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Background: The long-term effect of adipose-derived mesenchymal stromal cells (ASCs) to restore radiation-induced salivary gland hypofunction in previous head and neck cancer patients have not been validated in larger settings., Methods: The study was the 12-months follow-up of a randomised trial, including patients with hyposalivation. Patients were randomised to receive allogeneic ASCs or placebo in the submandibular glands. Primary endpoint was unstimulated whole saliva (UWS) followed by stimulated whole saliva, patient-reported outcomes (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Head and Neck Module and the Xerostomia Questionnaire) and safety., Results: Of the 120 enrolled patients, 117 (97.5%) were assessed at 12 months. Treatment with ASCs did not increase UWS compared to placebo: increase in UWS was 0.02 mL/min (95% CI 0.01 to 0.04) in the ASC group and 0.02 mL/min (95% CI 0 to 0.03) in the placebo group, p=0.56. ASCs reduced the symptom burden for dry mouth with -10.07 units (95% CI -13.39 to -6.75) compared to -4.15 units (95% CI -7.46 to -0.84) in the placebo group, p=0.01. Compared to placebo, ASCs did not improve sticky saliva (-9.27 vs. -4.55 units, p=0.13), swallowing (-4.50 vs. 3.49 units, p=0.5) or xerostomia -3.12 vs. -2.74 units, p=0.82). Treatment was safe and associated with a transient immune response., Conclusion: Intraglandular ACS therapy in the submandibular glands significantly relieved subjective dry mouth symptoms. Both ASCs and placebo increased UWS, but ASCs did not prove superior to placebo in restoring salivary gland function, based on salivary flow rate.

Materials and Methods: This study included patients registered in the national Danish Breast Cancer Group (DBCG) database between 2001 and 2015, with locoregional LNM as well as a bilateral negative mammography, ultrasonography, and physical examination of the breasts. Overall survival (OS) and invasive disease-free survival (IDFS) were compared by treatment groups, ALND + RT (axillary lymph node dissection and radiotherapy) or ALND + MAST ± RT (axillary lymph node dissection, mastectomy with or without radiotherapy)., Results: In total, 56 patients were included in the study, of which 37 were treated by ALND + RT, 16 by ALND + MAST ± RT, and the remaining three patients receiving different treatments. The median follow-up for the 53 OBC patients sorted by treatment group was 12.2 years (interquartile range: 10.1 years; 15.3 years). There was no significant difference in OS or IDFS between the treatment groups, except for a subgroup of 46 (out of 53) patients without verified in situ lesions before treatment, where ALND + RT treatment showed an improved OS (log-rank p =0.05)., Conclusion: Treating OBC patients with ALND and radiotherapy resulted in a similar outcome as treatment with ALND and mastectomy. This supports omission of mastectomy in favor of radiotherapy of the breast in these patients., Competing Interests: Ann Søegaard Knoop reports a relationship with Novartis that includes consulting or advisory and funding grants; reports a relationship with Seagen, Inc., that includes consulting or advisory; reports a relationship with AstraZeneca that includes consulting or advisory, funding grants, and travel reimbursement; reports a relationship with Pfizer that includes consulting or advisory; reports a relationship with Roche that includes funding grants; and reports a relationship with Daiichi Sankyo, Inc., that includes consulting or advisory and funding grants. Anne-Vibeke Lænkholm reports a relationship with AstraZeneca that includes consulting or advisory and funding grants and reports a relationship with MSD Denmark that includes consulting or advisory. Tove Filtenborg Tvedskov reports a relationship with Roche that includes speaking and lecture fees; reports a relationship with Pfizer that includes speaking and lecture fees; and reports a relationship with MSD Denmark that includes travel reimbursement., (Copyright © 2024 Andreas Werner Nærum et al.)

Background: Adipose-derived mesenchymal stem/stromal cells (ASCs) are proposed as a new xerostomia treatment. The study evaluated the long-term safety and effectiveness of allogeneic ASCs in radiation-induced xerostomia among patients with previous oropharyngeal cancer., Methods: This study constitutes 3-year follow-up on the original 10 patients who received allogeneic ASCs injections to the submandibular and parotid glands as part of the MESRIX-II trial. The MESRIX-II trial included the preliminary 4-month follow-up. The primary endpoint was long-term safety. Secondary endpoints were effectiveness evaluated by changes in salivary flow rate and patient-reported outcomes (PROs). Immune response was evaluated by assessing the development of donor-specific antibodies (DSA)., Findings: All 10 MESRIX-II patients completed the long-term follow-up (ie, no missing data). During the long-term follow-up, 2 patients encountered a significant adverse event, which was determined to be unrelated to the treatment. No DSAs were detectable at 3 years. The stimulated salivary flow rate increased significantly from an average of 0.66 mL/minute at baseline to 0.86 mL/minute at follow-up, corresponding to an increase of 0.20 [95% CI 0.08 to 0.30] mL/minute, or approximately 30%. Among the PROs, sticky saliva symptoms were reduced, with a -20.0 [95% CI -37.3 to -2.7] units., Interpretation: In conclusion, this study is the first to present long-term follow-up outcomes of allogeneic ASC treatment as a therapeutic option for radiation-induced xerostomia. The study found that ASC treatment appears safe, and there were no indications of adverse immune responses at the 3-year follow-up. Further studies are warranted to evaluate the findings in larger settings., (© The Author(s) 2024. Published by Oxford University Press.)

