Search Results (19)

Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and no curative therapies. Fibroblast activation by transforming growth factor β1 (TGFβ1) and disrupted metabolic pathways, including the arginine–polyamine pathway, play crucial roles in IPF development. Polyamines are agonists of the calcium/cation-sensing receptor (CaSR), activation of which is detrimental for asthma and pulmonary hypertension, but its role in IPF is unknown. To address this question, we evaluated polyamine abundance using metabolomic analysis of IPF patient saliva. Furthermore, we examined CaSR functional expression in human lung fibroblasts (HLFs), assessed the anti-fibrotic effects of a CaSR antagonist, NPS2143, in TGFβ1-activated normal and IPF HLFs by RNA sequencing and immunofluorescence imaging, respectively; and NPS2143 effects on polyamine synthesis in HLFs by immunoassays. Our results demonstrate that polyamine metabolites are increased in IPF patient saliva. Polyamines activate fibroblast CaSR in vitro, elevating intracellular calcium concentration. CaSR inhibition reduced TGFβ1-induced polyamine and pro-fibrotic factor expression in normal and IPF HLFs. TGFβ1 directly stimulated polyamine release by HLFs, an effect that was blocked by NPS2143. This suggests that TGFβ1 promotes CaSR activation through increased polyamine expression, driving a pro-fibrotic response. By halting some polyamine-induced pro-fibrotic changes, CaSR antagonists exhibit disease-modifying potential in IPF onset and development. Full article

Introduction: Epidural steroid injections (ESIs) are a common interventional treatment for managing spinal pain complaints. Despite their widespread use, practice patterns among physicians performing ESIs vary significantly. This study aimed to evaluate preprocedural imaging review by pain physicians who perform ESIs in the cervical, thoracic, and lumbar spine. Methods: A survey was distributed to a cohort of physicians who regularly perform ESIs. The survey comprised questions regarding preprocedural imaging review before performing ESIs in the cervical, thoracic, and lumbar spine. The respondents included a diverse group of pain management physicians from various specialties and practice settings. Results: The results revealed that the majority of interventional pain management physicians personally interpret their own imaging, followed by a significant percentage of physicians who rely on the radiology reports. There were no physicians who did not perform any imaging review prior to ESIs. Whereas all respondents reported some form of imaging review, only 63.86%, 53.75%, and 64.44% reviewed the actual images prior to cervical, thoracic, and lumbar access, respectively. Conclusions: This survey provides initial data regarding imaging reviews among physicians who perform ESIs. Our results demonstrate that physicians treat imaging review as an essential component of the preprocedural process for performing ESIs, as all physicians reported that they perform some form of imaging review before performing ESIs. However, there is only partial adherence to the multidisciplinary working group opinion that segmental imaging should be reviewed for adequacy of space prior to cervical epidural access. Full article

Human milk (HM) provides maximum health benefits for infants. This is due in part to the activity of its minor components, including HM proteins and oligosaccharides (HMOs). Where HM is unavailable, infant formulas (IFs) are normally used, the two most common types being cow milk- and goat milk-based formulas (CIF and GIF). The aim of this study was to compare the antioxidant properties of HM, CIF and GIF, together with those of their respective oligosaccharides (HMOs, CMOs and GMOs), using in vitro model systems. The ability of these oligosaccharides to attenuate inflammation (expression of IL-1α, TNFα, IL-6 and IL-8) was also assessed using a U937 cell culture model. Results showed that GIF and GMOs exhibited the highest antioxidant potential. The iron-reducing and iron-chelating properties of both IFs were comparable to those for HM, while the iron-chelating ability of the CMOs was lowest. None of the oligosaccharides significantly reduced U937 cytokine expression following induction of inflammation; however, GMOs consistently reduced expression of IL-1α, TNFα and IL-6 to a greater extent than the other oligosaccharides, presumably by competitive binding to immune receptors. In conclusion, GMOs have a greater antioxidant potential than CMOs and may have some inflammation-attenuating ability as well. Full article

