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Papillary thyroid carcinoma (PTC) is the most common form of well-differentiated thyroid cancer (WDTC) and generally has a favorable prognosis. However, subsets of these tumors can metastasize, leading to aggressive disease progression and poorer clinical outcomes. Radioactive iodine (RAI) therapy is routinely given in the adjuvant setting following thyroidectomy and lymph node dissection for WDTC. Nevertheless, its therapeutic efficacy is limited to tumors with high iodine avidity. Early post-surgical classification of thyroid cancers as either iodine-avid or refractory is crucial for enabling more personalized and effective treatment strategies. In this study, we aimed to identify transcriptomic determinants associated with RAI refractoriness (RAI-R) to improve prognostication. We collected clinicopathologic data and conducted RNA-seq on 36 tissue samples (18 high-avidity and 18 low-avidity), each uniquely characterized by ex vivo iodine concentration measurements taken directly from surgical specimens. Whole-transcriptomic analysis identified 63 differentially expressed genes, with six (S100A4, CRTC2, ANO1, WWTR1, DEPTOR, MT1G) showing consistent deregulation. The expression of ANO1, an established iodine transporter at the apical membrane of the thyroid follicular cells, correlated significantly with iodine avidity (r = 0.54). Validation via RT-qPCR confirmed differential expression trends. Gene ontology and pathway enrichment analyses highlighted thyroid hormone synthesis, PI3K-AKT, and MAPK signaling pathways as key regulators of RAI avidity. A refined multivariate predictive model incorporating ANO1 mRNA expression, histological subtypes, and sample type demonstrated strong predictive performance (adjusted R2 = 0.55). These findings suggest ANO1 as a promising biomarker for predicting iodine avidity in thyroid cancer. [ABSTRACT FROM AUTHOR]

Ventricular septal defect (VSD) is a serious complication of myocardial infarction (MI), with its global incidence significantly reduced in recent years due to advances in coronary reperfusion techniques. However, during the COVID-19 pandemic, there was an unexpected rise in the incidence of post-MI VSD, likely driven by delays in seeking treatment. This study retrospectively analyzed 10 cases of post-MI VSD treated at our hospitals from March 2018 to August 2023, comparing incidence rates across pre-pandemic, pandemic, and post-pandemic periods. The findings revealed a notable increase in VSD cases during the pandemic, with six cases occurring in two years, compared to only two cases in each of the pre-pandemic and post-pandemic periods. Despite these fluctuations, surgical intervention remained a crucial and effective treatment, with 60% of patients surviving the 30-day follow-up. The study underscores the impact of delayed treatment on VSD incidence during the pandemic and highlights the critical need for timely medical intervention to manage severe MI complications effectively. [ABSTRACT FROM AUTHOR]

De-escalation of thyroid cancer treatment is crucial to prevent overtreatment of indolent disease, but it remains important to identify clinically aggressive cases. TERT promoter mutations are molecular events frequently associated with high-risk thyroid tumors with poor outcomes and may identify cases at risk of dissemination. In various international guidelines, small minimally invasive follicular thyroid carcinoma and oncocytic thyroid carcinoma (miFTC/miOTC) are classified as low-risk lesions and are not recommended adjuvant treatment. Our study aimed to explore the association between size-based risk assessment and TERT promoter mutations. Between 2019 and May 2024, 84 miFTCs/miOTCs diagnosed at our department underwent digital droplet PCR analysis targeting TERT promoter mutational hotspots C228T and C250T in clinical routine. TERT promoter mutations were found in 10 out of 84 cases (11.9%). Mutated cases were pT1 (n = 1), pT2 (n = 3), or pT3 (n = 6). Patients with mutated tumors were older compared to patients with wild-type tumors (median age of 71 years vs. 57 years, p = 0.041). There were no significant differences regarding patient sex, tumor size, Ki-67 labeling index, or the presence of distant metastases. Notably, 30% of mutations displayed variant allele frequencies < 10%, possibly suggesting subclonal events. To conclude, TERT promoter mutations in miFTCs and miOTCs were associated with higher patient age and were often suspected to be subclonal. However, they did not affect clinical outcomes, possibly due to short follow-up. Reflex testing for this genetic alteration in miFTCs and miOTCs could be justified regardless of tumor size, though the clinical benefit remains uncertain. [ABSTRACT FROM AUTHOR]

Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion–mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat Prnp promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer's disease and other tau prion disorders. [ABSTRACT FROM AUTHOR]

Somatic and biallelic DICER1 mutations are reported in subsets of thyroid tumors, supporting the role of this gene in thyroid tumor development. As recent studies have brought attention to macrofollicular patterns, atrophic changes, and papillary structures as being associated with DICER1 mutations, we sought to explore these observations in a bi-institutional cohort. A total of 61 thyroid lesions (54 tumors and 7 cases of thyroid follicular nodular disease; TFND), including 26 DICER1 mutated and 35 DICER1 wildtype controls were subjected to histological re-investigation and clinical follow-up. DICER1-mutated lesions showed a statistically significant association with younger age at surgery (29.2 ± 12.5 versus 51.3 ± 18.8, p = 0.0001), a predominant macrofollicular growth pattern (20/26 mutated cases versus 18/35 wildtype; p = 0.01) and atrophic changes (20/26 mutated cases versus 2/35 wildtype; p = 0.0001). Similar results were obtained when excluding TFND cases. We also present clinical and histological triaging criteria for DICER1 sequencing of thyroid lesions, which led to the identification of DICER1 variants in 16 out of 26 cases (62%) when followed. Among these, 3 out of 12 cases with available data were found to carry a constitutional DICER1 mutation. This observation suggests that the majority of DICER1 mutations are somatic—however implies that sequencing of constitutional tissues could be clinically motivated. We conclude that DICER1 mutations are amassed in younger patients with macrofollicular-patterned tumors and, most strikingly, atrophic changes. Given the rate of constitutional involvement, our findings could be of clinical value, allowing the pathologist to triage cases for genetic testing based on histological findings. [ABSTRACT FROM AUTHOR]

