An overview of rehabilitation approaches for focal hand dystonia in musicians: A scoping review.

OBJECTIVE: To provide a comprehensive overview of rehabilitation treatment strategies for focal hand dystonia (FHD) in musicians, examining their evolution and effectiveness. DATA SOURCES: A systematic search of five databases, PubMed, PEDro, Cochrane Library, Trip, and Google Scholar, to identify relevant articles on FHD rehabilitation. The last search was performed on 20 December 2023. METHODS: Inclusion criteria were applied to 190 initially identified articles, resulting in 17 articles for review. Exclusions were made for duplicates, irrelevant titles, abstracts, and non-rehabilitation interventions. RESULTS: Ten different rehabilitation approaches were identified over 20 years. While no definitive intervention protocol exists, a multimodal approach is commonly recommended. CONCLUSIONS: This scoping review underscores the diversity of rehabilitation strategies for FHD. It suggests the potential of multimodal approaches, emphasizing the need for further large-scale clinical efficacy studies.

"Transcranial Direct Current Stimulation (tDCS) in managing pain and recovery: A clinical case of radial capitellum fracture".

INTRODUCTION: The management of pain and functional recovery following a radial capitellum fracture poses a significant clinical challenge, especially in individuals whose professions, such as physiotherapy, demand optimal joint functionality. Transcranial Direct Current Stimulation (tDCS) emerges as a potential non-pharmacological intervention for pain management, necessitating exploration in the context of orthopedic injuries. CASE PRESENTATION: A 41-year-old male physiotherapist presented with a MASON 2 radial capitellum fracture following a fall, experiencing notable pain (NPRS 6/7) and functional impairment (DASH 45/100, PRTEE 43/100). Conservative management, involving immobilization and potential surgical consideration, was employed, followed by tDCS for pain management. Post-tDCS, significant improvements were observed in pain and functional scores (NPRS to 0, DASH to 14.2, PRTEE to 7), alongside enhancements in range of motion and muscle strength. CLINICAL DISCUSSION: The application of tDCS showcased notable efficacy in pain reduction and functional improvement, highlighting its potential in augmenting pain management strategies post-fracture. However, the variability in responses and lack of standardized application protocols necessitate further research to optimize its clinical utility. The balance between immobilization for fracture healing and mobilization for preventing stiffness and facilitating recovery was pivotal in managing the fracture and ensuring functional improvement. CONCLUSIONS: This case underscores the potential of tDCS in managing pain and facilitating functional recovery in radial capitellum fractures, warranting further exploration and standardization of its application in clinical practice. The integrated, patient-centric approach, involving interdisciplinary collaboration and personalized care, was crucial in ensuring positive outcomes and provides a framework for managing similar orthopedic cases.

Psychological Well-Being, Self-Esteem, Quality of Life and Gender Differences as Determinants of Post-Traumatic Growth in Long-Term Knee Rotationplasty Survivors: A Cohort Study.

Rotationplasty (RP) is a special surgical technique for bone tumors of the lower limb and is the chosen procedure for children under 6 with bone sarcoma in the distal femur. Leg reconstruction results in an unusual aspect of the limb potentially giving life-long emotional outcomes, especially considering the young age of most RP patients. Although the high level of the quality of life of these patients has been previously reported, aspects related to long-term psychological well-being, self-esteem and life satisfaction, particularly regarding the gender, procreation and parenting, have never been explored. The aim of this study was to assess the general degree of psychological well-being of RP patients, with specific reference to gender, procreation and parenting. Twenty long-term RP survivors of high-grade bone sarcoma participated in the study. They were administered the following validated questionnaires: HADS for psychological well-being (degree of anxiety and depression), Temperament and Character Inventory (TCI), RSES for self-esteem, SF-36 for quality of life, SWLS extended to life satisfaction, and ABIS for body image integration. Data on education, marriage, employment and parenthood were gathered. All the scores obtained were very close to normal references. The only gender difference was found for the TCI Cooperativeness scale, which was higher in women than in men. A satisfactory psychological well-being in terms of both self-esteem and integration of the prosthetic joint limb into one's body image, with relatively limited amount of anxiety/depression, good quality of life, and good temperament and character traits, was found. No major gender differences were reported.

