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1.
Dystrophin- and Utrophin-Based Therapeutic Approaches for Treatment of Duchenne Muscular Dystrophy: A Comparative Review.
Szwec, S, Kapłucha, Z, Chamberlain, JS, Konieczny, P
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2024;(1):95-119
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Abstract
Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog, utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing utrophin levels. Our analyses highlight the importance of various dystrophin and utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.
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Comparison of the effect of topical triamcinolone 0.1% cream with sulfur 2.0% cream in the treatment of patients with hand eczema: A randomized controlled trial.
Asilian, A, Mohammadian, P, Hosseini, SM, Heidaripour, F, Yekta, A, Nateghi, MR
Journal of cosmetic dermatology. 2024;(5):1753-1757
Abstract
BACKGROUND Hand eczema (HE) is a common and heterogeneous condition. It has a wide range of etiologies and clinical manifestations. In this study the efficacy of triamcinolone 0.1% cream and sulfur 2% creams was compared in treating patients with HE. METHODS This randomized, triple-blind clinical trial was performed on 70 patients with HE (including 70 right and 70 left hands). In this study, two creams were used including triamcinolone 0.1% and sulfur 2.0%. Patients were treated with these creams twice a day (once in every 12 h) for 4 weeks. Follow-up was 4 weeks after treatment. Hand Eczema Severity Index (HECSI), itching, dryness, burning sensation, and erythema scores were collected three times during the study and compared between treatment regimens. RESULTS Findings showed that both triamcinolone (0.1%) and sulfur (2.0%) creams could significantly reduce the scores of HECSI, itching, dryness, burning sensation, and erythema, and the therapeutic effects lasted for at least 4 weeks after cessation of topical treatment. CONCLUSION Topical sulfur cream (2.0%) is as effective as triamcinolone (0.1%) cream in treatment of HE without any prominent adverse reactions.
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Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia.
Packer, M
American journal of nephrology. 2024;(2):255-259
Abstract
Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6-0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options.
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Mannitol versus furosemide in patients with thoracic malignancies who received cisplatin-based chemotherapy using short hydration: A randomized phase II trial.
Murakami, E, Akamatsu, H, Teraoka, S, Takakura, T, Takase, E, Tanaka, M, Kaki, T, Harutani, Y, Furuta, K, Sugimoto, T, et al
Cancer medicine. 2024;(4):e6839
Abstract
BACKGROUND Mannitol is exclusively recommended in the National Comprehensive Cancer Network guidelines for diuresis in cisplatin (CDDP)-based chemotherapy. The utility of furosemide, a widely used and convenient diuretic, thus requires clarification. METHODS This is a prospective, single-centered, open-label, noninferiority phase II study. Patients with thoracic malignancies who planned to receive CDDP-based chemotherapy were randomly assigned to receive either mannitol (arm A) or furosemide (arm B). The primary end point was set as the proportion of patients who experienced any grade of "creatinine (Cr) increased" based on the upper limit of the normal range (ULN) during the first cycle as assessed by Common Terminology Criteria for Adverse Events Version 4.0. Secondary end points were Cr increased based on the baseline value during the first cycle, Cr increased after the completion of CDDP, and the proportion of patients with phlebitis. RESULTS Between April 2018 and March 2022, 115 patients were enrolled and 106 were analyzed. Any grade of Cr increased based on the ULN during the first cycle was 17.3% (arm A) and 24.1% (arm B), respectively (p = 0.34). Therefore, the primary end point was not met. After completion of chemotherapy, any grade of Cr increased was observed in 23.1% (arm A) and 31.5% (arm B), respectively. However, the actual serum Cr level and Cr clearance during the courses were not different between the arms. Phlebitis occurred more frequently in arm A (28.8%) than arm B (16.7%). CONCLUSIONS Mannitol should remain the standard diuresis in CDDP-based chemotherapy assessed by conventional CTCAE grading, but furosemide can be room for consideration when assessed by actual serum Cr level and Cr clearance.
