Impact of thrombocytopenia-associated c.-118C>T and c.-140C>G ANKRD26 5'UTR variants in three-generational pedigree.

Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5' untranslated region of the ANKRD26 gene. This region is crucial in regulating the gene expression of ANKRD26, particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C>T ANKRD26 variant, while four healthy members carried the c.-140C>G ANKRD26 variant. We performed a functional analysis by studying platelet-specific ANKRD26 gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C>T variant showed a significant increase in ANKRD26 expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C>G variant exhibited normal platelet counts and no significant elevation in the ANKRD26 expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C>T ANKRD26 variant in THC2 and suggest the likely benign nature of the c.-140C>G variant.

What is the context?Inherited thrombocytopenias (ITs) are rare conditions characterized by low platelet counts. Inherited thrombocytopenia 2 (THC2) is caused by ANKRD26 gene changes leading to increased ANKRD26 expression as the main reason for subsequent thrombocytopenia. THC2 results in a mild-to-moderate decrease in platelet count and increases blood cancer risk. We focused on understanding two ANKRD26 variants in a family with a history of thrombocytopenia.What is new?We conducted functional analysis to understand the effect of variants on platelet function and gene expression. We identified three thrombocytopenic family members as carriers of ANKRD26 variant c.-118C>T. This variant is linked to increased expression of the ANKRD26 gene and confirmed as the likely cause of THC2. Another variant, c.-140C>G, was present in four healthy family members. Although it was considered causal for THC2 in the past, our study suggests that the c.-140C>G variant does not elevate ANKRD26 expression and does not cause thrombocytopenia.What is the impact?Understanding the genetic and functional implications of ANKRD26 gene variants is crucial for THC2 diagnosis and management. Our study emphasizes the necessity of conducting functional analyses to precisely evaluate the clinical significance of variants linked to inherited blood disorders. Carriers of the c.-118C>T variant should undergo vigilant monitoring for THC2 and potential cancer development. Conversely, the c.-140C>G variant does not pose a risk of THC2 or heightened cancer susceptibility.

Pulmonary fat embolism in non-survivors after cardiopulmonary resuscitation.

BACKGROUND: Blunt trauma acting against the human body presents the fundamental cause of pulmonary fat embolism (PFE) and fat embolism syndrome. The aim of the present study was to investigate PFE in non-survivors after cardiopulmonary resuscitation (CPR). METHODS: This was a prospective cohort study conducted in University Hospital Ostrava, Czech Republic. Within a 4-year study period, all non-survivors after CPR because of out-of-hospital cardiac arrest were assessed for the study eligibility. The presence/seriousness of PFE was determined by microscopic examination of cryo-sections of lung tissue (staining with Oil Red O). RESULTS: In total, 106 persons after unsuccessful CPR were enrolled in the study. The most frequent cause of death in the study population (63.2% of cases) was cardiac disease (ischemic heart disease); PFE was not determined as the cause of death in any of our study cases. Sternal fractures were identified 66.9%, rib fractures (usually multiple) in 80.2% of study cases; the median number of rib fractures was 10.2 fractures per person. Serious intra-thoracic injuries were found in 34.9% of cases. Microscopic examination of lung cryo-sections revealed PFE in 40 (37.7%) study cases; PFE was most frequently evaluated as grade I or II. Occurrence of sternal and rib fractures was significantly higher in persons with PFE than between persons without PFE (p = 0.033 and p = <0.001). Number of rib fractures was also significantly higher in persons with PFE. The occurrence of serious intra-thoracic injuries was comparable in both our study groups (p = 0.089). CONCLUSIONS: PFE presents a common resuscitation injury which can be found in more than 30% of persons after CPR. Persons with resuscitation skeletal chest fractures have significantly higher risk of PFE development. During autopsy of persons after unsuccessful CPR, it is necessary to distinguish CPR-associated injuries including PFE from injuries that arise from other mechanisms.

Pulmonary fat embolism after cardiopulmonary resuscitation.

