Author Correction: Novel Hexb-based tools for studying microglia in the CNS.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel Hexb-based tools for studying microglia in the CNS.

Microglia and central nervous system (CNS)-associated macrophages (CAMs), such as perivascular and meningeal macrophages, are implicated in virtually all diseases of the CNS. However, little is known about their cell-type-specific roles in the absence of suitable tools that would allow for functional discrimination between the ontogenetically closely related microglia and CAMs. To develop a new microglia gene targeting model, we first applied massively parallel single-cell analyses to compare microglia and CAM signatures during homeostasis and disease and identified hexosaminidase subunit beta (Hexb) as a stably expressed microglia core gene, whereas other microglia core genes were substantially downregulated during pathologies. Next, we generated HexbtdTomato mice to stably monitor microglia behavior in vivo. Finally, the Hexb locus was employed for tamoxifen-inducible Cre-mediated gene manipulation in microglia and for fate mapping of microglia but not CAMs. In sum, we provide valuable new genetic tools to specifically study microglia functions in the CNS.

Microglial Cytokines Mediate Plasticity Induced by 10 Hz Repetitive Magnetic Stimulation.

Microglia, the resident immune cells of the CNS, sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically used noninvasive brain stimulation technique, on microglia-mediated synaptic plasticity; 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from microglia in mouse organotypic brain tissue cultures of both sexes, while no significant changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor α (TNFα) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings, in vivo depletion of microglia abolished rTMS-induced changes in neurotransmission in the mPFC of anesthetized mice of both sexes. We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia.SIGNIFICANCE STATEMENT Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that induces cortical plasticity. Despite its wide use in neuroscience and clinical practice (e.g., depression treatment), the cellular and molecular mechanisms of rTMS-mediated plasticity remain not well understood. Herein, we report an important role of microglia and plasticity-promoting cytokines in synaptic plasticity induced by 10 Hz rTMS in organotypic slice cultures and anesthetized mice, thereby identifying microglia-mediated synaptic adaptation as a target of rTMS-based interventions.

The Amyloid Precursor Protein Regulates Synaptic Transmission at Medial Perforant Path Synapses.

The perforant path provides the primary cortical excitatory input to the hippocampus. Because of its important role in information processing and coding, entorhinal projections to the dentate gyrus have been studied in considerable detail. Nevertheless, synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells remains to be characterized. Here, we have used mouse organotypic entorhino-hippocampal tissue cultures of either sex, in which the entorhinal cortex (EC) to dentate granule cell (GC; EC-GC) projection is present, and EC-GC pairs can be studied using whole-cell patch-clamp recordings. By using cultures of wild-type mice, the properties of EC-GC synapses formed by afferents from the lateral and medial entorhinal cortex were compared, and differences in short-term plasticity were identified. As the perforant path is severely affected in Alzheimer's disease, we used tissue cultures of amyloid precursor protein (APP)-deficient mice to examine the role of APP at this synapse. APP deficiency altered excitatory neurotransmission at medial perforant path synapses, which was accompanied by transcriptomic and ultrastructural changes. Moreover, presynaptic but not postsynaptic APP deletion through the local injection of Cre-expressing adeno-associated viruses in conditional APPflox/flox tissue cultures increased the neurotransmission efficacy at perforant path synapses. In summary, these data suggest a physiological role for presynaptic APP at medial perforant path synapses that may be adversely affected under altered APP processing conditions.SIGNIFICANCE STATEMENT The hippocampus receives input from the entorhinal cortex via the perforant path. These projections to hippocampal dentate granule cells are of utmost importance for learning and memory formation. Although there is detailed knowledge about perforant path projections, the functional synaptic properties at the level of individual connected pairs of neurons are not well understood. In this study, we investigated the role of APP in mediating functional properties and transmission rules in individually connected neurons using paired whole-cell patch-clamp recordings and genetic tools in organotypic tissue cultures. Our results show that presynaptic APP expression limits excitatory neurotransmission via the perforant path, which could be compromised in pathologic conditions such as Alzheimer's disease.

