Nonpharmacological treatment of rumination syndrome in childhood: A systematic review of the literature.

Rumination syndrome (RS) is a complex functional disorder characterized by recurrent, repetitive regurgitation of recently swallowed food. RS may have medical and psychosocial implications, compromising the quality of life and causing high rates of school absenteeism. Pediatric RS has been poorly studied and little evidence regarding its treatment is available. This systematic review aims to evaluate the literature on the nonpharmacological treatment of RS in childhood. A systematic literature search was conducted on MEDLINE/PubMed, CINAHL, Cochrane Library, PsycINFO, and PEDro, from 2000 to 2023. The methodological quality of the publications was assessed by applying the guidelines proposed by the Equator network, according to the different designs of study, and the risk of bias was evaluated with the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I). Five hundred ninety-six studies were screened, and 7 studies were included in the review. Diaphragmatic breathing was the most used nonpharmacological treatment, and it was always combined with other therapeutic strategies. The vast heterogeneity of the physical or mental comorbidities and the methodology adopted in the publications did not allow a comparative analysis of the different treatments. Regardless of the type of treatment, high-intensity therapeutic programs and specific operators' training emerged as the most influencing factors for patients' outcomes. According to the available evidence, there is not enough high-quality evidence to suggest a defined therapeutic strategy. Large observational studies on selected patients accounting for possible confounders, with adequate follow-up times, and with clearly defined treatment regimens are needed to identify the best therapeutic approach.

FK506 bypasses the effect of erythroferrone in cancer cachexia skeletal muscle atrophy.

Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition typical of chronic pathologies, that still represents an unmet medical need. Bone morphogenetic protein (BMP)-Smad1/5/8 signaling alterations are emerging drivers of muscle catabolism, hence, characterizing these perturbations is pivotal to develop therapeutic approaches. We identified two promoters of "BMP resistance" in cancer cachexia, specifically the BMP scavenger erythroferrone (ERFE) and the intracellular inhibitor FKBP12. ERFE is upregulated in cachectic cancer patients' muscle biopsies and in murine cachexia models, where its expression is driven by STAT3. Moreover, the knock down of Erfe or Fkbp12 reduces muscle wasting in cachectic mice. To bypass the BMP resistance mediated by ERFE and release the brake on the signaling, we targeted FKBP12 with low-dose FK506. FK506 restores BMP-Smad1/5/8 signaling, rescuing myotube atrophy by inducing protein synthesis. In cachectic tumor-bearing mice, FK506 prevents muscle and body weight loss and protects from neuromuscular junction alteration, suggesting therapeutic potential for targeting the ERFE-FKBP12 axis.

Immunolocalization and Expression of JAK1 and JAK3 in the Skin of Dust Mite-Sensitive Beagle Dogs before and after Allergen Exposure.

Janus kinase (JAK) pathways have emerged as targets of treatment, yet localization and expression of JAK1 and JAK3 in canine atopic skin have not been studied. This study aimed to compare the localization and expression of JAK1 and JAK3 in the skin of atopic dogs before and after allergen exposure. Skin biopsies taken from atopic beagles sensitized to house dust mites (HDM) before (D0) and after four weeks (D28) of allergen exposure were stained. Staining was subjectively scored by examiners unaware of the source of the slides. Image J was used for the semiquantitative assessment of staining intensity. JAK1 and JAK3 staining was epidermal and dermal. JAK1 staining was cytoplasmic, primarily found in basal keratinocytes and dermal cells, while JAK 3 was nuclear (all epidermal levels and on dermal inflammatory cells). Epidermal thickness was significantly higher on D28 than on D0 (p < 0.0001). For JAK1, epidermal staining divided by epithelial thickness was significantly lower on D28 (p = 0.0002) compared to D0. For JAK3 staining, intensity in the dermis was significantly higher on D28 (p = 0.0405) compared to D0. We conclude that decreased expression of JAK1 in the epidermis and increased expression of JAK3 in the dermis of atopic dogs occur after allergen exposure.

NAD+ repletion with niacin counteracts cancer cachexia.

Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.