Pulmonary fat embolism (PFE) is usually observed in patients with long bone fractures, patients with extensive subcutaneous fat contusions or skin burns. Chest compressions during cardiopulmonary resuscitation (CPR) present powerful repetitive violence against victim's chest. Skeletal chest fractures are the most frequent complication of CPR, and probably the most important cause of PFE autopsy finding in persons, which have been resuscitated before death. The aim of the present paper was to investigate the prevalence and seriousness of PFE in non-survivors after out-of-hospital cardiac arrest. During autopsy, PFE can be diagnosed in 30 - 42 % of persons after unsuccessful CPR; skeletal chest fractures are associated with significantly higher prevalence of PFE. After successful CPR, fat embolism may contribute significantly to acute respiratory distress syndrome, or multiorgan failure. The issue of CPR associated injuries has two medical aspects - clinical and forensic. From clinical point of view, the presence of CPR associated injuries must be acknowledged when offering healthcare to patients after successful CPR. During autopsy, CPR associated injuries should be diagnosed and evaluated as these injuries may contribute to death or may be potentially lethal.

Laryngopharyngeal Reflux Is a Potential Risk Factor for Juvenile-Onset Recurrent Respiratory Papillomatosis.

INTRODUCTION: Human papillomavirus (HPV) causes juvenile-onset recurrent respiratory papillomatosis (JORRP). Although HPV is common in children, the prevalence of JORRP is low. It is likely that other factors contribute to the pathogenesis of JORRP, during either activation or reactivation of a latent HPV infection. There is evidence that laryngopharyngeal reflux (LPR) might be such a risk factor for adult-onset recurrent respiratory papillomatosis. This study investigated if LPR might also be a risk factor for JORRP. MATERIALS AND METHODS: Children with JORRP of the larynx that required microlaryngoscopy at a tertiary referral hospital were included in this prospective case-series study from November 2015 to November 2017. Using immunohistochemistry, HPV infection and pepsin associated with LPR were diagnosed from laryngeal biopsies. RESULTS: Eleven children (aged 4-14 years) were analyzed. No patient had a history of immunodeficiency or tobacco smoke exposure. All patients underwent at least three previous surgeries due to JORRP and had been vaccinated against HPV in the past. Five children were treated using antivirotics and immunomodulators. The only known maternal risk factor was that three mothers were primiparous. All 11 samples were infected with HPV (type 6 or 11). Pathologic LPR was diagnosed in 5/11 children (45.5%). CONCLUSION: LPR may be a risk factor for JORRP, contributing to its development by activating or reactivating a latent HPV infection. Results are in accordance with those from our previous study in adults.

Low intrapatient variability of histomorphological findings in periprosthetic tissues from revised metal/ceramic on polyethylene joint arthroplasties.

The type of tissue response to implant by-products can be determined by examination of periprosthetic tissues. However, little is known about the most suitable location for tissue sampling. The main goal of this study was to evaluate the extent of variability in tissue response in relation to location of tissue sampling, implant fixation, age and sex in total joint arthroplasties with metal-on-polyethylene or ceramic-on-polyethylene bearing pairs. We processed 236 histology slides from 21 patients and focused on the association between the location of tissue samples and histological features. The presence of the synovial hyperplasia showed a significant association with the particular sampling site. A higher density of high endothelial cell venules was seen in the samples from around the joint, and polyethylene particles were more abundant in noncemented TJA but both findings did not show statistically significant association with the sampling site. The results showed a relatively small variance in the tissue response to prosthetic by-products among tissues sampled from the same patient. Our findings indicate that tissue samples retrieved from similar distance from around the TJA during the revision operation show comparable results of histological analysis. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2008-2018, 2018.

Contributions of human tissue analysis to understanding the mechanisms of loosening and osteolysis in total hip replacement.

Aseptic loosening and osteolysis are the most frequent late complications of total hip arthroplasty (THA) leading to revision of the prosthesis. This review aims to demonstrate how histopathological studies contribute to our understanding of the mechanisms of aseptic loosening/osteolysis development. Only studies analysing periprosthetic tissues retrieved from failed implants in humans were included. Data from 101 studies (5532 patients with failure of THA implants) published in English or German between 1974 and 2013 were included. "Control" samples were reported in 45 of the 101 studies. The most frequently examined tissues were the bone-implant interface membrane and pseudosynovial tissues. Histopathological studies contribute importantly to determination of key cell populations underlying the biological mechanisms of aseptic loosening and osteolysis. The studies demonstrated the key molecules of the host response at the protein level (chemokines, cytokines, nitric oxide metabolites, metalloproteinases). However, these studies also have important limitations. Tissues harvested at revision surgery reflect specifically end-stage failure and may not adequately reveal the evolution of pathophysiological events that lead to prosthetic loosening and osteolysis. One possible solution is to examine tissues harvested from stable total hip arthroplasties that have been revised at various time periods due to dislocation or periprosthetic fracture in multicenter studies.