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Background. The transfer of the flexor hallucis longus (FHL) tendon is an established treatment for replacing a dysfunctional Achilles tendon. Objectives. (1) Describe a new technique for endoscopic FHL transfer for noninsertional Achilles tendinopathy and (2) describe the functional outcomes and complications after endoscopic and open FHL transfer. Materials and Method. Retrospective study of patients who underwent open or endoscopic FHL transfer between 2014 and 2016. The American Orthopaedic Foot & Ankle Society (AOFAS) ankle/hindfoot scale was used preoperatively and postoperatively to measure the functional results. Results. We included 18 endoscopic FHL transfers and 24 open FHL transfers. The mean age of endoscopic and open procedures was 47.5 years (range 25-77 years) and 61.2 years (range 43-72 years), respectively. An improvement on the average AOFAS of 52.8% (31.9 points) was observed in the endoscopy group during the follow-up from the baseline. The mean improvement in AOFAS score for the open group was 41.4% (24.5 points). Four and 7 cases reported complications in the endoscopy and open FHL transfer groups, respectively. Conclusion. While both procedures were effective in treating noninsertional Achilles tendinopathy, the described arthroscopic treatment led to a greater improvement in the AOFAS score and is slightly less prone to lasting complications. Level of Evidence: Level IV: Case series [ABSTRACT FROM AUTHOR]

De novo truncating variants in fibrosin-like 1 (FBRSL1), a member of the AUTS2 gene family, cause a disability syndrome, including organ malformations such as heart defects. Here, we use Xenopus laevis to investigate whether Fbrsl1 plays a role in heart development. Xenopus laevis fbrsl1 is expressed in tissues relevant for heart development, and morpholino-mediated knockdown of Fbrsl1 results in severely hypoplastic hearts. Our data suggest that Fbrsl1 is required for the development of the first heart field, which contributes to the ventricle and the atria, but not for the second heart field, which gives rise to the outflow tract. The morphant heart phenotype could be rescued using a human N-terminal FBRSL1 isoform that contains an alternative exon, but lacks the AUTS2 domain. N-terminal isoforms carrying patient variants failed to rescue. Interestingly, a long human FBRSL1 isoform, harboring the AUTS2 domain, also did not rescue the morphant heart defects. Thus, our data suggest that different FBRSL1 isoforms may have distinct functions and that only the short N-terminal isoform, appears to be critical for heart development., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Directed cell migration requires a local fine-tuning of Rho GTPase activity to control protrusion formation, cell-cell contraction, and turnover of cellular adhesions. The Rho guanine nucleotide exchange factor (GEF) TRIO is ideally suited to control RhoGTPase activity because it combines two distinct catalytic domains to control Rac1 and RhoA activity in one molecule. However, at the cellular level, this molecular feature also requires a tight spatiotemporal control of TRIO activity. Here, we analyze the dynamic localization of Trio in Xenopus cranial neural crest (NC) cells, where we have recently shown that Trio is required for protrusion formation and migration. Using live cell imaging, we find that the GEF2 domain, but not the GEF1 domain of Trio, dynamically colocalizes with EB3 at microtubule plus-ends. Microtubule-mediated transport of Trio appears to be relevant for its function in NC migration, as a mutant GEF2 construct lacking the SxIP motif responsible for microtubule plus-end localization was significantly impaired in its ability to rescue the Trio loss-of-function phenotype compared to wild-type GEF2. Furthermore, by analyzing microtubule dynamics in migrating NC cells, we observed that loss of Trio function stabilized microtubules at cell-cell contact sites compared to controls, whereas they were destabilized at the leading edge of NC cells. Our data suggest that Trio is transported by microtubules to distinct subcellular locations where it has different functions in controlling microtubule stability, cell morphology, and cell-cell interaction during directed NC migration., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Specialized chromatin-binding proteins are required for DNA-based processes during development. We recently established PWWP2A as a direct histone variant H2A.Z interactor involved in mitosis and craniofacial development. Here, we identify the H2A.Z/PWWP2A-associated protein HMG20A as part of several chromatin-modifying complexes, including NuRD, and show that it localizes to distinct genomic regulatory regions. Hmg20a depletion causes severe head and heart developmental defects in Xenopus laevis. Our data indicate that craniofacial malformations are caused by defects in neural crest cell (NCC) migration and cartilage formation. These developmental failures are phenocopied in Hmg20a-depleted mESCs, which show inefficient differentiation into NCCs and cardiomyocytes (CM). Consequently, loss of HMG20A, which marks open promoters and enhancers, results in chromatin accessibility changes and a striking deregulation of transcription programs involved in epithelial-mesenchymal transition (EMT) and differentiation processes. Collectively, our findings implicate HMG20A as part of the H2A.Z/PWWP2A/NuRD-axis and reveal it as a key modulator of intricate developmental transcription programs that guide the differentiation of NCCs and CMs., (© 2023. The Author(s).)