Background: Genetic evidence from Mendelian randomization (MR) analyses suggests that higher lean mass causally protects against Alzheimer’s disease (AD) and enhances cognitive function. However, the potential confounding role of height, which shares genetic etiology with lean mass, has not been fully examined. Methods: Genetic predictors of whole-body lean mass were obtained from a genome-wide association study (GWAS) performed in the UK Biobank cohort (UKB; n = 448,322). Genetic predictors of height were also obtained from UKB (height_0.5M = 455,332) and from a GWAS meta-analysis (height_1.5Mn = 1,578,425). The study outcomes included clinically diagnosed AD (21,982 cases and 41,944 controls) and cognitive performance (n = 269,867). All study participants were of European ancestry. We conducted univariable and multivariable MR analyses to examine the total and independent effects of lean mass and height on the specified outcomes under different statistical adjustment strategies. Results: In univariable MR analyses, genetically proxied lean mass (odds ratio [OR] per 1-standard deviation [SD] increase 0.81, 95% confidence interval [CI] 0.72–0.91, p = 3.8 × 10⁻⁴) and height (OR 0.90, 95% CI 0.84–0.96, p = 0.001) were associated with reduced risk of AD. Genetically proxied lean mass (β 0.10, 95% CI 0.08–0.12, p = 6.24 × 10⁻⁶) and height (β 0.07, 95% CI 0.05–0.08, p = 1.16 × 10⁻¹⁵) were further associated with improved cognitive performance. In multivariable MR analyses, adjustment for height_1.5M partially attenuated the lean mass association with AD (OR 0.91, 95% CI 0.74–1.12, p = 0.40), whereas the height_1.5M-AD association remained similar after adjusting for lean mass (OR 0.89, 95% CI 0.79–1.00, p = 0.04). Adjustment for height also attenuated the association of lean mass with cognitive performance (β 0.00, 95% CI −0.07–0.06, p = 0.94), whereas height maintained a similar association with improved cognitive performance after adjustment for lean mass (β 0.07, 95% CI 0.03–0.10, p = 0.001). Conclusions: Height may confound the genetic associations between lean mass and both cognitive performance and AD risk. Residual direct effects of lean mass on AD risk cannot be excluded due to limitations in statistical power and genetic instrument strength in MVMR. These findings emphasize the necessity of adjusting for height when using MR to investigate the clinical effects of lean mass. Full article

Diet–microbiota interactions are emerging as important contributors in the pathogenesis of inflammatory bowel diseases (IBD), characterized by chronic inflammation of the GI tract. The aryl hydrocarbon receptor (AhR) transcription factor regulates xenobiotic metabolism and is activated by exogenous ligands, including indole-3-carbinole (I3C), which is found in cruciferous vegetables. However, studies investigating the impact of dietary I3C and AhR in preclinical models resembling human IBD are lacking. Mice (WT or AhR KO in IECs, 6–8 weeks) or SAMP/YitFC and AKR/J control (4 weeks, m/f) were fed an AhR ligand-depleted or I3C (200 ppm)-supplemented diet. There were increased levels of LPS and exacerbated inflammation, resulting in increased mortality in AhR^ΔIEC mice fed the AhR ligand-depleted diet in response to chronic DSS. The mechanisms underlying the protective effects of I3C supplementation during colonic colitis involved amelioration of intestinal inflammation and restoration of the altered gut microbiota, particularly the families of clostridicae and lachnospriaceae. Furthermore, the AhR-depleted diet led to the emergence of pathobiont Parvibacter caecicola in WT mice. SAMP/YitFc mice with spontaneous ileitis showed significant recovery in epithelial abnormalities when fed dietary I3C. These data demonstrate the critical role of AhR and the mechanisms of dietary I3C in maintaining epithelial homeostasis and ameliorating inflammation. Full article