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequent in lung cancer patients. Here, we report a case with persistent hyponatremia, which suggested malignant SIADH and facilitated an early diagnosis of small cell lung cancer (SCLC). A combined radio-chemotherapy led to a partial remission and resolution of SIADH. An early relapse was indicated by reoccurring severe hyponatremia and increased copeptin levels, which were used as surrogate markers for the antidiuretic hormone (ADH). As palliative immunochemotherapy, together with fluid restriction and solute substitution, were unable to control hyponatremia, treatment with the ADH V2-receptor antagonist tolvaptan was initiated. Over time, the dose of tolvaptan needed to be increased, paralleled by a well-documented exponential increase of copeptin levels. In summary and conclusion, this is a rare case of a secondary failure to tolvaptan with unique documentary evidence of increasing copeptin levels. This observation supports the hypothesis that exceedingly high ADH levels may lead to competitive displacement of tolvaptan from the V2 receptor., 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., (Copyright © 2024 Menzi, Jaramillo, Pfister, Schefer and Jehle.)

HLA-DRB1*03:201 differs from HLA-DRB1*03:01 in exon 3 at codon 178 resulting in a proline to serine substitution., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Summary: Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A 64-year-old woman was referred to our endocrinology clinic for a switch in treatment (from dihydrotachysterol to calcitriol). She had progressive sensorineural deafness since the age of 18 and idiopathic hypoparathyroidism diagnosed at age of 36. Her medical history included osteoporosis with hip/spine fractures, nephrolithiasis and a family history of hearing loss, osteoporosis and kidney disease. The patient's clinical presentation indicated Barakat syndrome. Genetic analysis found a GATA3:c.916C>T nonsense variant. Further tests such as audiometry, labs and renal imaging supported the diagnosis. Due to rarity and manifold symptoms, diagnosis can be challenging. Optional GATA3 testing was suggested in 2018, except in cases of isolated sensorineural deafness or renal disease with pertinent family history. In isolated 'H' cases without 'D' and 'R', GATA3 studies are not required, as no haploinsufficiency cases were reported. Given the rise in genetic disorders, physicians should consistently consider rare genetic disorders in patients with suggestive symptoms, even decades after onset. Although diagnosis might not always impact management directly, it aids patients in accepting their condition and has broader family implications., Learning Points: There is currently an important increase in genetic and clinical characterization of new orphan diseases and their causative agents. Unbiased re-evaluation for possible genetic disorders is necessary at every consultation. It is essential to recognize the differential diagnosis of idiopathic hypoparathyroidism. The patient's clinical presentation and family history can be important to establish the correct diagnosis. Physicians should not hesitate to search a patient's signs and symptoms online.

Background: Chronic low back pain (CLBP) is a global health problem, and gabapentin and pregabalin are often used in the treatment of patients without associated radiculopathy or neuropathy. Therefore, determining their efficacy and safety is of enormous value., Objective: To examine the efficacy and safety of using gabapentin and pregabalin for CLBP without radiculopathy or neuropathy., Methods: We performed a search on the CENTRAL, MEDLINE, EMBASE, LILACS, and Web of Science data bases for clinical trials, cohorts, and case-control studies that evaluated patients with CLBP without radiculopathy or neuropathy for at least eight weeks. The data were extracted and inserted into a previously-prepared Microsoft Excel spreadsheet; the outcomes were evaluated using the Cochrane RoB 2 tool, and the quality of evidence, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system., Results: Of the 2,230 articles identified, only 5 were included, totaling 242 participants. In them, pregabalin was slightly less efficacious than amitriptyline, the combination of tramadol/acetaminophen, and celecoxib, and pregabalin added to celecoxib showed no benefit when compared to celecoxib alone (very low evidence for all). On the other hand, although one study with gabapentin did not support its use in a general sample of patients with low back pain, another found a reduction in the pain scale and improved mobility (moderate evidence). No serious adverse events were observed in any of the studies., Conclusion: Quality information to support the use of pregabalin or gabapentin in the treatment of CLBP without radiculopathy or neuropathy is lacking, although results may suggest gabapentin as a viable option. More data is needed to fill this current gap in knowledge., Competing Interests: The authors have no conflict of interests to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Introduction: While the incidence of reverse total shoulder arthroplasty (rTSA) is increasing constantly, newer implants with designs other than the classic Grammont geometry are gaining importance. More anatomic inclination angles and lateralization are supposed to have a positive impact on clinical results and complication rates. Presentation of midterm results therefore is important to support these assumptions. The aim of this study was to report the midterm clinical outcome of primary rTSA with an uncemented humeral short-stem prosthesis (USSP) with a humeral inclination angle of 145° and the analysis of different variables on the outcome., Methods: This is a retrospective study of all patients with primary rTSA using an USSP and a combined humeral inclination angle of 145° (Ascend™ flex, Stryker) with a minimum clinical follow-up of 2 years. The implant combines a 132.5° inclination for the humeral stem with an additional 12.5° for the polyethylene inlay. Primary outcomes were patient-reported outcome measures: ASES score, simple shoulder test (SST) and subjective shoulder value (SSV). Secondary outcomes were complication and revision rates. We analyzed different variables: preoperatively gender, age, indication for surgery and status of rotator cuff. Also, the glenoid morphology was classified according to Walch and a proximal humerus cortical bone thickness measurement (CBT avg) of 6 mm was used as a threshold for osteoporosis. Postoperatively, we analyzed different radiologic parameters: filling ratio, distalization and lateralization angles according to Boutsiadis., Results: A total of 84 out of 99 (85%) patients with a mean FU of 46.7 months (range 24-80 months) could be included: 62 women and 22 men with a mean age of 74.7 years. Mean ASES score significantly increased from 47 preoperatively to 85.8 at the last follow-up (p = 0.001). The postoperative SST reached an average of 65.3 and the mean SSV was 83%. None of the variable parameters analyzed could be identified as a risk factor for a lower outcome defined as a SSV < 70. Three patients (3.6%) had a complication: one incomplete lower plexus lesion, one dislocation and one major hematoma. Surgical revision was needed in two cases (2.4%)., Conclusion: The midterm clinical outcome of primary reverse total shoulder arthroplasty (rTSA) with an uncemented humeral short stem and a humeral inclination angle of 145° showed good-to-excellent results with a low complication and revision rate independent from a wide range of pre- and postoperative variables. PROMs are comparable to those reported for anatomic TSA with a low complication rate, different to historical studies especially with the Grammont design., Level of Evidence: Treatment study, Level IV., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The Samilson-Prieto classification (SPC) depending on the humeral osteophyte length on a-pX-rays today is widely used to classify glenohumeral osteoarthritis in general. For treatment planning and prognosis, the patho-morphology of the glenoid and static posterior subluxation of the humeral head classified according to Walch is of much higher importance. Here, usually a CT or MRI scan is required for a correct classification. A possible correlation between both classifications is poorly explored. Without it, the complexity of the case might be mis-interpreted using the SPC. The aim of this study was to investigate such a correlation, i.e. whether it correlates with the glenoid deformity and degree of humeral head subluxation., Patients and Methods: Radiological datasets (X-ray and CT or MRI) of 352 patients with primary OA of the shoulder were evaluated by two observers experienced in shoulder surgery. For the Samilson-Prieto classification, true a-p shoulder radiographs and for the modified Walch classification CT or MRI scans in the axial plane were interpreted using a validated method. To investigate a correlation between both classifications, the Fisher's exact test was used. For the interobserver reliability, the weighted kappa coefficient κ was determined., Results: For the Walch classification, both observers found a similar percentage for the different types, with decreasing numbers from normal (type A1) to severely altered glenoids In the Samilson-Prieto classification, OA grade I was predominant, while grade II and III showed a relatively equal distribution. Interobserver reliability was high both for the Walch classification with a κ 0.923 (95% confidence interval 0.892; 0.954) and) for the SPC with a κ 0.88 (95% confidence interval 0.843; 0.916). A correlation between the two classifications in Fischer's exact test could not be shown (p = 0.584)., Discussion: Since there is no correlation between both, using the Samilson-Prieto classification alone might miss relevant prognostic factors in gleno-humeral OA. Adequate imaging of the glenoid morphology also in the axial plane is absolutely mandatory to understand the complexity and chose the right treatment for each patient., Level of Evidence: Study of Diagnostic Test-Level II., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objective: To describe the technical specificities and feasibility of simulation of minimally invasive spine surgery in live pigs, as well as similarities and differences in comparison to surgery in humans., Methods: A total of 22 Large White class swine models, weighing between 60 and 80kg, were submitted to surgical simulations, performed during theoretical-practical courses for training surgical techniques (microsurgical and endoscopic lumbar decompression; percutaneous pedicular instrumentation; lateral access to the thoracic spine, and anterior and retroperitoneal to the lumbar spine, and management of complications) by 86 spine surgeons. For each surgical technique, porcine anatomy (similarities and differences in relation to human anatomy), access route, and dimensions of the instruments and implants used were evaluated. Thus, the authors describe the feasibility of each operative simulation, as well as suggestions to optimize training. Study results are descriptive, with figures and drawings., Results: Neural decompression surgeries (microsurgeries and endoscopic) and pedicular instrumentation presented higher similarities to surgery on humans. On the other hand, intradiscal procedures had limitations due to the narrow disc space in swines. We were able to simulate situations of surgical trauma in surgical complication scenarios, such as cerebrospinal fluid fistulas and excessive bleeding, with comparable realism to surgery on humans., Conclusion: A porcine model for simulation of minimally invasive spinal surgical techniques had similarities with surgery on humans, and is therefore feasible for surgeon training.