One of the major challenges of allogeneic stem cell transplantation (allo-SCT) is to reduce the risk of graft-versus-host disease (GVHD) while boosting the graft-versus-leukemia (GVL) effect. The reconstitution of natural killer (NK) cells following allo-SCT is of notable interest due to their known capability to induce GVL without GVHD. Here, in this study, we investigate the association between the incidence and severity of acute graft-versus-host disease (aGVHD) and the early reconstitution of NK cell subsets following allo-SCT. We analyzed 342 samples from 107 patients using flow cytometry, with a focus on immature CD56 high and mature cytotoxic CD56 dim NK cells. Longitudinal analysis of immune reconstitution after allo-SCT showed that the incidence of aGVHD was associated with a delayed expansion of the entire NK cell population, in particular the CD56 high subset. Notably, the disturbed reconstitution of the CD56 high NK cells also correlated with the severity of aGVHD.

Whereas innate immune cells, such as NK and innate lymphoid cells (ILCs), have been characterized in different human tissues, knowledge on the thymic CD56-expressing cell subsets is limited. In this study, the rare subpopulations of thymic CD56 + CD3 - cells from samples of >100 patients have been successfully analyzed. The results revealed fundamental differences between thymic and peripheral blood (PB) CD56 + CD3 - cells. Thymic tissues lacked immunoregulatory CD56 high CD16 dim NK cells but showed two Eomes + CD56 dim subsets on which common NK cell markers were significantly altered. CD56 dim CD16 high cells expressed high amounts of NKG2A, NKG2D, and CD27 with low CD57. Conversely, CD56 dim CD16 dim cells displayed high CD127 but low expression of KIR, NKG2D, and natural cytotoxicity receptors (NCRs). Thymic CD56 + CD3 - cells were able to gain cytotoxicity but were especially immunoregulatory cells, producing a broad range of cytokines. Finally, one population of thymic CD56 + cells resembled conventional NK cells, whereas the other represented a novel, noncanonical NK subset., (© Society for Leukocyte Biology.)

Objective: To determine the prevalence of antibodies against small ruminant lentivirus (SRLV), the causative agent of ovine progressive pneumonia (OPP), and to identify risk factors associated with OPP in Wyoming sheep flocks., Design: Cross-sectional study., Animals: 1,415 sheep from 54 flocks in Wyoming., Procedures: Flocks were surveyed as part of the National Animal Health Monitoring System (NAHMS) 2011 sheep study. Serum samples obtained from sheep in Wyoming were analyzed for anti-SRLV antibodies by use of a competitive-inhibition ELISA. The prevalence of seropositive animals overall and within each flock was calculated. Respective associations between flock OPP status and various demographic and management variables were assessed., Results: The estimated prevalence of sheep seropositive for anti-SRLV antibodies and OPP-infected flocks in Wyoming was 18.0% and 47.5%, respectively. Within OPP-infected flocks, the prevalence of seropositive sheep ranged from 3.9% to 96%. Flocks maintained on nonfenced range were more likely to be infected with OPP than were flocks maintained on fenced range (OR, 3.4; 95% confidence interval, 1.1 to 10.7). The estimated prevalence of OPP-infected flocks in Wyoming did not vary substantially from that at the regional or national level reported in the NAHMS 2001 sheep study. Compared with results of the NAHMS 2011 sheep study, Wyoming producers were more familiar with OPP than were other US sheep producers, but only 61% of Wyoming producers surveyed reported being very or somewhat familiar with the disease., Conclusions and Clinical Relevance: Results indicated that OPP is prevalent in many Wyoming sheep flocks, which suggested that continued efforts are necessary to increase producer knowledge about the disease and investigate practices to minimize economic losses associated with OPP.

This study involved 92 patients with clinically diagnosed pneumonia. Differences in the frequency of typical pattern were calculated for patients with mild pneumonia and for patients with severe pneumonia (confusion, respiratory rate, blood pressure, 65 years of age and older). The frequency of singular morphologic changes did not differ significantly between the two groups. Empyema and pleural effusion, as well as an atelectasis in combination with patchy infiltrates and a positive bronchogram/multisegmental infiltrates, seem to have an influence on severity of pneumonia.

