High serum levels of ustekinumab are associated with better clinical outcomes during maintenance treatment for inflammatory bowel disease.

Background: Ustekinumab (UST) is an effective treatment option in Crohn's disease (CD) and ulcerative colitis (UC). However, it still remains unclear if therapeutic drug monitoring could be helpful to guide clinicians. Objectives: The aim of our study was to analyze the relationship between UST through levels (USTTL) and clinical outcomes in real-world inflammatory bowel disease (IBD) patients. Design: We performed a unicentric retrospective study including patients with IBD under UST treatment with at least one level determination. Methods: The following variables were analyzed at the initiation of UST and at each USTTL measurement: clinical response and remission using the Harvey-Bradshaw Index (HBI) for CD and the Partial Mayo Score (pMayo) for UC; biochemical response and remission using fecal calprotectin and C-reactive protein, among others. Two periods were considered: P1 (time between induction and the first determination of USTTL) and P2 (time between USTTL1 and the second determination of USTTL). Results: We included 125 patients, 117 with CD. In P1, 62.4% of patients were on subcutaneous maintenance, and the median USTTL1 was 3.1 µg/mL (1.6-5.3). In 44.8% of CD patients (48/117), clinical remission was achieved, with USTTL1 significantly higher than those who did not achieve remission (3.7 µg/mL (2.3-5.4) vs 2.3 µg/mL (1.1-5.2); p = 0.04). In the 46 patients with two determinations, statistically significant differences were found between variables in P2 versus P1: clinical remission (73.9% vs 21.7%; p = 0.001); USTTL (7.2 µg/mL (4.7-11.7) vs 3.4 µg/mL (1.9-6.4); p < 0.001), HBI (4 (4-4.3) vs 8 (4-9); p < 0.001), pMayo (1 (1-3.3) vs 4.5 (3-5); p = 0.042), and corticosteroid use (26.1% vs 41.3%; p = 0.024). Receiver-Operating-Characteristic (ROC) curves were calculated for clinical remission in P2, with USTTL cutoff value of 6.34 µg/mL for clinical remission and a high rate of intensified patients (98%). Conclusion: High serum levels of UST were associated with clinical remission during treatment for IBD under intensification treatment, with a cutoff point of 6.3 µg/mL.

Renal fibroblasts are involved in fibrogenic changes in kidney fibrosis associated with dysfunctional telomeres.

Tubulointerstitial fibrosis associated with chronic kidney disease (CKD) represents a global health care problem. We previously reported that short and dysfunctional telomeres lead to interstitial renal fibrosis; however, the cell-of-origin of kidney fibrosis associated with telomere dysfunction is currently unknown. We induced telomere dysfunction by deleting the Trf1 gene encoding a telomere-binding factor specifically in renal fibroblasts in both short-term and long-term life-long experiments in mice to identify the role of fibroblasts in renal fibrosis. Short-term Trf1 deletion in renal fibroblasts was not sufficient to trigger kidney fibrosis but was sufficient to induce inflammatory responses, ECM deposition, cell cycle arrest, fibrogenesis, and vascular rarefaction. However, long-term persistent deletion of Trf1 in fibroblasts resulted in kidney fibrosis accompanied by an elevated urinary albumin-to-creatinine ratio (uACR) and a decrease in mouse survival. These cellular responses lead to the macrophage-to-myofibroblast transition (MMT), endothelial-to-mesenchymal transition (EndMT), and partial epithelial-to-mesenchymal transition (EMT), ultimately causing kidney fibrosis at the humane endpoint (HEP) when the deletion of Trf1 in fibroblasts is maintained throughout the lifespan of mice. Our findings contribute to a better understanding of the role of dysfunctional telomeres in the onset of the profibrotic alterations that lead to kidney fibrosis.

[Role of diet in the prevention and development of Crohn's Disease]. / Papel de la dieta en la prevención y el desarrollo de la enfermedad de Crohn.

