Theoretical estimation of the capacity of intracellular calcium stores in the Bergmann glial cell

We propose a mathematical model for calcium dynamics ([Ca2+]i) during metabotropic activation of a specialized astrocyte, the cerebellar Bergmann glial cell. The model adequately describes the experimentally observed behaviour of the prototype in response to single and repetitive metabotropic stimuli and to the inhibition of Ca2+ uptake into the store. By means of the model, the capacity of the intracellular calcium store for two types of calcium buffer was estimated. The estimated buffer capacity of the store lies within the following intervals: (0.8-15.5).10-19 mol calmodulin, and (0.6-12.3).10-19 mol calbindin. This result reveals, that, in the store of a small Ca2+-containing compartment optically detected in the Bergmann glial cell process after electrical stimulation of parallel fibres, the amount of releasable Ca2+ does not exceed 25,000 ions. The quantitative estimates were obtained from experimentally based theoretical relationships between the capacity and volume of the store and parameters of the cytoplasmic calcium buffer. In these relationships, the estimated store capacity was proportional to the total buffer concentration, inversely proportional to the constant of buffer affinity for calcium and was smaller for a greater relative store volume.     

What Are the Indications for Implant Revision in Three-component Total Ankle Arthroplasty?

BackgroundGiven the increasing usage of total ankle arthroplasty (TAA), a better understanding of the reasons leading to implant revision and the factors that might influence those indications is necessary to identify at-risk patients.Question/purposesUsing a single-design three-component ankle prosthesis, we asked: (1) What is the cumulative incidence of implant revision at 5 and 10 years? (2) What are the indications for implant revision in our population? (3) What factors are associated with an increased likelihood of implant revision during the time frame in question?MethodsBetween 2003 and 2017, primary TAA using a single-design three-component ankle implant was performed by or under the supervision of the implant designer in 1006 patients (1074 ankles) aged between 17 and 88 years to treat end-stage ankle osteoarthritis. No other TAA systems were used during the study period at the investigators’ institution. In 68 patients with bilateral surgery, only the first TAA was considered. Of the patients treated with the study implant, 2% (16 of 1006) were lost to follow-up 5 to 14 years after TAA and were not known to have died or undergone revision, and 5% (55 of 1006) were deceased due to reasons unrelated to the procedure, leaving 935 patients for evaluation in this retrospective study. The mean (range) follow-up for the included patients was 8.8 ± 4.2 (0.2 to 16.8) years. Implant revision was performed 0.5 to 13.2 years after TAA in 12% (121 of 1006) of our patients. Survivorship free from revision was calculated using cumulative incidence (competing risks) survivorship, with death as a competing risk. The reason for each revision was classified into one of six categories according to a modified version of a previously published protocol: aseptic loosening, cyst formation, instability, deep infection, technical error, and pain without another cause. Two foot and ankle surgeons reviewed the records of all patients who underwent implant revision and assigned each patient’s reason for revision to one of the six categories. The decision for assigning each patient to one of the six categories was made based on a consensus agreement. A subgroup classification of preoperative ankle alignment (neutral, mild, and major deformity) and variables of age, sex, BMI, etiology of ankle osteoarthritis, and number of preoperative and intraoperative hindfoot or midfoot procedures were used in a multinomial logistic regression and Cox regression analysis to estimate their association with reason for revision and implant survival until revision.ResultsThe cumulative incidence of implant revision at the mean (range) follow-up time of 8.8 ± 4.2 years (0.2 to 16.8) was 9.8% (95% confidence interval 7.7% to 11.8%). Five and 10 years after TAA, cumulative incidence was 4.8% (95% CI 3.4 to 6.1) and 12.1% (95% CI 9.7% to 14.5%), respectively. The most common reason for revision was instability (34% [41 of 121]), followed by aseptic loosening of one or more metallic components (28% [34 of 121]), pain without another cause (12% [14 of 121]), cyst formation (10% [12 of 121]), deep infection (9% [11 of 121]), and technical error (7% [9 of 121]). Ankles with a major hindfoot deformity before TAA were more likely to undergo revision than ankles with a minor deformity (hazard ratio 1.9 [95% CI 1.2 to 3.0]; p = 0.007) or neutral alignment (HR 2.5 [95% CI 1.5 to 4.4]; p = 0.001). A preoperative hindfoot valgus deformity increased revision probability compared with a varus deformity (HR 2.1 [95% CI 1.4 to 3.4]; p = 0.001).ConclusionInstability was a more common reason for implant revision after TAA with this three-component design than previously reported. All causes inducing either a varus or valgus hindfoot deformity must be meticulously addressed during TAA to prevent revision of this implant. Future studies from surgeons/institutions not involved in this implant design are needed to confirm these findings and to further investigate why a substantial number of patients had pain of unknown cause prompting revision.Level of EvidenceLevel III, therapeutic study.     