The 2- and 4-hydroxy metabolites of 17beta-estradiol (E2) and estrone (E1) are important for E2-mediated carcinogenesis due to the formation of genotoxic ortho-quinone metabolites. To assess the importance of metabolic conjugation for their genotoxicity, the DNA strand-breaking activity of the four catechol estrogens was determined in three cell lines with different activities of catechol-O-methyltransferase (COMT) and UDP-glucuronosyltransferase (UGT). Most DNA strand breaks were observed in V79 cells, which lack these metabolic activities. 2- and 4-hydroxy-E2 were 2.5 times more genotoxic than 2- and 4-hydroxy-E1. MCF-7 cells exhibit COMT activity, and the incidence of DNA strand breaks decreased with increasing methylation; only the 4-hydroxy metabolites of E1 and E2, which were poor substrates of COMT, exhibited low genotoxicity. HepG2 cells converted the catechol and methoxy metabolites of E2 to the respective E1 metabolites by 17beta-hydroxysteroid dehydrogenase (HSD). Moreover, methylation and glucuronidation took place. Only 4-hydroxy-E1 elicited a weak genotoxic response in these cells. The extensive metabolism in HepG2 cells is proposed to account for the failure of catechol estrogens to induce DNA strand breaks. Thus, metabolism by COMT and UGT and, to a minor extent, by HSD is a major determinant for the genotoxicity of catechol estrogens in target cells.

Purpose: The purpose of the study was to evaluate prospectively whether integrated 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) is more accurate for determination of malignancy in newly diagnosed pulmonary lesions compared to separate interpretation of CT and FDG-PET., Procedures: Two hundred and seventy-six patients with newly diagnosed lung lesions underwent FDG-PET/CT. Helical CT, FDG-PET, and FDG-PET/CT were interpreted separately to determine the performance of each imaging modality. Histopathology served as reference in all patients, and in further 60 patients, a benign lesion was verified at follow-up (mean follow-up of 1,040 days)., Results: Histology revealed malignant lung tumors in 216 of 276 patients. With PET and PET/CT, a significantly lower number of lesions were classified as equivocal compared to CT alone (p < 0.001). Assuming that equivocal lesions are benign, performance of diagnostic tests was as follows: sensitivity, specificity, and accuracy for CT was 94, 75, and 90%, for PET 97, 83, and 94% (p = 0.021), and for PET/CT 96, 87, and 94% (p = 0.010). Assuming that equivocal lesions are malignant, sensitivity, specificity, and accuracy for CT was 99, 37, and 86%, for PET 99, 77, and 94% (p < 0.001), and for PET/CT 98, 68, and 92% (p = 0.002). PET and PET/CT showed the highest concordance (K = 0.912; confidence interval 0.866-0.958). In lesions less than or equal to 3 cm, there was a significant difference in the performance of PET alone and multidetector row CT as well as PET/CT and multidetector row CT (p = 0.007), irrespective if equivocal findings were judged as malignant or benign., Conclusion: For differentiation of benign from malignant lung lesions, integrated FDG-PET/CT imaging was significantly more accurate than CT but not FDG-PET. The addition of metabolic imaging (FDG-PET) to morphological imaging (CT) leads to an increase in specificity and significantly reduced equivocal findings and is therefore recommended to further specify newly diagnosed lung lesions.

Aim: A retrospective study to evaluate the prognostic influence of the primary tumour and the anatomic level of spinal metastases was carried out., Material and Methods: Between January 1984 and May 2005, 217 patients were surgically treated because of spinal metastases. The prognostic influence for the survival was analysed for the entity of the primary tumour and the localisation of the spinal metastases., Results: The median survival of the study group was 8.0 months (range: 0-191.5 months). Mamma carcinoma was the most frequent primary tumour with 62 cases (28.6 %). The spinal level of the metastases did not influence the postoperative survival (p = 0.9058). The entity of the primary tumour showed a significant influence for the postoperative survival (p < 0.0001)., Conclusion: In spinal metastases, the entity of the primary tumour was of prognostic value; the localisation of the spinal metastases at different spinal levels did not influence the postoperative survival. Therefore, the evaluation of the primary tumour is mandatory for an estimation of the expected survival.