Follicular thyroid carcinoma (FTC) is recognized by its ability to invade the tumor capsule and blood vessels, although the exact molecular signals orchestrating this phenotype remain elusive. In this study, the spatial transcriptional landscape of an FTC is detailed with comparisons between the invasive front and histologically indolent central core tumor areas. The Visium spatial gene expression platform allowed us to interrogate and visualize the whole transcriptome in 2D across formalin-fixated paraffin-embedded (FFPE) tissue sections. Four different 6 × 6 mm areas of an FTC were scrutinized, including regions with capsular and vascular invasion, capsule-near area without invasion, and a central core area of the tumor. Following successful capturing and sequencing, several expressional clusters were identified with regional variation. Most notably, invasive tumor cell clusters were significantly over-expressing genes associated with pathways interacting with the extracellular matrix (ECM) remodeling and epithelial-to-mesenchymal transition (EMT). Subsets of these genes (POSTN and DPYSL3) were additionally validated using immunohistochemistry in an independent cohort of follicular thyroid tumors showing a clear gradient pattern from the core to the periphery of the tumor. Moreover, the reconstruction of the evolutionary tree identified the invasive clones as late events in follicular thyroid tumorigenesis. To our knowledge, this is one of the first 2D global transcriptional mappings of FTC using this platform to date. Invasive FTC clones develop in a stepwise fashion and display significant dysregulation of genes associated with the ECM and EMT — thus highlighting important molecular crosstalk for further investigations. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present study was to perform a survey administered to members of the Meniscus International Network (MenIN) Study Group, seeking to delineate the most contentious aspects of meniscal extrusion classification and provide a foundation for new, more comprehensive definitions and treatments for these pathologies. Methods: MenIN Study Group is a group of international experts treating and performing research on meniscus pathology and treatment. All MenIN Study Group members were asked to complete a survey aimed at establishing criteria for the optimal classification system for meniscal extrusion. Data obtained from the completed questionnaires were transferred into a spreadsheet and then analysed. All responses are presented as counts, percentages or means. Results: Forty‐seven (85.5%) MenIN Study Group members completed the survey and were included in this analysis. Key aspects recommended for inclusion in a comprehensive classification system for meniscal extrusion included laterality (93.6%), anatomical location (76.6%), patient age (76.6%), body mass index (BMI) (68.1%) and aetiology (68.1%). For classifying meniscal extrusion, 53.2% considered the distance in millimetres from the tibial plateau's outer margin as the most reliable measurement technique on imaging. Preferences for imaging modalities varied, with 44.7% favouring weight‐bearing magnetic resonance imaging (MRI) and 36.2% opting for weight‐bearing ultrasound due to its greater availability. Respondents advocated for a classification system addressing stability or progression of meniscal extrusion (66%), reducibility (53.2%), potential progression of knee osteoarthritis (OA) (83%), influencing treatment approaches (83%), a gradation system (83%), consideration of dynamic factors (66%), association with clinical outcomes and prognosis (76.6%) and investigation around centralization procedures (57.4%). Conclusions: In conclusion, the findings of this survey shed light on the global perspectives regarding meniscal extrusion classification. It was generally felt that a new classification of extrusion measured on MRI scans at the mid‐tibial plateau should be developed, which considers factors such as laterality, anatomical location, age, BMI and aetiology. Additionally, the results support the integration of dynamic factors and clinical outcomes in MRI‐based classifications to inform treatment approaches. Level of Evidence: Level IV. [ABSTRACT FROM AUTHOR]

This article discusses the management of atrial fibrillation (AF) and chronic kidney disease (CKD) in elderly patients. It highlights the use of oral anticoagulation (OAC) for stroke prevention in AF patients, with direct oral anticoagulants (DOACs) being preferred over vitamin K antagonists (VKAs). However, the role of DOACs in patients with severe renal impairment or end-stage renal disease (ESRD) is still unclear. The article also explores the safety and effectiveness of left atrial appendage occlusion (LAAO) as an alternative for stroke prevention in AF patients. The study suggests that DOACs may be associated with a lower risk of mortality compared to VKAs in elderly patients with AF and CKD. Additionally, the article discusses the potential benefits of performing LAAO without the use of contrast medium, which could reduce the risk of acute kidney injury in CKD patients. Overall, the findings suggest that LAAO may be a promising treatment option for elderly AF and CKD patients. [Extracted from the article]

Purpose: The aim of this ESSKA consensus is to give recommendations based on scientific evidence and expert opinion to improve the diagnosis, preoperative planning, indication and surgical strategy in Anterior Cruciate Ligament revision. Methods: Part 2, presented herein, followed exactly the same methodology as Part 1: the so-called ESSKA formal consensus derived from the Delphi method. Eighteen questions were ultimately asked. The quality of the answers received the following grades of recommendation: Grade A (high level scientific support), Grade B (scientific presumption), Grade C (low level scientific support) or Grade D (expert opinion). All answers were scored from 1 to 9 by the raters. Once a general consensus had been reached between the steering and rating groups, the question–answer sets were submitted to the peer-review group. A final combined meeting of all the members of the consensus was then held to ratify the document. Results: The review of the literature revealed a rather low scientific quality of studies examining the surgical strategy in cases of ACL reconstruction failure. Of the 18 questions, only 1 received a Grade A rating; 5, a Grade B rating; and 9, grades of C or D. The three remaining complex questions received further evaluations for each portion of the question and were looked at in more detail for the following grades: B and D; A, C and D; or A, B, C and D. The mean rating of all questions by the rating group was 8.0 + − 1.1. The questions and recommendations are listed in the article. Conclusion: ACL revision surgery, especially the surgical strategy, is a widely debated subject with many different opinions and techniques. The literature reveals a poor level of standardization. Therefore, this international European consensus project is of great importance and clinical relevance for guiding the management of ACL revision in adults. Level of evidence: Level II. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this ESSKA consensus is to give recommendations based on evidence and expert opinion to improve diagnosis, preoperative planning, indication and surgical strategy in ACL revision. Methods: The European expert surgeons and scientists were divided into four groups to participate in this consensus. A "literature group" (four surgeons); "steering group" (14 surgeons and scientists); "rating group" (19 surgeons) and finally "peer review group" (51 representatives of the ESSKA-affiliated national societies from 27 countries). The steering group prepared eighteen question–answer sets. The quality of the answers received grades of recommendation ranging from A (high-level scientific support), to B (scientific presumption), C (low level scientific support) or D (expert opinion). These question–answer sets were then evaluated by the rating group. All answers were scored from 1 to 9. The comments of the rating group were incorporated by the steering group and the consensus was submitted to the rating group a second time. Once a general consensus was reached between the steering and rating groups, the question–answer sets were submitted to the peer review group. A final combined meeting of all the members of the consensus was held to ratify the document. Results: The literature review for the diagnosis and preoperative planning of ACL revision revealed a rather low scientific quality. None of the 18 questions was graded A and six received a grade B. The mean rating of all the questions by the rating group was 8.4 ± 0.3. The questions and recommendations are listed below. Conclusion: ACL revision surgery is a widely debated subject with many different opinions and techniques. The literature reveals a poor level of standardisation. Therefore, this international consensus project is of great importance. Level of Evidence: II. [ABSTRACT FROM AUTHOR]

