Single-cell-led drug repurposing for Alzheimer's disease.

Alzheimer's disease is the most common form of dementia. Notwithstanding the huge investments in drug development, only one disease-modifying treatment has been recently approved. Here we present a single-cell-led systems biology pipeline for the identification of drug repurposing candidates. Using single-cell RNA sequencing data of brain tissues from patients with Alzheimer's disease, genome-wide association study results, and multiple gene annotation resources, we built a multi-cellular Alzheimer's disease molecular network that we leveraged for gaining cell-specific insights into Alzheimer's disease pathophysiology and for the identification of drug repurposing candidates. Our computational approach pointed out 54 candidate drugs, mainly targeting MAPK and IGF1R signaling pathways, which could be further evaluated for their potential as Alzheimer's disease therapy.

One-stage complete eradication and revision hip due to pseudotumor in metal-on-metal hip arthroplasty.

Background: The correct management and treatment of pseudotumors due to metal-on-metal (MOM) hip arthroplasty are still debated. The purpose of this study is to analyze the surgical treatment and the clinical and radiographic 3-year outcomes of MOM arthroplasty revisions due to pseudotumor treated with a strategy of excision and revision. Methods: Consecutive, retrospective series of 21 patients (8 males/13 females) with pseudotumor due to MOM hip arthroplasty was surgically treated at a single tertiary center. Demographic, clinical, radiological and implant-related features were collected pre-operatively. Post-revision clinical and radiographic parameters were evaluated. Chromium (Cr) and cobalt (Co) blood samples were collected before and after surgery. Results: Three patients (14.2%) with pseudotumor underwent a resection arthroplasty due to infection (perioperative finding) and could not be reimplanted due to septic relapses. Twenty (95.2%) pseudotumors were completely resected. Revisions [2 total hip reimplantations (11.1%) and 16 isolated component revisions (88.9%)] were performed with non-MOM couplings. A clinical improvement at a mean post-revision follow-up 3.3 years [standard deviation (SD), ±2.2 years] was observed, from 50.3 (SD, ±4.6) to 88.3 (SD, ±9.2) Harris hip score (HHS) points (P<0.001). Among revisions, there were 5 complications (23.8%): 1 dislocation, 1 psoas impingement, and 3 infections (14.2%). No re-revision was carried out. Three (14.2%) pseudotumors recurred: 1 was surgically treated, 1 was treated with selective arterial embolization, and 1 clinically followed. At the final follow-up, Cr and Co blood ions beyond the threshold decreased from 85.7% cases to 0% in the seven patients that could be evaluated. Conclusions: The one-stage strategy of radical excision and revision with non-MOM couplings in pseudotumors due to MOM hip arthroplasty achieved good 3-year outcomes. However, complications were frequent (23%). Recurrences were not rare (14%) and did not require implant re-revision.

Isolated arthroscopic treatment of intra-articular pathologies in mild hip dysplasia: a short-term case control study.

PURPOSE: The aim is to compare the results of isolated hip arthroscopy in patients with borderline dysplasia with Lateral center edge angle (LCEA) between 18° and 25° with a control group of patients with normal LCEA (> 25°). METHODS: Fifty hip arthroscopies performed in 45 patients were retrospectively evaluated. Exclusion criteria were: age > 40, hip arthritis > grade 2 according to Tonnis classification, femoral head avascular necrosis, pediatric's orthopaedics conditions and true dysplasia with LCEA < 18°.Two groups were identified: group A with 15 hips with LCEA between 25° and 18° and Group control B made of 35 hips with LCEA > 25°. RESULTS: The groups were homogeneous for demography and pre-operative WOMAC and HOOS. Osteoplasty for CAM were performed in 100% of patients in both groups, only in 12 hips (34.4%) in group B we had both femoral and acetabular osteoplasty. Labral repair was performed in 86% of patients in group A, in 60% of patients in group B, capsular plication in 93% of group A, in 5% of case of group B. WOMAC and HOOS statically significant improved in both groups at final follow-up (24 months). No cases in both groups required conversion to total hip arthroplasty. Clinical outcomes of study group were comparable to the control group. CONCLUSION: Even if the present small series is not conclusive, we suggest isolated arthroscopic management of patients with FAI and LCEA between 18° and 25°, but capsular plication and careful labral management are strongly recommended. LEVEL OF EVIDENCE: Level IV.