Rugby sevens has established itself on the world stage since its inclusion in the 2016 Olympics. Participation among New Zealand (NZ) youth has surged. Sevens games have specific high demands, but little is known about these competitive demands in regards to youth. Two NZ male youth squads (U15, n = 13; U19, n = 14) were monitored during a national sevens tournament. Microsensor technology captured heart rate (HR) and kinematic performance. The rating of perceived exertion (RPE) was collected for U15 matches only. U19 and U15 players ran 108 ± 11 and 116 ± 13 m·min⁻¹ at an average speed (V_AVG) of 6.5 ± 0.6 and 6.9 ± 0.8 km·h⁻¹. Peak speeds (V_PEAK) reached 33.7 km·h⁻¹, and high-intensity running distance (HIRD) averaged 252 ± 102 m. U15 (44.3 ± 9.2 game⁻¹) and U19 (39.4 ± 6.1 game⁻¹) showed different sprint rates. U15 covered more moderate-velocity distance (20–80% V_MAX) and less low-velocity distance (<20% V_MAX). RPE was 13 ± 1 (U15). An average HR of 90.0 ± 3.9% HR_MAX was recorded. Upwards of 57% of game time was played at >90% HR_MAX. Youth sevens competition is specifically demanding. U15 can experience greater loads than older peers in rugby. Coaches can use this information to optimize players’ physical development. Full article

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia in adults. It is well-established that CADASIL results in neurocognitive dysfunction and mood disturbance. There is also cumulative evidence that CADASIL patients are more susceptible to ischemic heart disease. The aim of this study is to review the current literature regarding the incidence of coronary artery disease in CADASIL patients with a focus on the various management options and the clinical challenges associated with each of these treatment strategies. We conducted a literature search using Cochrane, MEDLINE, and EMBASE for papers that reported the occurrence of coronary artery disease in patients with CADASIL. We supplemented the search with a manual search in Google Scholar. Only case reports, case series, and original articles were included. The search resulted in six reports indicating the association between coronary artery disease and CADASIL and its management. Evidence suggests that extracranial manifestations of CADASIL may include coronary artery disease, presenting as a more extensive burden of disease in younger patients. Surgical and percutaneous revascularization strategies are feasible, but the incidence of peri-procedural stroke remains significant and should be weighed against the potential benefit derived from either of these strategies. A multidisciplinary approach to therapy, with perspectives from neurologists, cardiologists, and cardiac surgeons, is needed to provide the appropriate treatment to the CADASIL patient with severe coronary artery disease. Future studies should be directed toward the development of targeted therapies that may help with the early detection and prevention of disease progress in these patients. Full article

Purpose of Review: Notalgia paresthetica (NP) is a chronic cutaneous neuropathy primarily characterized by localized pruritus and associated dysesthesias, including sensations of pain, numbness, and tingling. The sensory neuropathy characteristic of NP is thought to result from spinal nerve entrapment caused by degenerative changes in the spine or musculoskeletal compression. This review summarizes the current medical literature with a focus on the past five years regarding NP, its pathophysiology, presentation, and current treatment options. Recent Findings: Though treatments exist with varying efficacy, to date, there exists no definitive treatment for NP. Treatment options for NP are varied and range from topical and oral agents to interventional procedures and physical therapy. Of the treatments evaluated, topical capsaicin remains the most efficacious treatment for NP. Conclusions: The lack of established treatment guidelines makes treating NP complicated as it dramatically affects patients’ quality of life. Further research with larger sample sizes is needed to evaluate better the most effective treatment and dosing regimen for patients afflicted with NP. Full article

Dietary intake is an important consideration for rugby union (‘rugby’) players to ensure substrate provision for optimal performance and facilitate recovery. Within-day meal distribution is especially important for athletes, particularly those with congested schedules and multiple daily training sessions. In the present study, 10 provincial academy rugby players engaged in a holistic support protocol informed by behaviour-change techniques led by a full-time sports nutritionist. Dietary intake was estimated during a 4-week monitoring and 4-week intervention period using the remote food photography method on one high-volume training day (two training sessions) and two low-volume training days (≤1 training session) per week. Lean body mass did not change significantly in response to the intervention. Significant increases were observed for protein on both low-volume (breakfast, AM snack, evening snack) and high-volume (post-gym, AM snack, evening snack) training days. Carbohydrate intake post-intervention was significantly greater at the pre-gym eating occasion but lower at PM snack and dinner eating occasions on high-volume days. These data suggest that incorporating a holistic support protocol led by a sports nutritionist can influence within-day nutrient intake in rugby players; however, no change to lean body mass was observed, and the influence of these changes in nutrient intake on performance and recovery warrants further investigation. Full article

