Widespread Transcriptional Scanning in the Testis Modulates Gene Evolution Rates.

The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Our single-cell transcriptomic data of human and mouse spermatogenesis provide evidence that this widespread transcription maintains DNA sequence integrity in the male germline by correcting DNA damage through a mechanism we term transcriptional scanning. We find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary timescales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning shapes germline mutation signatures and modulates mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for faster evolution in a specific subset.

[Somatic dysfunction of the cervical spine and its complex clinical picture : The fundamentals of diagnostics of cervicobrachialgia and cervicocephalic syndrome through manual medicine]. / Die somatische Dysfunktion der Halswirbelsäule und ihr komplexes klinisches Bild : Grundlagen der manualmedizinischen Diagnostik von Zervikobrachialgie und zervikozephalem Syndrom.

Patients suffering from a segmental and somatic dysfunction of the cervical spine often present a wide variety of clinical symptoms related to cervicobrachial or cervicocephalic syndrome. These symptoms might evolve out of complex neural intersegmental or trigeminocervical interactions in the brain stem or the spinal cord of the cervical spine. After the exclusion of life-threatening preconditions, a careful physical examination with aspects of manual medicine aspects might unmask the cervical dysfunction as the primary cause of the symptoms. Treatment with manual medicine on the basis of a segmental antinociceptive proprioceptive input might then be an appropriate therapeutic approach.

[Segmental and somatic dysfunction : How does manual medicine work?] / Die segmentale und somatische Dysfunktion : Wie funktioniert Manuelle Medizin?

BACKGROUND: Manual medicine is based on neurophysiologic and biomechanical principles. Impaired senso-motor regulation causes segmental and somatic dysfunction. Via segmental mapping, somato-sensory and vegetative dysfunction arises. Local pain, referred pain, and vague symptoms can occur in the thoracic and abdominal regions. Myofascial structures can transfer these dysfunctions to other body areas, where segmental neuronal connections lead to further dysfunction. Manual medicine addresses these aspects. TECHNIQUES: Manual interventions work by influencing the proprioceptive system, improving senso-motor regulation. Furthermore, proprioceptive stimulation inhibits pain mechanisms in the CNS (spinal and cerebral). Manual techniques may focus on joints, myofascial, or visceral structures. The main common target is to induct proprioceptive stimulus into related spinal segments. PATHOLOGY: Knowledge of these neurophysiologic and biomechanical aspects can be a powerful tool in differential diagnostics, particularly in cases of apparently inconsistent clinical findings. Additionally, structural pathology can lead to reflex-mediated dysfunction. To determine whether structural pathology or functional derangement is accountable for symptomatology, a manual approach on a trial basis can be very helpful. Lege artis indicated and performed, manual medicine offers an excellent risk-benefit ratio.

[Manual medicine for the extremity joints : Successful treatment of complex symptom constellations]. / Manuelle Medizin an den Extremitätengelenken : Komplexe Symptomkonstellationen erfolgreich behandeln.

One important field of manual medicine is the special diagnosis and treatment of the extremities. Biomechanical and neurophysiologic knowledge allows identification and treatment of so-called kinetic chain syndromes. The manual diagnosis of the extremities follows clear criteria and enables the diagnosis of myofascial or joint dysfunction. The manual approach to the extremities has many parallels with spinal treatment, although in certain cases, it follows a distinct algorithm. This article addresses the manual diagnosis and treatment of the joints of the extremities. Three case reports demonstrate how symptoms and manual findings guide manipulative treatment and what impact this can have.

[Preparing for a pandemic]. / Vorbereitungen auf eine pandemische Welle.

On 16 March 2020 the government of Bavaria declared a state of emergency due to the coronavirus disease 2019 (COVID-19) pandemic. This confronted all clinics with completely new and difficult challenges. In accordance with the official requirements, pandemic officers were appointed at the Kempten Clinic and a clinical management team was established. It was important to keep a relevant proportion of employees off duty at all times, and thus to have a constant reserve available in the event of expected infection-related absences of physicians and nurses. These structural changes were complemented by staff briefings and the creation of a training program on the subject of COVID-19. Within a very short time, algorithms were designed and defined how to manage patients presenting in the hospital or in the emergency room. The surgical program was limited to operations that could not be postponed, such as extrauterine pregnancy or adnexal torsion, and oncological diagnoses without the possibility of primary systemic therapy. In the case of breast cancer, however, therapy was started in all cases in which primary systemic therapy (PST), whether cytotoxic or endocrinological, appeared possible and indicated. As of 1 April 2020, more than 50% of the usable beds in the Kempten Clinic were empty. The utilization of the intensive care unit had also been reduced so that higher numbers of patients requiring artificial respiration could have been cared for at any time.

