Young microglia restore amyloid plaque clearance of aged microglia.

Alzheimer's disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel ex vivo model by co-culturing organotypic brain slices from up to 20-month-old, amyloid-bearing AD mouse model (APPPS1) and young, neonatal wild-type (WT) mice. Surprisingly, co-culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis.

η-Secretase processing of APP inhibits neuronal activity in the hippocampus.

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-ß peptide. Two principal physiological pathways either prevent or promote amyloid-ß generation from its precursor, ß-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-ß fragments generated by the α- and ß-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (ß-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-ß). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury.

Sequence variations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to an increased risk for neurodegenerative disorders such as Alzheimer's disease and frontotemporal lobar degeneration. In the brain, TREM2 is predominantly expressed in microglia. Several disease-associated TREM2 variants result in a loss of function by reducing microglial phagocytosis, impairing lipid sensing, preventing binding of lipoproteins and affecting shielding of amyloid plaques. We here investigate the consequences of TREM2 loss of function on the microglia transcriptome. Among the differentially expressed messenger RNAs in wild-type and Trem2-/- microglia, gene clusters are identified which represent gene functions in chemotaxis, migration and mobility. Functional analyses confirm that loss of TREM2 impairs appropriate microglial responses to injury and signals that normally evoke chemotaxis on multiple levels. In an ex vivo organotypic brain slice assay, absence of TREM2 reduces the distance migrated by microglia. Moreover, migration towards defined chemo-attractants is reduced upon ablation of TREM2 and can be rescued by TREM2 re-expression. In vivo, microglia lacking TREM2 migrate less towards injected apoptotic neurons, and outgrowth of microglial processes towards sites of laser-induced focal CNS damage in the somatosensory cortex is slowed. The apparent lack of chemotactic stimulation upon depletion of TREM2 is consistent with a stable expression profile of genes characterizing the homoeostatic signature of microglia.

Tenodesis is not superior to tenotomy in the treatment of the long head of biceps tendon lesions.

PURPOSE: To compare the effectiveness of tenodesis and tenotomy in the treatment of long head of the biceps tendon (LHBT) lesions. The null hypothesis was that there is no difference in functional scores between the tenotomy and tenodesis groups. METHODS: A total of 69 patients with a combined supraspinatus tear and LHBT lesion aged over 40 years entered this prospective comparative study and were randomly assigned to the arthroscopic LHB tenotomy or tenodesis group. Fifty-five patients (31 in the tenotomy group and 24 in the tenodesis group) were available for the 6- and 24-month post-operative evaluations. RESULTS: There were no statistically significant differences in post-operative Constant and Murley score, quality of life, pain, and strengths between groups. Higher rates of Popeye's sign were noted 6 and 24 months post-operatively in the tenotomy group compared to tenodesis. CONCLUSIONS: Although tenotomy is affected by a higher incidence of cosmetic deformity, there is no superiority of arthroscopic tenodesis over tenotomy in the treatment of LHBT lesion as a concomitant procedure to an arthroscopic repair of the supraspinatus tendon in terms of functional outcomes, quality of life, pain, and strength measured 6 and 24 months post-operatively. LEVEL OF EVIDENCE: I.

Quality of Life and Functional Results of Arthroscopic Partial Repair of Irreparable Rotator Cuff Tears.