MYTHO is a novel regulator of skeletal muscle autophagy and integrity.

Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.

C-terminal agrin fragment as a biomarker of muscle wasting and weakness: a narrative review.

Ageing is accompanied by an inexorable loss of muscle mass and functionality and represents a major risk factor for numerous diseases such as cancer, diabetes and cardiovascular and pulmonary diseases. This progressive loss of muscle mass and function may also result in the insurgence of a clinical syndrome termed sarcopenia, exacerbated by inactivity and disease. Sarcopenia and muscle weakness yield the risk of falls and injuries, heavily impacting on health and social costs. Thus, screening, monitoring and prevention of conditions inducing muscle wasting and weakness are essential to improve life quality in the ageing modern society. To this aim, the reliability of easily accessible and non-invasive blood-derived biomarkers is being evaluated. C-terminal agrin fragment (CAF) has been widely investigated as a neuromuscular junction (NMJ)-related biomarker of muscle dysfunction. This narrative review summarizes and critically discusses, for the first time, the studies measuring CAF concentration in young and older, healthy and diseased individuals, cross-sectionally and in response to inactivity and physical exercise, providing possible explanations behind the discrepancies observed in the literature. To identify the studies investigating CAF in the above-mentioned conditions, all the publications found in PubMed, written in English and measuring this biomarker in blood from 2013 (when CAF was firstly measured in human serum) to 2022 were included in this review. CAF increases with age and in sarcopenic individuals when compared with age-matched, non-sarcopenic peers. In addition, CAF was found to be higher than controls in other muscle wasting conditions, such as diabetes, COPD, chronic heart failure and stroke, and in pancreatic and colorectal cancer cachectic patients. As agrin is also expressed in kidney glomeruli, chronic kidney disease and transplantation were shown to have a profound impact on CAF independently from muscle wasting. CAF concentration raises following inactivity and seems to be lowered or maintained by exercise training. Finally, CAF was reported to be cross-sectionally correlated to appendicular lean mass, handgrip and gait speed; whether longitudinal changes in CAF are associated with those in muscle mass or performance following physical exercise is still controversial. CAF seems a reliable marker to assess muscle wasting in ageing and disease, also correlating with measurements of appendicular lean mass and muscle function. Future research should aim at enlarging sample size and accurately reporting the medical history of each patient, to normalize for any condition, including chronic kidney disease, that may influence the circulating concentration of this biomarker.

Plasma proteome profiling of healthy subjects undergoing bed rest reveals unloading-dependent changes linked to muscle atrophy.

BACKGROUND: Inactivity and unloading induce skeletal muscle atrophy, loss of strength and detrimental metabolic effects. Bed rest is a model to study the impact of inactivity on the musculoskeletal system. It not only provides information for bed-ridden patients care, but it is also a ground-based spaceflight analogue used to mimic the challenges of long space missions for the human body. In both cases, it would be desirable to develop a panel of biomarkers to monitor muscle atrophy in a minimally invasive way at point of care to limit the onset of muscle loss in a personalized fashion. METHODS: We applied mass spectrometry-based proteomics to measure plasma protein abundance changes in response to 10 days of bed rest in 10 young males. To validate the correlation between muscle atrophy and the significant hits emerging from our study, we analysed in parallel, with the same pipeline, a cohort of cancer patients with or without cachexia and age-matched controls. Our analysis resulted in the quantification of over 500 proteins. RESULTS: Unloading affected plasma concentration of proteins of the complement cascade, lipid carriers and proteins derived from tissue leakage. Among the latter, teneurin-4 increased 1.6-fold in plasma at bed rest day 10 (BR10) compared with BR0 (6.E9 vs. 4.3E9, P = 0.02) and decreased to 0.6-fold the initial abundance after 2 days of recovery at normal daily activity (R + 2, 2.7E9, P = 3.3E-4); the extracellular matrix protein lumican was decreased to 0.7-fold (1.2E9 vs. 8.5E8, P = 1.5E-4) at BR10 and remained as low at R + 2. We identified six proteins distinguishing subjects developing unloading-mediated muscle atrophy (decrease of >4% of quadriceps cross-sectional area) from those largely maintaining their initial muscle mass. Among them, transthyretin, a thyroid hormone-binding protein, was significantly less abundant at BR10 in the plasma of subjects with muscle atrophy compared with those with no atrophy (1.6E10 vs. 2.6E10, P = 0.001). Haptoglobin-related protein was also significantly reduced in the serum of cancer patients with cachexia compared with that of controls. CONCLUSIONS: Our findings highlight a combination or proteomic changes that can be explored as potential biomarkers of muscle atrophy occurring under different conditions. The panel of significant proteomic differences distinguishing atrophy-prone and atrophy-resistant subjects after 10 days of bed rest need to be tested in a larger cohort to validate their potential to predict inactivity-triggered muscle loss in humans.