Oxidative stress-induced DNA damage and repair in primary human osteoarthritis chondrocytes: focus on IKKα and the DNA Mismatch Repair System.

During osteoarthritis development, chondrocytes are subjected to a functional derangement. This increases their susceptibility to stressful conditions such as oxidative stress, a characteristic of the aging tissue, which can further provoke extrinsic senescence by DNA damage responses. It was previously observed that IκB kinase α knockdown increases the replicative potential of primary human OA chondrocytes cultured in monolayer and the survival of the same cells undergoing hypertrophic-like differentiation in 3-D. In this paper we investigated whether IKKα knockdown could modulate oxidative stress-induced senescence of OA chondrocytes undergoing a DDR and particularly the involvement in this process of the DNA mismatch repair system, the principal mechanism for repair of replicative and recombinational errors, devoted to genomic stability maintenance in actively replicating cells. This repair system is also implicated in oxidative stress-mediated DNA damage repair. We analyzed microsatellite instability and expression of the mismatch repair components in human osteoarthritis chondrocytes after IKKα knockdown and H2O2 exposure. Only low MSI levels and incidence were detected and exclusively in IKKα proficient cells. Moreover, we found that IKKα proficient and deficient chondrocytes differently regulated MMR proteins after oxidative stress, both at mRNA and protein level, suggesting a reduced susceptibility of IKKα deficient cells. Our data suggest an involvement of the MMR system in the response to oxidative stress that tends to be more efficient in IKKαKD cells. This argues for a partial contribution of the MMR system to the better ability to recover DNA damage already observed in these cells.

Polyamine supplementation reduces DNA damage in adipose stem cells cultured in 3-D.

According to previous research, natural polyamines exert a role in regulating cell committment and differentiation from stemness during skeletal development. In order to assess whether distinct polyamine patterns are associated with different skeletal cell types, primary cultures of stem cells, chondrocytes or osteoblasts were dedicated for HPLC analysis of intracellular polyamines. Spermine (SPM) and Spermidine (SPD) levels were higher in adipose derived stem cells (ASC) compared to mature skeletal cells, i.e. chondrocytes and osteoblasts, confirming the connection of polyamine content with stemness. To establish whether polyamines can protect ASC against oxidative DNA damage in a 3-D differentiation model, the level of γH2AX was measured by western blot, and found to correlate with age and BMI of patients. Addition of either polyamine to ASC was able to hinder DNA damage in the low micromolecular range, with marked reduction of γH2AX level at 10 µM SPM and 5 µM SPD. Molecular analysis of the mechanisms that might underlie the protective effect of polyamine supplementation evidences a possible involvement of autophagy. Altogether, these results support the idea that polyamines are able to manage both stem cell differentiation and cell oxidative damage, and therefore represent appealing tools for regenerative and cell based applications.

Lithium Chloride Dependent Glycogen Synthase Kinase 3 Inactivation Links Oxidative DNA Damage, Hypertrophy and Senescence in Human Articular Chondrocytes and Reproduces Chondrocyte Phenotype of Obese Osteoarthritis Patients.