Background: Transport with extracorporeal membrane oxygenation (ECMO) in the hospital setting can become a challenge as well as in the out-of-hospital setting. In particular, the management of intra-hospital transport with ECMO support of the critically ill patient foresees his shift from the intensive care to the diagnostic areas, from the diagnostic areas to the interventional and surgical areas. Case presentation: In this context, we present a life-saving transport case with the veno-venous (VV) configuration of the ECMOLIFE Eurosets system, for right heart and respiratory failure in a 54-year-old woman, due to thrombosed obstruction of the right superior pulmonary vein, following mitral valve repair surgery in minimally invasive approach in a patient already operated on for complex congenital heart disease. After stabilizing the vital parameters with Veno-venous ECMO for 19 h, the patient was transported to hemodynamics for angiography of the pulmonary vessels, where the diagnosis of obstruction of the pulmonary venous return was made. Subsequently, the patient was brought back to the operating room for a procedure of unblocking the right superior pulmonary vein using a minimally invasive approach, passing from the ECMO to the support in extracorporeal circulation. Conclusions: The transportable ECMOLIFE Eurosets System was safe and effective during transport in maintaining the vital parameters of oxygenation and CO2 reuptake and systemic flow, allowing the patient to be mobilized for diagnostic tests instrumental to diagnosis. The patient was extubated 36 h after the surgical procedures and was discharged 10 days later from the hospital. [ABSTRACT FROM AUTHOR]

Background: Skeletal muscle has extraordinary regenerative capabilities against challenge, mainly owing to its resident muscle stem cells, commonly identified by Pax7+, which expediently donate nuclei to the regenerating multinucleated myofibers. This local reserve of stem cells in damaged muscle tissues is replenished by undifferentiated bone marrow stem cells (CD34+) permeating into the surrounding vascular system. Objective: The purpose of the study was to provide a quantitative estimate for the changes in Pax7+ muscle stem cells (satellite cells) in humans following an acute bout of exercise until 96 h, in temporal relation to circulating CD34+ bone marrow stem cells. A subgroup analysis of age was also performed. Methods: Four databases (Web of Science, PubMed, Scopus, and BASE) were used for the literature search until February 2022. Pax7+ cells in human skeletal muscle were the primary outcome. Circulating CD34+ cells were the secondary outcome. The standardized mean difference (SMD) was calculated using a random-effects meta-analysis. Subgroup analyses were conducted to examine the influence of age, training status, type of exercise, and follow-up time after exercise. Results: The final search identified 20 studies for Pax7+ cells comprising a total of 370 participants between the average age of 21 and 74 years and 26 studies for circulating CD34+ bone marrow stem cells comprising 494 participants between the average age of 21 and 67 years. Only one study assessed Pax7+ cells immediately after aerobic exercise and showed a 32% reduction in exercising muscle followed by a fast repletion to pre-exercise level within 3 h. A large effect on increasing Pax7+ cell content in skeletal muscles was observed 24 h after resistance exercise (SMD = 0.89, p < 0.001). Pax7+ cells increased to ~ 50% above pre-exercise level 24–72 h after resistance exercise. For a subgroup analysis of age, a large effect (SMD = 0.81, p < 0.001) was observed on increasing Pax7+ cells in exercised muscle among adults aged > 50 years, whereas adults at younger age presented a medium effect (SMD = 0.64, p < 0.001). Both resistance exercise and aerobic exercise showed a medium overall effect in increasing circulating CD34+ cells (SMD = 0.53, p < 0.001), which declined quickly to the pre-exercise baseline level after exercise within 6 h. Conclusions: An immediate depletion of Pax7+ cells in exercising skeletal muscle concurrent with a transient release of CD34+ cells suggest a replenishment of the local stem cell reserve from bone marrow. A protracted Pax7+ cell expansion in the muscle can be observed during 24–72 h after resistance exercise. This result provides a scientific basis for exercise recommendations on weekly cycles allowing for adequate recovery time. Exercise-induced Pax7+ cell expansion in muscle remains significant at higher age, despite a lower stem cell reserve after age 50 years. More studies are required to confirm whether Pax7+ cell increment can occur after aerobic exercise. Clinical Trial Registration: Registered at the International Prospective Register of Systematic Reviews (PROSPERO) [identification code CRD42021265457]. [ABSTRACT FROM AUTHOR]

Microglia are central to pathogenesis in many neurological conditions. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we show that CSF1R inhibitors given by multiple dosing paradigms in the Tg2541 tauopathy mouse model cause a sex-independent reduction in pathogenic tau and reversion of non-microglial gene expression patterns toward a normal wild type signature. Despite greater drug exposure in male mice, only female mice have functional rescue and extended survival. A dose-dependent upregulation of immediate early genes and neurotransmitter dysregulation are observed in the brains of male mice only, indicating that excitotoxicity may preclude functional benefits. Drug-resilient microglia in male mice exhibit morphological and gene expression patterns consistent with increased neuroinflammatory signaling, suggesting a mechanistic basis for sex-specific excitotoxicity. Complete microglial ablation is neither required nor desirable for neuroprotection and therapeutics targeting microglia must consider sex-dependent effects. Tau-mediated neurodegeneration is driven by disease-activated microglia and suppressed by their pharmacological blockade. The authors identified drug dose- and sex-dependent residual microglial phenotypes, neuronal excitotoxicity, and animal survival. [ABSTRACT FROM AUTHOR]

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy. Wang et al show that microglial NF-κB activation is essential for tau spreading and tau-mediated spatial learning and memory deficits in tauopathy mice. Inactivation of NF-κB reversed tau associated microglial states and rescued autophagy deficits. [ABSTRACT FROM AUTHOR]

Triathlon is a multisport composed of swim, cycle, and run segments and two transition periods. The swim-to-cycle transition is considered a critical period for the change in body position and the modifications in physiological (heart rate, VO2, lactate) and biomechanical parameters (cycling power and cadence, swimming stroke rate). Therefore, the aim of this review was to summarize the current evidence regarding the physiological and biomechanical changes and their interlink during the swim-to-cycle transition hinting at practical recommendations for coaches and athletes. The influence of the swim segment on cycle one is more evident for short-distance events. Greater modifications occur in athletes of lower level. The modulation of intensity during the swim segment affects the changes in the physiological parameters (heart rate, blood lactate, core temperature), with a concomitant influence on cycling gross efficiency. However, gross efficiency could be preserved by wearing a wetsuit or by swimming in a drafting position. A higher swim leg frequency during the last meters of the segment induces a higher cadence during the cycle segment. Training should be directed to the maintenance of a swimming intensity around 80–90% of a previous maximal swim test and with the use of a positive pacing strategy. When athletes are intended to train consecutively only swim and cycle segments, for an optimal muscle activation during cycling, triathletes could adopt a lower cadence (about 60–70% of their typical cadence), although an optimal pedaling cadence depends on the level and type of athlete. Future research should be focused on the combined measurements of physiological and biomechanical parameters using an intervention study design to evaluate training adaptations on swim kick rate and their effects on cycling performance. Coaches and athletes could benefit from the understanding of the physiological and biomechanical changes occurring during the swim-to-cycle transition to optimize the overall triathlon performance. [ABSTRACT FROM AUTHOR]