Introduction: Crohn's disease (CD) is a chronic recurrent inflammatory bowel disease (IBD) with frequent ileocolic location, although it can affect the entire gastrointestinal tract. It is characterized by the development of skipped lesions and transmural inflammation and its incidence is increasing. The etiology and pathogenesis are related to genetic susceptibility, intestinal microbiota, dysbiosis, immunological abnormalities and environmental factors (tobacco use, NSAIDs, oral contraceptives and diet). Diet may play a key role in the development and prevention of CD. Dietary patterns with high inflammatory potential (high intake of saturated fat, sugars, proteins, salt, as well as low consumption of fruits and vegetables) are associated with a higher risk of CD, while the consumption of a healthy diet, together with the practice of Exercise is a protective factor against relapses in IBD and reduces the risk of CD. Regarding dietary components, the consumption of fiber, as well as dietary polyphenols, has been related to the maintenance of the intestinal barrier by preventing erosion of the mucosal layer. ω-3 fatty acids, in addition to their anti-inflammatory activity, promote the balance of the intestinal microbiota and their supplementation reduces postoperative complications and accelerates recovery in patients with CD. Vitamin D also plays an important role in the integrity of the intestinal barrier by reducing permeability, in addition to having an immunomodulatory and anti-inflammatory effect, being a useful tool in the improvement of patients with CD. Prebiotics and probiotics may be useful in the treatment of IBD patients by stimulating mucus production, reducing inflammation and dysbiosis, and maintaining the integrity of the intestinal barrier.

Introducción: La enfermedad de Crohn (EC) es una enfermedad inflamatoria intestinal (EII) crónica recurrente con localización frecuente ileocólica, aunque puede afectar a todo el tracto gastrointestinal. Se caracteriza por el desarrollo de lesiones salteadas e inflamación transmural y su incidencia es cada vez mayor. La etiología y la patogénesis está relacionada con la susceptibilidad genética, la microbiota intestinal, la disbiosis, anomalías inmunológicas y factores ambientales (consumo de tabaco, AINE, anticonceptivos orales y la dieta). La dieta puede tener un papel clave en el desarrollo y en la prevención de la EC. Los patrones dietéticos con alto potencial inflamatorio (elevada ingesta de grasa saturada, azúcares, proteínas y sal, así como bajo consumo de frutas y verduras) se asocian con mayor riesgo de EC, mientras que el consumo de una dieta saludable, unida a la práctica de ejercicio, es un factor protector frente a recaídas en EII y disminuye el riesgo de EC. Respecto a los componentes alimentarios, el consumo de fibra, así como de polifenoles dietéticos, se ha relacionado con el mantenimiento de la barrera intestinal al prevenir la erosión de la capa mucosa. Los ácidos grasos ω-3, además de su actividad antiinflamatoria, favorecen el equilibrio de la microbiota intestinal y su suplementación disminuye las complicaciones posoperatorias y acelera la recuperación en pacientes con EC. También la vitamina D desempeña un papel importante en la integridad de la barrera intestinal al disminuir la permeabilidad, además de presentar un efecto inmunomodulador y antiinflamatorio. Es una herramienta útil en la mejora del paciente con EC. Los prebióticos y los probióticos pueden ser útiles en el tratamiento de pacientes con EII al estimular la producción de moco, reducir la inflamación y disbiosis y mantener la integridad de la barrera intestinal.

Cognitive functioning and falls in older people: A systematic review and meta-analysis.

OBJECTIVE: To identify which cognitive functions and specific neuropsychological assessments predict falls in older people living in the community. METHODS: Five electronic databases were searched until 30/08/2022 for studies assessing the association between specific cognitive functions and faller status (prospective and retrospective), in community-dwelling older people. Risk of bias was assessed with the Newcastle-Ottawa Scale. Meta-analyses synthesised the evidence regarding the associations between different neurocognitive subdomains and faller status. RESULTS: Thirty-eight studies (20 retrospective, 18 prospective) involving 37,101 participants were included. All but one study was rated high or medium quality. Meta-analyses were performed with data from 28 studies across 11 neurocognitive subdomains and four specific neuropsychological tests. Poor cognitive flexibility, processing speed, free recall, working memory and sustained attention were significantly associated with faller status, but poor verbal fluency, visual perception, recognition memory, visuo-constructional reasoning and language were not. The Trail Making Test B was found to have the strongest association with faller status. CONCLUSION: Poor performance in neurocognitive subdomains spanning processing speed, attention, executive function and aspects of memory are associated with falls in older people, albeit with small effect sizes. The Trail Making Test, a free-to-use, simple assessment of processing speed and mental flexibility, is recommended as the cognitive screening test for fall risk in older people.

Molecular screening of transitional B cells as a prognostic marker of improved graft outcome and reduced rejection risk in kidney transplant.