Hyperkinetic disorders or attention-deficit/hyperactivity disorders (ADHD) are among the psychiatric diagnoses most often encountered in children and adolescents. Symptoms include inattention, hyperactivity and impulsivity. Within the multi-modal treatment system, the therapy with psychostimulants (e. g. methylphenidate) proved to be an effective in patients with ADHD. A double-blind trial is indicated in cases of unclear efficacy of methylphenidate at initial application or if psychostimulants have regularly been applied for more than one year with an leave-out trial delivering unequivocal results. Further it is helpful in verifying potential undesirable side effects and improving patients' compliance.

17beta-Estradiol (E2) and its catechol and methoxy metabolites are believed to play important roles in the mechanism of E2-mediated tumor formation. Because conjugation with glucuronic acid lowers tissue levels by facilitating excretion, we have determined the kinetic parameters of the glucuronidation of E2, estrone (E1), and seven phase I metabolites using human liver microsomes. The catechol estrogens 2- and 4-hydroxy-E2/E1 exhibited the highest clearance, exceeding that of E2, E1, and the methoxy metabolites by factors of 6-44. Homotropic activation kinetics were observed for the 3-glucuronidation of E2 but not for any of the metabolites. None of the metabolites affected the kinetics of the 3-glucuronidation of E2. In contrast, the isoflavone daidzein stimulated the formation of E2-3-glucuronide, as has been reported previously. This heterotropic activation by daidzein appears to be specific for the glucuronidation of E2 because daidzein did not affect the glucuronidation of the 2- and 4-hydroxy metabolites of E2. However, daidzein may lower the glucuronidation of 2-methoxy-E2 in vivo due to its preferential glucuronidation. The decreased tissue levels of E2 and increased concentrations of 2-methoxy-E2, as implied by this study and the previous one, may contribute to the protective effect of daidzein against breast and endometrial cancer.

Aim: The aim of this study was the evaluation of surgical results and prognostic factors in spinal metastases of renal cancer., Methods: 37 surgical patients with spinal metastases of renal cell carcinoma were retrospectively analysed. In 2 patients the cervical, in 16 patients the thoracic, in 4 patients the thoraco-lumbar and in 16 patients the lumbar spine was involved., Results: In 11 cases (29.7 %) a combined posterior-anterior spondylodesis with vertebral body replacement, in 26 cases (70.3 %) a single posterior instrumentation was done. Perioperatively, 24 complications appeared, 4 of them were lethal. Postoperatively, the neurological situation was unchanged in 26 patients, dischanged in 4 patients and improved in 7 patients. The level of pain was unchanged in 10 patients, dischanged in 3 patients and improved in 24 patients. The mean postoperative survival was 13.6 months. For the postoperative survival the Karnofsky-Index and the Frankel-Score were univariate highly significant, the factors nutritional condition and latency between the primary tumor and the development of spinal metastases showed a lower significancy. No prognostical influence for the postoperative survival could be detected for the factors gender, age, localisation of the metastases, type of operation and the factor solitary/multiple metastases. The multivariate analyses did not attempt any of the univariate significant prognostic factors for the postoperative survival. The postoperative survival was significantly (p: 0.0030) influenced by postoperative adjuvant therapy (radio- and/or chemotherapy). The analysis of each adjuvant therapy form (i. e. chemo-, radio- and combined therapy) attempts this prognostic effect (p: 0.0229)., Conclusion: In most patients with spinal metastases of renal cell carcinoma, the singular posterior intrumentation combined with a decompression is a sufficient therapy. To avoid posterior implant failure, in patients with a prognosticated survival of more than one year, a combined posterior-anterior spondylodesis with vertebral body replacement should be done. The prognostic influence of an adjuvant postoperative treatment in the present study must be interpreted in the context of this small, highly selected patient collective. Further standardized studies should be performed to evaluate the prognostic influence of an adjuvant therapy.

We report two male adolescents who developed partial or complete retrograde ejaculation during risperidone treatment. Additionally, one patient complained of bladder outflow obstruction, and the other reported a reduced ejaculatory volume and decreased viscosity of semen. On rechallenge with risperidone, patient A showed a prompt recurrence of the ejaculatory dysfunction. The side effects were highly disturbing and led to reduced treatment compliance in both patients. The impact of risperidone, a strong alpha(1)-receptor antagonist, on the adrenergic system might induce retrograde ejaculation by altering the sympathetic tonus, allowing semen to pass retrogradely into the bladder during ejaculation. The reduced ejaculatory volume may be caused by risperidone-induced hyperprolactinemia. Clinicians should regularly inquire about sexual dysfunction and symptoms suggestive of hyperprolactinemia before starting risperidone treatment and regularly thereafter.