INTRODUCTION: Recent evidence suggests that GSK3 activity is chondroprotective in osteoarthritis (OA), but at the same time, its inactivation has been proposed as an anti-inflammatory therapeutic option. Here we evaluated the extent of GSK3ß inactivation in vivo in OA knee cartilage and the molecular events downstream GSK3ß inactivation in vitro to assess their contribution to cell senescence and hypertrophy. METHODS: In vivo level of phosphorylated GSK3ß was analyzed in cartilage and oxidative damage was assessed by 8-oxo-deoxyguanosine staining. The in vitro effects of GSK3ß inactivation (using either LiCl or SB216763) were evaluated on proliferating primary human chondrocytes by combined confocal microscopy analysis of Mitotracker staining and reactive oxygen species (ROS) production (2',7'-dichlorofluorescin diacetate staining). Downstream effects on DNA damage and senescence were investigated by western blot (γH2AX, GADD45ß and p21), flow cytometric analysis of cell cycle and light scattering properties, quantitative assessment of senescence associated ß galactosidase activity, and PAS staining. RESULTS: In vivo chondrocytes from obese OA patients showed higher levels of phosphorylated GSK3ß, oxidative damage and expression of GADD45ß and p21, in comparison with chondrocytes of nonobese OA patients. LiCl mediated GSK3ß inactivation in vitro resulted in increased mitochondrial ROS production, responsible for reduced cell proliferation, S phase transient arrest, and increase in cell senescence, size and granularity. Collectively, western blot data supported the occurrence of a DNA damage response leading to cellular senescence with increase in γH2AX, GADD45ß and p21. Moreover, LiCl boosted 8-oxo-dG staining, expression of IKKα and MMP-10. CONCLUSIONS: In articular chondrocytes, GSK3ß activity is required for the maintenance of proliferative potential and phenotype. Conversely, GSK3ß inactivation, although preserving chondrocyte survival, results in functional impairment via induction of hypertrophy and senescence. Indeed, GSK3ß inactivation is responsible for ROS production, triggering oxidative stress and DNA damage response.

Hard surface biocontrol in hospitals using microbial-based cleaning products.

BACKGROUND: Healthcare-Associated Infections (HAIs) are one of the most frequent complications occurring in healthcare facilities. Contaminated environmental surfaces provide an important potential source for transmission of many healthcare-associated pathogens, thus indicating the need for new and sustainable strategies. AIM: This study aims to evaluate the effect of a novel cleaning procedure based on the mechanism of biocontrol, on the presence and survival of several microorganisms responsible for HAIs (i.e. coliforms, Staphyloccus aureus, Clostridium difficile, and Candida albicans) on hard surfaces in a hospital setting. METHODS: The effect of microbial cleaning, containing spores of food grade Bacillus subtilis, Bacillus pumilus and Bacillus megaterium, in comparison with conventional cleaning protocols, was evaluated for 24 weeks in three independent hospitals (one in Belgium and two in Italy) and approximately 20000 microbial surface samples were collected. RESULTS: Microbial cleaning, as part of the daily cleaning protocol, resulted in a reduction of HAI-related pathogens by 50 to 89%. This effect was achieved after 3-4 weeks and the reduction in the pathogen load was stable over time. Moreover, by using microbial or conventional cleaning alternatively, we found that this effect was directly related to the new procedure, as indicated by the raise in CFU/m2 when microbial cleaning was replaced by the conventional procedure. Although many questions remain regarding the actual mechanisms involved, this study demonstrates that microbial cleaning is a more effective and sustainable alternative to chemical cleaning and non-specific disinfection in healthcare facilities. CONCLUSIONS: This study indicates microbial cleaning as an effective strategy in continuously lowering the number of HAI-related microorganisms on surfaces. The first indications on the actual level of HAIs in the trial hospitals monitored on a continuous basis are very promising, and may pave the way for a novel and cost-effective strategy to counteract or (bio)control healthcare-associated pathogens.

Human osteoarthritic cartilage shows reduced in vivo expression of IL-4, a chondroprotective cytokine that differentially modulates IL-1ß-stimulated production of chemokines and matrix-degrading enzymes in vitro.