Introduction: Understanding immune cell dynamics in kidney transplantation may provide insight into the mechanisms of rejection and improve patient management. B cells have gained interest with a special relevance of the "regulatory" subsets and their graft outcome prognostic value. In this study, we aimed to prove that the direct immunophenotyping and target gene expression analysis of kidney transplant patients' fresh whole blood will help to identify graft rejection risk and assist in the monitoring of kidney transplanted patients. Methods: We employed flow cytometry and qPCR techniques to characterize B and T cell subsets within fresh whole blood samples, with particular emphasis on transitional B cells (TrB) identified as CD19+CD24hiCD38hi. TrB are a relevant population in the context of kidney transplantation and are closely associated with regulatory B cells (Bregs) in humans. Patients were monitored, tracking pertinent clinical parameters and kidney-related events, including alterations in graft function and episodes of biopsy proven rejection. Results: Higher percentages of TrB cells at 3 months after transplantation were positively associated with better graft outcomes and lower biopsy-proven acute rejection risk. Furthermore, a novel panel of B cell regulatory associated genes was validated at 3 months post-transplantation by qPCR analysis of peripheral blood mononuclear cell (PBMC) mRNA, showing high predictive power of graft events and prognostic value. Discussion: These findings suggest that monitoring TrB may provide interesting patient management information, improve transplant outcomes, and allow for personalized drug regimens to minimize clinical complications.

Impact of combined intermittent fasting and high-intensity interval training on apoptosis and atrophy signaling in rat fast- and slow-twitch muscles.

This study aimed to evaluate the influence of combined intermittent fasting (IF) and high-intensity interval training (HIIT) on morphology, caspase-independent apoptosis signaling pathway, and myostatin expression in soleus and gastrocnemius (white portion) muscles from healthy rats. Sixty-day-old male Wistar rats (n = 60) were divided into four groups: control (C), IF, high-intensity-interval training (T), and high-intensity-interval training and intermittent fasting (T-IF). The C and T groups received ad libitum chow daily; IF and T-IF received the same standard chow every other day. Animals from T and T-IF underwent a HIIT protocol five times a week for 12 weeks. IF reduced gastrocnemius mass and increased pro-apoptotic proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in soleus and cleaved-to-non-cleaved PARP-1 ratio and myostatin expression in gastrocnemius white portion. HIIT increased AIF and apoptosis repressor with caspase recruitment domain expression in soleus and cleaved-to-total PARP-1 ratio in gastrocnemius muscle white portion. The combination of IF and HIIT reduced fiber cross-sectional area in both muscles, increased EndoG and AIF expression, and decreased cleaved-to-non-cleaved PARP-1 ratio in gastrocnemius muscle white portion. Muscle responses to IF and HIIT are directly impacted by the muscle fiber type composition and are modulated, at least in part, by myostatin and caspase-independent apoptosis signaling.

Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural-like dedifferentiation.

The mechanisms that work alongside BRAFV600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal BrafV600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1-depleted mice compared with BrafV600E-irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1-null irradiated mice exhibited deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural-like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with BrafV600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural-like dedifferentiation.

The Urinary Glycopeptide Profile Differentiates Early Cardiorenal Risk in Subjects Not Meeting Criteria for Chronic Kidney Disease.

Early diagnosis and treatment of chronic kidney disease (CKD) is a worldwide challenge. Subjects with albumin-to-creatinine ratio (ACR) ≥ 30 mg/g and preserved renal function are considered to be at no cardiorenal risk in clinical practice, but prospective clinical studies evidence increased risk, even at the high-normal (HN) ACR range (10-30 mg/g), supporting the need to identify other molecular indicators for early assessment of patients at higher risk. Following our previous studies, here we aim to stratify the normoalbuminuria range according to cardiorenal risk and identify the glycoproteins and N-glycosylation sites associated with kidney damage in subclinical CKD. Glycoproteins were analyzed in urine from hypertensive patients within the HN ACR range compared to control group (C; ACR < 10 mg/g) by mass spectrometry. A different cohort was analyzed for confirmation (ELISA) and sex perspective was evaluated. Patients' follow-up for 8 years since basal urine collection revealed higher renal function decline and ACR progression for HN patients. Differential N-glycopeptides and their N -glycosylation sites were also identified, together with their pathogenicity. N-glycosylation may condition pathological protein deregulation, and a panel of 62 glycoproteins evidenced alteration in normoalbuminuric subjects within the HN range. Haptoglobin-related protein, haptoglobin, afamin, transferrin, and immunoglobulin heavy constant gamma 1 (IGHG1) and 2 (IGHG2) showed increased levels in HN patients, pointing to disturbed iron metabolism and tubular reabsorption and supporting the tubule as a target of interest in the early progression of CKD. When analyzed separately, haptoglobin, afamin, transferrin, and IGHG2 remained significant in HN, in both women and men. At the peptide level, 172 N-glycopeptides showed differential abundance in HN patients, and 26 showed high pathogenicity, 10 of them belonging to glycoproteins that do not show variation between HN and C groups. This study highlights the value of glycosylation in subjects not meeting KDIGO criteria for CKD. The identified N-glycopeptides and glycosylation sites showed novel targets, for both the early assessment of individual cardiorenal risk and for intervention aimed at anticipating CKD progression.