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The effect of a multicomponent oral care regimen on gingival inflammation: A randomized controlled clinical trial.
do Amaral, GCLS, Hassan, MA, Saraiva, L, Nakao, LYS, Holzhausen, M, Malheiros, ZM, Stewart, B, Romito, GA, Villar, CC
Journal of periodontology. 2024;(4):350-359
Abstract
BACKGROUND Oral care regimens can be explored to improve oral health in patients with gingivitis. This study aimed to evaluate the efficacy of a multicomponent oral care regimen with a dual zinc plus arginine (DZA) toothpaste and cetylpyridinium chloride with zinc lactate (CPC + Zn) mouthwash in reducing gingival bleeding in patients with gingivitis. METHODS This randomized clinical trial included 94 participants with gingivitis who were randomized into two groups: the DZA/CPC + Zn group, which used a 1450-ppm fluoride toothpaste containing 0.96% zinc plus 1.5% arginine and a fluoride-containing mouthwash with 0.075% CPC and 0.28% zinc lactate, and the control group, which used a 1450-ppm fluoride toothpaste and a placebo mouthwash for 6 months. All participants were examined by a blinded examiner who measured the gingival index, plaque index, and gingival severity index. Data were analyzed using paired t test, independent t test, and analysis of covariance (ANCOVA). RESULTS Both groups presented statistically significant reductions in all clinical parameters compared to baseline. The DZA/CPC + Zn group exhibited significantly greater reductions in gingival index, gingival severity index, proximal gingival index, plaque index and proximal plaque index compared to the control group at 1, 3, and 6 months. Furthermore, DZA/CPC + Zn significantly decreased the percentage of patients with generalized gingivitis over a 6-month follow-up period. However, differences between the DZA/CPC + Zn and the control groups were not maintained after both groups established similar regimens with fluoride toothpaste. CONCLUSION The multicomponent oral care regimen consisting of DZA toothpaste and CPC + Zn mouthwash is effective in reducing gingival inflammation and supragingival biofilm in patients with gingivitis.
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Comparison of Yield Characteristics, Chemical Composition, Lignans Content and Antioxidant Potential of Experimentally Grown Six Linseed (Linum usitatissimum L.) Cultivars.
Jarošová, M, Lorenc, F, Bedrníček, J, Petrášková, E, Bjelková, M, Bártová, V, Jarošová, E, Zdráhal, Z, Kyselka, J, Smetana, P, et al
Plant foods for human nutrition (Dordrecht, Netherlands). 2024;(1):159-165
Abstract
Linseed represents a rich source of nutritional, functional and health-beneficial compounds. Nevertheless, the chemical composition and content of bioactive compounds may be quite variable and potentially affected by various factors, including genotype and the environment. In this study, the proximate chemical composition, lignans content and antioxidant potential of six experimentally grown linseed cultivars were assessed and compared. A diagonal cultivation trial in the University of South Bohemia Experimental Station in České Budějovice, Czech Republic, was established in three subsequent growing seasons (2018, 2019 and 2020). The results showed that the cultivar and growing conditions influenced most studied parameters. The lack of precipitation in May and June 2019 negatively affected the seed yield and the level of secoisolariciresinol diglucoside but did not decrease the crude protein content, which was negatively related to the oil content. The newly developed method for lignans analysis allowed the identification and quantification of secoisolariciresinol diglucoside and matairesinol. Their content correlated positively with the total polyphenol content and antioxidant assays (DPPH and ABTS radical scavenging activity), indicating the significant contribution to the biofunctional properties of linseed. On the other hand, we did not detect minor linseed lignans, pinoresinol and lariciresinol. The results of this study showed the importance of cultivar and growing conditions factors on the linseed chemical composition and the lignans content, determining its nutritional and medicinal properties.
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Comparison between ultrasonography and computed tomography for measuring skeletal muscle mass in critically ill patients with different body mass index.
Peres, LM, Luis-Silva, F, Menegueti, MG, Lovato, WJ, Espirito Santo, DAD, Donadel, MD, Sato, L, Malek-Zadeh, CH, Basile-Filho, A, Martins-Filho, OA, et al
Clinical nutrition ESPEN. 2024;:214-224
Abstract
BACKGROUND & AIM: Among critical patients, there is an early onset of changes in both the quantity and quality of muscle mass. It is essential to find tools that promptly identify this muscle mass loss. The aim of this study was to compare the ultrasonography of the quadriceps femoris to the gold standard, thigh computed tomography (CT) for assessing the musculature of critically ill patients with different body mass index who have suffered traumatic brain injury. METHODS This is a prospective validation study in an Intensive Care Unit (ICU) specialized in trauma care, located at a tertiary teaching hospital. Our study involved a convenience sample of patients. Sequential ultrasound and CT scans were performed at three distinct time intervals: upon admission, between 24 and 96 h' post-admission, and finally, between 96 and 168 h' post-admission. For all ultrasound measurements, we conducted simultaneous quadriceps CT measurements. The correlation between measurements obtained by ultrasound and computed tomography at three different times and in three BMI ranges was analyzed, in individuals with normal weight, overweight and obese. RESULTS Results: We analyzed 252 images in 49 patients in time 1, 40 patients in time 2, and 37 in time 3 to compare the thickness quadriceps muscle using US and CT. Of these, 18 patients had a BMI ≤ 24.9 kg/m2 (normal weight), 18 patients from 25 to 29.9 kg/m2 (overweight), and 8 patients had a BMI ≥ 30 kg/m2 (obese). The mean age was 37 years, the majority (94%) were male and the main comorbidities were: hypertension 12%, diabetes 4% and 14% smoking. The results revealed minor discrepancies between measurements obtained through the two methods, these changes were not influenced by the body mass index, with these variations being practically insignificant in the context of clinical application. Thus, the correlation and concordance between the values obtained found a strong positive correlation with good limits of agreement. The Spearman's correlation coefficients obtained were r = 0.89, 0.91 and 0.88, p < 0.01 at T1, T2 and T3 respectively for normal weight, r = 0.91, 0.80 and 0.81, p < 0.01 at T1, T2 and T3 respectively for overweight and r = 0.89, 0.94 and 0.84, p < 0.01 at T1, T2 and T3 respectively for obesity. In addition to a positive correlation, we observed a high agreement between the methods. The Bland & Altman analysis at time 1 showed, respectively, the bias of 1.46, 2.03 and 0.76. At time 2, the bias was 0.42, 3.11 and 2.12. At time 3, the bias was 2.26, 3.38 and 2.11 mm. CONCLUSION Our findings suggest that measure femoral quadriceps muscle thickness ultrasound-based exhibits a comparable performance to thigh CT. This conclusion stems from the excellent correlation and good agreement observed between ultrasound and CT, which is considered the gold standard for muscle assessment in critically ill patients. TRIAL REGISTRATION This clinical trial is registered at REBEC https://ensaiosclinicos.gov.br/ identifier: RBR-2bzspnz. The protocol was approved, on July 30, 2019, by the Research Ethics Committee of the Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto - Trial Registration Number: 3,475,851.
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A prospective comparison study utilizing patient-reported outcomes of taxane-related peripheral neuropathy between nab-paclitaxel and standard paclitaxel in patients with breast cancer.
Kida, K, Yamada, A, Shimada, K, Narui, K, Sugae, S, Shimizu, D, Doi, T, Oba, M, Endo, I, Ishikawa, T
Breast cancer (Tokyo, Japan). 2024;(3):409-416
Abstract
UNLABELLED BACKGROUND Characteristics of taxane-induced peripheral neuropathy (PN) could be different between paclitaxel and nab-paclitaxel. The purpose of this prospective observational multicenter cohort study was to compare tri-weekly nab-paclitaxel to weekly standard paclitaxel regarding the severity, onset and recovery of sensory and motor PN in patients with breast cancer. METHODS Patients with histologically confirmed breast cancer who were scheduled to receive standard weekly paclitaxel (80 mg/m2) or tri-weekly nab-paclitaxel (260 mg/m2) at institutions in our multicenter group were eligible for this study. Sensory and motor PN were evaluated every 3 weeks until PN improved for up to one year using patient-reported outcome. RESULTS Between February 2011 and April 2013, 115 patients were enrolled, including 57 and 58 in the paclitaxel and nab-paclitaxel groups, respectively. The incidence of moderate or severe sensory PN was not significantly different between the two groups (p = 0.40). The incidence of moderate or higher motor PN was more frequent in the nab-paclitaxel group than in the paclitaxel group (p = 0.048). The median period for demonstrating PN were shorter in the nab-paclitaxel group than in the paclitaxel group (sensory, p = 0.003; motor, p = 0.001). The recovery of motor PN was slower in the nab-paclitaxel group than in the paclitaxel group (p = 0.035), while the recovery period of sensory PN was not statistically different. CONCLUSION Nab-paclitaxel induced sensory PN sooner than paclitaxel, and no difference was observed in the severity and recovery duration between the two agents. Motor PN was more severe, started sooner, and improved over a longer period in the nab-paclitaxel-treated patients than in the paclitaxel-treated patients.
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9.
Predictors of racial differences in weight loss: the PROPEL trial.
Newton, RL, Zhang, D, Johnson, WD, Martin, CK, Apolzan, JW, Denstel, KD, Brantley, PJ, Davis, TC, Arnold, C, Sarpong, DF, et al
Obesity (Silver Spring, Md.). 2024;(3):476-485
Abstract
OBJECTIVE Studies have consistently shown that African American individuals lose less weight in response to behavioral interventions, but the mechanisms leading to this result have been understudied. METHODS Data were derived from the PROmoting Successful Weight Loss in Primary CarE in Louisiana (PROPEL) study, which was a cluster-randomized, two-arm trial conducted in primary care clinics. In the PROPEL trial, African American individuals lost less weight compared with patients who belonged to other racial groups after 24 months. In the current study, counterfactual mediation analyses among 445 patients in the intervention arm of PROPEL were used to determine which variables mediated the relationship between race and weight loss. The mediators included treatment engagement, psychosocial, and lifestyle factors. RESULTS At 6 months, daily weighing mediated 33% (p = 0.008) of the racial differences in weight loss. At 24 months, session attendance and daily weighing mediated 35% (p = 0.027) and 66% (p = 0.005) of the racial differences in weight loss, respectively. None of the psychosocial or lifestyle variables mediated the race-weight loss association. CONCLUSIONS Strategies specifically targeting engagement, such as improving session attendance and self-weighing behaviors, among African American individuals are needed to support more equitable weight losses over extended time periods.
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Intermittent fasting regimens for metabolic dysfunction-associated steatotic liver disease: a systematic review and network meta-analysis of randomized controlled trials.
Abuelazm, MT, Mohamed, I, Naeem, A, Khlidj, Y, Tanashat, M, Katamesh, BE, Abusuilik, H, Altobaishat, O, Abdelnabi, M, Abdelazeem, B
European journal of gastroenterology & hepatology. 2024;(4):371-381
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by excessive hepatic fat accumulation. Intermittent fasting (IF) has emerged as a potential therapeutic strategy with the ability to induce weight loss, improve insulin sensitivity and reduce hepatic steatosis. We aim to compare the efficacy of different IF regimens for MASLD management. A systematic review and network meta-analysis of randomized controlled trials investigating different IF regimens for MASLD. PubMed , EMBASE , WOS , SCOPUS and Cochrane Central Register of Controlled Trials were searched until 10 April 2023. Analysis was performed using R software with the meta and netmeta packages. Mean difference (MD) was used to pool continuous outcomes with 95% confidence intervals (CIs). Our meta-analysis was registered in PROSPERO (CRD42023418467). Our meta-analysis included eight randomized controlled trials with a total of 635 participants. The 5 : 2 diet significantly improved liver stiffness (MD, -0.32; 95% CI, -0.55 to -0.09; P < 0.01). Time-restricted feeding significantly improved liver steatosis (controlled attenuation parameter score) (MD, -39.83; 95% CI, -64.78 to -14.87; P < 0.01). No significant changes were observed in asparate aminotransferase, gamma-glutamyl transpeptidase, low-density lipoproteins cholesterol, total cholesterol, triglyceride levels, basal metabolic index, blood pressure, Homeostatic Model Assessment of Insulin Resistance, fasting blood sugar, lean body mass or waist circumference across all IF regimens. However, alternate-day fasting showed positive results in anthropometric measures, including significant improvements in lean body mass, waist circumference, fat mass and weight reduction ( P < 0.05). IF regimens showed various positive effects on clinical outcomes in MASLD patients; however, these effects were not consistent. Therefore, a patient-tailored IF regimen should be considered.