Automatic string generation for estimating in vivo length changes of the medial patellofemoral ligament during knee flexion

Modeling ligaments as three-dimensional strings is a popular method for in vivo estimation of ligament length. The purpose of this study was to develop an algorithm for automated generation of non-penetrating strings between insertion points and to evaluate its feasibility for estimating length changes of the medial patellofemoral ligament during normal knee flexion. Three-dimensional knee models were generated from computed tomography (CT) scans of 10 healthy subjects. The knee joint under weight-bearing was acquired in four flexion positions (0°–120°). The path between insertion points was computed in each position to quantify string length and isometry. The average string length was maximal in 0° of flexion (64.5 ± 3.9 mm between femoral and proximal patellar point; 62.8 ± 4.0 mm between femoral and distal patellar point). It was minimal in 30° (60.0 ± 2.6 mm) for the proximal patellar string and in 120° (58.7 ± 4.3 mm) for the distal patellar string. The insertion points were considered to be isometric in 4 of the 10 subjects. The proposed algorithm appears to be feasible for estimating string lengths between insertion points in an automatic fashion. The length measurements based on CT images acquired under physiological loading conditions may give further insights into knee kinematics.     

Heterozygous TREM2 mutations in frontotemporal dementia

A causative association was recently demonstrated between homozygous TREM2 mutations and frontotemporal dementia (FTD)-like syndrome and between heterozygous TREM2 exon2 genetic variations and late-onset Alzheimer's disease (AD). The objective of this study was to evaluate whether heterozygous TREM2 genetic variations might be associated to the risk of FTD. TREM2 exon 2 was sequenced in a group of 1030 subjects—namely, 352 patients fulfilling clinical criteria for FTD, 484 healthy control subjects (HCs), and 194 patients with AD. The mutation frequency and the associated clinical characteristics were analyzed. We identified 8 missense and nonsense mutations in TREM2 exon 2 in 24 subjects. These mutations were more frequent in patients with FTD than in HCs (4.0% vs. 1.0%, p = 0.005). In particular, TREM2 Q33X, R47H, T66M, and S116C mutations were found in FTD and were absent in HCs. These mutations were associated with either the semantic variant of primary progressive aphasia or the behavioral variant FTD phenotypes. The FTD and AD groups were not significantly different with regard to TREM2 genetic variation frequency (AD: 2.6%, p = 0.39). Heterozygous TREM2 mutations modulate the risk of FTD in addition to increasing susceptibility to AD. Additional studies are warranted to investigate the possible role of these mutations in the pathogenesis of neurodegenerative disorders.     

High-load resistance exercise with superimposed vibration and vascular occlusion increases critical power, capillaries and lean mass in endurance-trained men

Purpose

It is a widely accepted premise in the scientific community and by athletes alike, that adding resistance exercise to a regular regimen of endurance training increases endurance performance in endurance-trained men. However, critical power (CP), capillarization, and myofiber size remain unaffected by this addition. Therefore, we tested whether the superimposition of resistance exercise with whole-body vibration and vascular occlusion (vibroX) would improve these variables in endurance-trained males relative to resistance exercise alone.

Methods

Twenty-one young, endurance-trained males were randomly assigned either to a vibroX (n = 11) or resistance (n = 10) training group. Both groups trained in a progressive mode twice a week for 8 weeks. Pre and post training, histochemical muscle characteristics, thigh muscle size, endurance and strength parameters were determined.

Results

vibroX increased CP (P = 0.001), overall capillary-to-fiber ratio (P = 0.001) and thigh lean mass (P < 0.001), while these parameters were unaffected by resistance training. The gain in CP by vibroX was positively correlated with the gain in capillarization (R ² = 0.605, P = 0.008), and the gain in thigh lean mass was paralleled by increases in MyHC-1 and MyHC-2 fiber cross-sectional areas and strength. Maximum voluntary torque and the finite work capacity above CP (W′) increased significantly only following resistance training.

Conclusions

We achieved a proof of concept by demonstrating that modification of resistance exercise by superimposing side-alternating whole-body vibration and sustained vascular occlusion induced further improvements in CP, capillarization and hypertrophy, all of which were not observed with resistance training alone.     