Zebrafish as a Human Muscle Model for Studying Age-Dependent Sarcopenia and Frailty.

Currently, there is an increase in the aging of the population, which represents a risk factor for many diseases, including sarcopenia. Sarcopenia involves progressive loss of mass, strength, and function of the skeletal muscle. Some mechanisms include alterations in muscle structure, reduced regenerative capacity, oxidative stress, mitochondrial dysfunction, and inflammation. The zebrafish has emerged as a new model for studying skeletal muscle aging because of its numerous advantages, including histological and molecular similarity to human skeletal muscle. In this study, we used fish of 2, 10, 30, and 60 months of age. The older fish showed a higher frailty index with a value of 0.250 ± 0.000 because of reduced locomotor activity and alterations in biometric measurements. We observed changes in muscle structure with a decreased number of myocytes (0.031 myocytes/µm2 ± 0.004 at 60 months) and an increase in collagen with aging up to 15% ± 1.639 in the 60-month group, corresponding to alterations in the synthesis, degradation, and differentiation pathways. These changes were accompanied by mitochondrial alterations, such as a nearly 50% reduction in the number of intermyofibrillar mitochondria, 100% mitochondrial damage, and reduced mitochondrial dynamics. Overall, we demonstrated a similarity in the aging processes of muscle aging between zebrafish and mammals.

ß-lactamase expression induces collateral sensitivity in Escherichia coli.

Major antibiotic groups are losing effectiveness due to the uncontrollable spread of antimicrobial resistance (AMR) genes. Among these, ß-lactam resistance genes -encoding ß-lactamases- stand as the most common resistance mechanism in Enterobacterales due to their frequent association with mobile genetic elements. In this context, novel approaches that counter mobile AMR are urgently needed. Collateral sensitivity (CS) occurs when the acquisition of resistance to one antibiotic increases susceptibility to another antibiotic and can be exploited to eliminate AMR selectively. However, most CS networks described so far emerge as a consequence of chromosomal mutations and cannot be leveraged to tackle mobile AMR. Here, we dissect the CS response elicited by the acquisition of a prevalent antibiotic resistance plasmid to reveal that the expression of the ß-lactamase gene blaOXA-48 induces CS to colistin and azithromycin. We next show that other clinically relevant mobile ß-lactamases produce similar CS responses in multiple, phylogenetically unrelated E. coli strains. Finally, by combining experiments with surveillance data comprising thousands of antibiotic susceptibility tests, we show that ß-lactamase-induced CS is pervasive within Enterobacterales. These results highlight that the physiological side-effects of ß-lactamases can be leveraged therapeutically, paving the way for the rational design of specific therapies to block mobile AMR or at least counteract their effects.

Exercise, mTOR Activation, and Potential Impacts on the Liver in Rodents.

The literature offers a consensus on the association between exercise training (ET) protocols based on the adequate parameters of intensity and frequency, and several adaptive alterations in the liver. Indeed, regular ET can reverse glucose and lipid metabolism disorders, especially from aerobic modalities, which can decrease intrahepatic fat formation. In terms of molecular mechanisms, the regulation of hepatic fat formation would be directly related to the modulation of the mechanistic target of rapamycin (mTOR), which would be stimulated by insulin signaling and Akt activation, from the following three different primary signaling pathways: (I) growth factor, (II) energy/ATP-sensitive, and (III) amino acid-sensitive signaling pathways, respectively. Hyperactivation of the Akt/mTORC1 pathway induces lipogenesis by regulating the action of sterol regulatory element binding protein-1 (SREBP-1). Exercise training interventions have been associated with multiple metabolic and tissue benefits. However, it is worth highlighting that the mTOR signaling in the liver in response to exercise interventions remains unclear. Hepatic adaptive alterations seem to be most outstanding when sustained by chronic interventions or high-intensity exercise protocols.