BACKGROUND: In osteoarthritis (OA), an inflammatory environment is responsible for the imbalance between the anabolic and catabolic activity of chondrocytes and, thus, for articular cartilage derangement. This study was aimed at providing further insight into the impairment of the anabolic cytokine IL-4 and its receptors in human OA cartilage, as well as the potential ability of IL-4 to antagonize the catabolic phenotype induced by IL-1ß. METHODOLOGY/PRINCIPAL FINDINGS: The in vivo expression of IL-4 and IL-4 receptor subunits (IL-4R, IL-2Rγ, IL-13Rα1) was investigated on full thickness OA or normal knee cartilage. IL-4 expression was found to be significantly lower in OA, both in terms of the percentage of positive cells and the amount of signal per cell. IL-4 receptor type I and II were mostly expressed in mid-deep cartilage layers. No significant difference for each IL-4 receptor subunit was noted. IL-4 anti-inflammatory and anti-catabolic activity was assessed in vitro in the presence of IL-1ß and/or IL-4 for 24 hours using differentiated high density primary OA chondrocyte also exhibiting the three IL-4 R subunits found in vivo. Chemokines, extracellular matrix degrading enzymes and their inhibitors were evaluated at mRNA (real time PCR) and protein (ELISA or western blot) levels. IL-4 did not affect IL-1ß-induced mRNA expression of GRO-α/CXCL1, IL-8/CXCL8, ADAMTS-5, TIMP-1 or TIMP-3. Conversely, IL-4 significantly inhibited RANTES/CCL5, MIP-1α/CCL3, MIP-1ß/CCL4, MMP-13 and ADAMTS-4. These results were confirmed at protein level for RANTES/CCL5 and MMP-13. CONCLUSIONS/SIGNIFICANCE: Our results indicate for the first time that OA cartilage has a significantly lower expression of IL-4. Furthermore, we found differences in the spectrum of biological effects of IL-4. The findings that IL-4 has the ability to hamper the IL-1ß-induced release of both MMP-13 and CCL5/RANTES, both markers of OA chondrocytes, strongly indicates IL-4 as a pivotal anabolic cytokine in cartilage whose impairment impacts on OA pathogenesis.

p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis.

INTRODUCTION: Recent evidence suggests that tissue accumulation of senescent p16INK4a-positive cells during the life span would be deleterious for tissue functions and could be the consequence of inherent age-associated disorders. Osteoarthritis (OA) is characterized by the accumulation of chondrocytes expressing p16INK4a and markers of the senescence-associated secretory phenotype (SASP), including the matrix remodeling metalloproteases MMP1/MMP13 and pro-inflammatory cytokines interleukin-8 (IL-8) and IL-6. Here, we evaluated the role of p16INK4a in the OA-induced SASP and its regulation by microRNAs (miRs). METHODS: We used IL-1-beta-treated primary OA chondrocytes cultured in three-dimensional setting or mesenchymal stem cells differentiated into chondrocyte to follow p16INK4a expression. By transient transfection experiments and the use of knockout mice, we validate p16INK4a function in chondrocytes and its regulation by one miR identified by means of a genome-wide miR-array analysis. RESULTS: p16INK4a is induced upon IL-1-beta treatment and also during in vitro chondrogenesis. In the mouse model, Ink4a locus favors in vivo the proportion of terminally differentiated chondrocytes. When overexpressed in chondrocytes, p16INK4a is sufficient to induce the production of the two matrix remodeling enzymes, MMP1 and MMP13, thus linking senescence with OA pathogenesis and bone development. We identified miR-24 as a negative regulator of p16INK4a. Accordingly, p16INK4a expression increased while miR-24 level was repressed upon IL-1-beta addition, in OA cartilage and during in vitro terminal chondrogenesis. CONCLUSIONS: We disclosed herein a new role of the senescence marker p16INK4a and its regulation by miR-24 during OA and terminal chondrogenesis.

Polyamine delivery as a tool to modulate stem cell differentiation in skeletal tissue engineering.

The first step in skeleton development is the condensation of mesenchymal precursors followed by any of two different types of ossification, depending on the type of bone segment: in intramembranous ossification, the bone is deposed directly in the mesenchymal anlagen, whereas in endochondral ossification, the bone is deposed onto a template of cartilage that is subsequently substituted by bone. Polyamines and polyamine-related enzymes have been implicated in bone development as global regulators of the transcriptional and translational activity of stem cells and pivotal transcription factors. Therefore, it is tempting to investigate their use as a tool to improve regenerative medicine strategies in orthopedics. Growing evidence in vitro suggests a role for polyamines in enhancing differentiation in both adult stem cells and differentiated chondrocytes. Adipose-derived stem cells have recently proved to be a convenient alternative to bone marrow stromal cells, due to their easy accessibility and the high frequency of stem cell precursors per volume unit. State-of-the-art "prolotherapy" approaches for skeleton regeneration include the use of adipose-derived stem cells and platelet concentrates, such as platelet-rich plasma (PRP). Besides several growth factors, PRP also contains polyamines in the micromolar range, which may also exert an anti-apoptotic effect, thus helping to explain the efficacy of PRP in enhancing osteogenesis in vitro and in vivo. On the other hand, spermidine and spermine are both able to enhance hypertrophy and terminal differentiation of chondrocytes and therefore appear to be inducers of endochondral ossification. Finally, the peculiar activity of spermidine as an inducer of autophagy suggests the possibility of exploiting its use to enhance this cytoprotective mechanism to counteract the degenerative changes underlying either the aging or degenerative diseases that affect bone or cartilage.