The projected increase of vertebral osteomyelitis in Germany implies a demanding challenge for future healthcare management of aging populations.

PURPOSE: Since an increase in the occurrence of native vertebral osteomyelitis (VO) is expected and reliable projections are missing, it is urgent to provide a reliable forecast model and make it a part of future health care considerations. METHODS: Comprehensive nationwide data provided by the Federal Statistical Office of Germany were used to forecast total numbers and incidence rates (IR) of VO as a function of age and gender until 2040. Projections were done using autoregressive integrated moving average model on historical data from 2005 to 2019 in relation to official population projections from 2020 to 2040. RESULTS: The IR of VO is expected to increase from 12.4 in 2019 to 21.5 per 100,000 inhabitants [95% CI 20.9-22.1] in 2040. The highest increase is predicted in patients over 75 years of age for both men and women leading to a steep increase in absolute numbers, which is fourfold higher compared to patients younger than 75 years. While the IR per age group will not increase any further after 2035, the subsequent increase is due to a higher number of individuals aged 75 years or older. CONCLUSIONS: Our data suggest that increasing IR of VO will seriously challenge healthcare systems, particularly due to demographic change and increasing proportions of populations turning 75 years and older. With respect to globally fast aging populations, future health care policies need to address this burden by anticipating limitations in financial and human resources and developing high-level evidence-based guidelines for prevention and interdisciplinary treatment.

Regional Microglial Response in Entorhino-Hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation.

Microglia and astrocytes are essential in sustaining physiological networks in the central nervous system, with their ability to remodel the extracellular matrix, being pivotal for synapse plasticity. Recent findings have challenged the traditional view of homogenous glial populations in the brain, uncovering morphological, functional, and molecular heterogeneity among glial cells. This diversity has significant implications for both physiological and pathological brain states. In the present study, we mechanically induced a Schaffer collateral lesion (SCL) in mouse entorhino-hippocampal slice cultures to investigate glial behavior, i.e., microglia and astrocytes, under metalloproteinases (MMPs) modulation in the lesioned area, CA3, and the denervated region, CA1. We observed distinct response patterns in the microglia and astrocytes 3 days after the lesion. Notably, GFAP-expressing astrocytes showed no immediate changes post-SCL. Microglia responses varied depending on their anatomical location, underscoring the complexity of the hippocampal neuroglial network post-injury. The MMPs inhibitor GM6001 did not affect microglial reactions in CA3, while increasing the number of Iba1-expressing cells in CA1, leading to a withdrawal of their primary branches. These findings highlight the importance of understanding glial regionalization following neural injury and MMPs modulation and pave the way for further research into glia-targeted therapeutic strategies for neurodegenerative disorders.

Dense dopaminergic innervation of the peri-infarct cortex despite dopaminergic cell loss after a pure motor-cortical stroke in rats.

After ischemic stroke, the cortex directly adjacent to the ischemic core (i.e., the peri-infarct cortex, PIC) undergoes plastic changes that facilitate motor recovery. Dopaminergic signaling is thought to support this process. However, ischemic stroke also leads to the remote degeneration of dopaminergic midbrain neurons, possibly interfering with this beneficial effect. In this study, we assessed the reorganization of dopaminergic innervation of the PIC in a rat model of focal cortical stroke. Adult Sprague-Dawley rats either received a photothrombotic stroke (PTS) in the primary motor cortex (M1) or a sham operation. 30 days after PTS or sham procedure, the retrograde tracer Micro Ruby (MR) was injected into the PIC of stroke animals or into homotopic cortical areas of matched sham rats. Thus, dopaminergic midbrain neurons projecting into the PIC were identified based on MR signal and immunoreactivity against tyrosine hydroxylase (TH), a marker for dopaminergic neurons. The density of dopaminergic innervation within the PIC was assessed by quantification of dopaminergic boutons indicated by TH-immunoreactivity. Regarding postsynaptic processes, expression of dopamine receptors (D1- and D2) and a marker of the functional signal cascade (DARPP-32) were visualized histologically. Despite a 25% ipsilesional loss of dopaminergic midbrain neurons after PTS, the number and spatial distribution of dopaminergic neurons projecting to the PIC was not different compared to sham controls. Moreover, the density of dopaminergic innervation in the PIC was significantly higher than in homotopic cortical areas of the sham group. Within the PIC, D1-receptors were expressed in neurons, whereas D2-receptors were confined to astrocytes. The intensity of D1- and DARPP-32 expression appeared to be higher in the PIC compared to the contralesional homotopic cortex. Our data suggest a sprouting of dopaminergic fibers into the PIC and point to a role for dopaminergic signaling in reparative mechanisms post-stroke, potentially related to recovery.

