet‐derived microparticles were analyzed in aged (24 months old) female wild type (WT) and estrogen receptor beta knockout (βERKO) mice. In intact, unstimulated platelets, ERβ did not co‐localized with mitochondria. Platelet lactate production, mitochondrial membrane potential and superoxide generation were similar in both groups, but activities of cytochrome bc 1 and cytochrome c oxidase were significantly less (P<0.05) in platelets of βERKO mice. Total numbers of platelet‐derived microparticles and those positive for procoagulant phosphatidylserine (PS) were two to three times higher (P<0.05) in βERKO than WT mice. Greater than 40% of procoagulant microparticles were derived from cells other than platelets in both groups of mice. Thrombin generating capacity of microvesicles was also greater in βERKO mice. Thus, loss of βER leads to significant changes in activities of enzymes of the mitochondrial electron transport system, and to increases in circulating procoagulant microparticles which may contribute to an increased thrombotic risk with aging in persons with βER gene polymorphisms. This study is supported by HL78638, AHA30503Z and Mayo Foundation.

Infection increases the risk of thrombotic disease. Platelets contribute to defense against infection and to thrombosis. Gram negative bacteria produce lipopolysaccharides (LPS) that activate Toll‐like‐receptor‐4 (TLR4) in the host and initiate inflammatory responses to infection. Platelets express TLR4, but whether or how LPS affects platelet functions that contribute to thrombotic disease is not understood. To determine if TLR4 signaling influences platelet functions that contribute to thrombotic disease, we studied responses of platelets from normal mice (C57BL/10SnJ; n=10) and mice that do not express TLR4 (C57BL/10ScN; dTLR4, n=10). Prior to LPS exposure, the number of circulating platelets, platelet RNA content and expression of P‐selectin following stimulation with thrombin were diminished in mice that lack TLR4 compared to wild type mice, while platelet aggregation and secretion of ATP were unchanged. These results suggest that loss of TLR4 function affects platelet production and membrane binding characteristics of the circulating platelet pool. One week following a single intravenous injection of LPS (200μg/kg/iv), the time it takes for the circulating platelet pool to turnover, both wild‐type and dTLR4 mice had similar numbers of circulating platelets, and thrombin‐induced expression of P‐selectin and platelet aggregation to collagen increased comparably in both groups of mice. These results indicate that TLR4 function is required for normal platelet homeostasis. Exposure to LPS stimulates a TLR4‐independent shift of the platelet pool toward a reactive phenotype, which could contribute to increased thrombotic risk during or following infection.

Infection and oral estrogen treatments are risk factors for thrombosis. Experiments were designed to evaluate in vitro effects of priming doses of LPS and physiological doses of estrogen on platelets from healthy, newly menopausal women. Blood was collected from early postmenopausal women (42–56 years old) with a menopausal age between 6 months to 3 years into anticoagulants (citrate, hirudin and TAP). Platelet rich plasma was prepared and preincubated with LPS (ultrapure LPS from E. Coli: 10ng‐1000ng/mL) and/or 17β‐estradiol(10 −10 M/mL) Four groups were studied: control, LPS, 17β‐estradiol, 17β‐estradiol+LPS). Platelet aggregation was measured by lumiaggregometry. Thrombin receptor agonist peptide (TRAP 10μM) was used as an agonist. Platelet dense granules ATP secretion was measured by luciferin bioluminescence. Only the highest concentration of LPS (100ng/ml) decreased the maximum and rate of ATP secretion from dense granules and aggregation. At physiological concentrations, 17β‐estradiol did not affect platelet aggregation alone or in combination with LPS. These data suggest that LPS and estrogen may not increase thrombotic risk by direct activation of platelets; effects most likely require the interaction of the platelets with other cells in the circulation. (Supported by NIH HL78638, the Mayo Foundation, Kronos Longevity Institute and Japanese Menopause Society)