ALLCOPOL: inferring allele co-ancestry in polyploids.

BACKGROUND: Inferring phylogenetic relationships of polyploid species and their diploid ancestors (leading to reticulate phylogenies in the case of an allopolyploid origin) based on multi-locus sequence data is complicated by the unknown assignment of alleles found in polyploids to diploid subgenomes. A parsimony-based approach to this problem has been proposed by Oberprieler et al. (Methods Ecol Evol 8:835-849, 2017), however, its implementation is of limited practical value. In addition to previously identified shortcomings, it has been found that in some cases, the obtained results barely satisfy the applied criterion. To be of better use to other researchers, a reimplementation with methodological refinement appears to be indispensable. RESULTS: We present the AllCoPol package, which provides a heuristic method for assigning alleles from polyploids to diploid subgenomes based on the Minimizing Deep Coalescences (MDC) criterion in multi-locus sequence datasets. An additional consensus approach further allows to assess the confidence of phylogenetic reconstructions. Simulations of tetra- and hexaploids show that under simplifying assumptions such as completely disomic inheritance, the topological errors of reconstructed phylogenies are similar to those of MDC species trees based on the true allele partition. CONCLUSIONS: AllCoPol is a Python package for phylogenetic reconstructions of polyploids offering enhanced functionality as well as improved usability. The included methods are supplied as command line tools without the need for prior programming knowledge.

Taming the Red Bastards: Hybridisation and species delimitation in the Rhodanthemum arundanum-group (Compositae, Anthemideae).

Delineating species boundaries in a group of recently diverged lineages is challenging due to minor morphological differences, low genetic differentiation and the occurrence of gene flow among taxa. Here, we employ traditional Sanger sequencing and restriction-site associated DNA (RAD) sequencing, to investigate species delimitation in the close-knit Moroccan daisy group around Rhodanthemum arundanum B.H.Wilcox & al. that diverged recently during the Quaternary. After evaluation of genotyping errors and parameter optimisation in the course of de-novo assembly of RADseq reads in Ipyrad, we assess hybridisation patterns in the study group based on different data assemblies and methods (Neighbor-Net networks, FastStructure and ABBA-BABA tests). RADseq data and Sanger sequences are subsequently used for delimitation of species, using both, multi-species coalescent methods (Stacey and Snapp) and a novel approach based on consensus k-means clustering. In addition to the unveiling of two novel subspecies in the R. arundanum-group, our study provides insights into the performance of different species delimitation methods in the presence of hybridisation and varying quantities of data.

'At the crossroads towards polyploidy': genomic divergence and extent of homoploid hybridization are drivers for the formation of the ox-eye daisy polyploid complex (Leucanthemum, Compositae-Anthemideae).

Polyploidy plays a paramount role in phytodiversity, but the causes of this evolutionary pathway require further study. Here, we use phylogenetic methods to examine possible polyploidy-promoting factors by comparing diploid representatives of the comprehensive European polyploid complex Leucanthemum with members of its strictly diploid North African counterpart Rhodanthemum. We investigate genetic divergence and gene flow among all diploid lineages of both genera to evaluate the role of genomic differentiation and hybridization for polyploid speciation. To test whether hybridization in Leucanthemum has been triggered by the geological conditions during its diversification, we additionally generate a time-calibrated phylogeny of 46 species of the subtribe Leucantheminae. Leucanthemum shows a significantly higher genetic divergence and hybridization signal among diploid lineages compared with Rhodanthemum, in spite of a similar crown age and diversification pattern during the Quaternary. Our study demonstrates the importance of genetic differentiation among diploid progenitors and their concurrent affinity for natural hybridization for the formation of a polyploid complex. Furthermore, the role of climate-induced range overlaps on hybridization and polyploid speciation during the Quaternary is discussed.

Copper-Induced Stimulation of Nitrification in Biological Rapid Sand Filters for Drinking Water Production by Proliferation of Nitrosomonas spp.