Purpose: Exposure to ionizing radiation, especially during childhood, is a well-established risk factor for thyroid cancer. The vast majority of radiation-induced cancers are papillary carcinomas (PTCs). These tumors typically have gene fusions in contrast to point mutations prevalent in sporadic PTCs. The aim of this study was to investigate the molecular profiles of PTC patients with workplace exposure to ionizing radiation. Methods: A retrospective review of 543 patients who underwent surgery with diagnosis of PTC was performed. A cohort of nine healthcare specialists previously exposed to radiation sources during their professional practice was selected and analyzed using the ThyroSeq mutation panel for point mutations and gene fusions associated with thyroid cancer. Results: The molecular analysis of surgical samples of PTCs was informative and revealed genetic alterations in five patients. BRAF V600E was found in four (67%) cases whereas RET/PTC1 fusion in one (17%) and one sample (17%) was wild type for point mutations and fusions. One sample completely failed molecular analysis while two others were negative for genes fusions but failed DNA analysis; these three samples were excluded. Conclusions: In this limited cohort of healthcare workers exposed to low dose of ionizing radiation at the workplace and developed PTC, the molecular profiling determined BRAF V600E point mutation as the most common event, arguing against the role of workplace radiation exposure in the etiology of these tumors. [ABSTRACT FROM AUTHOR]

Infective endocarditis represents a surgical challenge associated with perioperative mortality. The aim of this study is to evaluate the predictors of operative mortality and long-term outcomes in high-risk patients. We retrospectively analyzed 123 patients operated on for infective endocarditis from January 2011 to December 2020. Logistic regression model was used to identify prognostic factors of in-hospital mortality. Long term follow-up was made to asses late prognosis. Preoperative renal failure, an elevation EuroSCORE II and prior aortic valve re-replacement were found to be preoperative risk factors significantly associated with mortality. In-hospital mortality was 27% in patients who had previously undergone aortic valve replacement (n = 4 out of 15 operated, p = 0.01). Patients who were operated on during the active phase of infective endocarditis showed a higher mortality rate than those operated on after the acute phase (16% vs. 0%; p = 0.02). The type of prosthesis used (biological or mechanical) was not associated with mortality, whereas cross-clamp time significantly correlated with mortality (mean cross-clamp time 135 ± 65 min in dead patients vs. 76 ± 32 min in surviving patients; p = 0.0005). Mean follow up was 57.94 ± 30.9 months. Twelve patients died (11.65%). Among the twelve mortalities, five were adjudicated to cardiac causes and seven were non-cardiac (two cancers, one traumatic accident, one cerebral hemorrhage, two bronchopneumonia, one peritonitis). Overall survival probability (freedom from death, all causes) at 3, 5, 7 and 8 years was 98.9% (95% CI 97–100%), 96% (95% CI 92–100%), 85.9% (95% CI 76–97%), and 74% (95% CI 60–91%) respectively. Our study demonstrates that an early surgical approach may represent a valuable treatment option for high-risk patients with infective endocarditis, also in case of prosthetic valve endocarditis. Although several risk factors are associated with higher mortality, no patient subset is inoperable. These findings can be helpful to inform decision-making in heart team discussion. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the clinical outcomes of the implantation of an aliphatic polyurethane scaffold for the treatment of partial loss of meniscal tissue at a mean follow-up of 36 months.Methods: A retrospective review on prospectively collected data was performed on patients who underwent implantation of an aliphatic polyurethane-based synthetic meniscal scaffold. Patients were evaluated for demographics data, lesion and implant characteristics (sizing, type and number of meniscal sutures), previous and combined surgeries and complications. Clinical parameters were rated using NRS, IKDC subjective, Lysholm, KOOS, and Tegner activity score, both preoperatively and at final follow-up.Results: Sixty-seven patients were evaluated at a mean follow-up of 36 months (48 M and 19 F; mean age 40.8 ± 10.6 years; mean BMI 25.4 ± 4.3). The scaffold was implanted on the medial side in 54 cases, and on the lateral one in 13. Forty-seven patients had undergone previous surgical treatment at the same knee and 45 required combined surgical procedures. All evaluated scores improved significantly from the baseline. Among possible prognostic factors, a delayed scaffold implantation had lower post-operative clinical scores: IKDC subjective (P = 0.049), KOOS Sport (P = 0.044), KOOS total (p = 0.011), and Tegner (P = 0.03) scores at follow-up.Conclusions: The polyurethane meniscal scaffold implantation led to a significant clinical benefit in a large number of patients. A delayed intervention correlated with worse results.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

The altered biomechanical function of the knee following partial meniscectomy results in ongoing articular cartilage overload, which may lead to progressive osteoarthritis (OA). An artificial medial meniscus implant (NUsurface® Meniscus Implant, Active Implants LLC., Memphis, TN, USA) was developed to mimic the native meniscus and may provide an effective long-term solution for OA patients, alleviate pain, and restore joint function. The goal of the current study was to investigate the potential effect of an artificial medial meniscus implant on the function of the lateral compartment of the knee and on the potential alterations in load distribution between the two compartments under static axial loading, using advanced piezo-resistive sensors. We used an integrated in situ/in vivo experimental approach combining contact pressure measurements of cadaveric knees with MRI joint space measurements of 72 mild OA patients. We employed this integrated approach to evaluate the mechanical consequences in both the medial (treated) and lateral knee compartments of two levels of meniscectomy and implantation of an artificial meniscus implant. Partial and subtotal meniscectomies of the medial meniscus resulted in statistically significant decrease in contact areas (p = 0.008 and p < 0.0001, respectively) and increased contact pressures in the medial compartment; however, implantation of the artificial meniscus implant restored the average contact pressure to 93 ± 14% of its pre-meniscectomy, intact value. Additionally, we found that neither the two different grades of medial meniscectomies, nor implantation of the artificial medial meniscus implant affected the lateral compartment of the knee. The MRI data from the patient cohort facilitated the integration of real-life clinical results together with the laboratory measurements from our cadaveric study, as these two approaches complement each other. We conclude that the use of the artificial medial meniscus implant may re-establish normal load distribution across the articulating surfaces of the medial compartment and not increase loading across the lateral knee compartment. [ABSTRACT FROM AUTHOR]

