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Abstract Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy, and various non-neurological symptoms. In addition to neurological alterations, Creatine Transporter knockout (CrT−/y) mice exhibit severe muscle atrophy and functional impairments. This study provides the first characterization of the skeletal muscle phenotype in CrT−/y mice, revealing profound ultrastructural abnormalities accompanied by reduced fiber cross-sectional area and muscle performance. Notably, mitochondria are involved, as evidenced by disrupted cristae, increased mitochondrial size, impaired Ca2+ uptake, reduced membrane potential and ATP production. Mechanistically, the expression of atrophy-specific E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway, regulated by mitochondrial Ca2+ levels, further support the atrophic phenotype. These findings highlight the profound impact of Cr deficiency on skeletal muscle, emphasizing the need for targeted therapeutic strategies to address both the neurological and peripheral manifestations of CTD. Understanding the underlying mechanisms, particularly mitochondrial dysfunction, could lead to novel interventions for this disorder.

Mitochondria regulate several physiological functions through mitochondrial Ca2+ dynamics. However, role of mitochondrial Ca2+ signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca2+ uptake. In vitro gain and loss of function studies demonstrate that mitochondrial Ca2+ uniporter (MCU) is crucial for melanogenesis while MCU rheostat, MCUb negatively control melanogenesis. Zebrafish, MCU+/- and MCUb-/- mice models show that MCU complex drives pigmentation in vivo. Mechanistically, MCU silencing activates transcription factor NFAT2 to induce expression of keratin (5, 7, and 8) filaments. Interestingly, keratin5 in turn augments mitochondrial Ca2+ uptake and potentiates melanogenesis by regulating melanosome biogenesis and maturation. Hence this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca2+ signaling and pigmentation. Notably, mitoxantrone, an FDA approved drug that inhibits MCU, reduces pigmentation thereby highlighting therapeutic potential of targeting mitochondrial Ca2+ uptake for clinical management of pigmentary disorders. Taken together, we reveal an MCU-NFAT2-Keratin5 driven signaling axis that acts as a critical determinant of mitochondrial Ca2+ uptake and pigmentation. Given the vital role of mitochondrial Ca2+ signaling and keratin filaments in cellular physiology, this feedback loop could be operational in a variety of other patho-physiological processes.

Summary: Intimate partner violence (IPV) is a significant public health concern whose neurological/behavioral sequelae remain to be mechanistically explained. Using a mouse model recapitulating an IPV scenario, we evaluated the female brain neuroendocrine alterations produced by a reiterated male-to-female violent interaction (RMFVI). RMFVI prompted anxiety-like behavior in female mice whose hippocampus displayed a marked neuronal loss and hampered neurogenesis, namely reduced BrdU-DCX-positive nuclei and diminished dendritic arborization in the dentate gyrus (DG): effects paralleled by a substantial downregulation of the estrogen receptor β (ERβ). After RMFVI, the DG harbored reduced brain-derived neurotrophic factor (BDNF) pools and tyrosine kinase receptor B (TrkB) phosphorylation. Accordingly, ERβ knockout (KO) mice had heightened anxiety and curtailed BDNF levels at baseline while dying prematurely during the RMFVI procedure. Strikingly, injecting an ERβ antagonist or agonist into the wild-type (WT) female hippocampus enhanced or reduced anxiety, respectively. Thus, reiterated male-to-female violence jeopardizes hippocampal homeostasis, perturbing the ERβ/BDNF axis and ultimately instigating anxiety and chronic stress.

Ca2+ ions serve as pleiotropic second messengers in the cell, regulating several cellular processes. Mitochondria play a fundamental role in Ca2+ homeostasis since mitochondrial Ca2+ (mitCa2+) is a key regulator of oxidative metabolism and cell death. MitCa2+ uptake is mediated by the mitochondrial Ca2+ uniporter complex (MCUc) localized in the inner mitochondrial membrane (IMM). MitCa2+ uptake stimulates the activity of three key enzymes of the Krebs cycle, thereby modulating ATP production and promoting oxidative metabolism. As Paracelsus stated, “Dosis sola facit venenum,”in pathological conditions, mitCa2+ overload triggers the opening of the mitochondrial permeability transition pore (mPTP), enabling the release of apoptotic factors and ultimately leading to cell death. Excessive mitCa2+ accumulation is also associated with a pathological increase of reactive oxygen species (ROS). In this article, we review the precise regulation and the effectors of mitCa2+ in physiopathological processes.