Copper is a cofactor of the ammonia monooxygenase, an essential enzyme for the activity of ammonia oxidizing prokaryotes (AOP). Copper dosing at less than 1 µg/L stimulated ammonium removal in the poorly nitrifying biological filters of three full-scale drinking water treatment plants. Upon copper dosing, the ammonium concentration in the effluent decreased from up to 0.18 to less than 0.01 mg NH4+-N/L. To investigate how copper dosing affected the filter microbial community, we applied amplicon sequencing and qPCR targeting key nitrifying groups, including complete ammonia oxidizing (comammox) Nitrospira. Copper dosing increased the abundance of different nitrifiers. Multiple Nitrosomonas variants (betaproteobacterial ammonia oxidizers), which initially collectively represented 1% or less of the total community, increased almost 10-fold. Comammox Nitrospira were abundant and increased too, but their relative abundance within the AOP decreased because of Nitrosomonas proliferation. No other consistent change in the filter communities was detected, as well as no adverse effect of copper on the filters functionality. Our results show that copper dosing in three independent treatment plants was associated with consistent growth of AOP and that efficient nitrification was achieved through the joint contribution of comammox Nitrospira and an increasing fraction of betaproteobacterial ammonia oxidizers.

Calculation of postoperative bone healing of cystic lesions of the jaw-a retrospective study.

OBJECTIVES: There is a long history of studies into cystic lesions of the jaws. However, there is little data on postoperative bone regeneration. The aim of the study was to calculate the size of the residual bone lesions after cystostomies and cystectomies to predict the postoperative bone healing. MATERIAL AND METHODS: This retrospective study focused on patients undergoing cystectomy (n = 114) or cystostomy (n = 86), who were treated for cystic lesions between 2010 and 2015. New formulas were developed to measure the decrease in lesion sizes using the craniocaudal and mesiodistal diameters from preoperative as well as postoperative radiographs (panoramic radiographs, CT scans, CBCT). With these predictive models (calculated by linear regression analyses), it is possible to calculate how the lesions would shrink using initial size of the cyst and time after surgery for both dimensions. RESULTS: After cystostomy, the mesiodistal size was initial size 6.0 + 0.7 × initial size - 9.4 × time. The craniocaudal size was 5.1 + 0.7 × initial size - 7.3 × time. After cystectomy, the mesiodistal size was 0.4 + 0.7 × initial size - 8.4 × time. The craniocaudal size was 0.4 + 0.5 × initial size - 6.4 × time (R2 = 0.59 and 0.67, respectively). CONCLUSION: These formulas are suggested to be used to calculate residual size of bone lesion after cystostomy and cystectomy to predict postoperative bone healing. CLINICAL RELEVANCE: The formulas are based on deliberately simple measurement using only panoramic radiographs to encourage their application in daily clinical practice.

Fiber-Reinforced Resin Fixed Prostheses on 4 Short Implants in Severely Atrophic Maxillas: 1-Year Results of a Prospective Cohort Study.

PURPOSE: The aim of this study was to report on 1-year outcomes of fixed full-arch fiber-reinforced resin bridges on short implants in atrophic maxillary jaws. MATERIALS AND METHODS: A prospective cohort study was designed and patients with severely atrophic maxillas, corresponding to Cawood and Howell Classes V and VI, were included. Mesial and distal peri-implant bone levels were assessed on panoramic radiographs that were taken at the time of implant insertion (baseline) and during follow-up visits. RESULTS: Eighteen patients with 72 implants inserted in atrophic maxillary jaws were included in this study. All patients had a follow-up visit 1 year after loading. The cumulative 1-year patient-based implant survival rate was 88.8%, and the cumulative 1-year implant-based survival rate was 97.2%. The marginal bone level (MBL) was -0.5 ± 0.5 mm at the time of loading (n = 72) and -0.8 ± 0.6 mm (n = 72) after 1 year. The MBL depended substantially on the depth at the time of insertion. No prosthetic failure, such as chipping or fracture, occurred within the first year of loading. CONCLUSION: Prosthetic rehabilitation of atrophic maxillas with prostheses supported by 4 4.0- × 5.0-mm or 3.0- × 8.0-mm implants seems to be a viable and cost-effective treatment option in the short-term.

Fixed, Fiber-Reinforced Resin Bridges on 5.0-mm Implants in Severely Atrophic Mandibles: Up to 5 Years' Follow-Up of a Prospective Cohort Study.