Development and validation of an owner-assessed Visual Analog Scale for feline pruritus severity scoring (VAScat).

BACKGROUND: Assessment of the severity of pruritus is difficult in cats, because they manifest discomfort by increased licking, increased scratching or both. HYPOTHESIS/OBJECTIVES: Our objective was to develop and validate a feline-specific pruritus scale (VAScat). METHODS: The scale was designed as a double Visual Analog Scale (VAS), one VAS for licking and one for scratching, with severity and behavioural descriptors. The highest score (VAS-max) on either VAS was taken as the pruritus score for each cat. Owners of 153 cats with skin diseases and of 108 healthy cats scored their pet's pruritus using the VAScat. Ninety-six of 153 cats with skin diseases also were re-evaluated after four to eight weeks of treatment. RESULTS: Pearson's correlation value between VAS-licking and VAS-scratching scores was r = 0.26 (p < 0.01), and Cronbach's alpha was 0.41. Both indexes indicated that the two scales measure different manifestations of pruritus and supported the use of a dual assessing system. Comparison with a numerical pruritus severity scale (0, absent; 1, mild; 2, moderate; 3, severe) suggested that VAS-licking and VAS-scratching scales taken alone are unsuitable for measuring absent to mild pruritus (grades 0-1), while VAS-max is (p = 0.001). VAS-licking, VAS-scratching and VAS-max all were suitable to assess higher levels of pruritus (grades 2-3, p < 0.01). The VAScat was able to measure pruritus improvement following therapy, as post-treatment scores were significantly decreased compared to pre-treatment ones (p < 0.0001). CONCLUSIONS AND CLINICAL IMPORTANCE: The VAScat proved to be a useful tool to assess pruritus in cats and for monitoring the response to treatment for pruritus.

CONTEXTE: L'évaluation de la gravité du prurit est difficile chez les chats, car ils manifestent une gêne par un léchage accru et/ou un grattage accru. Hypothèses/Objectifs : Notre objectif était de développer et de valider une échelle de prurit spécifique au félin (EVAcat). Méthodes : L'échelle a été conçue comme une double échelle visuelle analogique (EVA), une EVA pour le léchage et une pour le grattage, avec des descripteurs de gravité et de comportement. Le score le plus élevé (VAS-max) sur l'un ou l'autre VAS a été pris comme score de prurit pour chaque chat. Les propriétaires de 153 chats atteints de maladies de la peau et de 108 chats en bonne santé ont noté le prurit de leur animal à l'aide du VAScat. Quatre-vingt-seize des 153 chats atteints de maladies de peau ont également été réévalués après quatre à huit semaines de traitement. Résultats : La valeur de corrélation de Pearson entre les scores de léchage VAS et de grattage VAS était de r = 0,26 (p < 0,01) et l'alpha de Cronbach était de 0,41. Les deux indices ont indiqué que les deux échelles mesurent différentes manifestations de prurit et ont soutenu l'utilisation d'un système d'évaluation double. La comparaison avec une échelle numérique de sévérité du prurit (0, absent ; 1, léger ; 2, modéré ; 3, sévère) a suggéré que les échelles EVA de léchage et de grattage prises seules ne conviennent pas pour mesurer le prurit absent à léger (grades 0-1), tandis que VAS-max l'est (p = 0,001). Le léchage VAS, le grattage VAS et le VAS-max étaient tous appropriés pour évaluer des niveaux plus élevés de prurit (grades 2-3, p < 0,01). Le VAScat a pu mesurer l'amélioration du prurit après le traitement, car les scores post-traitement ont été significativement diminués par rapport à ceux avant traitement (p < 0,0001). Conclusions et importance clinique : Le VAScat s'est avéré être un outil utile pour évaluer le prurit chez le chat et pour surveiller la réponse au traitement du prurit.