IKKα/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation.

BACKGROUND: The non-canonical NF-κB activating kinase IKKα, encoded by CHUK (conserved-helix-loop-helix-ubiquitous-kinase), has been reported to modulate pro- or anti- inflammatory responses, cellular survival and cellular differentiation. Here, we have investigated the mechanism of action of IKKα as a novel effector of human and murine chondrocyte extracellular matrix (ECM) homeostasis and differentiation towards hypertrophy. METHODOLOGY/PRINCIPAL FINDINGS: IKKα expression was ablated in primary human osteoarthritic (OA) chondrocytes and in immature murine articular chondrocytes (iMACs) derived from IKKα(f/f):CreERT2 mice by retroviral-mediated stable shRNA transduction and Cre recombinase-dependent Lox P site recombination, respectively. MMP-10 was identified as a major target of IKKα in chondrocytes by mRNA profiling, quantitative RT-PCR analysis, immunohistochemistry and immunoblotting. ECM integrity, as assessed by type II collagen (COL2) deposition and the lack of MMP-dependent COL2 degradation products, was enhanced by IKKα ablation in mice. MMP-13 and total collagenase activities were significantly reduced, while TIMP-3 (tissue inhibitor of metalloproteinase-3) protein levels were enhanced in IKKα-deficient chondrocytes. IKKα deficiency suppressed chondrocyte differentiation, as shown by the quantitative inhibition of.Alizarin red staining and the reduced expression of multiple chondrocyte differentiation effectors, including Runx2, Col10a1 and Vegfa,. Importantly, the differentiation of IKKα-deficient chondrocytes was rescued by a kinase-dead IKKα protein mutant. CONCLUSIONS/SIGNIFICANCE: IKKα acts independent of its kinase activity to help drive chondrocyte differentiation towards a hypertrophic-like state. IKKα positively modulates ECM remodeling via multiple downstream targets (including MMP-10 and TIMP-3 at the mRNA and post-transcriptional levels, respectively) to maintain maximal MMP-13 activity, which is required for ECM remodeling leading to chondrocyte differentiation. Chondrocytes are the unique cell component in articular cartilage, which are quiescent and maintain ECM integrity during tissue homeostasis. In OA, chondrocytes reacquire the capacity to proliferate and differentiate and their activation results in pronounced cartilage degeneration. Τηυσ, our findings are also of potential relevance for defining the onset and/or progression of OA disease.

CCAAT enhancer binding protein δ plays an essential role in memory consolidation and reconsolidation.

A newly formed memory is temporarily fragile and becomes stable through a process known as consolidation. Stable memories may again become fragile if retrieved or reactivated, and undergo a process of reconsolidation to persist and strengthen. Both consolidation and reconsolidation require an initial phase of transcription and translation that lasts for several hours. The identification of the critical players of this gene expression is key for understanding long-term memory formation and persistence. In rats, the consolidation of inhibitory avoidance (IA) memory requires gene expression in both the hippocampus and amygdala, two brain regions that process contextual/spatial and emotional information, respectively; IA reconsolidation requires de novo gene expression in the amygdala. Here we report that, after IA learning, the levels of the transcription factor CCAAT enhancer binding protein δ (C/EBPδ) are significantly increased in both the hippocampus and amygdala. These increases are essential for long-term memory consolidation, as their blockade via antisense oligodeoxynucleotide-mediated knockdown leads to memory impairment. Furthermore, C/EBPδ is upregulated and required in the amygdala for IA memory reconsolidation. C/EBPδ is found in nuclear, somatic, and dendritic compartments, and a dendritic localization of C/EBPδ mRNA in hippocampal neuronal cultures suggests that this transcription factor may be translated at synapses. Finally, the induction of long-term potentiation at CA3-CA1 synapses by tetanic stimuli in acute slices, a cellular model of long-term memory, leads to an accumulation of C/EBPδ in the nucleus. We conclude that the transcription factor C/EBPδ plays a critical role in memory consolidation and reconsolidation.