PURPOSE: The aim of this study was to evaluate the midterm outcomes of fixed, full-arch, fiber-reinforced resin bridges on ultrashort implants in terms of marginal bone loss and overall implant survival. PATIENTS AND METHODS: Patients with severely atrophic mandibles, corresponding to Cawood and Howell class V and class VI, were included in this prospective temporal cohort study. Mesial and distal peri-implant bone levels were measured on panoramic radiographs taken at the time of implant insertion (baseline) and at follow-up visits. RESULTS: A total of 17 patients with atrophic mandibular jaws with an average follow-up period of 2.9 ± 1.5 years were included. The cumulative 1-, 3-, and 5-year patient-based implant survival rates were 94.1%, and the cumulative implant survival rates were 98.5%. The marginal bone level (MBL) of the mesial implants was 0.0 ± 0.3 mm at the time of loading (n = 33), -0.1 ± 0.3 mm (n = 20) after 1 year, -0.4 ± 0.5 mm (n = 10) after 3 years, and -1.5 ± 1.0 mm (n = 4) after 5 years. The mesial bone level depended significantly on time and insertion depth. The MBL of the distal implants was -0.4 ± 0.4 mm (n = 34) at the time of implantation, -0.4 ± 0.6 mm (n = 20) after 1 year, -0.5 ± 0.5 mm (n = 10) after 3 years, and -2.2 ± 1.7 mm (n = 4) after 5 years. The distal bone level depended significantly on time and insertion depth. CONCLUSIONS: Fixed, full-arch, fiber-reinforced resin bridges retained by 4 ultrashort implants provide a comparatively cost-effective, safe, stable alternative for prosthetic restoration of the severely atrophic mandible. The overall implant survival rate and the MBL after 5 years are equivalent to those of threaded implants of conventional lengths.

Soft Tissue Changes in Patients Undergoing Intraoral Quadrangular Le Fort II Osteotomy Versus Conventional Le Fort I Osteotomy.

PURPOSE: The aim of this study was to evaluate soft tissue changes after intraoral quadrangular Le Fort II osteotomy (IOQLFII) and correlate those changes to underlying osseous changes. MATERIALS AND METHODS: Twenty-six non-growing patients with midfacial deficiency and Class III malocclusion were analyzed. A study group of 13 patients who underwent IOQLFII was compared with 13 patients who underwent conventional Le Fort I osteotomy (LFI). After fusion of pre- and postoperative computed tomograms, each patient's hard and corresponding soft tissue changes were measured. Measurement points were defined at 3 levels in the IOQLFII group (infraorbital rim [IR], sinus floor [SF], and lateral incisor tip [LI]) and at 2 levels in the LFI group (SF and LI). Linear models were created to test for correlations between hard and soft tissues. RESULTS: The slope (a1 coefficient) between anteroposterior hard and soft tissue changes was found to be highly significant at each measurement point for all groups. In the IOQLFII group, soft tissue advancement was 69% (confidence interval [CI], 62 to 77%) of the hard tissue advancement at the IR, 90% (CI, 84 to 96%) at the SF, and 73% (CI, 64 to 82%) at the LI. In the LFI group, the corresponding percentages were 90% (83 to 97%) at SF and 84% (77 to 90%) at LI. CONCLUSION: IOQLFII results in predictable correction of midfacial deficiency. At the IR, bony advancement always resulted in markedly less soft tissue advancement than at the SF level. These results indicate that the planned infraorbital advancement should not be too conservative because soft tissue changes are smaller in this region.

Lifetime study in mice after acute low-dose ionizing radiation: a multifactorial study with special focus on cataract risk.

Because of the increasing application of ionizing radiation in medicine, quantitative data on effects of low-dose radiation are needed to optimize radiation protection, particularly with respect to cataract development. Using mice as mammalian animal model, we applied a single dose of 0, 0.063, 0.125 and 0.5 Gy at 10 weeks of age, determined lens opacities for up to 2 years and compared it with overall survival, cytogenetic alterations and cancer development. The highest dose was significantly associated with increased body weight and reduced survival rate. Chromosomal aberrations in bone marrow cells showed a dose-dependent increase 12 months after irradiation. Pathological screening indicated a dose-dependent risk for several types of tumors. Scheimpflug imaging of the lens revealed a significant dose-dependent effect of 1% of lens opacity. Comparison of different biological end points demonstrated long-term effects of low-dose irradiation for several biological end points.

"Fix Me Another Marguerite!": Species delimitation in a group of intensively hybridizing lineages of ox-eye daisies (Leucanthemum Mill., Compositae-Anthemideae).