Introducción- la evaluación de la severidad del prurito es difícil en gatos, porque manifiestan malestar lamiéndose o rascándose más o ambos a la vez. Hipótesis/Objetivos- Nuestro objetivo fue desarrollar y validar una escala de prurito específica para felinos (VAScat). Métodos- La escala fue diseñada como una doble Escala Visual Análoga (EVAS), una VAS para lamido y otras para rascado, con descriptores de severidad y comportamiento. La puntuación más alta (VAS-max) en cualquiera de las VAS se tomó como la puntuación de prurito para cada gato. Los propietarios de 153 gatos con enfermedades de la piel y de 108 gatos sanos calificaron el prurito de sus mascotas con el VAScat. Noventa y seis de 153 gatos con enfermedades de la piel también fueron reevaluados después de cuatro a ocho semanas de tratamiento. Resultados- el valor de correlación de Pearson entre las puntuaciones de VAS-lamerse y VAS-rascarse fue r = 0,26 (p < 0,01), y el alfa de Cronbach fue 0,41. Ambos índices indicaron que las dos escalas miden diferentes manifestaciones de prurito y apoyaron el uso de un sistema de evaluación dual. La comparación con una escala numérica de gravedad del prurito (0, ausente; 1, leve; 2, moderado; 3, severo) sugirió que las escalas VAS-lamerse y VAS-rascarse tomadas solas no son adecuadas para medir el prurito ausente o leve (grados 0-1) , mientras que VAS-max sí que lo es (p = 0,001). VAS-lamerse, VAS-rascarse y VAS-max fueron adecuados para evaluar niveles más altos de prurito (grados 2-3, p < 0,01). El VAScat pudo medir la mejora del prurito después de la terapia, ya que las puntuaciones posteriores al tratamiento se redujeron significativamente en comparación con las anteriores al tratamiento (p < 0,0001). Conclusiones e importancia clínica- El VAScat demostró ser una herramienta útil para evaluar el prurito en gatos y para monitorizar la respuesta al tratamiento del prurito.

Contexto - A avaliação da gravidade do prurido em gatos é difícil, pois eles manifestam desconforto pelo aumento da lambedura, coçam-se mais ou os dois. Hipótese/Objetivos: Nosso objetivo foi desenvolver e validar uma escala de prurido específica para felinos (VAScat). Métodos - A escala foi desenvolvida como uma escala analógica visual (VAS) dupla, uma VAS para lambedura e uma para coceira, com descrição de gravidade e de comportamento. O escore mais alto (VAS-max) em ambas as VAS foi considerado o escore de prurido para cada gato. Donos de 153 gatos com doença de pele e de 108 gatos saudáveis classificaram o prurido dos seus animais utilizando o VAScat. Noventa e seis de 153 gatos com doenças de pele também foram reavaliados após quatro de oito semanas de tratamento. Resultados - O valor de correlação de Pearson entre os escores de VAS-lambedura e o VAS-coceira foi r = 0,26 (p < 0,01), e o alfa de Cronbach foi 0,41. Ambos os índices indicaram que as duas escalas de mensuraram manifestações diferentes de prurido e confirmaram a necessidade do uso de um sistema duplo de avaliação. A comparação com uma escala numérica de gravidade de prurido (0, ausente; 1, leve; 2, moderado; 3, grave) sugeriu que as escalas VAS-lambedura e VAS-coceira isoladamente são ineficazes para a mensuração de prurido ausente a leve (notas 0-1), enquanto o VAS-max é adequado para tal (p = 0,001). VAS-lambedura, VAS-coceira e VAS-max são todas eficazes para avaliar graus de prurido mais altos (notas 2-3, p < 0.01). A VAScat foi capaz de mensurar a melhora do prurido após o tratamento, os escores pós-tratamento foram significativamente menores comparados aos pré-tratamento (p < 0.0001). Conclusões e importância clínica - O VAScat provou ser uma ferramenta útil para avaliar o prurido em gatos e para o monitoramento da resposta ao tratamento para prurido.