Integrated miRNA-mRNA Analysis Reveals Critical miRNAs and Targets in Diet-Induced Obesity-Related Glomerulopathy.

This study aimed to investigate obesity-related glomerulopathy (ORG) at cellular, structural, and transcriptomic levels. Thirty Wistar rats were randomized into two groups: 15 rats were fed with a standard diet (SD-rats), and 15 rats were fed with a high-fat diet (HFD-rats). After 10 weeks, the weight, kidney function, histological features, and transcriptomic changes were assessed. HFD-rats gained significantly more weight (55.8% vs. 29.2%; p < 0.001) and albuminuria (10,384.04 ng/mL vs. 5845.45 ng/mL; p < 0.001) compared to SD-rats. HFD-rats exhibited early stages of ORG, with predominant mesangial matrix increase and podocyte hypertrophy (PH). These lesions correlated with differentially expressed (DE) genes and miRNAs. Functional analysis showed that miR-205, which was DE in both the kidneys and urine of HFD-rats, negatively regulated the PTEN gene, promoting lipid endocytosis in podocytes. The downregulation of PTEN was proved through a higher PTEN/nephrin ratio in the SD-rats and the presence of lipid vacuoles in HFD-podocytes. This study has found a specific targetome of miRNAs and gene expression in early stages of ORG. Also, it emphasizes the potential value of miR-205 as a urinary biomarker for detecting podocyte injury in ORG, offering a tool for early diagnosis, and opening new avenues for future therapeutic research of obesity-related glomerulopathy.

[Frailty, Sarcopenia and Osteoporosis]. / Fragilidad, sarcopenia y osteoporosis.

Frailty, sarcopenia and osteoporosis are entities specific to the elderly, who share some risk factors. For this reason, their relationship has been studied in different works, which have provided disparate results, probably because these studies have not always focused on the same aspects. This article reviews the relationship of frailty and sarcopenia with osteoporosis.

iMS-Bmal1-/- mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies.

Sarcopenia is an age-related disease characterized by a reduction in muscle mass, strength, and function and, therefore, a deterioration in skeletal muscle health and frailty. Although the cause of sarcopenia is still unknown and, thus, there is no treatment, increasing evidence suggests that chronodisruption, particularly alterations in Bmal1 clock gene, can lead to those deficits culminating in sarcopenia. To gain insight into the cause and mechanism of sarcopenia and the protective effect of a therapeutic intervention with exercise and/or melatonin, the gastrocnemius muscles of male and female skeletal muscle-specific and inducible Bmal1 knockout mice (iMS-Bmal1-/- ) were examined by phenotypic tests and light and electron microscopy. Our results revealed a disruption of the normal activity/rest rhythm, a drop in skeletal muscle function and mass, and increased frailty in male and female iMS-Bmal1-/- animals compared to controls. A reduction in muscle fiber size and increased collagenous tissue were also detected, accompanied by reduced mitochondrial oxidative capacity and a compensatory shift towards a more oxidative fiber type. Electron microscopy further supports mitochondrial impairment in mutant mice. Melatonin and exercise ameliorated the damage caused by loss of Bmal1 in mutant mice, except for mitochondrial damage, which was worsened by the latter. Thus, iMS-Bmal1-/- mice let us to identify Bmal1 deficiency as the responsible for the appearance of sarcopenia in the gastrocnemius muscle. Moreover, the results support the exercise and melatonin as therapeutic tools to counteract sarcopenia, by a mechanism that does not require the presence of Bmal1.

Sexual dysfunction in patients with cancer, a challenge in oncology practice: results of the CLARIFY project.

BACKGROUND: Sexual dysfunction (SD) associated with oncological treatment is a common and understudied disorder. Our aim was to characterize SD in a cohort of Spanish patients. METHODS: Analytic observational study in patients included in the CLARIFY H2020 project at the Hospital Universitario Puerta de Hierro. Clinical variables and validated measures of sexual function were collected from October 2020 to May 2022. Frequency and quality of sexual activity were assessed. Descriptive, trend associations, and logistic regression analyses were performed. RESULTS: A total of 383 patients were included: breast cancer 68.14% (261), lung cancer 26.37% (101), and lymphoma 5.50% (21). Mean age was 56.5 years (range 33-88). 19.58% (75) were men and 80.42% (308) were women. 69% and 31% of men and women, respectively, reported being sexually active. The absolute frequency of overall sexual dissatisfaction was 76% in women and 24% in men. Women with breast cancer were most likely to have severe sexual dysfunction. Those with early disease had resolved complaints after 5 years. In multinomial logistic regression, significant associations were found in women with metastatic breast cancer and severe disorders of arousal (p 0.000), lubrication (p 0.002), orgasm (p 0.000), as well as dissatisfaction with sexual performance (p 0.000) and global sexual dissatisfaction (p 0.000). Women with lung cancer have severe arousal dysfunction (p 0.016) and global sexual dissatisfaction (p 0.044). CONCLUSIONS: Our population has a high prevalence of SD, which supports the need to increase awareness of this disorder among the medical oncology team and the importance of including sexual health assessment in oncological patient follow-up.

NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.

Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1ß release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1ß release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.

From Chronodisruption to Sarcopenia: The Therapeutic Potential of Melatonin.

Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria and organelle, where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.

Effects of an organic diet intervention on the levels of organophosphorus metabolites in an adult cohort.

Pesticides are a group of organic compounds used to control weeds or insect infestations in agriculture. Diet is the major route of human exposure to these compounds, which can cause serious health problems, even when the intake occurs at low concentrations. Hence, the consumption of organic food is an appropriate strategy to minimize the exposure to pesticides. A prospective, randomized study was conducted to assess the impact of an organic dietary intervention on the levels of urinary dialkyl phosphates (DAP). A screening of 204 pesticides was also carried out in order to confirm the absence of these compounds in organic food. The analytical results showed that only 20 of the 204 pesticides (9.8 %) had concentrations above the limit of quantification in one or more samples of the organic food consumed by the participants. It is substantially lower than the levels of pesticides found in other studies analysing conventional food, confirming the diet as suitable for the organic dietary intervention. A general reduction of most DAP metabolites in urine was found, being significant (p < 0.05) the decrease of dimethyl phosphate (DMP) (0.49 µg/g creatinine in Day 1 vs. 0.062 µg/g creatinine in Day 6), dimethyl thiophosphate (DMTP) (0.49 µg/g creatinine in Day 1 vs. 0.093 µg/g creatinine in Day 6) and diethyl phosphate (DEP) (0.28 µg/g creatinine in Day 1 vs. 0.12 µg/g creatinine in Day 6). In addition, the molar score for the total dimethyl DAP (ΣMP) and total dialkyl phosphate (ΣDAP) also showed significant differences after changing a conventional diet by an organic diet, being reduced from 0.008 µmol/g to 0.002 µmol/g for ΣMP and from 0.012 µmol/g to 0.003 µmol/g for ΣDAP. To the best of our knowledge, this is the first study that evaluates both the impact of an organic diet in the exposure to DAP and the levels of 204 pesticides in the organic food provided to the participants. In summary, the consumption of organic products decreases the dietary intake of pesticides, thus reducing also the potential adverse effects on human health.

Etiologia e fisiopatologia da fibromialgia / Etiology and pathophysiology of fibromyalgia

A fibromialgia é uma condição crônica de etiologia desconhecida e desvinculada de marcadores laboratoriais específicos para diagnóstico, devido à pobre caracterização da etiopatogenia. Em geral, as alterações comuns à fibromialgia também são observadas em outras condições de dor crônica, tornando a patogênese controversa entre diferentes condições patológicas. A etiologia desconhecida dificulta o diagnóstico e, consequentemente, repercute em um tratamento não tão eficaz de pacientes com fibromialgia. A restauração de desordens sistêmicas confere amplo espectro de possibilidades terapêuticas com potencial de orientar profissionais a estabelecer metas e métodos de avaliação. Diante disso, essa revisão narrativa se volta para debater hipóteses etiológicas e fisiopatológicas no desenvolvimento da fibromialgia.

Fibromyalgia is a chronic condition of unknown etiology unrelated to specific laboratory markers for diagnosis because of poor etiopathogenesis. In general, the changes common to fibromyalgia are also seen in other chronic pain conditions, making the pathogenesis controversial among different pathological conditions. The unknown etiology makes the diagnosis difficult and consequently has repercussions on a not so effective treatment of patients with fibromyalgia. The restoration of systemic disorders provides a wide spectrum of therapeutic possibilities with the potential to guide professionals in establishing goals and evaluation methods. Therefore, this narrative review discusses the etiological and pathophysiological hypotheses involved in the development of fibromyalgia.