In this article I discuss the nature and sense of legal reasoning as reasonableness, i.e. as judgement and equilibrium between normativity and factuality, and as constant approximation between these two dimensions. By (re)phrasing the intertwinement between legal hermeneutics and the nature and function of writing, the structure of the article is constructed so that the focus is on the changes currently occurring with the so-called 'digital revolution': in imagining a juridical system administrated through data analysis and algorithms, some contradictions emerge, especially concerning the nature, sense and task(s) of legal hermeneutics. The current shift of paradigm should be first of all addressed starting from the grammatological nature of the revolution at stake. Only from this perspective can the shift be entirely grasped and, at the same time, only from this perspective can the methodological conundrum be deconstructed. [ABSTRACT FROM AUTHOR]

Anterior cruciate ligament (ACL) reconstruction is generally regarded as a safe and effective procedure with high return to sport and low rerupture rates (4.9% rerupture rate after a mean FU time of 8.1 years according to the Norwegian Knee Ligament Registry) [[10]]. Nonetheless, due to the increasing number of ACL reconstructions performed annually, the number of ACL revisions (ACL-Rs) is rising automatically. Surgeons should be aware that ACL-R is associated with an increased risk of 30-day hospital readmission (0.6% vs. 1.9%), reoperation (0.5% vs. 1.9%), and surgical complications (0.5% vs. 1.9%) compared with primary ACL reconstruction [[11]]. [Extracted from the article]

Background: Residual rotational instability remains a controversial factor when analysing failure rates of anterior cruciate ligament (ACL) reconstruction. Anatomical and biomechanical studies have demonstrated a very important role of anterolateral structures for rotational control. Revision ACL is considered one of the main indications for a lateral extra-articular tenodesis (LET). Yet, few series evaluating these procedures are published.Purpose: To perform a systematic review of studies that assessed outcomes in patients treated with revision ACL surgery associated with a lateral extra-articular procedure.Study Design: Systematic review.Methods: A comprehensive literature search was performed in February 2018 using PubMed, Scopus, Web of Search and Cochrane. Inclusion criteria were series of ACL revision reconstructions associated with lateral extra-articular procedures. Clinical outcomes (Lysholm, subjective IKDC, KOOS, Cincinnati and WOMAC), joint stability measures (Lachman test, pivot-shift, arthrometer assessment and navigation assessment), graft type, reported chondral and meniscal injury, radiographic outcomes, complications and failures were recorded. Articles were assessed for level of evidence and methodology using a modification of the ACL Methodology Score (AMS) system.Results: Twelve studies met the inclusion criteria out of the 231 abstracts; 9 retrospective evaluations, two prospective cohorts and one combination of two populations (a retrospective and prospective series). A total of 851 patients evaluated with a mean age of 28.8 years (range 16-68 years) and a weighted mean follow-up of 4.9 years (range 1-10 years). The mean time from primary ACL reconstruction to revision was 5.3 years (reported in 7 studies, including 710 patients). The Lysholm, IKDC, and KOOS scores indicated favorable results in studies that reported these outcomes. Objective evaluations reported 86% objective A and B IKDC results, 2.6 mm mean side-to-side arthrometric difference and 80% negative pivot-shift. About 74% of patients returned to their previous sport (evaluated in six studies). Few studies reported radiological evaluation. Fifty-nine complications (8.0%) and 24 failures (3.6%) were reported. The mean modified ACL Methodology Score was 55.5 (range 32-72).Conclusion: Good mid-term results were obtained for combined revision ACL reconstruction and lateral extra-articular procedures. Despite the fact that in clinical practice LET are a common indication associated with revision ACL, there are no high-level studies supporting this technique.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

Revision anterior cruciate ligament reconstruction remains a challenge, especially optimising outcome for patients with a compromised knee where previous autogenous tissue has been used for reconstruction. Allograft tissue has become a recognized choice of graft for revision surgery but questions remain over the risks and benefits of such an option. Allograft tendons are a safe and effective option for revision ACL reconstruction with no higher risk of infection and equivalent failure rates compared to autografts provided that the tissue is not irradiated, or any irradiation is minimal. Best scenarios for use of allografts include revision surgery where further use of autografts could lead to high donor site morbidity, complex instability situations where additional structures may need reconstruction, and in those with clinical and radiologic signs of autologous tendon degeneration. A surgeon needs to be able to select the best option for the challenging knee facing revision ACL reconstruction, and in the light of current data, allograft tissue can be considered a suitable option to this purpose.Level of evidence IV. [ABSTRACT FROM AUTHOR]

Purpose: Currently both autograft and allograft tissues are available for reconstruction of posterior cruciate, collateral and multi-ligament knee injuries. Decision-making is based on a complex interplay between anatomical structures, functional bundles and varying biomechanical requirements. Despite theoretically better biological healing and reduced risk of disease transmission autografts are associated with donor site morbidity as well as being limited by size and quantity. The use of allografts eliminates donor-site morbidity but raises cost and issues of clinical effectiveness. The purpose of this paper is to review current concepts and evidence for the use of allografts in primary posterior cruciate, collateral and multi-ligament reconstructions.Methods: A narrative review of the relevant literature was conducted for PCL, collateral ligament and multi-ligament knee reconstruction. Studies were identified using a targeted and systematic search with focus on recent comparative studies and all clinical systematic reviews and meta-analyses. The rationale and principles of management underpinning the role of allograft tissue were identified and the clinical and functional outcomes were analysed. Finally, the position of postoperative physiotherapy and rehabilitation was identified.Results: The review demonstrated paucity in high quality and up-to-date results addressing the issue especially on collaterals and multi-ligament reconstructions. There was no significant evidence of superiority of a graft type over another for PCL reconstruction. Contemporary principles in the management of posterolateral corner, MCL and multi-ligament injuries support the use of allograft tissue.Conclusion: The present review demonstrates equivalent clinical results with the use of autografts or allografts. It remains, however, difficult to generate a conclusive evidence-based approach due to the paucity of high-level research. When confronted by the need for combined reconstructions with multiple grafts, preservation of synergistic muscles, and adapted postoperative rehabilitation; the current evidence does offer support for the use of allograft tissue.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