Efficacy of physiotherapy treatments in children and adolescents with somatic symptom disorder and other related disorders: systematic review of the literature.

According to the latest version of the Diagnostic and Statistical Manual of Mental Disorders, somatic symptom and related disorders (SSRDs) are defined as psychopathological manifestations characterized by physical signs not attributable to organic pathology. Their incidence has grown dramatically over the past few decades, and treatment is challenging. Besides other interventions on the child and the family, physiotherapy is considered an integral part of the treatment, although there is no evidence for its efficacy.The study aimed to review the available proof on the effectiveness of physiotherapy in children and adolescents with SSRDs. A systematic literature search was conducted on MEDLINE/PubMed, CINAHL, Cochrane Library, PsycINFO, and PEDro, including 1999 to 2021. The methodological quality of the publications was assessed by applying the guidelines proposed by the Equator network, according to the different study designs. The scientific bibliography on the subject was minimal and had poor methodological quality. The choice of outcome indicators and the scales to measure them varied from study to study and were not standardized, making comparison and meta-analysis challenging.Conclusion: According to the available evidence, it is impossible to answer the review question regarding the effectiveness of physiotherapy in children and adolescents with SSRDs. It is necessary to improve the methodological quality of the studies. Definition of standard rehabilitation treatments, identification of appropriate result indicators, and adoption of standardized evaluation scales are needed.

Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.

Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor-bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor-bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer-induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases.

Activation of Akt-mTORC1 signalling reverts cancer-dependent muscle wasting.

BACKGROUND: Cancer-related muscle wasting occurs in most cancer patients. An important regulator of adult muscle mass and function is the Akt-mTORC1 pathway. While Akt-mTORC1 signalling is important for adult muscle homeostasis, it is also a major target of numerous cancer treatments. Which role Akt-mTORC1 signalling plays during cancer cachexia in muscle is currently not known. Here, we aimed to determine how activation or inactivation of the pathway affects skeletal muscle during cancer cachexia. METHODS: We used inducible, muscle-specific Raptor ko (mTORC1) mice to determine the effect of reduced mTOR signalling during cancer cachexia. On the contrary, in order to understand if skeletal muscles maintain their anabolic capacity and if activation of Akt-mTORC1 signalling can reverse cancer cachexia, we generated mice in which we can inducibly activate Akt specifically in skeletal muscles. RESULTS: We found that mTORC1 signalling is impaired during cancer cachexia, using the Lewis lung carcinoma and C26 colon cancer model, and is accompanied by a reduction in protein synthesis rates of 57% (P < 0.01). Further reduction of mTOR signalling, as seen in Raptor ko animals, leads to a 1.5-fold increase in autophagic flux (P > 0.001), but does not further increase muscle wasting. On the other hand, activation of Akt-mTORC1 signalling in already cachectic animals completely reverses the 15-20% loss in muscle mass and force (P < 0.001). Interestingly, Akt activation only in skeletal muscle completely normalizes the transcriptional deregulation observed in cachectic muscle, despite having no effect on tumour size or spleen mass. In addition to stimulating muscle growth, it is also sufficient to prevent the increase in protein degradation normally observed in muscles from tumour-bearing animals. CONCLUSIONS: Here, we show that activation of Akt-mTORC1 signalling is sufficient to completely revert cancer-dependent muscle wasting. Intriguingly, these results show that skeletal muscle maintains its anabolic capacities also during cancer cachexia, possibly giving a rationale behind some of the beneficial effects observed in exercise in cancer patients.

The ERG1A K+ Channel Is More Abundant in Rectus abdominis Muscle from Cancer Patients Than that from Healthy Humans.