Adult Osteosclerotic Metaphyseal Dysplasia With Progressive Osteonecrosis of the Jaws and Abnormal Bone Resorption Pattern Due to a LRRK1 Splice Site Mutation

Osteosclerotic metaphyseal dysplasia (OSMD) is a rare autosomal recessive sclerosing skeletal dysplasia. We report on a 34-year-old patient with sandwich vertebrae, platyspondyly, osteosclerosis of the tubular bones, pathologic fractures, and anemia. In the third decade, he developed osteonecrosis of the jaws, which was progressive in spite of repeated surgical treatment over a period of 11 years. An iliac crest bone biopsy revealed the presence of hypermineralized cartilage remnants, large multinucleated osteoclasts with abnormal morphology, and inadequate bone resorption typical for osteoclast-rich osteopetrosis. After exclusion of mutations in TCIRG1 and CLCN7 we performed trio-based exome sequencing. The novel homozygous splice-site mutation c.261G>A in the gene LRRK1 was found and co-segregated with the phenotype in the family. cDNA sequencing showed nearly complete skipping of exon 3 leading to a frameshift (p.Ala34Profs*33). Osteoclasts differentiated from the patient's peripheral blood monocytes were extremely large. Instead of resorption pits these cells were only capable of superficial erosion. Phosphorylation of L-plastin at position Ser5 was strongly reduced in patient-derived osteoclasts showing a loss of function of the mutated LRRK1 kinase protein. Our analysis indicates a strong overlap of LRRK1-related OSMD with other forms of intermediate osteopetrosis, but an exceptional abnormality of osteoclast resorption. Like in other osteoclast pathologies an increased risk for progressive osteonecrosis of the jaws should be considered in OSMD, an intermediate form of osteopetrosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Behavior of ordered sodium in enzymatically depleted cartilage tissue.

The onset of cartilage tissue disorders can be characterized by a loss of proteoglycans (PGs) and diagnosed by contrast-enhanced proton ((1)H) MRI techniques, as well as sodium MRI. The behavior of sodium located in anisotropic environments, is examined as a function of cartilage degeneration. PGs are proteolytically depleted from the cartilage samples, which gives rise to a decrease of the ordered sodium content. More surprisingly, however, the residual quadrupolar couplings are shown to increase with increasing depletion levels. Since the residual quadrupolar couplings are intimately related to local order and anisotropic motion, measuring their distribution in cartilage may provide insight into the structural changes that occur within the tissue upon degradation. In this study relatively mild orientational dependence of the couplings was found. Little or no free sodium was observed in the cartilage specimens under study.     

A dual role for interleukin-1 in LTP in mouse hippocampal slices

Interleukin-1 (IL-1) exerts numerous effects in the central nervous system and has been implicated in synaptic plasticity. The objective of this study was to investigate the role of endogenous as well as exogenous IL-1 on long-term potentiation (LTP). Hippocampal slices incubated at 34-36 degrees C show enhanced levels of IL-1alpha and IL-1beta compared to slices incubated at 21-24 degrees C. IL-1 inhibits LTP induced by theta-burst stimulation (TBS) at either temperature. IL-1 receptor antagonist (IL-1ra) had no effect on LTP at 21-24 degrees C, but displayed a concentration-dependent inhibition of LTP at 34-36 degrees C. Under control conditions, the magnitude of LTP was not temperature dependent. These data suggest that IL-1 is required for LTP under physiological conditions but at higher doses, as encountered in pathological conditions, IL-1 inhibits LTP.     

Heating of non-ferromagnetic total hip endoprostheses during magnetic resonance imaging in an animal model

To determine the heating effects of magnetic resonance imaging (MRI) on non-ferromagnetic total hip endoprostheses, hip endoprostheses were tested in vitro and in an ex vivo animal model. The MRI protocol on a 1.5 T scanner consisted of five sequences with a total duration of 23 min. The maximum heating of prosthetic material was 0.17 K in vitro and 0.90 K ex vivo; the maximum heating of bone surrounding tissue was 0.73 K ex vivo. Slight heating of the prostheses and the surrounding tissue was noted, which should not have any side effects in patients with titanium total hip endoprostheses.