Enhanced osteoblastogenesis of adipose-derived stem cells on spermine delivery via ß-catenin activation.

The molecular mechanisms underlying spermine osteo-inductive activity on human adipose-derived stem cells (ASCs) grown in 3-dimensional (3D) cultures were investigated. Spermine belongs to the polyamine family, naturally occurring, positively charged polycations that are able to control several cellular processes. Spermine was used at a concentration close to that found in platelet-rich plasma (PRP), an autologous blood product containing growth and differentiation factors, which has recently become popular in in vitro and in vivo bone healing and engineering. Adipose tissue was surgically obtained from the hypodermis of patients undergoing hip arthroplasty. Patient age negatively affected both ASC yield and ASC ability to form 3D constructs. ASC 3D cultures were seeded in either non differentiating or chondrogenic conditions, with or without the addition of 5 µM spermine to evaluate its osteogenic potential across 1, 2, and 3 weeks of maturation. Osteogenic medium was used as a reference. The effects of the addition of spermine on molecular markers of osteogenesis, at both gene and protein level, and mineralization were evaluated. The effects of spermine were temporally defined and responsible for the progression from the early to the mature osteoblast differentiation phases. Spermine initially promoted gene and protein expression of Runx-2, an early marker of the osteoblast lineage; then, it increased ß-catenin expression and activation, which led to the induction of Osterix gene expression, the mature osteoblast commitment factor. The finding that spermine induces ASC to differentiate toward mature osteoblasts supports the use of these easily accessible mesenchymal stem cells coupled with PRP for orthopedic applications.

Impairments of synaptic plasticity in aged animals and in animal models of Alzheimer's disease.

Aging is associated with a gradual decline in cognitive functions, and more dramatic cognitive impairments occur in patients affected by Alzheimer's disease (AD). Electrophysiological and molecular studies performed in aged animals and in animal models of AD have shown that cognitive decline is associated with significant modifications in synaptic plasticity (i.e., activity-dependent changes in synaptic strength) and have elucidated some of the cellular mechanisms underlying this process. Morphological studies have revealed a correlation between the quality of memory performance and the extent of structural changes of synaptic contacts occurring during memory consolidation. We briefly review recent experimental evidence here.

Dynamin binding protein gene expression and memory performance in aged rats.

Previous studies have shown that messenger RNA (mRNA) of the dynamin-binding protein (DNMBP), a scaffold protein regulating actin cytoskeleton and synaptic vesicle pools, is lower in neuropathologically-confirmed Alzheimer's brains. Here we investigated whether a deficit in long term memory formation during physiological aging is also associated with lower DNMBP expression. Hippocampal DNMBP mRNA was quantified by quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) following inhibitory avoidance task in aged (26- to 27-month-old) rats that, according to memory performance, were ranked as good responders (GR) and bad responders (BR), in adult (3-month-old), late-adult (19-month-old), and aged (26-27-month-old) naive animals. We found that DNMBP mRNA levels were significantly higher in naive adults versus late adult and aged naive rats, in GR versus BR, and in pooled GR and BR versus aged-matched controls. Our data provide the first evidence that hippocampal DNMBP mRNA expression is reduced during physiological aging, and suggest that the capability to increase the expression of this mRNA may be a requirement for preserving long term memory formation during aging.

Matrix metalloproteinase 13 loss associated with impaired extracellular matrix remodeling disrupts chondrocyte differentiation by concerted effects on multiple regulatory factors.

