Genotype-Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia.

Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5'-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

Blast injury on harbour porpoises (Phocoena phocoena) from the Baltic Sea after explosions of deposits of World War II ammunition.

Harbour porpoises are under pressure from increasing human activities. This includes the detonation of ammunition that was dumped in large amounts into the sea during and after World War II. In this context, forty-two British ground mines from World War II were cleared by means of blasting in the period from 28 to 31 August 2019 by a NATO unit in the German Exclusive Economic Zone within the marine protected area of Fehmarn Belt in the Baltic Sea, Germany. Between September and November 2019, 24 harbour porpoises were found dead in the period after those clearing events along the coastline of the federal state of Schleswig-Holstein and were investigated for direct and indirect effects of blast injury. Health evaluations were conducted including examinations of the brain, the air-filled (lungs and gastrointestinal tract) and acoustic organs (melon, acoustic fat in the lower jaw, ears and their surrounding tissues). The bone structure of the tympano-periotic complexes was examined using high-resolution peripheral quantitative computed tomography (HR-pQCT). In 8/24 harbour porpoises, microfractures of the malleus, dislocation of middle ear bones, bleeding, and haemorrhages in the melon, lower jaw and peribullar acoustic fat were detected, suggesting blast injury. In addition, one bycaught animal and another porpoise with signs of blunt force trauma also showed evidence of blast injury. The cause of death of the other 14 animals varied and remained unclear in two individuals. Due to the vulnerability and the conservation status of harbour porpoise populations in the Baltic Sea, noise mitigation measures must be improved to prevent any risk of injury. The data presented here highlight the importance of systematic investigations into the acute and chronic effects of blast and acoustic trauma in harbour porpoises, improving the understanding of underwater noise effects and herewith develop effective measures to protect the population level.

Allograft Chip Incorporation in Acetabular Reconstruction: Multiscale Characterization Revealing Osteoconductive Capacity.

BACKGROUND: Impacted bone-grafting with morselized allograft chips is commonly used to reconstruct acetabular bone defects in revision total hip arthroplasty (THA). While the overall clinical outcome of this procedure is described to be excellent, the microstructural basis and histological determinants of allograft incorporation remained to be further elucidated. METHODS: The acetabula of 23 individuals with documented previous use of allograft chips during revision THA were explanted post mortem. The time that the allografts were in situ averaged 10.3 ± 4.5 years (range, 1.2 to 19.8 years). The host bone (HB)-allograft bone (AB) interface was characterized using a suite of high-resolution (HR) imaging techniques including HR-peripheral quantitative computed tomography (HR-pQCT), histological analysis, cellular histomorphometry, and scanning electron microscopy. RESULTS: AB could be identified in 16 of the 23 cases. The HB and AB showed overlap (i.e., ingrowth) in 91.3% of the total interface. The mean ingrowth was 2.2 ± 1.0 mm with a maximum of 4.7 ± 2.1 mm. The periphery of the AB showed a tight interconnection with the HB associated with increased bone remodeling indices and increased trabecular thickness. While no association between the time in situ and the ingrowth was observed, the bone defect area was positively associated with the thickness of a fibrosis layer separating the ingrowth zone from the AB. CONCLUSIONS: Allograft chips in revision THA form an adequate osseous foundation with successful incorporation through ingrowth of the HB (i.e., osteoconduction). While complete remodeling was not observed, larger defects were associated with fibrosis formation, which may compromise stability. CLINICAL RELEVANCE: Our study provides the first systematic, multiscale long-term evaluation of chip allograft incorporation in revision THA to underscore its successful clinical use. As larger defects were associated with fibrous ingrowth, structural allografts may be superior for larger defects in terms of long-term outcomes.