PURPOSE: To evaluate the minimum 2-year results and possible outcomes of arthroscopic partial repair in different patterns of irreparable rotator cuff tears (RCTs). METHODS: Patients suffering from an irreparable supraspinatus and a reparable infraspinatus tendons who underwent arthroscopic partial repair with a minimum 24-month follow-up were included in this study. The Constant and Murley score (CMS) was used to assess patients' functionality pre- and postoperatively. Postoperative patient assessment included the Simple Shoulder Test (SST) and the Short Form Health Survey questionnaire (SF-36). A postoperative range of motion, CMS, and strength were compared with the contralateral side. Postoperative SF-36 was compared with age- and sex-matched norms. RESULTS: Ninety patients (95 shoulders) were reviewed after a mean follow-up of 7 (range 2-12) years. The subscapularis tendon was intact in 80 shoulders and torn but completely reparable in the remaining 15 shoulders. The CMS improved from 39.1 ± 8.4 (10-61) to 76.3 ± 9.7 (32-93) (P < .001). The mean postoperative SST was 9.1 ± 2.2 (1-12). Although the patients had lower postoperative abduction and internal rotation, strength in abduction and CMS in comparison with the measurements from the contralateral side, the median postoperative SF-36 physical and mental component summaries were 98% and 100% of the matched norms. No significant differences were found in postoperative outcomes according to the RCT pattern. Males showed significantly higher strengths in abduction (B = -1.384, 95% confidence interval [CI] -2.144 to -0.624, η2 = 0.123, P < .001, 95% power), external rotation (B = -3.646, 95% CI -5.2 to -2.092, η2 = 0.189, P < .001, 100% power), and internal rotation (B = -3.867, 95% CI -5.676 to -2.057, η2 = 0.162, P < .001, 99% power) than females. Significantly higher ranges of abduction (η2 = 0.431, P = .019, 98% power) and external rotation (η2 = 0.417, P < .03, 97% power) were noted in younger patients. Higher strengths in abduction (η2 = 0.495, P = .002, 100% power) and internal rotation (η2 = 0.464, P = .006, 99% power) were also reported in these patients. CONCLUSIONS: When there is an irreparable supraspinatus but there is still the possibility to repair the infraspinatus and subscapularis, the arthroscopic partial cuff repair should be considered as an effective surgical option. Indeed, a significant clinical improvement can be achieved and, differently from pure symptomatic surgical procedures, this technique represents a reasonable effort to restore, at least in part, the shoulder joint functionality. Successful and reliable results can be expected at an average 7-year follow-up, regardless of the RCT pattern. Female and older patients have a greater likelihood of lower functional outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

The Effect of Fracture Patterns, Pinning Configuration, Surgeon Experience and Subspecialty on Short-Term Radiological Outcomes of Pediatric Supracondylar Humeral Fractures Treated in the Prone Position: A Case-Series.

BACKGROUND: The most common treatment modality for supracondylar humerus fractures (SCHFs) in children is closed reduction and percutaneous pinning (CRPP). Nonetheless, debate persists regarding the optimal technique used. Therefore, the purpose of our study was to investigate the impact of surgeon experience, surgeon subspecialty and pin configuration on short-term radiological outcomes following CRPP of displaced SCHFs. METHODS: Patients less than 14 years of age who underwent CRPP for displaced SCHFs in the prone position between January 2018 and December 2022 were analyzed. Patients were separated into subgroups based on fracture type (low vs. high sagittal), pin configuration (lateral, cross, other), number and configuration of K-wires and first operator surgical experience. The following outcome measurements were collected: postoperative Baumann angle (BA), Shaft-Condylar angle (SCA), surgical duration (SD), duration of radiation exposure (DRE) and number of clinical and radiological follow-ups (FU). RESULTS: A total of 44 patients with a mean age of 6 ± 2.5 years were included in the final analysis. The mean post-operative BA and SCA were 74.8° ± 4.9° and 37.7° ± 10.2°, respectively. No significant differences were found in the post-operative Baumann's angle or SCA among the subgroups. Regarding secondary outcomes, no differences were found among each subgroup regarding SD, DRE and FUs. CONCLUSION: Short-term radiological outcomes following the treatment of SCHFs treated in the prone position are not affected by fracture patterns and pinning configuration, regardless of the surgeon's years of experience or subspecialty.

Short-term outcomes of extracorporeal shock wave therapy for the treatment of chronic non-calcific tendinopathy of the supraspinatus: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: There is evidence supporting the use of extracorporeal shock wave therapy (ESWT) in calcific tendinopathy of the rotator cuff, but the best current evidence does not support its use in non-calcifying tendinopathy. We conducted a randomized placebo-controlled trial to investigate the efficacy and safety of low energy ESWT for non-calcifying tendinopathy of the rotator cuff. METHODS: 20 patients with non-calcifying supraspinatus tendinopathy (NCST) were randomized to an active or a sham treatment group. Physical, blood, roentgenographic, and MRI examinations of the shoulder were conducted to verify that patients met the inclusion and exclusion criteria. These examinations were repeated six and twelve weeks after treatments. Effectiveness was determined by comparison of the mean improvement in the Constant and Murley score (CMS) between the treatment and the placebo groups at three months. Safety was assessed by analyzing the number and severity of adverse events. RESULTS: All the patients completed the investigation protocol. At the final follow-up, significant improvement in the total CMS score and most of the CMS subscales was observed in the ESWT group when compared to the baseline values. Significantly higher total CMS, and significantly higher scores for CMS pain and ROM were observed in the ESWT group when compared to the placebo. No serious adverse events were noted after ESWT. CONCLUSIONS: Patients suffering from NCST may benefit from low energy ESWT, at least in short-term. The application protocol of ESWT is likely to play a key-role in a successful treatment. Future investigations should be undertaken on the long-term effects of this technique for the treatment of NCST. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41236511.