HLA-DQA1*01:65 differs from HLA-DQA1*01:03 in exon 1 at amino acid -7 a valine to methionine substitution., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DPA1*01:46 differs from HLA-DPA1*01:03 in exon 2 at amino acid 85; Aspartate to Asparagine substitution., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Allogeneic haematopoietic stem cell transplantation is a clinical example of precision medicine, as one individual donor is selected for one individual patient based on genetic findings in the human leukocyte antigen (HLA) system. Unrelated donor search for Danish patients is based on an international collaboration between global registries hosting more than 37 million potential donors worldwide for patients in need. The implementation of next-generation sequencing technologies has been a revolution in donor registry typing due to more precise, detailed and cheaper HLA analyses, which is discussed in this review.

Diet has been hypothesized to be associated with neurodegenerative disorders. The aim was to conduct an umbrella review to summarize and evaluate the current evidence of prospective associations between any dietary factors and the incidence of neurodegenerative disorders. We conducted a systematic search in PubMed, Embase, and the Cochrane library up to November 2019 to identify systematic reviews with meta-analyses of prospective studies investigating the association between dietary factors (dietary patterns, foods and beverages, nutrients, and phytochemicals) and neurodegenerative disorders (cognitive decline, cognitive impairment, Alzheimer disease, all-cause dementia, and Parkinson disease). Summary risk ratios (SRRs) and 95% CIs were recalculated using a random effects model. We evaluated the risk of bias of identified meta-analyses and the quality of evidence for all associations. In total, 20 meta-analyses including 98 SRRs were identified. All original meta-analyses were rated as being at high risk of bias. Methodological concerns related mainly to the inappropriate synthesis, assessment, and discussion of the risk of bias of primary studies. For the recalculated meta-analyses, quality of evidence was moderate for inverse associations between higher adherence to the Mediterranean diet (SRR: 0.63; 95% CI: 0.48, 0.82; n = 4 primary studies) and higher fish intake (SRR: 0.72; 95% CI: 0.59, 0.89; n = 6) and Alzheimer disease, as well as for tea consumption and all-cause dementia (SRR: 0.74; 95% CI: 0.63, 0.88; n = 2) and Parkinson disease (SRR per 2 cups/d: 0.69; 95% CI: 0.54, 0.87; n = 5). This umbrella review provides a comprehensive overview of the available evidence on dietary factors and neurodegenerative disorders. The results indicate that the Mediterranean diet, fish, and tea could be inversely associated with neurodegenerative disorders. However, the quality of evidence was generally low, suggesting that further studies are likely to change the overall estimates. Thus, more well-conducted research, also investigating other dietary factors in association with neurodegenerative disorders, is warranted., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