Delineating species boundaries in the framework of the multi-species coalescent (MSC) proves to be a reliable, objective, and reproducible method in an increasing number of studies. However, the underlying model assumes the lack of gene flow after speciation; an assumption which may be frequently violated in plant evolution. This study evaluates the robustness of currently available species delimitation methods implemented in beast (BFD, BFD*, and dissect) in the closely-knit ox-eye daisy group around Leucanthemum ageratifolium Pau. Comprising five taxa being allopatrically distributed between northern Spain and southern Italy this study group shows signs of hybridization with the widespread and codistributed species Leucanthemum vulgare (Vaill.) Lam. to various extent. As expected, our empirical analyses based on both AFLP fingerprinting and sequence data demonstrate that the robustness of species delimitation results is considerably influenced by the intensity of hybridization among species and the number of hybrid individuals included. Therefore, we set up a methodological pipeline with a first step of identification and subsequent removal of individuals showing admixed genetic patterns caused by actual interbreeding using AFLP-fingerprint and morphometric data, followed by application of different Bayesian MSC species delimitation methods based on the remnant individuals using both AFLP-fingerprint and sequence data (four nuclear markers, five concatenated intergenic spacer regions of the plastid genome). The results argue for acknowledgement of Leucanthemum laciniatum, L. legraeanum, and L. ligusticum as independent species, show the close relationship of L. ageratifolium, L. monspeliense, and L. vulgare, and give rise to the description of three nothospecies new to science.

Semi-automated delineation of breast cancer tumors and subsequent materialization using three-dimensional printing (rapid prototyping).

OBJECTIVE: Three-dimensional (3D) printing has become widely available, and a few cases of its use in clinical practice have been described. The aim of this study was to explore facilities for the semi-automated delineation of breast cancer tumors and to assess the feasibility of 3D printing of breast cancer tumors. METHODS: In a case series of five patients, different 3D imaging methods-magnetic resonance imaging (MRI), digital breast tomosynthesis (DBT), and 3D ultrasound-were used to capture 3D data for breast cancer tumors. The volumes of the breast tumors were calculated to assess the comparability of the breast tumor models, and the MRI information was used to render models on a commercially available 3D printer to materialize the tumors. RESULTS: The tumor volumes calculated from the different 3D methods appeared to be comparable. Tumor models with volumes between 325 mm3 and 7,770 mm3 were printed and compared with the models rendered from MRI. The materialization of the tumors reflected the computer models of them. CONCLUSION: 3D printing (rapid prototyping) appears to be feasible. Scenarios for the clinical use of the technology might include presenting the model to the surgeon to provide a better understanding of the tumor's spatial characteristics in the breast, in order to improve decision-making in relation to neoadjuvant chemotherapy or surgical approaches. J. Surg. Oncol. 2017;115:238-242. © 2016 Wiley Periodicals, Inc.

Distinct global shifts in genomic binding profiles of limb malformation-associated HOXD13 mutations.

Gene regulation by transcription factors (TFs) determines developmental programs and cell identity. Consequently, mutations in TFs can lead to dramatic phenotypes in humans by disrupting gene regulation. To date, the molecular mechanisms that actually cause these phenotypes have been difficult to address experimentally. ChIP-seq, which couples chromatin immunoprecipitation with high-throughput sequencing, allows TF function to be investigated on a genome-wide scale, enabling new approaches for the investigation of gene regulation. Here, we present the application of ChIP-seq to explore the effect of missense mutations in TFs on their genome-wide binding profile. Using a retroviral expression system in chicken mesenchymal stem cells, we elucidated the mechanism underlying a novel missense mutation in HOXD13 (Q317K) associated with a complex hand and foot malformation phenotype. The mutated glutamine (Q) is conserved in most homeodomains, a notable exception being bicoid-type homeodomains that have lysine (K) at this position. Our results show that the mutation results in a shift in the binding profile of the mutant toward a bicoid/PITX1 motif. Gene expression analysis and functional assays using in vivo overexpression studies confirm that the mutation results in a partial conversion of HOXD13 into a TF with bicoid/PITX1 properties. A similar shift was not observed with another mutation, Q317R, which is associated with brachysyndactyly, suggesting that the bicoid/PITX1-shift observed for Q317K might be related to the severe clinical phenotype. The methodology described can be used to investigate a wide spectrum of TFs and mutations that have not previously been amenable to ChIP-seq experiments.