Skeletal muscle, one of the most abundant tissue in the body, is a highly regenerative tissue. Indeed, compared to other tissues that are not able to regenerate after injury, skeletal muscle can fully regenerate upon mechanically, chemically, and infection-induced trauma. Several injury models have been developed to thoroughly investigate the physiological mechanisms regulating skeletal muscle regeneration. This protocol describes how to induce muscle regeneration by taking advantage of a cardiotoxin (CTX)-induced muscle injury model. The overall steps include CTX injection of tibialis anterior (TA) muscles of BL6N mice, collection of regenerating muscles at different time points after CTX injury, and histological characterization of regenerating muscles. Our protocol, compared with others such as those for freeze-induced injury models, avoids laceration or infections of the muscles since it involves neither surgery nor suture. In addition, our protocol is highly reproducible, since it causes homogenous myonecrosis of the whole muscle, and further reduces animal pain and stress. Graphical abstract

Calcium (Ca2+) ions act as a second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. A lot of evidence demonstrates that the dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been shown.

This paper presents the main surgical techniques applied in the treatment of anterior recurrent shoulder dislocation, aiming the achievement of the normality of articulate movements. This was obtained by combining distinct surgical procedures, which allowed the recovery of a complete functional capacity of the shoulder, without jeopardizing the normality of movement, something that has not been recorded in the case of the tense sutures of the surgical procedures of Putti-Platt, Bankart, Latarjet, Dickson-O'Dell and others.The careful review of the methods applied supports the conclusion that recurrent shoulder dislocation can be cured, since cure has been obtained in 97% of the treated cases. However, some degree of limitation in the shoulder movement has been observed in most of the treated cases.Our main goal was to achieve a complete shoulder functional recovery, by treating simultaneously all of the anatomical–pathological lesions, without considering the so-called essential lesions.The period of post-operatory immobilization only last for the healing of soft parts; this takes place in a position of neutral shoulder rotation, since the use of vascular bone graft eliminates the need for long time immobilization, due to the shoulder stabilization provided by rigid fixation of the coracoid at the glenoid edge, as in the Latarjet's technique.Our procedure, used since 1959, comprises the association of several techniques, which has permitted shoulder healing without movement limitation. That was because of the tension reduction in the sutures of the subescapularis, capsule, and coracobraquialis muscles.

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Stress corrosion cracking (SCC) is a common corrosion form that involves undetected premature failures during service life of structures. Since SCC is a combination of electrochemical and mechanical phenomena, coupled acoustic emission and electrochemical noise techniques were proposed to investigate the evolution of SCC damage tomartensitic stainless steel samples. Tests were carried out using a precipitation hardening martensitic stainless steel in an aqueous MgCl2 environment at 100°C, with an applied mechanical stress equal to the 90% of 0.2% yield strength. The synergistic use of the two non-destructive analysis technique was performed using a synchronisation process. The combination of two advanced multivariate analysis techniques (Principal Component Analysis and Self Organising Map neural network) highlighted damage-sensitive features. Characteristic clusters of variables related to specific damage mechanisms were identified discriminating electrochemical activation processes (i.e. pitting), SCC initiation and propagation until final failure phenomena during SCC. [ABSTRACT FROM AUTHOR]

Aim of the work is to investigate by using acoustic emission technique (AE) the hydrogen assisted Stress Corrosion Cracking (SCC) phenomena, in a martensitic stainless steel. In particular a study based on time domain approach was carried out in order to analyse the corrosion phenomena by using data variables evolution. An appropriate set of variables was presented, some of them directly related to the acoustic phenomena, such as Amplitude, Duration and other descriptors of the AE waveform, while others have been derived from them, such as b-value and Ib-value, that are descriptors about the time domain distribution of the AE event energy. Tests were carried out on a X12Cr13 martensitic stainless steel, according to NACE TM 0177 standard, using a modified sour corrosive environment (5% NaCl, 2.5% Acetic Acid and 10-2M Na2S2O3). [ABSTRACT FROM AUTHOR]