We present the case of a kidney transplant patient (Cockroft-Gault estimated creatinine clearance 14 ml/min) who was inadvertently eight-fold overdosed with a single dose of 500 mg intravenous ganciclovir. To prevent the immunosuppressed patient from being exposed to severe risks of prolonged ganciclovir overdosing, including potentially fatal bone marrow suppression and severe neurotoxicity, the patient was treated with hemodiafiltration (HDF) to enhance drug elimination. Since the product label reports a 50% decrease of ganciclovir plasma concentrations after intermittent hemodialysis (HD), two HDF sessions were considered necessary to achieve a ≥75% elimination of the drug by precaution, despite targeted intense HDF prescription. Ganciclovir plasma concentration data were obtained during both HDF sessions and were analyzed retrospectively. Pharmacokinetic analysis revealed that prescribed HDF successfully decreased drug plasma concentrations by ≥90%. This ganciclovir reduction ratio matched the urea reduction ratio achieved (≥92%). Model-based assessment of ganciclovir dialysis clearance (estimated to be 445 ml/min), accounting for its two-compartmental kinetics, was higher than urea dialysis clearance (estimated to be 310 ml/min). This suggests potential relevant accumulation of ganciclovir into blood cells, at least in this patient after overdosing. The amount (fraction) of drug removed by 1 st HDF was estimated to 269 mg (93% of total amount of 288 mg eliminated during the 1 st HDF session; estimated amount in the body prior to 1 st HDF: 380 mg). A literature review was performed to summarize and systematically compare available information on ganciclovir elimination during intermittent renal replacement therapy. In conclusion, the high ganciclovir HDF clearance measured in our patient largely exceeded previously reported elimination during HD, meaning that HDF prescription was highly efficient in the present case, and that a second HDF session might not have been necessary. This finding may be considered to guide renal replacement therapy in the scope of drug overdosing. It may also be evaluated for ganciclovir dose adjustment in patients on chronic HD or HDF with high small solute clearance, since a strong correlation between ganciclovir and urea elimination efficiency was observed., (Copyright © 2020 Gotta, Leuppi-Taegtmeyer, Gessler, Pfister, Müller and Jehle.)

Carcinoma showing thymus-like elements (CASTLE) is a rare tumor, most commonly found in the thyroid gland. Here we report a case of CASTLE tumor localized to the parotid gland, recognized in retrospect after a late manifestation of symptomatic pleural carcinomatosis. The original tumor in the parotid gland was treated by surgery followed by radiotherapy. Ten years later, a metastatic disease with recurrent pleural effusions occurred. Pleural carcinomatosis was strongly positive for CD5, CD117, and p63 as was the original tumor of the parotid, which allowed the diagnosis of a CASTLE tumor. Additionally, the pleural tumor expressed high levels of programmed death ligand 1 (PD-L1), and the patient underwent treatment with the monoclonal PD-L1 inhibitor pembrolizumab achieving a partial remission. To the best of our knowledge, this is the first patient with a metastatic CASTLE tumor treated with a PD-L1 inhibitor.

Introduction: Lumbar pain of facet origin is a common problem worldwide. For those patients not responding to traditional treatment, one approach may be intra-articular infiltration of corticoid and anaesthetic. However, despite the increasing demand for this procedure, no consensus exists regarding its therapeutic value. The selection of eligible participants may be a determining factor since only those with an inflammatory process will benefit from the use of corticosteroids. This study aims to identify differences in disability, pain and quality of life scores in individuals with and without facet joint inflammation who were diagnosed using MRI., Method and Analysis: This prospective cohort will include individuals older than 18 years with a clinical diagnosis of facet syndrome who underwent intra-articular infiltration. Changes in scores of pain, disability and quality of life questionnaires at 1, 3, 6 and 12 months of follow-up compared with baseline will be analysed. An MRI examination performed before infiltration will help to distinguish between exposed (with inflammation) and non-exposed (non-inflammation) groups with facet syndrome. The primary outcome will be the disability questionnaire (Roland Morris), and the secondary outcomes will be the score questionnaires for pain (Visual Analogue Scale), quality of life (EuroQol Quality of Life Questionnaire) and disability (Oswestry)., Ethics and Dissemination: The Internal Review Board approved this study, which started only after the approval number (5291417.0.0000.0071) was received. All recruited participants will receive a verbal explanation about the purpose of the study, and their decision to participate will be free and voluntary. All participants enrolled in the study will provide a signed informed consent form including confidentiality terms. The results obtained in this study will be presented at national and international conferences and published in peer-reviewed scientific journals to disseminate the knowledge., Trials Registration Number: NCT03304730; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Degenerative lumbar spinal stenosis is a condition related to aging in which structural changes cause narrowing of the central canal and intervertebral foramen. It is currently the leading cause for spinal surgery in patients over 65 years. Interspinous process devices (IPDs) were introduced as a less invasive surgical alternative, but questions regarding safety, efficacy, and cost-effectiveness are still unanswered., Objectives: The aim of this study was to provide complete and reliable information regarding benefits and harms of IPDs when compared to conservative treatment or decompression surgery and suggest directions for forthcoming RCTs., Methods: We searched MEDLINE, EMBASE, Cochrane Library, Scopus, and LILACS for randomized and quasi-randomized trials, without language or period restrictions, comparing IPDs to conservative treatment or decompressive surgery in adults with symptomatic degenerative lumbar spine stenosis. Data extraction and analysis were conducted following the Cochrane Handbook. Primary outcomes were pain assessment, functional impairment, Zurich Claudication Questionnaire, and reoperation rates. Secondary outcomes were quality of life, complications, and cost-effectiveness. This systematic review was registered at Prospero (International prospective register of systematic reviews) under number 42015023604., Results: The search strategy resulted in 17 potentially eligible reports. At the end, nine reports were included and eight were excluded. Overall quality of evidence was low. One trial compared IPDs to conservative treatment: IPDs presented better pain, functional status, quality of life outcomes, and higher complication risk. Five trials compared IPDs to decompressive surgery: pain, functional status, and quality of life had similar outcomes. IPD implant presented a significantly higher risk of reoperation. We found low-quality evidence that IPDs resulted in similar outcomes when compared to standard decompression surgery. Primary and secondary outcomes were not measured in all studies and were often published in incomplete form. Subgroup analysis was not feasible. Difficulty in contacting authors may have prevented us of including data in quantitative analysis., Conclusions: Patients submitted to IPD implants had significantly higher rates of reoperation, with lower cost-effectiveness. Future trials should improve in design quality and data reporting, with longer follow-up periods., Competing Interests: The authors have declared that no competing interests exist.