The genomic heterogeneity of pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly appreciated. We aimed to evaluate the ability of a triple biomarker panel (S100A4, Ca-125, and mesothelin) to predict: (i) genetic PDAC subtypes; (ii) clinical phenotypes; and (iii) the optimal treatment strategy (neoadjuvant vs. surgery-first) in resectable and borderline resectable PDAC. Patients who underwent resection for resectable and borderline resectable PDAC were included from one single-institutional cohort and one multi-institutional cohort from the Australian Pancreatic Genome Initiative (APGI). Tumors were immunohistochemically evaluated for S100A4, Ca-125, and mesothelin, and a subset from the APGI cohort underwent RNA sequencing. This study included 252 and 226 patients from the single institution and the APGI cohorts, respectively. Triple-negative biomarker status correlated with non-squamous PDAC genotypes (p = 0.020), lower rates of distant recurrence (p = 0.002), and longer median overall survival (mOS) with the surgery-first approach compared with neoadjuvant treatment (33.3 vs. 22.2 mths, p = 0.038) in resectable PDAC. In contrast, the triple-positive disease was associated with longer mOS with neoadjuvant treatment compared with the surgery-first approach (29.5 vs. 13.7 mths, p = 0.021) in resectable and borderline resectable PDAC. In conclusion, the triple biomarker panel predicts genetic PDAC subtypes, clinical phenotypes, and optimal treatment strategies in resectable and borderline resectable PDAC. Full article

The inaugural Early-Age-Onset Colorectal Cancer Symposium was convened in June 2021 to discuss the implications of rapidly rising rates of early-age-onset colorectal cancer (EAO-CRC) in Canadians under the age of 50 and the impactful outcomes associated with this disease. While the incidence of CRC is declining in people over the age of 50 in Canada and other developed countries worldwide, it is significantly rising in younger people. Canadians born after 1980 are 2 to 2.5 times more likely to be diagnosed with CRC before the age of 50 than previous generations at the same age. While the etiology of EAO-CRC is largely unknown, its characteristics differ in many key ways from CRC diagnosed in older people and warrant a specific approach to risk factor identification, early detection and treatment. Participants of the symposium offered directions for research and clinical practice, and developed actionable recommendations to address the unique needs of these individuals diagnosed with EAO-CRC. Calls for action emerging from the symposium included: increased awareness of EAO-CRC among public and primary care practitioners; promotion of early detection programs in younger populations; and the continuation of research to identify unique risk factor profiles, tumour characteristics and treatment models that can inform tailored approaches to the management of EAO-CRC. Full article

Background: Previous studies have shown that compression garments may aid recovery in acute settings; however, less is known about the long-term use of compression garments (CG) for recovery. This study aimed to assess the influence of wearing CG on changes in physical performance, subjective soreness, and sleep quality over 6 weeks of military training. Methods: Fifty-five officer-trainees aged 24 ± 6 y from the New Zealand Defence Force participated in the current study. Twenty-seven participants wore CG every evening for 4–6 h, and twenty-eight wore standard military attire (CON) over a 6-week period. Subjective questionnaires (soreness and sleep quality) were completed weekly, and 2.4 km run time-trial, maximum press-ups, and curl-ups were tested before and after the 6 weeks of military training. Results: Repeated measures ANOVA indicated no significant group × time interactions for performance measures (p > 0.05). However, there were small effects in favour of CG over CON for improvements in 2.4 km run times (d = −0.24) and press-ups (d = 0.36), respectively. Subjective soreness also resulted in no significant group × time interaction but displayed small to moderate effects for reduced soreness in favour of CG. Conclusions: Though not statistically significant, CG provided small to moderate benefits to muscle-soreness and small benefits to aspects of physical-performance over a 6-week military training regime. Full article