The analysis of three corrosion phenomena (uniform corrosion, pitting corrosion and stress corrosion cracking) has been carried out through the use of acoustic emission technique. Corrosion attacks have been obtained on three different types of martensitic stainless steel (X12Cr13, X4CrNiMo16-5-1, 17-4 PH) in a FeCl3 solution, using conditions set by the ASTM G48 standard. These alloys are characterized by different mechanical, microstructural and electrochemical properties, for each which lead to develop specific corrosion forms, albeit subject to the same environmental conditions. A multivariate statistical analysis approach, based on PCA (Principal Component Analysis), has been adopted to evaluate AE data and to have highlight damage-sensitive features. Specific clusters of variables related to specific corrosion phenomena have been identified, promoting this approach as a procedure for discriminating onset of specific corrosion mechanism. [ABSTRACT FROM AUTHOR]

Objective: to evaluate how orthopedic surgeons in Latin America define the working length for distinct patterns of femoral shaft fracture., Methods: a survey was developed presenting different options of working length in four femoral fracture patterns. The survey was submitted to the participants using Google Forms tool. The association between professional characteristics and medical management options according to each type of fracture was analyzed by Chi-square test, with 5% significance level., Results: seven hundred and seven professionals from all Latin America answered the survey. The majority prefered a smaller working length for all situations presented in the study. There was a significant association between the main interest area and the medical preference for the management in fracture types AO 32-B3 and 32-C2 (p<0.05). Other professional characteristics had no significant association at the level of 5%., Conclusion: most of the study participants preferred constructions with smaller working length, representing approximately one-third of the total length of the plate, regardless of fracture pattern. There was a significant association between the main interest area (orthopedic trauma) and medical management options for fracture type AO 32-B3 and 32-C2. This can be attributed in part to the fact that these two types of fractures are considered, in the view of the authors, intermediate patterns in terms of strain. This study reinforces the importance of understanding the concept of working length, showing that its calculation remains more based on the surgeons' experience than grounded by strong biomechanical concepts governing the fracture healing process.

Objective: : to evaluate the histologic and morphometric characteristics of bone biopsies of the anterior iliac crest of patients of different age groups., Methods: : we studied 30 bone samples from the iliac crest, using brightfield optical microscopy. We divided the samples by donors' age groups in three groups: Group 1 (n = 10), subjects aged between 25 and 39 years; Group 2 (n = 10), subjects aged between 40 and 64 years; Group 3 (n = 10), individuals aged 65 years and over. We randomly divided the samples into two sets with 15 specimens. In the first study segment (n = 15), we used histological to assess the osteogenic property of the graft, through the analysis of cell reserve in the periosteum, the number of osteocytes in the lacunae and the number of Haversian and Volkmann's canals. In the second study segment (n = 15), we investigated the morphology of osteoconductive property of the graft, through quantification of the trabecular meshwork (Vv) and trabecular area (Sv)., Results: : histologically, we observed degeneration of bone occurring with age, characterized by thinning of the periosteum, with gradual replacement of the steogenic layer by fibrous tissue, small amount of Haversian and Volkmann's canals, osteocyte lacunae voids and fine spongy bone trabeculae, allowing ample medullary space, usually occupied by fat cells and adipocytes. Morphologically, with respect to the quantification of the trabecular meshwork (Vv), we found statistically significant differences between Groups 1 and 3 and between Groups 2 and 3, with reduction of the trabecular meshwork of about 45% in the elderly over 65 years old ; there was no statistically significant difference between Groups 1 and 2. There was also no statistical difference between the Groups regarding Sv., Conclusion: : the results of this experiment suggest that, in the elderly (over 65 years old), the osteogenic property of autologous bone graft decreases and the osteoconductive property is compromised., Objetivo: avaliar as características histológicas e morfométricas de biópsias ósseas da região anterior da crista ilíaca de pacientes de diferentes faixas etárias., Métodos: foram estudadas 30 amostras de osso da crista ilíaca, utilizando-se microscopia óptica de campo claro. As amostras foram divididas pela faixa etária dos doadores em três grupos: Grupo 1 (n = 10), indivíduos com idade entre 25 e 39 anos; Grupo 2 (n = 10), indivíduos com idade entre 40 e 64 anos; Grupo 3 (n = 10), indivíduos com idade igual ou superior a 65 anos. As amostras foram separadas aleatoriamente em dois conjuntos com 15 peças. No primeiro segmento do estudo (n = 15), foi avaliada histologicamente a propriedade osteogênica do enxerto, através da análise da reserva celular no periósteo, do número de osteócitos nas lacunas e da quantidade de canais de Havers e de Volkmann. No segundo segmento do estudo (n = 15), investigou-se morfologicamente a propriedade osteocondutora do enxerto, através da quantificação da rede trabecular (Vv) e da área trabecular (Sv)., Resultados: histologicamente, observou-se que ocorre degeneração do tecido ósseo com a idade, caracterizada pelo adelgaçamento do periósteo, com substituição gradual da camada osteogênica por tecido fibroso, pequena quantidade de canais de Havers e de Volkmann, osteoplastos vazios e trabéculas finas de osso esponjoso, permitindo amplo espaço medular, em geral ocupado por células lipídicas e adipócitos. Morfologicamente, com relação à quantificação da rede trabecular (Vv), foi observada diferença estatisticamente significante entre os Grupos 1 e 3 e entre os Grupos 2 e 3, com redução da rede trabecular de cerca de 45% no idoso acima de 65 anos de idade; não foi observada diferença estatisticamente significante entre os Grupos 1 e 2. Não foi observada diferença estatística entre os grupos quanto à Sv., Conclusão: os achados do presente experimento sugerem que nos indivíduos idosos (acima de 65 anos de idade), a propriedade osteogênica do enxerto ósseo autólogo diminui e a propriedade osteocondutora está comprometida.

Objective: To analyze the natural exit of the wire guides in major trochanter through retrograde femoral approach, in cadaver specimens., Material and Method: 100 femurs had been perforated between the femoral condyles, at 1.2 cm of the intercondylar region. A 3-mm straight wire guide was introduced, through retrograde approach, until the proximal extremity of femur was reached. Femurs were assessed for posterosuperior and anterosuperior portions of major trochanter, pear-shaped cavity, and upper median line between the head-neck and the major trochanter., Results: in 62%, the straight wire guides exited at the anterior surface of major trochanter. In the pear-shaped cavity, the median distance found was 1.0 cm and the interquartile range was 0.5 cm, initially expressing, in relation to pear-shaped cavity, better accuracy., Conclusion: the central axis of the medullar canal, at coronal plane, projected better accuracy in the region of the pear-shaped cavity.

Objective: To assess the intramedullary nail entry point in the proximal region of the tibia, through a questionnaire., Methods: 230 participants undergoing treatment for tibial fractures were interviewed. The questionnaire was created with three sections that could be answered in a "Yes" or "No" format and a fourth section that had two figures representing anteroposterior (AP) and lateral view x-rays that could be answered in an "A, "B" or "C" format., Results: The most frequent reason was "ease of access" (67.8%), followed by "better nail insertion access" (60.9%) and, in third place, "to prevent knee pain" (27.4%). The reasons for choosing the access so as to "prevent knee pain" and "avoid tendinitis" had a significant relationship with points "A" and "C" of the schematic AP x-ray figure, especially "C" (medial tibial crest). There were no significant differences between the types of access to the patellar ligament in the schematic AP and lateral x-ray figures between age groups., Conclusion: The greater the age was, the larger the proportion choosing the question "to avoid valgus deformity" was. The reasons from a medical (practical) perspective related to the type of access in the transpatellar ligament, while the reasons from a patient (functional) perspective related to medial parapatellar access. Transpatellar access was chosen by most of the participants (66.5%).