BACKGROUND: The potassium channel encoded by the ether-a-gogo-related gene 1A (erg1a) has been detected in the atrophying skeletal muscle of mice experiencing either muscle disuse or cancer cachexia and further evidenced to contribute to muscle deterioration by enhancing ubiquitin proteolysis; however, to our knowledge, ERG1A has not been reported in human skeletal muscle. METHODS AND RESULTS: Here, using immunohistochemistry, we detect ERG1A immunofluorescence in human Rectus abdominis skeletal muscle sarcolemma. Further, using single point brightness data, we report the detection of ERG1A immunofluorescence at low levels in the Rectus abdominis muscle sarcolemma of young adult humans and show that it trends toward greater levels (10.6%) in healthy aged adults. Interestingly, we detect ERG1A immunofluorescence at a statistically greater level (53.6%; p < 0.05) in the skeletal muscle of older cancer patients than in age-matched healthy adults. Importantly, using immunoblot, we reveal that lower mass ERG1A protein is 61.5% (p < 0.05) more abundant in the skeletal muscle of cachectic older adults than in healthy age-matched controls. Additionally, we report that the ERG1A protein is detected in a cultured human rhabdomyosarcoma line that may be a good in vitro model for the study of ERG1A in muscle. CONCLUSIONS: The data demonstrate that ERG1A is detected more abundantly in the atrophied skeletal muscle of cancer patients, suggesting it may be related to muscle loss in humans as it has been shown to be in mice experiencing muscle atrophy as a result of malignant tumors.

Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia.

Most patients with advanced solid cancers exhibit features of cachexia, a debilitating syndrome characterized by progressive loss of skeletal muscle mass and strength. Because the underlying mechanisms of this multifactorial syndrome are incompletely defined, effective therapeutics have yet to be developed. Here, we show that diminished bone morphogenetic protein (BMP) signaling is observed early in the onset of skeletal muscle wasting associated with cancer cachexia in mouse models and in patients with cancer. Cancer-mediated factors including Activin A and IL-6 trigger the expression of the BMP inhibitor Noggin in muscle, which blocks the actions of BMPs on muscle fibers and motor nerves, subsequently causing disruption of the neuromuscular junction (NMJ), denervation, and muscle wasting. Increasing BMP signaling in the muscles of tumor-bearing mice by gene delivery or pharmacological means can prevent muscle wasting and preserve measures of NMJ function. The data identify perturbed BMP signaling and denervation of muscle fibers as important pathogenic mechanisms of muscle wasting associated with tumor growth. Collectively, these findings present interventions that promote BMP-mediated signaling as an attractive strategy to counteract the loss of functional musculature in patients with cancer.

The Prognostic Value of Low Muscle Mass in Pancreatic Cancer Patients: A Systematic Review and Meta-Analysis.

Low muscle mass is associated with reduced survival in patients with different cancer types. The interest in preoperative sarcopenia and pancreatic cancer has risen in the last decade as muscle mass loss seems to be associated with poorer survival, higher postoperative morbidity, and mortality. The aim of the present study was to review the literature to compare the impact of low muscle mass on the outcomes of patients undergoing surgery for pancreatic adenocarcinoma. An extensive literature review was conducted according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and 10 articles were analyzed in detail and included in the meta-analysis. Data were retrieved on 2811 patients undergoing surgery for pancreatic cancer. Meta-analysis identified that patients with low muscle mass demonstrated a significantly reduced OS when compared to patients without alterations of the muscle mass (ROM 0.86; 95% CI: 0.81-0.91, p < 0.001), resulting in a 14% loss for the former. Meta-analysis failed to identify an increase in the postoperative complications and length of stay of patients with low muscle mass. Our analysis confirms the role of low muscle mass in influencing oncologic outcomes in pancreatic cancer. Its role on surgical outcomes remains to be established.

Mechanisms of muscle atrophy and hypertrophy: implications in health and disease.

Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing.

Exercise-dependent increases in protein synthesis are accompanied by chromatin modifications and increased MRTF-SRF signalling.