The aim of the present study was to document the changes in bone mineral density (BMD) 1 year after denosumab loss-of-effect following long-term treatment with subcutaneous denosumab 60 mg Q6M during 7 or 10 years and in the absence of any treatment with a bone active substance. All postmenopausal women with osteoporosis who participated to the randomized placebo-controlled FREEDOM core trial and its open-label extension at the University Hospital of Bern, Switzerland, and who accepted to undergo off-treatment follow-up during 1 year after discontinuation, were included (N = 12). After 10 years of denosumab, mean lumbar spine (LS) BMD had increased by 21.2% vs. baseline. One year after discontinuation LS BMD had decreased by - 9.1% vs. Year 10, resulting in a net gain of 10.2% vs. baseline. At total hip (TH) and femoral neck (FN), BMD had increased by 8.3 and 8.1% in Year 10 vs. baseline, respectively. 1 Year after discontinuation, BMD had decreased by - 12.7 and - 11.0% vs. Year 10, respectively, corresponding to net BMD losses of - 5.5 and - 3.8% vs. baseline, respectively. Similar albeit less pronounced changes were observed in those treated with denosumab during 7 years. Stopping denosumab after long-term exposure resulted in BMD losses of large order of magnitude at all measured sites, suggesting that treatment duration may predict the rate and amount of bone lost.

Progressive kidney diseases affect approximately 500 million people worldwide. Podocytes are terminally differentiated cells of the kidney filter, the loss of which leads to disease progression and kidney failure. To date, there are no therapies to promote podocyte survival. Drug repurposing may therefore help accelerate the development of cures in an area of tremendous unmet need. In a newly developed high-throughput screening assay of podocyte viability, we identified the BRAF V600E inhibitor GDC-0879 and the adenylate cyclase agonist forskolin as podocyte-survival-promoting compounds. GDC-0879 protects podocytes from injury through paradoxical activation of the MEK/ERK pathway. Forskolin promotes podocyte survival by attenuating protein biosynthesis. Importantly, GDC-0879 and forskolin are shown to promote podocyte survival against an array of cellular stressors. This work reveals new therapeutic targets for much needed podocyte-protective therapies and provides insights into the use of GDC-0879-like molecules for the treatment of progressive kidney diseases., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background/objective: Spatial knowledge of the anatomy of the proximal humerus is critical for effective treatment, particularly in patients affected by fragility fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) imaging with medical image processing techniques enable three dimensional (3D) analysis of volumetric bone mineral density (vBMD) of bones of different sizes and shapes., Methods: To elucidate the bony anatomy and to create 3D reference data, we conducted a computerized HR-pQCT-based study in intact postmortem samples of the proximal humerus to highlight the anatomy with particular emphasis on the size, shape, and bone stock distribution pattern.Fifty-eight defrozen intact humerus samples from 28 female and 30 male donors, who were aged 61-98 years old (mean age ± standard deviation, 80.6 ± 9 years), were scanned in the proximal third using the extended standard HR-pQCT protocol. A 3D statistical bone and averaged bone density models with low, middle, and high total vBMDs were computed. We examined the 3D patterns of size and shape variations using principal component analysis, and the vBMD distributions and variabilities using volume-rendering and virtual bore probing., Results: The computer models revealed a highly variable bony anatomy in which size was the predominant variation in the first principal component (PC). In the second PC, we observed notable variabilities in the shape of the head and shaft inclination. A distinct 3D pattern of bone stock distribution was detected in which the lowest vBMD values were identified in the medullary cavity, middle values were identified in the central zone, and the highest values were identified in the cortex and humeral head-particularly in the subarticular zones. In the presence of bone loss, the vBMD values were ubiquitously decreased, but the pattern of 3D bone stock distribution was maintained., Conclusion: The new anatomical 3D data that we acquired will improve the understanding of the normal bony anatomy of the proximal humerus. The extended HR-pQCT protocol and computer models may be used for other skeletal sites and used as 3D reference models that can be applied to systematically improve implant design and anchorage.

Diabetic nephropathy is the most common cause of end-stage renal disease and is associated with a high morbidity and mortality. Early diagnosis is important as tight control of albuminuria and hypertension improves the renal prognosis. Similarly, good control of hyperglycemia is critical, but emphasis should be given on individualization of treatment goals. Once the estimated GFR is < 60 ml/min/1.73 m2 the antidiabetic medication needs to be reviewed and a dose reduction of many drugs is necessary. The risk for hypoglycemia is particularly high for the sulfonylureas glibenclamide and glimepiride and they are contraindicated once the GFR is < 60 ml/min/1.73 m2. Because of the increased risk of lactic acidosis, metformin requires a dose adjustment if the GFR is < 60 ml/min/1.73 m2 and the drug should be stopped once the GFR falls < 45 ml/min/1.73 m2. In addition, metformin needs to be paused if acute renal failure is imminent. Inhibitors of the DPP-4 enzyme can be employed with impaired renal function, but their use usually requires dose adjustments. Prescription of GLP-1 receptor agonists is possible with a moderately impaired renal function but they should be discontinued if the GFR falls < 30/min/1.73 m2. From the new class of SGLT2 inhibitors canagliflozin and empagliflozin can be used in an adjusted dose as long as the GFR is > 45 ml/min/1.73 m2.

Podocyte injury and loss critically contribute to the pathogenesis of proteinuric kidney diseases including diabetic nephropathy. Deregulated lipid metabolism with disturbed free fatty acid (FFA) metabolism is a characteristic of metabolically unhealthy obesity and type 2 diabetes and likely contributes to end-stage kidney disease irrespective of the underlying kidney disease. In the current review, we summarize recent findings related to FFAs and altered renal FFA metabolism with a special focus on podocytes. We will outline the opposing effects of saturated and monounsaturated FFAs and a particular emphasis will be given to the underlying molecular mechanisms involving insulin resistance and endoplasmic reticulum homeostasis. Finally, recent data suggesting a critical role of renal FFA metabolism to adapt to an altered lipid environment will be discussed.

Study Design: A systematic review and meta-analysis of randomized controlled trials., Objective: To assess treatment effects (benefits and harms) of radiofrequency denervation for patients with facet joint-related chronic low back pain., Summary of Background Data: There is no consensus regarding the treatment efficacy of facet joint radiofrequency denervation (FJRD) and how it compares with nerve blockades and joint infiltration with anesthetics and/or corticosteroids., Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS for randomized controlled trials that compared FJRD with blockades, infiltrations, or placebo. Primary outcomes were pain, functional status, and quality of life. Secondary outcomes were cost-effectiveness and complications., Results: Fifteen studies were selected and 9 were eligible. Overall quality of evidence was rated low to moderate. The evidence favored FJRD regarding pain control. There was no sufficient evidence for cost-effectiveness and complications., Conclusion: The available evidence reviewed in this study should be interpreted with caution. The data indicate that FJRD is more effective than placebo in pain control and functional improvement and is also possibly more effective than steroid injections in pain control. Complications and adverse effects were not sufficiently reported to allow comparisons, and there was no evidence for cost-effectiveness. High-quality randomized controlled trials addressing pain, function, quality of life, complications, and cost-effectiveness are urgently needed., Level of Evidence: 1.

Background: In allogeneic hematopoietic stem cell (HSC) transplantation, collection of a sufficient number of HSCs at a fixed time point is crucial. For HSC mobilization into the peripheral blood, the standard regimen, that is, granulocyte-colony-stimulating factor (G-CSF), may be inadequate. Use of plerixafor as adjuvant to G-CSF is so far off-label in healthy donors., Study Design and Methods: We present six cases in which the "just-in-time" addition of plerixafor ensured proper CD34+ collection from healthy donors with insufficient G-CSF mobilization. In four of these cases a high number of CD34+ cells was needed due to subsequent CD34+ selection or haploidentical transplantation., Results: From all six donors a sufficient number of CD34+ cells was obtained by using plerixafor as an adjuvant to G-CSF. This treatment regimen resulted in only mild side effects for the donor., Conclusion: We have presented six cases with different causes leading to insufficient G-CSF mobilization in allogeneic donors and in which the administration of plerixafor just-in-time ensured a proper graft for transplantation., (© 2013 American Association of Blood Banks.)

Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.

This study evaluated the effects of supplemental low- and high-purity glycerine on silage intake, milk yield and composition, plasma metabolites and body condition score (BCS) in dairy cows. A total of 42 cows of the Swedish Red Breed, housed in individual tie stalls, were fed 0.25 kg of low- or high-purity glycerine on top of concentrate, twice daily, during the first 4 weeks of lactation. One-third of the cows acted as controls, receiving no glycerine. Silage was fed for ad libitum intake and concentrate was fed at restricted level of intake, about 6 kg/day for primiparous cows and 7 kg/day for multiparous cows. Feed refusals were weighed daily. Cows were milked twice daily, milk yield was recorded on four occasions per week and milk samples were collected simultaneously. Blood samples were drawn from the coccygeal vessel once a week. Low- and high-purity glycerine had no effect on silage or total dry matter intake (P = 0.38 and P = 0.75, respectively) or on BCS (P = 0.45). Cows fed high-purity glycerine tended to have higher milk yield than control cows (P = 0.06). Milk composition tended to differ among treatments. No main effects of treatment on concentration of glycerine (P = 0.44), glucose (P = 0.78), insulin (P = 0.33), non-esterified fatty acids (P = 0.33) and β-hydroxybutyrate (P = 0.15) in plasma. These data indicate that high-purity glycerine has the potential to increase milk yield, as well as enhance the milk protein concentration and milk fat + protein yield.

Objective: It is well-known that migraine attacks can be precipitated by various stimuli. More than 50% of patients with migraine with aura (MA) know of at least one stimulus that always or often triggers their MA attacks. The objective of this study was to expose patients with MA to their self-reported trigger factors in order to assess the causal relation between trigger factors and attacks., Methods: We recruited 27 patients with MA who reported that bright or flickering light or strenuous exercise would trigger their migraine attacks. The patients were experimentally provoked by different types of photo stimulation, strenuous exercise, or a combination of these 2 factors. During and following provocation, the patients would report any aura symptoms or other migraine-related symptoms., Results: Of 27 provoked patients with MA, 3 (11%) reported attacks of MA following provocation. An additional 3 patients reported migraine without aura attacks. Following exercise, 4 out of 12 patients reported migraine, while no patients developed attacks following photo stimulation., Conclusion: Experimental provocation using self-reported natural trigger factors causes MA only in a small subgroup of patients with MA. Prospective confirmation is important for future studies of migraine trigger factors and in the clinical management of patients with migraine.