The mitochondrial pyruvate carrier (MPC) is an inner-mitochondrial membrane protein complex that has emerged as a drug target for treating a variety of human conditions. A heterodimer of two proteins, MPC1 and MPC2, comprises the functional MPC complex in higher organisms; however, the structure of this complex, including the critical residues that mediate binding of pyruvate and inhibitors, remain to be determined. Using homology modeling, we identified a putative substrate-binding cavity in the MPC dimer. Three amino acid residues (Phe66 (MPC1) and Asn100 and Lys49 (MPC2)) were validated by mutagenesis experiments to be important for substrate and inhibitor binding. Using this information, we developed a pharmacophore model and then performed a virtual screen of a chemical library. We identified five new non-indole MPC inhibitors, four with IC₅₀ values in the nanomolar range that were up to 7-fold more potent than the canonical inhibitor UK-5099. These novel compounds possess drug-like properties and complied with Lipinski’s Rule of Five. They are predicted to have good aqueous solubility, oral bioavailability, and metabolic stability. Collectively, these studies provide important information about the structure-function relationships of the MPC complex and for future drug discovery efforts targeting the MPC. Full article

Poa annua is a cosmopolitan, cool-season grass species regarded as one of the most significant weeds of turfgrass. It is mainly controlled by herbicides; however, repeated use of herbicides in golf turf has resulted in the evolution of multiple-herbicide resistant P. annua. Four field experiments were performed in autumn and spring in golf turf to identify effective herbicide options to control multiple herbicide-resistant P. annua. In herbicide resistance screening, the trial site population (SA1) was found to be susceptible to amicarbazone and terbuthylazine, but resistant to simazine and metribuzin at the field rate of each herbicide. Consistent with the results of the pot study, the PSII-inhibiting herbicides amicarbazone and terbuthylazine provided the best control (80–100%) of P. annua in both autumn and spring trials with minimal damage to the turf. In contrast, the other two PSII-inhibiting herbicides, metribuzin and simazine, were relatively ineffective in controlling P. annua in the field. Indaziflam also performed well in both autumn trials and reduced P. annua occurrence by >75%. Pyroxasulfone and s-metolachlor only provided moderate weed control in both the autumn and spring trials, reducing P. annua occurrence by 50%. Among the nine different herbicides, amicarbazone and terbuthylazine were found to be most effective for spring and autumn application in turf. As resistance to some PSII-inhibiting herbicides has already evolved in this field population, the use of amicarbazone and terbuthylazine needs to be integrated with other herbicide modes of action and non-chemical tactics to delay the onset of resistance to them. Full article

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global health care emergency. Anti-SARS-CoV-2 serological profiling of critically ill COVID-19 patients was performed to determine their humoral response. Blood was collected from critically ill ICU patients, either COVID-19 positive (+) or COVID-19 negative (−), to measure anti-SARS-CoV-2 immunoglobulins: IgM; IgA; IgG; and Total Ig (combined IgM/IgA/IgG). Cohorts were similar, with the exception that COVID-19+ patients had a greater body mass indexes, developed bilateral pneumonias more frequently and suffered increased hypoxia when compared to COVID-19- patients (p < 0.05). The mortality rate for COVID-19+ patients was 50%. COVID-19 status could be determined by anti-SARS-CoV-2 serological responses with excellent classification accuracies on ICU day 1 (89%); ICU day 3 (96%); and ICU days 7 and 10 (100%). The importance of each Ig isotype for determining COVID-19 status on combined ICU days 1 and 3 was: Total Ig, 43%; IgM, 27%; IgA, 24% and IgG, 6%. Peak serological responses for each Ig isotype occurred on different ICU days (IgM day 13 > IgA day 17 > IgG persistently increased), with the Total Ig peaking at approximately ICU day 18. Those COVID-19+ patients who died had earlier or similar peaks in IgA and Total Ig in their ICU stay when compared to patients who survived (p < 0.005). Critically ill COVID-19 patients exhibit anti-SARS-CoV-2 serological responses, including those COVID-19 patients who ultimately died, suggesting that blunted serological responses did not contribute to mortality. Serological profiling of critically ill COVID-19 patients may aid disease surveillance, patient cohorting and help guide antibody therapies such as convalescent plasma. Full article