Implantable loop recorder monitoring after concomitant surgical ablation for atrial fibrillation (AF): insights from more than 200 continuously monitored patients.

Different follow-up methods have been used to report success rates after AF ablation. Recent studies have shown that intermittent rhythm monitoring underestimates the actual AF recurrence rate. We therefore report our experience with continuous rhythm monitoring by implantable loop recorder (ILR) in a large patient cohort. Between 09/2008 and 12/2012, 343 cardiac surgical patients underwent concomitant surgical AF ablation. ILR implantation was performed in 206 patients. ILR interrogation was accomplished at 3, 6 and 12 months postoperatively. Successful ablation was defined as AF Burden <0.5 %. Primary outcome of the study was freedom from AF at 12-month follow-up. Mean patient's age was 70.5 ± 7.4 years. No major ablation- or ILR-related complications occurred. In 4 patients (1.9 %) ILR had to be explanted due to ILR-related wound infection (n = 2) or chronic pain (n = 2). Survival rate at 1-year follow-up was 96.6 %. Freedom from AF rate after 1-year follow-up was 68.5 and 63.6 % off antiarrhythmic drugs, respectively. Statistically significant predictors for successful ablation at 1-year follow-up were smaller LA diameter, shorter duration of AF and preoperative paroxysmal AF. Demographic data, indication for surgery, lesion set and used energy source had no impact on freedom from AF after 1 year. Continuous ILR monitoring after concomitant surgical AF ablation was safe and feasible, with registered freedom from AF rate of 68.5 % at 1-year follow-up. Thus continuous rhythm monitoring provides reliable outcome data and helps to guide antiarrhythmic therapy.

Clinical outcome and osteoarthritic changes after surgical treatment of isolated capitulum humeri fractures with a minimum follow-up of five years.

PURPOSE: The aim of this study was to evaluate the functional outcome of patients treated for a fracture of the capitulum humeri and to analyze the grade of osteoarthritic changes. METHODS: Patients undergoing surgical reconstruction of isolated capitulum humeri fractures were included in a retrospective comparative analysis. Fractures were classified according to the Arbeitsgemeinschaft für Osteosynthesefragen (AO) and Dubberley and were functionally evaluated by the American Shoulder and Elbow Surgeons Score (ASES) and the Mayo Elbow Performance Index (MEPI). Levels of arthritic changes were measured with the Broberg and Morrey Score. Frequency of complications was evaluated whereby all results were compared to the ipsilateral, unaffected side. RESULTS: Thirteen patients, ten females (76.9 %) and three males (23.1 %), with a mean age of 48.7 ± 13.3 years were included in the study. Long-term follow-up range of motion (ROM) in the sagittal plane was significantly influenced by time of surgery (p < 0.001), and long-term follow-up with respect to pronation and supination by ROM of the healthy control (p < 0.05). The average ASES score was 37.8, and the Mayo Elbow Performance Index (MEPI) was 92.7. The mean level of degenerative arthritic changes was 1.9 ± 0.6 on the fractured side and significantly less (0.8 ± 0.8) on the healthy side (pF-test < 0.001). At a mean follow-up of 118.5 ± 52.4 months neither nonunion nor avascular necrosis were observed in any case. However, six cases of heterotopic ossification were identified. CONCLUSIONS: Satisfying functional outcomes and a low rate of osteoarthritic changes can be expected after the presented open reduction and internal fixation of capitulum humeri fractures. LEVEL OF EVIDENCE: Level IV - Case series; therapeutic study.

ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity.

Mutations in the ClC-7/Ostm1 ion transporter lead to osteopetrosis and lysosomal storage disease. Its lysosomal localization hitherto precluded detailed functional characterization. Using a mutated ClC-7 that reaches the plasma membrane, we now show that both the aminoterminus and transmembrane span of the Ostm1 ß-subunit are required for ClC-7 Cl(-)/H(+)-exchange, whereas the Ostm1 transmembrane domain suffices for its ClC-7-dependent trafficking to lysosomes. ClC-7/Ostm1 currents were strongly outwardly rectifying owing to slow gating of ion exchange, which itself displays an intrinsically almost linear voltage dependence. Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry. Several disease-causing CLCN7 mutations accelerated gating. Such mutations cluster to the second cytosolic cystathionine-ß-synthase domain and potential contact sites at the transmembrane segment. Our work suggests that gating underlies the rectification of all endosomal/lysosomal CLCs and extends the concept of voltage gating beyond channels to ion exchangers.