Objective: To compare the duration of exposure to radiation among patients with fractures of the distal third of the tibia treated with an intramedullary nail or with a bridge plate., Methods: Intramedullary nails were used for 33 fractures, and bridge plates were used for 41 fractures. In the nail group, according to the AO classification, 14 patients had type A fractures, 15 had type B and four had type C. Twelve patients had closed fractures and 21 had open fractures. In the plate group, 10 patients had type A fractures, 22 had type B and nine had type C. Twenty-seven patients had closed fractures and 14 had open fractures., Results: There was a significant difference in the duration of exposure to radiation between the patients treated using a nail and those treated using a plate (p = 0.0001). The group treated using a nail had significantly greater exposure to radiation than did the group treated using a plate. Comparing the type of fracture (A, B or C), it was observed that there was no significant difference in the duration of exposure to radiation between the nail technique (p = 0.19) and the plate technique (p = 0.80)., Conclusion: Fractures of the distal third of the tibia treated with an intramedullary nail present significantly greater exposure to radiation than do fractures treated with a bridge plate, independent of the fracture type.

Objective: To clinically and anatomically compare the limits of the fibular nerve in Gerdy's safe zone in cadavers., Methods: Fifty anatomical knee specimens were clinically measured (before dissection) to determine the distances and angles between Gerdy's tubercle and the posterior region of the fibula (cm); the angle between the line corresponding to the posterior region of the fibula and the tibial crest (degrees); and the angle between Gerdy's tubercle and the tibial crest (degrees). After dissection of the anatomical specimens, the knees were measured again, to determine the distances and angles between Gerdy's tubercle and the fibular nerve (cm); the angle between the fibular nerve, in the posterior region of the fibula, and the tibial crest (degrees); and the angle between Gerdy's tubercle and the tibial crest (degrees)., Results: There was a significant increase in the distance between Gerdy's tubercle and the posterior region of fibula (cm), after dissection: an average of 0.26 cm (p = 0.018), corresponding to 8.6% (p = 0.007). There was also a significant reduction in the angle between the posterior region of the fibula and the tibial crest after dissection: an average of 3° (p = 0.047), corresponding to 2.1% (p = 0.06)., Conclusion: Despite the difference from before to after dissection, Gerdy's safe zone can be considered safe for orthopedic procedures involving the proximal region of the tibia, thereby avoiding damage to the fibular nerve and its branches.

Objective: To compare the existence of agreement between measurements of anteversion of the femoral neck and the degrees of osteoarthritis and abnormality of the neck-shaft angle in patients with unilateral idiopathic hip osteoarthritis, among three evaluators., Methods: Forty-two patients with unilateral hip osteoarthritis were evaluated by means of simple radiography and computed tomography., Results: It was observed that there was no significant variation in femoral anteversion between the diseased and healthy hips. There was strongest agreement between observers 1 and 2 in relation to both the diseased hips (cases) and the healthy hips (controls). Moreover, no significant agreement was found between observers 1 and 3 (p = 0.13) and between observers 2 and 3 (p = 0.12), in relation to the neck-shaft angle of the control hips., Conclusion: Although there was no relationship between femoral anteversion and the neck-shaft angle in the patients with unilateral hip osteoarthritis, the present study showed that there was also no relationship with these angular deviations.

Objective: The present study aimed to evaluate whether patient education level interferes in the percentage of pain relief or increase using visual analogue scale (VAS) and subjective pain perception., Patients and Methods: Ninety-five patients presenting acute shoulder pain due to enthesitis were evaluated. They were asked to quantify the pain using VAS before steroid articular infiltration. One week later, patients reevaluated the pain using VAS and orally stated the percentage of perceived pain increase or relief. The information gathered was then compared among three patient educational levels (elementary, high school, and university)., Results: Percentages of improvement stated orally and utilizing VAS presented no statistically significant differences among the three educational status levels (p = 0.804)., Conclusion: Patient educational status caused no impact in the results of acute pain self-assessment with VAS and oral evaluation.