Purpose: The increasing awareness on the role of subchondral bone in the etiopathology of articular surface lesions led to the development of osteochondral scaffolds. While safety and promising results have been suggested, there are no trials proving the real potential of the osteochondral regenerative approach. Aim was to assess the benefit provided by a nanostructured collagen-hydroxyapatite (coll-HA) multilayer scaffold for the treatment of chondral and osteochondral knee lesions.Methods: In this multicentre randomized controlled clinical trial, 100 patients affected by symptomatic chondral and osteochondral lesions were treated and evaluated for up to 2 years (51 study group and 49 control group). A biomimetic coll-HA scaffold was studied, and bone marrow stimulation (BMS) was used as reference intervention. Primary efficacy measurement was IKDC subjective score at 2 years. Secondary efficacy measurements were: KOOS, IKDC Knee Examination Form, Tegner and VAS Pain scores evaluated at 6, 12 and 24 months. Tissue regeneration was evaluated with MRI MOCART scoring system at 6, 12 and 24 months. An external independent agency was involved to ensure data correctness and objectiveness.Results: A statistically significant improvement of all clinical scores was obtained from basal evaluation to 2-year follow-up in both groups, although no overall statistically significant differences were detected between the two treatments. Conversely, the subgroup of patients affected by deep osteochondral lesions (i.e. Outerbridge grade IV and OCD) showed a statistically significant better IKDC subjective outcome (+12.4 points, p = 0.036) in the coll-HA group. Statistically significant better results were also found for another challenging group: sport active patients (+16.0, p = 0.027). Severe adverse events related to treatment were documented only in three patients in the coll-HA group and in one in the BMS group. The MOCART score showed no statistical difference between the two groups.Conclusions: This study highlighted the safety and potential of a biomimetic implant. While no statistically significant differences were found compared to BMS for chondral lesions, this procedure can be considered a suitable option for the treatment of osteochondral lesions.Level Of Evidence: I. [ABSTRACT FROM AUTHOR]

The role of 4.1 or 8.2 μM meta-topolin ( mT) on shoot multiplication, rooting and ex vitro acclimatization of micropropagated Corylus colurna L., a promising non-suckering rootstock for hazelnut ( Corylus avellana L.), was examined in comparison to N-benzyladenine (BA), the most used cytokinin in tissue culture of Corylus spp. The influence of 8.2 μM mT and BA on photosynthetic pigments content and antioxidant enzymes activity, catalase (CAT) and guaiacol peroxidase (POD), in regenerated shoots, and on the preparation of the rootstock for micrografting was also evaluated. The highest shoot multiplication was recorded on medium containing 8.2 μM mT and an overall positive effect of mT on growth and quality of micropropagated shoots was found. The highest chlorophyll a content (1.236 mg g fresh weight, FW) and chlorophyll a/b ratio (2.48), and the lowest total carotenoids content (0.292 mg g FW) and CAT activity (25.8 μmol min mg protein) were detected after 8.2 μM mT application, while no significant differences were found in chlorophyll b content and POD activity between the two cytokinins. The best rhizogenesis response (98% for 4.1 μM and 100% for 8.2 μM mT) and ex vitro acclimatization competence (higher than 78%) were exhibited from shoots multiplied on mT. Furthermore, the multiplication of rootstock on mT allowed obtaining the highest (70%) response of successful micrografting. The present findings provide the first evidence of the successful applicability of mT in C. colurna tissue culture and development of micrografted plantlets. [ABSTRACT FROM AUTHOR]

There is an increasing awareness on the importance in identifying early phases of the degenerative processes in knee osteoarthritis (OA), the crucial period of the disease when there might still be the possibility to initiate treatments preventing its progression. Early OA may show a diffuse and ill-defined involvement, but also originate in the cartilage surrounding a focal lesion, thus necessitating a separate assessment of these two entities. Early OA can be considered to include a maximal involvement of 50 % of the cartilage thickness based on the macroscopic ICRS classification, reflecting an OARSI grade 4. The purpose of this paper was to provide an updated review of the current status of the diagnosis and definition of early knee OA, including the clinical, radiographical, histological, MRI, and arthroscopic definitions and biomarkers. Based on current evidence, practical classification criteria are presented. As new insights and technologies become available, they will further evolve to better define and treat early knee OA. [ABSTRACT FROM AUTHOR]

It is widely accepted that partial meniscectomy leads to early onset of osteoarthritis (OA). A strong correlation exists between the amount and location of the resected meniscus and the development of degenerative changes in the knee. On the other hand, osteoarthritic changes of the joint alter the structural and functional integrity of meniscal tissue. These alterations might additionally compromise the limited healing capacity of the meniscus. In young, active patients without cartilage damage, meniscus therapy including partial meniscectomy, meniscus suture, and meniscus replacement has proven beneficial effects in long-term studies. Even in an early osteoarthritic milieu, there is a relevant regenerative potential of the meniscus and the surrounding cartilage. This potential should be taken into account, and meniscal surgery can be performed with the correct timing and the proper indication even in the presence of early OA. [ABSTRACT FROM AUTHOR]

Patellofemoral joint cartilage lesions are associated with a variety of clinical situations including blunt trauma, lateral patella dislocations, or as a secondary development in the setting of abnormal joint loading. There is a need for more clarity on how to best address these lesions. Most specifically, when is it necessary to surgically treat these lesions of the patella and trochlea and which technique to use? This review will focus on the spectrum of patellofemoral disease/injury and their treatment strategies, with special emphasis on cartilage damage and early osteoarthritis. Chapter sections will review the most common scenarios of cartilage damage in the patellofemoral joint, with an attempt to summarize current treatment, their outcomes, remaining challenges and unanswered questions. [ABSTRACT FROM AUTHOR]

Total knee replacement is an accepted standard of care for the treatment of advanced knee osteoarthritis with good results in the vast majority of older patients. The use in younger and more active populations, however, remains controversial due to concerns over activity restrictions, implant survival, and patient satisfaction with the procedure. It is in these younger patient populations that alternatives to arthroplasty are increasingly being explored. Historically, osteotomy was utilized to address unicompartmental pain from degeneration and overload, for example, after meniscectomy. Utilization rates of osteotomy have fallen in recent years due to the increasing popularity of partial and total knee arthroplasty. This article explores the indications and outcomes of traditional unloading osteotomy, as well as newer options that are less invasive and offer faster return to function. [ABSTRACT FROM AUTHOR]