Edible flowers as a new source of natural antioxidants for oxidative protection of cold-pressed oils rich in omega-3 fatty acids.

This study aimed to evaluate and compare the effect of methanolic extracts from 23 lyophilized Polish edible flowers on the oxidative stability of two cold-pressed oils rich in omega-3 fatty acids. Two popular oils (flax and chia seed oils) were used in the study and characterized for their chemical composition, quality and oxidative stability. Hydro- and lipophilic components, and antioxidant activity were determined in the flower extracts. The effectiveness of the edible flower extracts in oxidative protection of cold-pressed oils was evaluated in the Rancimat test. The edible flower extracts differed significantly in their composition and antioxidant activity. Among the extracts, the richest source of phenolic compounds were those obtained from red begonia (996.80 ppm), red geranium (1028.16 ppm), and small leaved lime (1003.62 ppm) flowers; whereas red begonia and red geranium flower extracts were also found to be valuable sources of flavonoids, 343.70 and 307.34 ppm, respectively. The extracts from lyophilized edible flowers had a low content of lipophilic pigments (0.97-9.01 ppm for chlorophylls and 0.03-12.34 ppm for carotenoids), while the content of tocopherols varied greatly (0.70-193.34 ppm). Most of the analyzed extracts were characterized by a high DPPH radical inhibition value (>10 µM TE/mL). Almost all studied edible flower extracts improved oxidative stability of the cold-pressed flax and chia seed oils. More favorable effects were observed in chia seed oil, in particular after the addition of extracts from nasturtium, marigold scattered, dog rose, and daylilies flowers (the changes were more than 50% higher compared to the control sample).

Biotechnical Properties of Poly(HEMA-co-HPMA) Hydrogels Are Governed by Distribution among Water States.

Controlling the biotechnical properties of synthetic hydrogels allows their application in a wide range of biomedical fields. Cross-linker concentration and monomer mole ratio of poly(2-hydroxyethylmethacrylate-co-N-(2-hydroxypropyl) methacrylamide) [poly(HEMA-co-HPMA)]-based hydrogels were used to control the degree of hydration and water distribution within constructs. Cross-linker concentrations corresponding to 0.1, 0.5, 1.0, and 3.0 mol % tetraethylene glycol (TEGDA) with HEMA/HPMA mole ratios of 1:0 and 4:1, and poly(HEMA-co-HPMA) of cross-linker concentration corresponding to 1.0 mol % TEGDA with a HEMA/HPMA ratio of 1:1 were investigated for their degree of hydration, water distribution, and corresponding physiochemical and mechanical properties. Copolymerization of HEMA and HPMA was confirmed by Fourier-transform infrared spectroscopy. Both cross-linker concentration and chemical composition (HEMA/HPMA) systematically changed the water content and free/bound water distribution in the polymer, which resulted in different biochemical and transport properties. The addition of 20% HPMA (poly(HEMA-co-HPMA) (4:1)) increased total hydration (25%) and glass-transition temperature (9%) and decreased elastic modulus (31%) and nonfreezable bound water (33%) of the hydrogel. Increasing cross-linker concentration resulted in a stiffer hydrogel with less total water but larger nonfreezable water content. Evaluation of poly(HEMA-co-HPMA) (1:1) revealed that further increase of HPMA content increased the degree of hydration by 25% and decreased nonfreezable water content and elastic modulus by 33 and 16%, respectively, compared to that of poly(HEMA-co-HPMA) (4:1). The hydrogel correspondingly had a higher void fraction and rougher freeze-fractured surface. The diffusion-related processes depended more on water distribution within the hydrogel. The poly(HEMA) showed the fastest swelling kinetics with a concomitant burst release profile of fluorescein isothiocyanate-dextran (a drug surrogate), while the compositions containing HPMA showed a sustained release pattern. The biotechnical properties are illustrative examples of key properties that are influenced by the water distribution rather than the absolute water content of hydrogels.

Arthroscopic Partial Repair of Irreparable, Massive Rotator Cuff Tears.

Several treatment options for chronic, massive rotator cuff tears exist, and they include debridement with possible biceps tenotomy or tenodesis, open or arthroscopic partial repair, muscle or tendon transfer, superior capsule reconstruction, synthetic patch augmentation, and reverse total shoulder arthroplasty. The aim of this technique article is to describe our preferred surgical option for irreparable, massive rotator cuff tears with an irreparable supraspinatus, a reparable infraspinatus, and an intact or reparable subscapularis tendon.