The influence of bearing surfaces on revisions due to dislocations in total hip arthroplasty.

INTRODUCTION: Recurrent dislocations are still the most frequent reason for revision in total hip arthroplasty (THA). The impact of bearing surfaces on dislocations is still controversial. We hypothesized that: (1) bearing surfaces influence the revisions due to dislocations; (2) ceramic-on-ceramic reduced the revisions for dislocations in adjusted models; (3) Delta-on-Delta bearings reduced the revisions for dislocations in comparison to surfaces with cross-linked polyethylene. MATERIALS AND METHODS: The regional arthroplasty registry was enquired about bearing surfaces and revisions for dislocations and instability. Unadjusted and adjusted rates were provided, including sex, age (<65 years or ≥65 years), head diameter (≤28 mm or >28 mm; <36 mm or ≥36 mm) as variables. 44,065 THAs were included. RESULTS: The rate of revisions for dislocations was significantly lower in ceramic-on-ceramic and metal-on-metal bearings (unadjusted rates). After adjusting for age, sex, and head size (36 and 28 mm), hard-on-hard bearings were protective (p < 0.05): ceramic-on-ceramic had a lower risk of revisions due to dislocation than ceramic-on-polyethylene (HR 1.6, 95% CI 1.2-2.2 p = 0.0009). The rate of revisions for dislocation was similar in bearings with cross-linked polyethylene and Delta-on-Delta articulations, in unadjusted and adjusted models. CONCLUSION: Bearings with conventional polyethylene were more predisposed to dislocations. Currently adopted bearings exerted no significant influence on revisions due to dislocations. These findings could be primarily related to wear, but due to the time distribution, soft tissue envelopes and surface tension may also play a role. Pre-clinical biomechanical evaluations and prospective matched cohort studies are required to draw definitive conclusions.

lsolated acetabular revisions of articular surface replacement (ASR) XL implants with highly porous titanium cups and Delta bearings.

INTRODUCTION: Articular surface replacement (ASR) XL implants exhibit higher-than-expected revision rates, blood ion concentrations and soft tissue lesions, making revisions troublesome and potentially unsatisfying. Appropriate techniques and outcomes in ASR XL revisions are rarely documented. The aims of this study were the assessments of pre-revision data, post-revision clinical and radiographic outcomes and ion levels in isolated acetabular ASR XL revisions performed using highly porous titanium cups and Delta ceramic articulations. METHODS: 18 isolated acetabular ASR XL revisions in 16 patients were performed using Ti-Por cups (Adler Ortho, Milan, Italy) and Delta bearings (CeramTec, Plochingen, Germany). Pre-revision demographic, clinical, radiological and implant-related features were assessed. Clinical and radiographic parameters (cup positioning, osseointegration) after revisions were evaluated at a minimum follow-up of 5 years. Ion concentrations in blood and urine were collected in pre-revision setting and 1 year after revision. RESULTS: 4 complications occurred in 3 different revisions (16.7%), 1 dislocation, 2 infections, 1 psoas impingement. No re-revision was performed at 5 years (1 scheduled arthroscopy). Good clinical outcomes were achieved (HHS score: 88.3 ± 9.2). All the cups showed reassuring signs of osseointegration (>3 parameters). Blood ion concentrations significantly decreased: patients with Co blood ion concentration over the threshold (7 µg/l) decreased from 76.5% to 0%. No pre-revision or intraoperative data influenced the revision outcomes. CONCLUSIONS: Highly porous titanium cups and Delta ceramic articulations provided reliable mid-term clinical and radiographic outcomes in isolated acetabular ASR XL revisions. Ion concentrations significantly decreased. Multicentre prospective controlled studies are required to confirm these preliminary outcomes.

Arthroscopic tendon release for iliopsoas impingement after primary total hip arthroplasty: a retrospective, consecutive series.