Correlation between kidney function and mortality in pyogenic spondylodiscitis: the glomerular filtration rate (GFR) as new predictive parameter?

OBJECTIVE: Pyogenic spondylodiscitis is a severe medical condition, often requiring surgical intervention. Numerous risk factors are known, such as obesity, neurological impairment and old age. In-hospital mortality remains high, therefore other factors may be contributing to the increased mortality. To evaluate kidney function as a risk factor for increased morbidity of pyogenic spondylodiscitis, the glomerular filtration rate (GFR) was correlated with the patients' clinical course. MATERIALS AND METHODS: We retrospectively reviewed the cases of 366 patients and 255 were included for analysis. Clinical, laboratory and surgical data were recorded with a minimum follow-up of three months. For clinical outcome measurement, mortality, length of stay and perioperative complications were analysed. RESULTS: The study included 255 patients (173 men, 82 women; mean age 66.3 years). Patients with a GFR < 59 mL/min spent an average of 5 days longer in the hospital than those with a GFR ≥ 60 mL/min (p = 0.071). The mortality rate increased significantly with a decrease in GFR: A GFR of 30-59 mL/min had a mortality rate of 17.6%, whereas a GFR of < 29 mL/min had one of 30.4% (p = 0.003). Patients with impaired GFR showed an increased rate of postoperative complications (OR 4.7 p = 0.002) and higher rate of intensive care unit (ICU) stay (OR 8.7 p = < 0.001). DISCUSSION: Preoperative GFR values showed a significant correlation with in-hospital mortality in patients with spondylodiscitis, when graded according to the KDIGO stages. Furthermore, a GFR of < 29 ml/mL contributes to a longer ICU stay, postoperative complications and a longer total hospital stay. Therefore, the preoperative GFR could be a marker of kidney function and as a valuable predictive risk factor regarding the clinical in-hospital course of patients suffering from pyogenic spondylodiscitis.

Severity of spinal degeneration does not affect the pain reduction under continuous epidural analgesia.

PURPOSE: To outline clinical effectiveness of continuous epidural analgesia (CEA) in patients with failed back surgery syndrome (FBSS) or lumbar spinal stenosis (LSS) depending on severity of spinal degeneration. METHODS: In this retrospective cohort study, all patients with FBSS or LSS who underwent CEA within an inpatient rehabilitation program were evaluated. The pain reduction was measured by VAS on an hourly basis. Substantial pain reduction was defined as a minimal clinically important difference (MCID) > 50%. Severity of spinal degeneration, side effects and patient-specific characteristics were documented. RESULT: We included a total of 148 patients with 105 patients suffering from FBSS and 48 with LSS. The average pain reduction was - 37.6 ± 19.2 in FBSS and - 38.1 ± 17.8 in LSS group (p < .001 and p < .001, respectively). In the FBSS group, sensory deficits (p = .047) and numbness (p = .002), and in the LSS group, a severe disability measured by ODI (38.2 ± 15.4 vs. 57.3 ± 11.3, p < .001) significantly contributed to a worse outcome. The severity of the spinal degeneration and psychological disorders did not affect the pain reduction in terms of MCID. CONCLUSIONS: This study provides new evidence about CEA in the treatment of FBSS and LSS. CEA provides a significant pain reduction even under intensified physiotherapeutic exercising in patients with severe spinal degeneration and a broad variety of secondary diagnoses. Neurologic deficits in case of FBSS and severe disability in case of LSS may be risk factors for less favorable outcome.

Projections From Surgical Use Models in Germany Suggest a Rising Number of Spinal Fusions in Patients 75 Years and Older Will Challenge Healthcare Systems Worldwide.

BACKGROUND: Spinal fusion is a well-established procedure in the treatment of degenerative spinal diseases. Previous research shows that the use of this operative treatment has been growing in recent decades in industrialized countries and has become one of the most cost-intensive surgical procedures. It seems that in some countries such as Germany-with its large, industrialized, European population-this increase is mainly driven by demographic changes with low fertility rates, increasing life expectancy, and an aging population. Based on current projections, however, Germany faces a population trend that many other countries are likely to follow within a few decades. An increasingly shrinking and aging working population may eventually put the healthcare system under enormous pressure, with greater demands for spinal fusions and associated higher costs. Thus, we aimed to provide reliable projections regarding the future demand for posterior spinal fusion procedures including age- and gender-related trends up to 2060, which will be necessary for future resource planning and possible improvements in actual treatment strategies. QUESTIONS/PURPOSES: (1) How is the use of posterior spinal fusions in Germany expected to change from 2019 through 2060, if currents trends continue? (2) How is the use of posterior spinal fusions in Germany expected to change depending on patients' age and gender during this time period? METHODS: Comprehensive nationwide data provided by the Federal Statistical Office, the official institution for documenting all data on operations and procedures performed in Germany, were used to quantify posterior spinal fusion rates as a function of calendar year, age, and gender. Because there is a lack of evidence regarding future trends in the use of posterior spinal fusions, an autoregressive integrated moving average model on historical procedure rates from 2005 to 2019 in relation to official population projections from 2020 to 2060 was chosen to forecast future absolute numbers and incidence rates of this procedure in Germany. Long-term forecasting is more prone to unexpected disruptions than forecasting over short-term periods; however, longer spans facilitate estimates of how trends may challenge future healthcare systems if those trends continue, and thus are useful for research and planning. RESULTS: The incidence rate of posterior spinal fusion was projected to increase by approximately 83% (95% CI 28% to 139%) to 102% per 100,000 inhabitants (95% CI 71% to 133%) in 2060, with a 1.3-fold higher rate of women undergoing surgery in terms of absolute numbers. The highest increase identified by the model occurred in patients 75 years and older with 38,974 (95% CI 27,294 to 50,653) posterior spinal fusions in 2060, compared with 14,657 in 2019. This trend applied for both women and men, with a 246% (95% CI 138% to 355%) increase in the total number of posterior spinal fusions for women 75 years and older and a 296% (95% CI 222% to 370%) increase for men 75 years and older. At the same time, posterior spinal fusions in all age groups younger than 55 years were projected to follow a constant or even negative trend up to 2060. CONCLUSION: Our findings suggest that increasing use of posterior spinal fusion, particularly in patients 75 years and older, will challenge healthcare systems worldwide if current trends persist. This study may serve as a model for many other industrialized countries facing similar demographic and procedure-specific developments in the future. This emphasizes the need to focus on frailty research as well as appropriate financial and human resource management. Effective perioperative medical management, multidisciplinary treatment, and interinstitutional protocols are warranted, especially in older patients as we attempt to manage these trends in the future. LEVEL OF EVIDENCE: Level III, economic and decision analysis.

Influence of rotator cuff preload on fracture configuration in proximal humerus fractures: a proof of concept for fracture simulation.