OBJECTIVE: To link matrix metalloproteinase 13 (MMP-13) activity and extracellular matrix (ECM) remodeling to alterations in regulatory factors leading to a disruption in chondrocyte homeostasis. METHODS: MMP-13 expression was ablated in primary human chondrocytes by stable retrotransduction of short hairpin RNA. The effects of MMP-13 knockdown on key regulators of chondrocyte differentiation (SOX9, runt-related transcription factor 2 [RUNX-2], and beta-catenin) and angiogenesis (vascular endothelial growth factor [VEGF]) were scored at the protein level (by immunohistochemical or Western blot analysis) and RNA level (by real-time polymerase chain reaction) in high-density monolayer and micromass cultures under mineralizing conditions. Effects on cellular viability in conjunction with chondrocyte progression toward a hypertrophic-like state were assessed in micromass cultures. Alterations in SOX9 subcellular distribution were assessed using confocal microscopy in micromass cultures and also in osteoarthritic cartilage. RESULTS: Differentiation of control chondrocyte micromasses progressed up to a terminal phase, with calcium deposition in conjunction with reduced cell viability and scant ECM. MMP-13 knockdown impaired ECM remodeling and suppressed differentiation in conjunction with reduced levels of RUNX-2, beta-catenin, and VEGF. MMP-13 levels in vitro and ECM remodeling in vitro and in vivo were linked to changes in SOX9 subcellular localization. SOX9 was largely excluded from the nuclei of chondrocytes with MMP-13-remodeled or -degraded ECM, and exhibited an intranuclear staining pattern in chondrocytes with impaired MMP-13 activity in vitro or with more intact ECM in vivo. CONCLUSION: MMP-13 loss leads to a breakdown in primary human articular chondrocyte differentiation by altering the expression of multiple regulatory factors.

Differences in gene expression in the hippocampus of aged rats are associated with better long-term memory performance in a passive avoidance test.

Microarray analysis was used to identify genes differentially expressed in the hippocampus of aged rats showing diverse long-term (3 and 6 h) spatial-associative memory performance in a single-trial inhibitory avoidance task. The transcription of 43 genes (including genes functionally linked to signal transduction, cell growth and differentiation, translation, energy metabolism, and nucleic acid processing) was significantly upregulated in good- versus bad-performing animals, whereas that of 18 genes (including genes functionally linked to transcription, cell growth and differentiation, apoptosis, and protein transport) was significantly downregulated in good- versus bad-performing animals. The differential expression of 14 of these genes was confirmed by real-time polymerase chain reaction.

A ketogenic diet increases succinic dehydrogenase (SDH) activity and recovers age-related decrease in numeric density of SDH-positive mitochondria in cerebellar Purkinje cells of late-adult rats.

Ketogenic diets (KDs) have been applied in the therapy of paediatric epilepsy for nearly a century. Recently, beneficial results have also been reported on metabolic disorders and neurodegeneration, designating aged individuals as possible recipients. However, KDs efficacy decrease after the suckling period, and very little is known about their impact on the aging brain. In the present study, the effect on the neuronal energetic supply of a KD containing 20% of medium chain triglycerides (MCT) was investigated in Purkinje cells of the cerebellar vermis of late-adult (19-month-old) rats. The animals were fed with the KD for 8 weeks, and succinic dehydrogenase (SDH) activity was cytochemically determined. The following parameters of SDH-positive mitochondria were evaluated by the use of a computer-assisted image analysis system connected to a transmission electron microscope: numeric density (Nv), average volume (V), volume density (Vv), and cytochemical precipitate area/mitochondrial area (R). Young, age-matched, and old animals fed with a standard chow were used as controls. We found significantly higher Nv in MCT-KD-fed rats vs. all the control groups, in young vs. late-adult and old controls, and in late-adult vs. old controls. V and Vv showed no significant differences among the groups. R was significantly higher in MCT-KD-fed rats vs. all the control animals, and in old vs. young and late-adult controls. Present data indicate that the ketogenic treatment counteracted age-related decrease in numeric density of SDH-positive mitochondria, and enhanced their metabolic efficiency. Given the central role of mitochondrial impairment in age-related physio-pathological changes of the brain, these findings may represent a starting point to examine novel potentialities for KDs.