Purpose: In the last year, we have performed a new technique for combined medial collateral ligament (MCL) and posterior oblique ligament (POL) reconstruction in chronic setting of anterior cruciate ligament and MCL complex deficiency. Autogenous semitendinosus tendon with the tibial attachment preserved has been used for the medial/posteromedial compartment reconstruction. We describe the operative technique.Methods: Between January and December 2014, 12 consecutive patients with multiligamentous injuries underwent concomitant MCL/POL using a novel technique. The usefulness of the novel technique is the semitendinosus sling on the semimembranosus tendon and the POL fixation with the knee in full extension.Results: An ideal anteroposterior and rotational stability avoiding the medial compartment over constraint was achieved, in the immediate after surgery, due to the sequence of the bundle fixations and to the semitendinosus sling below the semimembranosus tendon.Conclusions: This technique is easily reproducible and useful and restores the medial stability immediately after surgery. [ABSTRACT FROM AUTHOR]

Cancer cells form three-dimensional (3D) multicellular aggregates (or spheroids) under non-adherent culture conditions. In ovarian cancer (OC), spheroids serve as a vehicle for cancer cell dissemination in the peritoneal cavity, protecting cells from environmental stress-induced anoikis. To identify new targetable molecules in OC spheroids, we investigated gene expression profiles and networks upregulated in 3D vs traditional monolayer culture conditions. We identified ALDH1A1, a cancer stem cell marker as being overexpressed in OC spheroids and directly connected to key elements of the β-catenin pathway. β-Catenin function and ALDH1A1 expression were increased in OC spheroids vs monolayers and in successive spheroid generations, suggesting that 3D aggregates are enriched in cells with stem cell characteristics. β-Catenin knockdown decreased ALDH1A1 expression levels and β-catenin co-immunoprecipitated with the ALDH1A1 promoter, suggesting that ALDH1A1 is a direct β-catenin target. Both short interfering RNA-mediated β-catenin knockdown and A37 ((ethyl-2-((4-oxo-3-(3-(pryrrolidin-1-yl)propyl)-3,4-dihydrobenzo [4,5]thioeno [3,2-d]pyrimidin-2-yl)thio)acetate)), a novel ALDH1A1 small-molecule enzymatic inhibitor described here for the first time, disrupted OC spheroid formation and cell viability (P<0.001). β-Catenin knockdown blocked tumor growth and peritoneal metastasis in an OC xenograft model. These data strongly support the role of β-catenin-regulated ALDH1A1 in the maintenance of OC spheroids and propose new ALDH1A1 inhibitors targeting this cell population. [ABSTRACT FROM AUTHOR]

Several experimental approaches have demonstrated that transglutaminase 2 (TG2) increased activity is involved in monocyte activation and inflammatory response. Preliminary results also demonstrate a TG-mediated post-translational modification of phospholipase A (PLA2), which catalyzes the release of arachidonic acid from its lipid storage sites. The control of PLA2-mediated production of eicosanoids has been found to be of great benefit for inflammatory disease treatment. However, the identification of the mechanisms of PLA2 activation is a very complex issue, because of the presence of multiple PLA2 forms. The aim of this study was to characterize the interactions between TG2 and sPLA2 in LPS-stimulated THP-1 cells, which were treated with TPA to induce early differentiated macrophage-type model. We demonstrated that increases in TG2 enzyme activity and protein expression may be considered an early event in monocyte/macrophage activation by LPS. Under these conditions, TG2 protein was co-immunoprecipitated with PLA2 by monoclonal antibody directed against the secretory form of the enzyme (sPLA2-V). Concomitantly, the PLA2 enzyme activity increased in TPA-treated cells exposed to LPS; these high levels of enzyme activity were significant reduced by R283, a site-specific inhibitor of TG2. Moreover, confocal laser scanning microscopy analysis of double-immunostained cytochemical specimens confirmed a co-localization of BAPA-labeled proteins and sPLA2-V in LPS-treated cells. These findings give evidence of a complex TG2/sPLA2-V, suggesting the possibility that sPLA2-V is a substrate for TG2. These results demonstrated that TG2 increases produced a sustained activation of PLA2 activity, suggesting a functional interaction between these enzymes in the regulation of inflammatory response. [ABSTRACT FROM AUTHOR]

Zonisamide (ZNS), an antiepileptic drug having beneficial effects also against Parkinson’s disease symptoms, has proven to display an antioxidant effects in different experimental models. In the present study, the effects of ZNS on rotenone-induced cell injury were investigated in human neuroblastoma SH-SY5Y cells differentiated towards a neuronal phenotype. Cell cultures were exposed for 24 h to 500 nM rotenone with or without pre-treatment with 10–100 μM ZNS. Then, the following parameters were analyzed: (a) cell viability; (b) intracellular reactive oxygen species production; (c) mitochondrial transmembrane potential; (d) cell necrosis and apoptosis; (e) caspase-3 activity. ZNS dose-dependently suppressed rotenone-induced cell damage through a decrease in intracellular ROS production, and restoring mitochondrial membrane potential. Similarly to ZNS effects, the treatment with N-acetyl-cysteine (100 μM) displayed significant protective effects against rotenone-induced ROS production and Δψ m at 4 and 12 h respectively, reaching the maximal extent at 24 h. Additionally, ZNS displayed antiapoptotic effects, as demonstrated by flow cytometric analysis of annexin V/propidium iodide double staining, and significant attenuated rotenone-increased caspase 3 activity. On the whole, these findings suggest that ZNS preserves mitochondrial functions and counteracts apoptotic signalling mechanisms mainly by an antioxidant action. Thus, ZNS might have beneficial effect against neuronal cell degeneration in different experimental models involving mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Transglutaminase 2 has been postulated to be involved in the pathogenesis of central nervous system neurodegenerative disorders. However, its role in neuronal cell death remains to be elucidated. Excitotoxicity is a common event underlying neurodegeneration. We aimed to evaluate the protein targets for transglutaminase 2 in cell response to NMDA-induced excitotoxic stress, using SH-SY5Y neuroblastoma cells which express high tranglutaminase 2 levels upon retinoic acid-driven differentiation toward neurons. NMDA-evoked calcium increase led to transglutaminase 2 activation that mediated cell survival, as at first suggested by the exacerbation of NMDA toxicity in the presence of R283, a synthetic competitive inhibitor of transglutaminase active site. Assays of R283-mediated transglutaminase inhibition showed the involvement of enzyme activity in NMDA-induced reduction in protein basal levels of pro-apoptotic caspase-3 and the stress protein Hsp20. However, this occurred in a way different from protein cross-linking, given that macromolecular assemblies were not observed in our experimental conditions for both proteins. Co-immunoprecipitation experiments provided evidence for the interaction, in basal conditions, between transglutaminase 2 and Hsp20, as well as between Hsp20 and Hsp27, a major anti-apoptotic protein promoting caspase-3 inactivation and degradation. NMDA treatment disrupted both these interactions that were restored upon transglutaminase 2 inhibition with R283. These results suggest that transglutaminase 2 might be protective against NMDA-evoked excitotoxic insult in neuronal-like SH-SY5Y cells in a way, independent from transamidation that likely involves its interaction with the complex Hsp20/Hsp27 playing a pro-survival role. [ABSTRACT FROM AUTHOR]

Agmatine is a novel neuromodulator that plays a protective role in the CNS in several models of cellular damage. However, the mechanisms involved in these protective effects in neurodegenerative diseases are poorly understood. Fourier transform infrared (FTIR) spectroscopy analysis detects biomolecular changes in disordered cells and tissues. In this report, we utilize FTIR spectroscopy to characterize the changes in rotenone-induced damage in neuronal-like differentiated SH-SY5Y neuroblastoma cells in the presence or absence of agmatine. The analysis of the FTIR spectra demonstrates significant alterations in rotenone-treated cells, whereas the FTIR spectra obtained after pre-incubation with agmatine (250 nM) significantly reduces these redox alterations and more closely resembles those of the control cells. In particular, rotenone-damaged cells demonstrate spectral alterations related to amide I, which correspond to an increase in β-sheet components, and decreases in the amide II absorption intensity, suggesting a loss of N-H bending and C-N stretching. These alterations were also evident by Fourier self-deconvolution analysis. Thus, rotenone-induced increases in the levels of stretching vibration band related to the protein carboxyl group would account for a significant amount of misfolded proteins in the cell. Agmatine effectively reduces these effects of rotenone on protein structure. In conclusion, antioxidant and scavenging properties of agmatine reduce rotenone-produced cellular damage at the level of protein structure. These, together with other previous observations, demonstrate the therapeutic potential of agmatine in the treatment of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Transglutaminase 2 (TG2) is a multifunctional calcium-dependent enzyme which catalyzes the post-translational protein crosslinking with formation of intra- or inter-molecular epsilon(gamma-glutamyl)lysine bonds or polyamine incorporation. The up-regulation and activation of TG2 have been reported in a variety of physiological events, including cell differentiation, signal transduction, apoptosis, and wound healing, as well as in cell response to stress evoked by different internal and external stimuli. Here we review TG2 role in cell response to redox state imbalance both under physiological and pathological conditions, such as neurodegenerative disorders, inflammation, autoimmune diseases and cataractogenesis, in which oxidative stress plays a pathogenetic role and also accelerates disease progression. The increase in TG activity together with mitochondrial impairment and collapse of antioxidant enzymatic cell defences have been reported to be the prominent biochemical alterations becoming evident prior to neurodegeneration. Moreover, oxidative stress-induced TG2 pathway is involved in autophagy inhibition and aggresome formation, and TG2 has been suggested to function as a link between oxidative stress and inflammation by driving the decision as to whether a protein should undergo SUMO-mediated regulation or proteasomal degradation. Literature data suggest a strong association between oxidative stress and TG2 up-regulation, which in turn may result in cell survival or apoptosis, depending on cell type, kind of stressor, duration of insult, as well as TG2 intracellular localization and activity state. In particular, it may be suggested that TG2 plays a pro-survival role when the alteration of cell redox state homeostasis is not associated with intracellular calcium increase triggering TG2 transamidation activity. [ABSTRACT FROM AUTHOR]

Shoot apices of in vitro-grown plantlets of white mulberry, Morus alba L. cv Florio, were cryopreserved using either encapsulation-dehydration or vitrification. For encapsulation-dehydration, alginate beads containing apices were dehydrated for 1, 3, 5 or 7 days in a liquid medium containing various sucrose concentrations (0.5, 0.75, 1.0 or 1.25 M). Bead desiccation was performed using silica gel for either 0, 4, 6, 8, 9 or 14 h. For vitrification, apices were directly immersed for either 5, 15, 30 or 60 min in a vitrification solution (PVS2). Following encapsulation-dehydration, treatment of alginate beads with 0.75 M sucrose was more effective in promoting re-growth of explants after immersion in liquid nitrogen than in the presence of 0.5 M sucrose for either 1 or 3 days. Re-growth of explants was also observed following vitrification and this reached 47% with increasing duration of the PVS2 treatment from 5 to 30 min. Overall, the highest frequency of explant re-growth was obtained when explants were subjected to encapsulation-dehydration in the presence of 0.75 M along with a 3 day sucrose dehydration pre-treatment and followed by desiccation for 9 h in silica gel. [ABSTRACT FROM AUTHOR]

The presence and severity of cerebrovascular pathological findings have been shown to increase the risk and stage of cognitive decline observed in Alzheimer's disease and vascular dementia. Thus, the modification of vascular risk factors seems useful to reduce the risk of dementia regardless of type. Hyperhomocysteinemia has long been known as a major independent risk factor for vascular dysfunction. In this study, we evaluated the relationships between plasma homocysteine levels and genetic risk factors for hyperhomocysteinemia, i.e., the presence of gene variants for methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (eNOS) in patients with cognitive impairment. Genotyping for MTHFR C677T and eNOS 894G > T polymorphisms was carried out in 69 patients with probable diagnosis of AD and anamnestic mild cognitive impairment, matched for age and gender with 69 healthy volunteers. Patients with MTHFR TT677 genotype showed higher plasma Hcy levels than controls, even after adjustment for folate levels ( P < 0.05). Moreover, Hcy plasma levels were higher in cases than controls for any given eNOS genotype. In particular, the presence of eNOS TT894 genotype in patients with cognitive decline resulted significantly associated with increased plasma Hcy levels when compared with controls having the same genotype or patients having other eNOS genotypes ( P = 0.02). These data suggest that both MTHFR C677T and eNOS G894T variants should be regarded as genetic risk factors for hyperhomocysteinemia in patients with cognitive decline. [ABSTRACT FROM AUTHOR]

Four platinum(II) complexes of general formula [PtCl(η-CH)L] [where L is 1,2-bis(diphenylphosphino)ethane (dppe) 1 or cycloocta-1,5-diene (cod) 3] and [PtClL] (where L is dppe 2 or cod 4) were studied. Inhibition growth assays on human tumor cell lines evidenced for 1 and 3 an antiproliferative effect and, interestingly, the cytotoxic effect exerted by 1 is similar to that of cisplatin. Electrochemical and NMR measurements allowed us to determine the structural and redox properties. Investigation of the mechanism of action responsible for the cytotoxicity demonstrated a weak capacity of interacting with DNA. Some experiments performed on rat liver mitochondria indicate that 1 acts as an inducer of the mitochondrial permeability transition, thus leading to the release of proapoptotic factors, such as cytochrome c and apoptosis-inducing factor. [ABSTRACT FROM AUTHOR]