Background and aims NXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5HT-1B/1D receptor agonist which has previously shown efficacy in the acute treatment of migraine. Nitric oxide (NO) is involved in the pathogenesis of migraine pain and is formed after cortical spreading depression. Therefore NXN-188 could perhaps prevent the development of the headache phase in migraine with aura if taken during the aura. The aims of the present study were to evaluate the efficacy and safety of 600mg NXN-188 in the acute treatment of migraine when dosed during the aura. Methods A single-centre, randomized, double-blind, placebo-controlled, two-way crossover trial. The study medication was taken during the aura and the patients kept a study diary for 48h post-dose. Results Of 615 patients screened, 50 patients were included in the study and randomized. Only 18 patients completed both treatments in compliance with the study procedures. 22% of patients reported freedom of headache at 2h after intake of NXN-188 compared with only 11% of patients after placebo. Conclusions The dual-action drug NXN-188 with 5HT-1B/1D agonism and nNOS inhibition, taken orally during the aura phase did not have a statistically substantial effect on migraine headache in this study. This study was limited by a high drop-out rate and small sample of included patients who were able to complete the cross-over protocol. Therefore, efficacy of the treatment cannot be refuted with certainty. Implications This study illustrates the difficulties of doing well controlled studies in migraine patients with aura. nNOS inhibition is expected to be effective mostly in the aura phase, i.e. the oral administration may have had too slow pharmacokinetics to have effect. Parenteral administration may overcome this obstacle. 5HT-1B/1D agonism is not effective when dosed during migraine aura. Repeated dosing of the NXN-188 during and immediately following the aura may have exploited more the dualaction. The high drop-out rate may be reduced in future studies by having the patients familiarize themselves with the study procedure by filling out the attack report form while treating one attack with their own medication before entering the trial. A parallel group comparison may be a more effective trial design for treatment during an aura.

Objective: The aim was to identify and describe migraine trigger factors in patients with familial hemiplegic migraine (FHM) from a population-based sample., Methods: 127 FHM patients were sent a questionnaire listing 16 trigger factors. Distinction was made between attacks of hemiplegic migraine (HM) and migraine with aura (MA) or without aura (MO) within each patient., Results: The response rate was 59% (75/127) of whom 57 (76%) had current HM attacks. Sixty-three per cent (47/75) reported at least one factor triggering HM, and 36% (27/75) reported at least one factor that often or always caused HM. Twenty per cent (15/75) reported only HM, whereas FHM in combinations with MA and MO were reported by 80% (60/75). Stress (with attacks either following or during the stress), bright light, intense emotional influences and sleeping too much or too little were the trigger factors mentioned by most., Conclusion: Many FHM patients report trigger factors and one-third reported at least one trigger factor often or always triggering FHM. The typical triggers are the same as for MA. Patients should be educated to avoid these factors. The role of trigger factors in the onset of new or first attacks of FHM remains unknown.

Objective: The aim of the present study was to characterize perceived consistent triggers of migraine with aura (MA)., Method: Questionnaires specifically designed to characterize various trigger factors were sent to 181 participants identified in an earlier study. All participants had formerly identified at least one factor that often or always triggered an MA attack. They only answered questions regarding this or these factor(s)., Results: The response rate to the questionnaire was 70% (126/179). A number of subtype triggers were mentioned by a high proportion of patients: too much work (under the stress category 54/64), reflected sunlight (under the light category 35/44), too little sleep (under the sleep category 19/24), red wine (under the alcohol category 20/22), passive smoking (under the smoke category 11/11), menstruation (under the menstruation or break from the pill category 12/14) and perfume (under the fumes/heavy scents category 12/15). Hormones, light and stress were reported to cause at least 50 % of MA attacks in 62%, 47% and 42% of participants, respectively. No participants reported alcohol to be the trigger of 50% or more of their attacks. In the groups of participants with "light", "fumes/heavy scents", "smoke" or "physical effort" as triggers, nearly all patients reported that an exposure time to the trigger of less than 3 hours (90-100% of patients) was necessary to trigger an attack and a latency to onset of attack of less than 3 hours (90-100% of patients)., Conclusion: Our study has provided new knowledge about factors that in particular patients consistently trigger MA. In daily routine practice this information should be helpful in identifying factors to avoid. Patients with trigger factors that always or usually trigger attacks of MA will be highly useful for imaging and other experimental studies.

Introduction: Calcitonin gene-related peptide (CGRP) is a key molecule in migraine pathogenesis. Intravenous CGRP infusion triggers delayed migraine-like attacks in patients with migraine without aura (MO). In contrast to patients with MO, in prior studies patients with familial hemiplegic migraine (FHM) did not report more migraine-like attacks compared to controls. Whether CGRP triggers migraine in patients with typical (non-hemiplegic) migraine with aura is (MA) unknown. In the present study we examined the migraine inducing effect of CGRP infusion in patients suffering from MA and healthy controls., Methods: Fourteen patients suffering exclusively from migraine with typical aura (MA) and 11 healthy volunteers received a continuous intravenous infusion of 1.5 µg/min CGRP over 20 minutes. Headache and other migraine symptoms were scored every 10 minutes for one hour and self recorded hourly thereafter and until 13 hours post-infusion., Results: CGRP infusion induced significantly more delayed headaches in MA patients (12 out of 14) than in controls (2 out of 11) (p = 0.001). Furthermore, significantly more MA patients (57%; 8 out of 14) fulfilled criteria for an experimentally induced migraine attack after CGRP than controls (0%; 0 out of 11) (P = 0.003). Four patients (28%) reported aura symptoms after CGRP infusion., Conclusion: CGRP triggered migraine-like attacks without aura in patients suffering exclusively from MA. It also triggered a typical aura in 28% of the patients. These data indicate similar neurobiological pathways responsible for triggering migraine headache in MA and MO patients, and suggest differences between MA/MO and FHM.