Diagnostic utility of cell-block from bronchial washing in pulmonary neoplasms

In order to evaluate the usefulness of cell-block (CB) from bronchial washing in the diagnosis of pulmonary neoplasms, we examined cytological samples of 1,145 bronchoscopies; CBs could be prepared in 777 cases (67.9%) and 201 cases, positive or suspicious for malignancy, were selected for the study (173/201 smears: 86.1%; 174/201 CBs: 86.6%). CBs were positive in 12 cases while the corresponding smears were negative (10 cases) or suspicious (2 cases); 2 cases had suspicious CBs with negative smears. Thus, the use of CBs increased the positive diagnosis from 173 to 185 cases, for an increase of 6.5%. We can conclude that CB could be a routine, inexpensive method, helpful in pulmonary neoplasm's diagnosis; moreover, CB has the advantage of being an histologic specimen, often the only one, useful for other diagnostic procedures. Diagn Cytopathol 1996;15:191–192. © 1996 Wiley-Liss, Inc.     

Activity of PD-1 blockade with nivolumab among patients with recurrent atypical/anaplastic meningioma: phase II trial results

BackgroundProgrammed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy.MethodsTwenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale.ResultsEnrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO.ConclusionNivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.     

RPE65-Associated Retinopathies in the Italian Population: A Longitudinal Natural History Study

PurposeTo investigate the course of inherited retinal degenerations (IRD) due to mutations in the RPE65 gene.MethodsThis longitudinal multicentric retrospective chart-review study was designed to collect best corrected visual acuity (BCVA), Goldman visual field, optical coherence tomography (OCT), and electroretinography (ERG) measurements. The data, including imaging, were collected using an electronic clinical research form and were reviewed at a single center to improve consistency.ResultsFrom an overall cohort of 60 Italian patients with RPE65-associated IRD, 43 patients (mean age, 27.8 ± 19.7 years) were included and showed a mean BCVA of 2.0 ± 1.0 logMAR. Time-to-event analysis revealed a median age of 33.8 years and 41.4 years to reach low vision and blindness based on BCVA, respectively. ERG (available for 34 patients) showed undetectable responses in most patients (26; 76.5%). OCT (available for 31 patients) revealed epiretinal membranes in five patients (16.1%). Central foveal thickness significantly decreased with age at a mean annual rate of −0.6%/y (P = 0.044). We identified 43 different variants in the RPE65 gene in the entire cohort. Nine variants were novel. Finally, to assess genotype-phenotype correlations, patients were stratified according to the number of RPE65 loss-of-function (LoF) alleles. Patients without LoF variants showed significantly (P < 0.05) better BCVA compared to patients with one or two LoF alleles.ConclusionsWe described the natural course of RPE65-associated IRD in an Italian cohort showing for the first time a specific genotype-phenotype association. Our findings can contribute to a better management of RPE65-associated IRD patients.     

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated “risk of bias” tool to assess study quality. Four separate Phase I–II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5–34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I–III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.     

Fluoroscopic and Gait Analyses for the Functional Performance of a Custom-Made Total Talonavicular Replacement

The present study evaluated the restoration of joint function in a special clinical case: a professional rock climber who underwent an original total talonavicular replacement with a custom-made prosthesis after a complex articular fracture. Full body gait analysis and 3-dimensional joint kinematics using single-plane fluoroscopy were performed on the same day at the 30-month follow-up examination. Gait analysis was performed using stereophotogrammetric, dynamometric, electromyographic, and baropodometric systems. Gait analysis showed good restoration of rotation, as well as moment patterns in the main lower limb and foot joints in the operated leg. At the artificial tibiotalar joint, videofluoroscopic analysis revealed a flexion capability of about 20°, together with a few degrees of motion in the frontal and transverse planes. The neighboring joints of the foot did not present with severe kinematic abnormalities. A full talonavicular replacement can be a viable and effective solution for complex ankle injury sequelae, even in patients with highly demanding functionality.