INTRODUCTION: Aim of this study was to describe the clinical outcomes of 16 patients with iliopsoas (IP) impingement after primary total hip arthroplasty (THA), treated with an arthroscopic tendon release. METHODS: 16 patients (11 females/5 males), with a mean age of 57.8 ± 11.1 years (age at THA: 54.4 ± 11 years) and a diagnosis of IP impingement after primary THA, were treated with the Wettstein tenotomy. Preoperatively, every patient underwent a diagnostic ultrasonography guided peritendinous injection and a computed tomography (CT) scan. Every patient was clinically evaluated using WOMAC score. Subjective pain relief and active hip flexion strength were measured. RESULTS: No complications related to arthroscopy were detected. Every cup was prominent with a mean axial overhang of 13 ± 4.8 mm (range 5-20 mm). At a mean follow-up of 27 ± 20.1 months (range 6-48 months), the WOMAC score was 83.7 ± 10.1 points. 13 patients out of 16 (81.3%) had a complete pain relief. 14 patients out of 16 (88%) regained full active hip flexion strength at the final follow-up. 1 patient was scheduled for cup revision after 6 months, due to persistent symptomatology. No demographic data or CT measurements about cup position statistically influenced the outcome. CONCLUSIONS: When preceded by an appropriate diagnosis, arthroscopic tenotomy proved safe and effective for IP impingement, regardless the magnitude of cup protrusion.

Achilles tendon reconstruction with peroneus tendon transfer following epithelioid sarcoma resection: a rare case report at 5 years follow-up.

BACKGROUND: Soft-tissue sarcomas (STS) are rare in hand and foot. In this paper we present a case of reconstruction of Achilles tendon defect with peroneus brevis transfer reinforced with medial gastrocnemius fascia and plantaris tendon after excision of a local recurrence of epithelioid sarcoma. CASE PRESENTATION: Fifty-five years-old female. MRI showed a lump of 5 × 2,5 × 2 cm into Achille's tendon with invasion of the anterior fat tissue but no invasion of the surrounding bones. The patient underwent excision of the tumour and reconstruction of the tendinous defect with peroneus brevis transfer. Surgical technique has been widely described. DISCUSSION AND CONCLUSIONS: Epithelioid sarcoma arising from the Achilles tendon is an extremely rare malignant tumour in an atypical site and may easily be confused with other soft tissue masses. It presents a technical challenge because of the large tendon defect remaining following wide resection. Reconstruction with peroneus brevis transfer, reinforced with medial gastrocnemius fascia and plantaris tendon, restore appropriate structural continuity and resistance. Functional results are satisfactory.

Middle term results of tantalum acetabular cups in total hip arthroplasty following pelvic irradiation.

OBJECTIVES: The aim of this study was to evaluate the middle term cup survival, assess the functional implementation and the radiographic evolution of tantalum acetabular cups implanted on patients with a history of pelvic radiotherapy. METHODS: From 2005 to 2013, we performed 12 THA replacements (4 males 8 females; mean age: 46.6 years (range 25-75)) on irradiated bone with Trabecular metal acetabular cups, 8 primary implants and 4 revision implants. The mean radiation dose delivered was 5500 cGy (range 3000 cGy-13,600 cGy). The mean follow-up was 68 months, ranging from 38 to 136. Postoperative follow-up time was assessed at 1, 3, 6 and 12 months, then annually. Double projection radiographs were requested at each control. Radiographic signs of loosening were investigated by X-rays looking for radiolucent lines. We used the Harris hip score for the clinical and functional evaluation. RESULTS: To now none of the 12 patients in the series needed any revision surgery for aseptic loosening. In the revision group one patient have been revised for septic loosening, two patients have been treated by conservative procedure for hip dislocation. Post-operative Harris hip score improved from an average of 46 points to 85.3 points. At last follow-up we found only in one case radiographic signs of progressive lucent line, without clinical sign of failure. CONCLUSION: In a clinical setting, tantalum cup seems to provide a good stability due to the integration of the trabecular metal to the underline cancellous bone. The reported results, in agreement with literature data, propose the use of tantalum cups in irradiated bone. LEVEL OF EVIDENCE: Level IV, therapeutic study.

The importance of clinical suspicion in diagnosing pulmonary embolism: a case of false-positive high probability radionuclide perfusion lung scan.

The accuracy of scintigraphic evidence of perfusion defects, even when classified as 'high probability' by matching with ventilation techniques or thoracic roentenograms is unsatisfactory when used without a pre-test clinical evaluation of probability. Although unusual, a complete or near-complete unilateral absence of perfusion in a lung with normal perfusion controlaterally must alert clinicians to the possibility of a false-positive result. In such instances, the administration of therapeutic dosages of fibrinolitic and antithrombotic agents (or even surgery) may lead to deleterious consequences. We report a patient with malignancy causing extrinsic narrowing of the pulmonary artery leading to a drastic impairment in the perfusion of an entire lung, compatible with, but not diagnostic of massive pulmonary embolism.