Apoptosis of podocytes is considered critical in the pathogenesis of diabetic nephropathy (DN). Free fatty acids (FFAs) are critically involved in the pathogenesis of diabetes mellitus type 2, in particular the regulation of pancreatic β cell survival. The objectives of this study were to elucidate the role of palmitic acid, palmitoleic, and oleic acid in the regulation of podocyte cell death and endoplasmic reticulum (ER) stress. We show that palmitic acid increases podocyte cell death, both apoptosis and necrosis of podocytes, in a dose and time-dependent fashion. Palmitic acid induces podocyte ER stress, leading to an unfolded protein response as reflected by the induction of the ER chaperone immunoglobulin heavy chain binding protein (BiP) and proapoptotic C/EBP homologous protein (CHOP) transcription factor. Of note, the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of CHOP, thereby preventing cell death. Similarly, gene silencing of CHOP protects against palmitic acid-induced podocyte apoptosis. Our results offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward unsaturated FFAs can delay the progression of DN.

Introduction: Specific problems occur in clinical treatment trials for migraine with aura that differ from those encountered in treatment trials for migraine without aura., Discussion: Based on our experience with four such trials, we point to a number of possible solutions and outline areas for future inquiry. We make recommendations about subject selection; the choice, definition and assessment of outcome measures; optimal treatments in relation to aura and headache; and we provide samples of study report forms used to record occurrence of aura and headache in this population.

This study investigated the effects of varying doses of L-NAME on arterial pressure (AP), baroreflex control, and heart rate (HR)/AP variability in the STZ-diabetic rat. Fifty-two male Wistar rats were injected with 50 mg/kg IV STZ (diabetes, D, n = 24) or citrate (controls, C, n = 28) 30 days before recordings. After 16 days, they received 14 days of oral L-NAME, 10 (H10) or 30 (H30) mg/kg, or water. Catheters were implanted into the femoral artery and vein (PE-10) for measurements in conscious rats; recorded data were analyzed on a beat-to-beat basis. Mean AP was higher in CH30 versus C and in DH10 and DH30 versus D rats. Reflex tachycardia was blunted in CH30 and DH30 rats (b = -1.81, -1.41, -0.48 in C, CH10, and CH30, respectively, P < 0.05 and b = -1.45, -1.19, -0.28 in D, DH10, and DH30, respectively, P < 0.05). Although HR and AP variability were reduced in CH30 and DH30 rats versus C and D rats, the DH30 rat had more accentuated dysfunction. All doses of L-NAME produced similar AP responses in experimental versus control groups, independent of the disease state (diabetes). Thus, autonomic dysfunction is more related to the L-NAME dose used and to the association of diabetes and hypertension than to AP values.

Foraminal and extra-foraminal disc herniations comprise up to 11.7% of all lumbar disc herniations. Facetectomy, which had been the classic approach, is now recognized as cause of pain and instability after surgery. Otherwise, posterior lateral approaches through a trans-muscular or a para-muscular technique offer no significant damage to key structures for spinal stability. The surgical anatomy of these approaches has already been described, but they were not compared. In order to quantify the angle of vision towards the intervertebral foramen offered by each technique, 12 fresh cadavers were dissected and studied regarding these approaches. The angle presented by trans-muscular approach was wider in all studied lumbar levels. Surgery through the trans-muscular approach is performed with a better working angle, requiring a smaller resection of surrounding tissues. Therefore, minor surgical trauma can be expected. Our measurements support previously published data that point the trans-muscular approach as the best surgical option.

Purpose: The goal of this study was to evaluate the intra-articular pathology in patients with atraumatic shoulder instability who did not respond to conservative treatment., Type of Study: Prospective case series., Methods: Of 226 patients treated for shoulder instability over a 2-year-period, 43 patients (average age, 27.5 years; 26 men and 17 women) were classified as having atraumatic instability. None had responded to physiotherapy. The intra-articular pathology was documented during diagnostic arthroscopy before the definitive surgical procedure., Results: Three types of lesions of the capsulolabral complex were defined: incomplete labral lesions, pathologic elongation of the capsule or "non-Bankart lesions" (type I), classic Bankart lesions (type II), and complex lesions of the labrum and capsule (type III). Type I was found in 19 patients (44.2%); type II lesions were seen in 13 (30.2%); and type III in 11 (25.6%) patients. Hill-Sachs lesions were found in 26 shoulders (60.5%). Chondral lesions of the glenoid were seen in 10 shoulders (23%); SLAP lesions in 5 (11.7%); and partial, articular-side defects of the supraspinatus tendon in 3 (6.9%) patients., Conclusions: Atraumatic onset of shoulder instability does not imply the absence of intra-articular lesions, at least in patients not showing a response to physiotherapy. Arthroscopy is helpful to diagnose the definite intra-articular pathology., Level of Evidence: Level IV.

ATP-binding cassette transporter 1 (ABCA1), the defective transporter in Tangier disease, binds and promotes cellular cholesterol and phospholipid efflux to apolipoprotein I (apoA-I). Based on a high degree of sequence homology between ABCA1 and ABCA7, a transporter of unknown function, we investigated the possibility that ABCA7 might be involved in apolipoprotein binding and lipid efflux. Similarly to cells expressing ABCA1, HEK293 cells overexpressing ABCA7 showed specific binding and cross-linking of lipid-poor apoA-I. ABCA7 expression increased cellular phosphatidylcholine and sphingomyelin efflux to apoA-I in a manner similar to ABCA1 but had no effect on cholesterol efflux. Western analysis showed a high protein level of ABCA7 in mouse spleen, lung, adrenal, and brain but low expression in liver. In contrast to ABCA1, ABCA7 showed moderate basal mRNA and protein levels in macrophages and lymphocytes but no induction by liver X receptor activation. These studies show that ABCA7 has the ability to bind apolipoproteins and promote efflux of cellular phospholipids without cholesterol, and they suggest a possible role of ABCA7 in cellular phospholipid metabolism in peripheral tissues.