INTRODUCTION: In regard of surgical training, the reproducible simulation of life-like proximal humerus fractures in human cadaveric specimens is desirable. The aim of the present study was to develop a technique that allows simulation of realistic proximal humerus fractures and to analyse the influence of rotator cuff preload on the generated lesions in regards of fracture configuration. MATERIALS AND METHODS: Ten cadaveric specimens (6 left, 4 right) were fractured using a custom-made drop-test bench, in two groups. Five specimens were fractured without rotator cuff preload, while the other five were fractured with the tendons of the rotator cuff preloaded with 2 kg each. The humeral shaft and the shortened scapula were potted. The humerus was positioned at 90° of abduction and 10° of internal rotation to simulate a fall on the elevated arm. In two specimens of each group, the emergence of the fractures was documented with high-speed video imaging. Pre-fracture radiographs were taken to evaluate the deltoid-tuberosity index as a measure of bone density. Post-fracture X-rays and CT scans were performed to define the exact fracture configurations. Neer's classification was used to analyse the fractures. RESULTS: In all ten cadaveric specimens life-like proximal humerus fractures were achieved. Two III-part and three IV-part fractures resulted in each group. The preloading of the rotator cuff muscles had no further influence on the fracture configuration. High-speed videos of the fracture simulation revealed identical fracture mechanisms for both groups. We observed a two-step fracture mechanism, with initial impaction of the head segment against the glenoid followed by fracturing of the head and the tuberosities and then with further impaction of the shaft against the acromion, which lead to separation of the tuberosities. CONCLUSION: A high energetic axial impulse can reliably induce realistic proximal humerus fractures in cadaveric specimens. The preload of the rotator cuff muscles had no influence on initial fracture configuration. Therefore, fracture simulation in the proximal humerus is less elaborate. Using the presented technique, pre-fractured specimens are available for real-life surgical education. LEVEL OF EVIDENCE: III.

Clinical outcome after lumbar spinal fusion surgery in degenerative spondylolisthesis: a 3-year follow-up.

INTRODUCTION: Lumbar spinal fusion surgery is a widely accepted surgical treatment in degenerative causes of lumbar spondylolisthesis. The benefit of reduction of anterior displacement and restoration of sagittal parameters is still controversially debated. Purpose of the underlying publication was to analyze the influence of radiographic sagittal parameters of the spine in aspects of changes in postoperative clinical outcome. MATERIALS AND METHODS: By prospective analysis, we included patients with low-grade degenerative lumbar spondylolisthesis (Meyerding grades I and II) with mono- or bisegmental fusion surgery with a minimum follow-up data of 3 years. For clinical outcome measures, COMI, ODI and EQ-5D were used. Spinopelvic parameters (sacral inclination, pelvic tilt, sacral slope and pelvic incidence, lumbar lordosis and lumbar index as well as anterior displacement and sagittal rotation) were measured on plain radiographs. RESULTS: We could observe a significant benefit in clinical outcome after lumbar fusion surgery in low-grade spondylolisthesis in our mid-term follow-up data including 32 patients. By surgical reduction, we could see significant restoration of anterior displacement and sagittal rotation. Interestingly, a significant correlation between restoration of both sagittal rotation and sacral inclination and clinical outcome score was observed in the 3-year follow-up. CONCLUSION: In low-grade spondylolisthesis, spinal fusion surgery is a well-established surgical procedure; however, the impact of sagittal parameters and reduction of anterior displacement remains controversial. Within our findings, restoration of sagittal parameters showed significant correlation to improvement in clinical outcome in our mid-term follow-up data.

Selecting stimulation intensity in repetitive transcranial magnetic stimulation studies: A systematic review between 1991 and 2020.

Repetitive transcranial magnetic stimulation (rTMS) is an increasingly used, non-invasive brain stimulation technique in neuroscience research and clinical practice with a broad spectrum of suggested applications. Among other parameters, the choice of stimulus intensity and intracranial electric field strength substantially impacts rTMS outcome. This review provides a systematic overview of the intensity selection approaches and stimulation intensities used in human rTMS studies. We also examined whether studies report sufficient information to reproduce stimulus intensities for basic science research models. We performed a systematic review by focusing on original studies published between 1991 and 2020. We included conventional (e.g., 1 or 10 Hz) and patterned protocols (e.g., continuous or intermittent theta burst stimulation). We identified 3,784 articles in total, and we manually processed a representative portion (20%) of randomly selected articles. The majority of the analyzed studies (90% of entries) used the motor threshold (MT) approach and stimulation intensities from 80% to 120% of the MT. For continuous and intermittent theta burst stimulation, the most frequent stimulation intensity was 80% of the active MT. Most studies (92% of entries) did not report sufficient information to reproduce the stimulation intensity. Only a minority of studies (1.03% of entries) estimated the rTMS-induced electric field strengths. We formulate easy-to-follow recommendations to help scientists and clinicians report relevant information on stimulation intensity. Future standardized reporting guidelines may facilitate the use of basic science approaches aiming at better understanding the molecular, cellular, and neuronal mechanisms of rTMS.

Suggestion of a safe zone for C1 pedicle screws depending on anatomical peculiarities.

OBJECTIVE: For surgical treatment of instable upper cervical injuries, the Harms technique using lateral mass screws provides rigid fixation and favourable clinical outcomes. The use of the posterior arch of C1 as a "pedicle" allows for screw anchorage, giving improved biomechanical stability. Therefore, the aim of this study was to introduce a bilateral safe zone for C1 pedicle screws, regarding screw angulation and pedicle height. MATERIAL AND METHODS: We retrospectively reviewed the CT scans of 500 patients. Three-dimensional reformats were generated for detailed measurements. Centre screw entry point (EP), length of lateral mass as screw trajectory, lateral mass width (LMW), length of screw trajectory (ST), maximal divergence (DI) and maximal convergence (CON) from EP without perforation, and pedicle height (PH) of the posterior arch were measured. RESULTS: The 500 cases consisted of 335 males and 165 females, with a mean age of 49.5 years. Measurements did not demonstrate significant side-related differences. The mean screw entry point was 22.8 mm from the midline-axis (left 22.6 mm; right 23.0 mm). From this point, a safe zone between 11.6° of divergence and 19.6° of convergence was detected. Measurements of female patients were generally smaller, with significant differences from male patients (p < 0.05). 158 subjects (31.6%) had a PH < 4 mm. DISCUSSION: C1 pedicle screws were feasible in the majority of patients. Proposing a safe zone for screw angulation may provide safety and avoid screw perforation. However, detailed knowledge of the individual C1 anatomy and the preoperative measurement is essential in the operative planning.

Scoliosis and Prognosis-a systematic review regarding patient-specific and radiological predictive factors for curve progression.

INTRODUCTION: Idiopathic scoliosis, defined as a > 10° curvature of the spine in the frontal plane, is one of the most common spinal deformities. Age, initial curve magnitude and other parameters define whether a scoliotic deformity will progress or not. Still, their interactions and amounts of individual contribution are not fully elaborated and were the aim of this systematic review. METHODS: A systematic literature search was conducted in the common databases using MESH terms, searching for predictive factors of curve progression in adolescent idiopathic scoliosis ("adolescent idiopathic scoliosis" OR "ais" OR "idiopathic scoliosis") AND ("predictive factors" OR "progression" OR "curve progression" OR "prediction" OR "prognosis"). The identified and analysed factors of each study were rated to design a top five scale of the most relevant factors. RESULTS: Twenty-eight investigations with 8255 patients were identified by literature search. Patient-specific risk factors for curve progression from initial curve were age (at diagnosis < 13 years), family history, bone mineral status (< 110 mg/cm3 in quantitative CT) and height velocity (7-8 cm/year, peak 11.6 ± 1.4 years). Relevant radiological criteria indicating curve progression included skeletal maturity, marked by Risser stages (Risser < 1) or Sanders Maturity Scale (SMS < 5), the initial extent of the Cobb angle (> 25° progression) and curve location (thoracic single or double curve). DISCUSSION: This systematic review summarised the current state of knowledge as the basis for creation of patient-specific algorithms regarding a risk calculation for a progressive scoliotic deformity. Curve magnitude is the most relevant predictive factor, followed by status of skeletal maturity and curve location.

Complications Within 6 Months After Arthroscopic Rotator Cuff Repair: Registry-Based Evaluation According to a Core Event Set and Severity Grading.

PURPOSE: To report complications after arthroscopic rotator cuff repairs (ARCRs) in a large patient cohort based on clinical application of a newly defined core event set (CES) and severity grading. METHODS: Consecutive primary ARCRs documented in a local clinical registry between February 2010 and September 2016 were included. Clinicians documented adverse events (AEs) reported until the final, 6-month postoperative follow-up according to the CES. The CES is an organized list of relevant AEs sorted into 3 intraoperative event groups (device, osteochondral, and soft tissue) and 9 postoperative event groups (device, osteochondral, pain, rotator cuff, surgical-site infection, peripheral neurologic, vascular, superficial soft tissue, and deep soft tissue). Severity was determined using an adaptation of the Clavien-Dindo classification. Cumulative complication risks were calculated per event group and stratified by severity and rotator cuff tear extent. RESULTS: A total of 1,661 repairs were documented in 1,594 patients (mean age, 57 years [standard deviation, 9 years]; 38% women); 21% involved partial tears. All events were recorded according to the CES. Intraoperative events occurred in 2.2% of repairs. We identified 329 postoperative events in 307 repairs (305 patients); 93% had 1 AE. The cumulative AE risk at 6 months was 18.5%; AE risks were 21.8% for partial tears, 15.8% for full-thickness single-tendon tears, 18.0% for tears with 2 ruptured tendons, and 25.6% for tears with 3 ruptured tendons. AE risks per event group were as follows: 9.4% for deep soft tissue, with shoulder stiffness (7.6%) being the most common event; 3.4% for persistent or worsening pain; 3.1% for rotator cuff defects; 1.7% for neurologic lesions; 0.8% for surgical-site infection; 0.7% for device; 0.4% for osteochondral; 0.2% for superficial soft tissue, and 0.1% for vascular. Most AEs had severity grades I (160 [49%]) and II (117 [36%]). CONCLUSIONS: Comprehensive local AE documentation according to the CES and severity grading was possible and showed that about one-fifth of ARCRs were affected, mostly by one AE of low severity. Shoulder stiffness was the most frequent event. LEVEL OF EVIDENCE: Level IV, case series.

Repair of Lafosse I subscapularis lesions brings no benefit in anterosuperior rotator cuff reconstruction.

PURPOSE: Optimal management of partial anterosuperior rotator cuff tears is unknown. Our aim was to compare clinical and subjective outcomes of supraspinatus (SSP) repair patients treated with or without repair of an associated superior subscapularis (SSC) partial tear. METHODS: SSP repair patients with an associated partial (Lafosse I) tear of the superior SSC tendon were retrospectively examined. Baseline and operative data and the outcomes of shoulder range of motion (ROM), pain level, strength, Constant-Murley Score, complications at 6 months as well as patient-reported Oxford Shoulder Score, Subjective Shoulder Value, and satisfaction at 6- and 24-month post-surgery were compared between patients with and without a repaired SSC tear. Mixed models and propensity-score matching were used to adjust baseline group differences. RESULTS: Of 75 eligible patients, 34 had an SSC repair and were younger with better baseline function. Non-repair surgeries were significantly shorter by 34 min (95% CI 23-45; p < 0.001). There were no group differences in the clinical and patient-rated outcome scores at both follow-ups (n.s.) as well as in pain, muscle strength in abduction, ROM, the 6-month complication risk (risk difference - 1.9%), and satisfaction with postoperative shoulder condition (n.s.). CONCLUSION: We could not show a functional or subjective benefit of repairing cranial partial tears of the SSC tendon over debridement only in the setting of an SSP reconstruction with 24 months of follow-up. A longer operative duration is expected if a partial SSC tear repair is performed. LEVEL OF EVIDENCE: III.

WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals.

Development of the metanephric kidney depends on tightly regulated interplay between self-renewal and differentiation of a nephron progenitor cell (NPC) pool. Several key factors required for the survival of NPCs have been identified, including fibroblast growth factor (FGF) signaling and the transcription factor Wilms' tumor suppressor 1 (WT1). Here, we present evidence that WT1 modulates FGF signaling by activating the expression of growth arrest-specific 1 (Gas1), a novel WT1 target gene and novel modulator of FGF signaling. We show that WT1 directly binds to a conserved DNA binding motif within the Gas1 promoter and activates Gas1 mRNA transcription in NPCs. We confirm that WT1 is required for Gas1 expression in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs. Although kidney development in Gas1 knockout mice progresses normally until E15.5, NPCs show decreased rates of proliferation at this stage and are depleted as of E17.5. Lastly, we show that Gas1 is selectively required for FGF-stimulated AKT signaling in vitro. In summary, our data suggest a model in which WT1 modulates receptor tyrosine kinase signaling in NPCs by directing the expression of Gas1.

Pilocarpine-Induced Status Epilepticus Is Associated with Changes in the Actin-Modulating Protein Synaptopodin and Alterations in Long-Term Potentiation in the Mouse Hippocampus.

Epilepsy is a complex neurological disorder which can severely affect neuronal function. Some patients may experience status epilepticus, a life-threatening state of ongoing seizure activity associated with postictal cognitive dysfunction. However, the molecular mechanisms by which status epilepticus influences brain function beyond seizure activity remain not well understood. Here, we addressed the question of whether pilocarpine-induced status epilepticus affects synaptopodin (SP), an actin-binding protein, which regulates the ability of neurons to express synaptic plasticity. This makes SP an interesting marker for epilepsy-associated alterations in synaptic function. Indeed, single dose intraperitoneal pilocarpine injection (250 mg/kg) in three-month-old male C57BL/6J mice leads to a rapid reduction in hippocampal SP-cluster sizes and numbers (in CA1 stratum radiatum of the dorsal hippocampus; 90 min after injection). In line with this observation (and previous work using SP-deficient mice), a defect in the ability to induce long-term potentiation (LTP) of Schaffer collateral-CA1 synapses is observed. Based on these findings we propose that status epilepticus could exert its aftereffects on cognition at least in part by perturbing SP-dependent mechanisms of synaptic plasticity.

Synaptopodin regulates denervation-induced homeostatic synaptic plasticity.

Synaptopodin (SP) is a marker and essential component of the spine apparatus (SA), an enigmatic cellular organelle composed of stacked smooth endoplasmic reticulum that has been linked to synaptic plasticity. However, SP/SA-mediated synaptic plasticity remains incompletely understood. To study the role of SP/SA in homeostatic synaptic plasticity we here used denervation-induced synaptic scaling of mouse dentate granule cells as a model system. This form of plasticity is of considerable interest in the context of neurological diseases that are associated with the loss of neurons and subsequent denervation of connected brain regions. In entorhino-hippocampal slice cultures prepared from SP-deficient mice, which lack the SA, a compensatory increase in excitatory synaptic strength was not observed following partial deafferentation. In line with this finding, prolonged blockade of sodium channels with tetrodotoxin induced homeostatic synaptic scaling in wild-type, but not SP-deficient, slice cultures. By crossing SP-deficient mice with a newly generated transgenic mouse strain that expresses GFP-tagged SP under the control of the Thy1.2 promoter, the ability of dentate granule cells to form the SA and to homeostatically strengthen excitatory synapses was rescued. Interestingly, homeostatic synaptic strengthening was accompanied by a compensatory increase in SP cluster size/stability and SA stack number, suggesting that activity-dependent SP/SA remodeling could be part of a negative feedback mechanism that aims at adjusting the strength of excitatory synapses to persisting changes in network activity. Thus, our results disclose an important role for SP/SA in homeostatic synaptic plasticity.