AIM: Resistance exercise increases muscle mass over time. However, the early signalling events leading to muscle growth are not yet well-defined. Here, we aim to identify new signalling pathways important for muscle remodelling after exercise. METHODS: We performed a phosphoproteomics screen after a single bout of exercise in mice. As an exercise model we used unilateral electrical stimulation in vivo and treadmill running. We analysed muscle biopsies from human subjects to verify if our findings in murine muscle also translate to exercise in humans. RESULTS: We identified a new phosphorylation site on Myocardin-Related Transcription Factor B (MRTF-B), a co-activator of serum response factor (SRF). Phosphorylation of MRTF-B is required for its nuclear translocation after exercise and is accompanied by the transcription of the SRF target gene Fos. In addition, high-intensity exercise also remodels chromatin at specific SRF target gene loci through the phosphorylation of histone 3 on serine 10 in myonuclei of both mice and humans. Ablation of the MAP kinase member MSK1/2 is sufficient to prevent this histone phosphorylation, reduce induction of SRF-target genes, and prevent increases in protein synthesis after exercise. CONCLUSION: Our results identify a new exercise signalling fingerprint in vivo, instrumental for exercise-induced protein synthesis and potentially muscle growth.

A Case of Sebaceous Adenitis and Concurrent Meibomian Gland Dysfunction in a Dog.

Sebaceous adenitis and concurrent meibomian gland dysfunction (MGD) were diagnosed in a two-year-old mongrel dog presenting with hypotrichosis, exfoliative dermatitis and blepharitis. Diagnosis of sebaceous adenitis was based on history, clinical signs, the histological demonstration of multifocal lymphohistiocytic and neutrophilic inflammation targeting the sebaceous glands and sebaceous glands loss. MGD was diagnosed by non-contact infrared meibography followed by tear film lipid layer interferometric evaluation. Ciclosporin and sebolytic shampoos controlled the dermatological condition, while doxycycline, warm compresses, palpebral massages and tobramycin/dexamethasone ointment controlled the blepharitis. This case report should stimulate clinicians to investigate MGD in dogs suffering from sebaceous adenitis, because the meibomian and sebaceous glands share similar anatomy and physiology.

Nasal Planum Vasculopathy in a Scottish Terrier Dog Treated with Ciclosporin and Endonasal Stents.

A two-year-old, intact female Scottish Terrier presented with one-and-a-half-year history of erosive and ulcerative lesions affecting the nasal planum. Clinical appearance, history, histopathology, and response to therapy were suggestive of a rare vasculopathy of the nasal planum that has been previously described in Scottish Terrier dogs. In previously published reports, medical treatments of the disease had failed, leading to euthanasia of five dogs, while a short-term follow-up was available for one case that was controlled with prednisolone and ciclosporin. The dog reported herein was successfully treated with medical therapy consisting initially of a combination of ciclosporin and prednisolone and endonasal stents applied over the first six months. Stents were inserted in order to prevent abnormal scarring and nostril stenosis. More than one and a half years after diagnosis, the dog is still being administered ciclosporin once daily, breathes normally, and has an optimal quality of life.

Ciclosporin and the cat: Current understanding and review of clinical use.

Practical relevance: Ciclosporin (CsA) is a systemic immuno-modulatory drug widely used to treat immune-mediated diseases in humans and veterinary species. CsA was registered for use in cats in the USA and Europe in 2011, and is indicated for the treatment of chronic allergic dermatitis at a recommended daily dose of 7 mg/kg PO. AUDIENCE: This review will be of interest to all veterinarians working with cats, given the wide range of potential applications of CsA and its safety profile. Although the drug is currently only licensed to treat chronic allergic dermatitis in cats, a small number of reports describe its use in non-dermatological conditions. Evidence base: This article reviews the mechanism of action, pharmacokinetics, drug interactions, adverse effects and clinical use of CsA, both for the licensed indication and for off-label use in the feline patient. Information presented has been summarised from the existing literature on CsA, with specific interest in studies carried out in cats. For its licensed indication, chronic allergic dermatitis, evidence provided includes randomised, placebo or prednisolone-controlled studies (EBM grade I) and prospective or retrospective open trials.

Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival.

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia.