Covalent isothiocyanate inhibitors of macrophage migration inhibitory factor as potential colorectal cancer treatments.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with roles in innate and adaptive human immune responses, as well as inflammation. MIF exerts its biological activity by binding to the cell surface receptor CD74 as well as intracellular signalling proteins. MIF also possesses keto-enol tautomerase activity. Inhibition of the tautomerase activity has been associated with loss of biological activity of MIF and a potential anticancer target. Isothiocyanates (ITCs) are a class of compounds present in cruciferous vegetables that inhibit the MIF tautomerase activity via covalent modification of the N-terminal proline. A range of substituted ITCs featuring benzyl, phenethyl and phenyl propyl isothiocyanates were designed, synthesised and tested to determine any structure activity relationship for inhibiting MIF. Crystal structures of covalent compounds 8 and 9 in complex with rhMIF revealed key hydrogen bonding and edge-to-face π stacking interactions. Compound 9 and 11 with sub micromolar activity were tested in the NCI60 cancer cell lines panel. Both compounds showed tissue-specific reduced growth in colon and renal cancer cell lines, while one of these showed potent, dose-dependent inhibition of growth against all seven colon cancer cell lines (GI50 < 2.5 µM) and all eight renal cancer cell lines (GI50 < 2.2 µM).

Long-term effectiveness and persistence rate of ustekinumab dose intensification in a South East Asian inflammatory bowel disease center.

BACKGROUND AND AIMS: Ustekinumab (UST) is an effective biologic for treatment of inflammatory bowel disease (IBD). However, some patients treated with UST have suboptimal clinical response with standard dosing. The aims of this study were to determine the effectiveness of UST dose intensification (DI), identify factors associated with DI, cumulative incidence of DI and persistence of UST among treated patients. METHODS: Clinical data of patients with Crohn's disease (CD) and ulcerative colitis (UC) who received UST from September 2017 to October 2022 in Singapore General Hospital were collected. Primary outcome was defined as achieving corticosteroid-free clinical remission, biochemical remission, endoscopic healing and/or transmural healing (CD). Statistical analysis was performed to identify factors, which are predictive of UST DI and effectiveness of UST DI. RESULTS: Forty-two patients (34 CD and 8 UC) underwent UST DI to either 6-weekly (n = 19, 45.2%) or 4-weekly (n = 23, 35.9%) and the median time to intensification was 31.1 weeks (17.8-65.7). Presence of perianal disease in CD (HR 4.9; 1.47-16.4) was associated with DI. After DI, 16 (38%) patients achieved primary outcome by week 52. The overall drug persistence rates at 1 year and 2 years were 75.7% (95% CI 62.9-84.6) and 63.5% (95% CI 49.9-74.3), respectively. CONCLUSION: Two third of IBD patients underwent DI while on UST treatment and the median time to DI was about 6 months after induction. CD patients with perianal disease is more likely to undergo DI. More than one third of dose-intensified patients achieved remission by week 52.

Plasminogen Receptors Promote Lipoprotein(a) Uptake by Enhancing Surface Binding and Facilitating Macropinocytosis.

BACKGROUND: High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB100-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a). METHODS: Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting. RESULTS: The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis. CONCLUSIONS: These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and some antidepressant compounds.

Percutaneous Coil Embolization of Coronary Artery Fistula Complicated by Refractory Ventricular Fibrillation and Cardiogenic Shock.

We present a case of a 56-year-old patient with a symptomatic right coronary artery to pulmonary artery fistula who underwent coil embolization. Post-procedure, the patient developed ventricular fibrillation that was refractory to antiarrhythmic medications and numerous attempts at defibrillation. (Level of Difficulty: Intermediate.).

Case Series of Percutaneous Mechanical Aspiration of Mitral Valve Endocarditis.

Infective endocarditis of the mitral valve that is refractory to medical therapy requires surgical debridement. However, patients who are high risk for surgery have limited options. We report 3 cases of refractory infective endocarditis involving the mitral valve that were treated with percutaneous mechanical aspiration with an embolic protection system. (Level of Difficulty: Intermediate.).

pH variability at volcanic CO2 seeps regulates coral calcifying fluid chemistry.

Coral reefs are iconic ecosystems with immense ecological, economic and cultural value, but globally their carbonate-based skeletal construction is threatened by ocean acidification (OA). Identifying coral species that have specialised mechanisms to maintain high rates of calcification in the face of declining seawater pH is of paramount importance in predicting future species composition, and growth of coral reefs. Here, we studied multiple coral species from two distinct volcanic CO2 seeps in Papua New Guinea to assess their capacity to control their calcifying fluid (CF) chemistry. Several coral species living under conditions of low mean seawater pH, but with either low or high variability in seawater pH, were examined and compared with those living in 'normal' (non-seep) ambient seawater pH. We show that when mean seawater pH is low but highly variable, corals have a greater ability to maintain constant pHcf in their CF, but this characteristic was not linked with changes in abundance. Within less variable low pH seawater, corals with limited reductions in pHcf at the seep sites compared with controls tended to be more abundant at the seep site than at the control site. However, this finding was strongly influenced by a single species (Montipora foliosa), which was able to maintain complete pHcf homeostasis. Overall, although our findings indicate that there might be an association between ecological success and greater pHcf homeostasis, further research with additional species and at more sites with differing seawater pH regimes is required to solidify inferences regarding coral ecological success under future OA.

Update on cardiogenic shock: The evolving landscape of a multidisciplinary and collaborative approach.

ABSTRACT: The American Heart Association scientific statement on cardiogenic shock and the National Cardiogenic Shock Initiative have provided the impetus to advance knowledge and development of national guidelines for cardiogenic shock. We evaluate the current state of knowledge surrounding cardiogenic shock and limitations to the development of national guidelines.

Characteristics of Injury in Collegiate Rodeo.

OBJECTIVE: The purpose of this study was to investigate injury occurrence sustained by collegiate rodeo athletes during practice and competition. DESIGN: Descriptive epidemiology. SETTING: Eleven National Intercollegiate Rodeo Association member institutions across the United States. PARTICIPANTS: Participants included 264 male and female college rodeo athletes. Athletic trainers (ATs) from each institution reported injury and exposure data using the National Collegiate Athletic Association Injury Surveillance Program. INTERVENTIONS: Institutional ATs reported athlete exposures (AEs) and injuries that occurred from collegiate rodeo practices and competitions. MAIN OUTCOME MEASURE: Injury and AEs from practices and competitions for one college rodeo season were analyzed. Injury rates and ratios were calculated for non-time loss (NTL) and time loss (TL) with 95% confidence intervals (CI). RESULTS: Data revealed a higher proportion of TL than NTL injuries [2.47 vs 1.77 per 1000 AE; injury rate ratios (IRRs) = 1.39; 95% CI: 0.93-2.08]. There was a higher injury rate during competition as compared with practice (10.98 vs 3.09 per 1000 AE; IRR = 3.56; 95% CI: 2.36-5.35), but more injuries were reported in practice (62.2%). CONCLUSIONS: Although the injury rate during rodeo competition was significantly higher than during practice in this study, a greater number of injuries were reported during practice. This indicates all college rodeo athletes can potentially benefit from available medical care.

The growth patterns of the medical technology profession in South Africa.

BACKGROUND: Constant appraisal of healthcare workforce trends is vital; this measure determines the adequacy of the workforce in meeting its society's healthcare demands. This includes determining the number of the incoming workforce (students, interns) and the active or practising workforce relevant registries. OBJECTIVE: This study aimed to examine patterns of workforce growth in the medical technology profession (students, interns and practitioners) from 2008 to 2018 in South Africa. METHODS: Student, intern and practitioner medical technology registries, from the 2012/2013, 2016/2017 and 2017/2018 Health Professions Council of South Africa (HPCSA) annual reports, were analysed. The number of National Health Laboratory Service and private laboratory posts were secured from the National Health Laboratory Service plan performance report. A comparison between the total number of South African medical technology (private and public) posts occupied versus the HPCSA practitioner 2016 register was completed, to determine the saturation status. RESULTS: Annual student, intern, and practitioner registries indicated a mean growth of 6.8%, 28.9%, and 0.7% from 2008 to 2018. The transition of interns to practitioners is progressively dwindling (2015-2018). The practitioner register showed a 1.2% decline in registration from 2013 until 2018. In 2016, only 55.9% of the HPCSA registered medical technologists were employed (p < 0.001). CONCLUSION: There are more medical technologists than available public and private sector posts. The progressively growing student register compared to the dwindling practitioner register indicates attrition in the profession. An investigation identifying the reasons why graduates neglect to register as practising medical technologists should be undertaken.

Global declines in coral reef calcium carbonate production under ocean acidification and warming.

Ocean warming and acidification threaten the future growth of coral reefs. This is because the calcifying coral reef taxa that construct the calcium carbonate frameworks and cement the reef together are highly sensitive to ocean warming and acidification. However, the global-scale effects of ocean warming and acidification on rates of coral reef net carbonate production remain poorly constrained despite a wealth of studies assessing their effects on the calcification of individual organisms. Here, we present global estimates of projected future changes in coral reef net carbonate production under ocean warming and acidification. We apply a meta-analysis of responses of coral reef taxa calcification and bioerosion rates to predicted changes in coral cover driven by climate change to estimate the net carbonate production rates of 183 reefs worldwide by 2050 and 2100. We forecast mean global reef net carbonate production under representative concentration pathways (RCP) 2.6, 4.5, and 8.5 will decline by 76, 149, and 156%, respectively, by 2100. While 63% of reefs are projected to continue to accrete by 2100 under RCP2.6, 94% will be eroding by 2050 under RCP8.5, and no reefs will continue to accrete at rates matching projected sea level rise under RCP4.5 or 8.5 by 2100. Projected reduced coral cover due to bleaching events predominately drives these declines rather than the direct physiological impacts of ocean warming and acidification on calcification or bioerosion. Presently degraded reefs were also more sensitive in our analysis. These findings highlight the low likelihood that the world's coral reefs will maintain their functional roles without near-term stabilization of atmospheric CO2 emissions.

Raising names from the dead: A time-calibrated phylogeny of frog shells (Bursidae, Tonnoidea, Gastropoda) using mitogenomic data.

With 59 Recent species, Bursidae, known as «frog shells¼, are a small but widely distributed group of tropical and subtropical gastropods that are most diverse in the Indo-West Pacific. The present study is aimed at reconstructing phylogenetic relationships of bursid gastropods based on extensive and representative taxon sampling. Five genetic markers (cytochrome c oxidase subunit I (cox1), 16 s and 12 s rRNA mitochondrial genes, 28 s rRNA and Histone H3 nuclear gene) were sequenced for over 30 species in every known genus but Crossata. Furthermore, we sequenced the complete mt-genome of 9 species (10 specimens) (Aspa marginata, Marsupina bufo, Korrigania quirihorai, Korrigania fijiensis, Tutufa rubeta, Bursa lamarckii, Lampasopsis rhodostoma (twice), Bufonaria perelegans and Bursa aff. tuberosissima). Our analysis recovered Bursidae as a monophyletic group, whereas the genus Bursa was found to be polyphyletic. The genera Talisman and Dulcerana are resurrected and the genera Alanbeuella gen. nov. and Korrigania gen. nov. are described. Dating analysis using 21 extinct taxa for node and simplified tip calibrations was performed, showing a diversification of the group in two phases. Diversification may be linked to tectonic events leading to biodiversity relocation from the western Tethys toward the Indo-Pacific.

Comparison of Post-Activation Potentiating Stimuli on Jump and Sprint Performance.

Post-activation potentiation (PAP) is a phenomenon characterized by improved muscle performance based on the previous contractile activity of the muscle. The purpose of this study was to determine the effect of different potentiating stimuli on jump and sprint performance in 13 resistance trained, college-aged men and women. After determining back squat 1 repetition max, subjects returned for testing on separate days to complete one of four interventions (dynamic resistance, weighted plyometric, isometric, or control) in a randomized order. A standardized warmup was performed, followed by a baseline countermovement jump (CMJ) and 20m sprint. Following warm-up and baseline measurements, subjects performed one of the four experimental conditions. CMJ and 20m sprint measurements were completed again at 20-seconds, 4, 8, 12, 16, and 20-minutes. Results revealed significantly faster 0-20m sprint times (p < .05) at the 4, 8, 12, 16, and 20-minute time points compared to baseline and 20-second time points. Significantly faster 0-20m sprint times (p < .05) were also shown for the squat intervention compared to control at 4-minutes, the plyometric and squat intervention compared to control at 8-minutes, the isometric intervention compared to control at 12 and 16-minutes, and the isometric intervention compared to the squat at 20-minutes. These findings indicate that while all PAP stimuli utilized can be effective at improving sprint performance, specific optimal time points may exist.

Stress-resistant corals may not acclimatize to ocean warming but maintain heat tolerance under cooler temperatures.

Naturally heat-resistant coral populations hold significant potential for facilitating coral reef survival under rapid climate change. However, it remains poorly understood whether they can acclimatize to ocean warming when superimposed on their already thermally-extreme habitats. Furthermore, it is unknown whether they can maintain their heat tolerance upon larval dispersal or translocation to cooler reefs. We test this in a long-term mesocosm experiment using stress-resistant corals from thermally-extreme reefs in NW Australia. We show that these corals have a remarkable ability to maintain their heat tolerance and health despite acclimation to 3-6 °C cooler, more stable temperatures over 9 months. However, they are unable to increase their bleaching thresholds after 6-months acclimation to + 1 °C warming. This apparent rigidity in the thermal thresholds of even stress-resistant corals highlights the increasing vulnerability of corals to ocean warming, but provides a rationale for human-assisted migration to restore cooler, degraded reefs with corals from thermally-extreme reefs.

iCAST Balloon-Expandable Covered Stent for Iliac Artery Lesions: 3-Year Results from the iCARUS Multicenter Study.

PURPOSE: To evaluate safety and effectiveness of the iCAST Covered Stent for treatment of iliac artery atherosclerotic lesions. MATERIALS AND METHODS: The iCARUS trial (ClinicalTrials.gov Identifier: NCT00593385) was a single-arm, prospective, multicenter study that enrolled 152 per protocol subjects at 25 sites in the United States and Germany. Subjects with multiple lesions and/or stents were eligible. The primary endpoint was the composite rate of death within 30 days, target lesion revascularization (TLR) within 9 months, or restenosis at 9 months after procedure. Secondary endpoints included major adverse vascular events (MAVEs), primary patency, freedom from TLR, and clinical success. RESULTS: Device and acute procedural success were achieved in 98.7% and 92.7% of cases, respectively. MAVE rate was 4.6% at 30 days. The 9-month primary composite endpoint rate was 8.1% (10/123), which was below the performance goal of 16.57%. Nine-month primary patency, defined as continuous flow without revascularization, bypass, or target limb amputation, was 96.4%. Freedom from TLR at 9 months and 3 years was 97.2% and 86.6%, respectively. Early clinical success was seen in 88.7% of subjects at 30 days with sustained clinical benefit in 72.4% of subjects at 3 years. CONCLUSIONS: The iCARUS study demonstrated that the iCAST Covered Stent was safe and effective for treatment of atherosclerotic iliac artery lesions with sustained clinical benefit out to 3 years.

Acclimatization of massive reef-building corals to consecutive heatwaves.

Reef-building corals typically live close to the upper limits of their thermal tolerance and even small increases in summer water temperatures can lead to bleaching and mortality. Projections of coral reef futures based on forecasts of ocean temperatures indicate that by the end of this century, corals will experience their current thermal thresholds annually, which would lead to the widespread devastation of coral reef ecosystems. Here, we use skeletal cores of long-lived Porites corals collected from 14 reefs across the northern Great Barrier Reef, the Coral Sea, and New Caledonia to evaluate changes in their sensitivity to heat stress since 1815. High-density 'stress bands'-indicative of past bleaching-first appear during a strong pre-industrial El Niño event in 1877 but become significantly more frequent in the late twentieth and early twenty-first centuries in accordance with rising temperatures from anthropogenic global warming. However, the proportion of cores with stress bands declines following successive bleaching events in the twenty-first century despite increasing exposure to heat stress. Our findings demonstrate an increase in the thermal tolerance of reef-building corals and offer a glimmer of hope that at least some coral species can acclimatize fast enough to keep pace with global warming.

Investigating marine bio-calcification mechanisms in a changing ocean with in vivo and high-resolution ex vivo Raman spectroscopy.

Ocean acidification poses a serious threat to marine calcifying organisms, yet experimental and field studies have found highly diverse responses among species and environments. Our understanding of the underlying drivers of differential responses to ocean acidification is currently limited by difficulties in directly observing and quantifying the mechanisms of bio-calcification. Here, we present Raman spectroscopy techniques for characterizing the skeletal mineralogy and calcifying fluid chemistry of marine calcifying organisms such as corals, coralline algae, foraminifera, and fish (carbonate otoliths). First, our in vivo Raman technique is the ideal tool for investigating non-classical mineralization pathways. This includes calcification by amorphous particle attachment, which has recently been controversially suggested as a mechanism by which corals resist the negative effects of ocean acidification. Second, high-resolution ex vivo Raman mapping reveals complex banding structures in the mineralogy of marine calcifiers, and provides a tool to quantify calcification responses to environmental variability on various timescales from days to years. We describe the new insights into marine bio-calcification that our techniques have already uncovered, and we consider the wide range of questions regarding calcifier responses to global change that can now be proposed and addressed with these new Raman spectroscopy tools.

Six weeks of oral Echinacea purpurea supplementation does not enhance the production of serum erythropoietin or erythropoietic status in recreationally active males with above-average aerobic fitness.

The purpose of this study was to investigate the effect of 6 weeks of oral Echinacea purpurea supplementation on serum erythropoietin (EPO) and erythropoietic status. Twenty-four males (mean ± SE; age = 25.2 ± 1.4 years, height = 178.1 ± 1.4 cm, body mass = 78.1 ± 1.6 kg, body fat = 12.7 ± 0.9%, maximal oxygen uptake = 52.9 ± 0.9 mL·kg-1·min-1) were randomly grouped using a matched-pair, double-blind design and self-administered 8000 mg·day-1 of either E. purpurea (n = 12) or placebo (n = 12) for 42 consecutive days. Blood samples were collected prior to supplementation (day 0) and every 2 weeks during the supplementation period (days 14, 28, and 42) and were analyzed for EPO, red blood cell count, hemoglobin concentration, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Separate 2 × 4 (group × time) factorial ANOVA with repeated measures on time were used to determine statistical differences with significance set at p ≤ 0.05. There were no significant interaction, group, or time effects observed for EPO or erythropoietic status markers for any of the measurement points (p ≤ 0.05). The present study indicated that 6 weeks of oral E. purpurea supplementation in recreationally active males with above average aerobic fitness did not enhance EPO or erythropoietic status. These findings are in contrast with previous reports of E. purpurea supplementation in untrained participants with average fitness levels, but consistent with observations in trained endurance athletes.

Environmental and physiochemical controls on coral calcification along a latitudinal temperature gradient in Western Australia.

The processes that occur at the micro-scale site of calcification are fundamental to understanding the response of coral growth in a changing world. However, our mechanistic understanding of chemical processes driving calcification is still evolving. Here, we report the results of a long-term in situ study of coral calcification rates, photo-physiology, and calcifying fluid (cf) carbonate chemistry (using boron isotopes, elemental systematics, and Raman spectroscopy) for seven species (four genera) of symbiotic corals growing in their natural environments at tropical, subtropical, and temperate locations in Western Australia (latitudinal range of ~11°). We find that changes in net coral calcification rates are primarily driven by pHcf and carbonate ion concentration [ CO 3 2 - ]cf in conjunction with temperature and DICcf . Coral pHcf varies with latitudinal and seasonal changes in temperature and works together with the seasonally varying DICcf to optimize [ CO 3 2 - ]cf at species-dependent levels. Our results indicate that corals shift their pHcf to adapt and/or acclimatize to their localized thermal regimes. This biological response is likely to have critical implications for predicting the future of coral reefs under CO2 -driven warming and acidification.

Similar controls on calcification under ocean acidification across unrelated coral reef taxa.

Ocean acidification (OA) is a major threat to marine ecosystems, particularly coral reefs which are heavily reliant on calcareous species. OA decreases seawater pH and calcium carbonate saturation state (Ω), and increases the concentration of dissolved inorganic carbon (DIC). Intense scientific effort has attempted to determine the mechanisms via which ocean acidification (OA) influences calcification, led by early hypotheses that calcium carbonate saturation state (Ω) is the main driver. We grew corals and coralline algae for 8-21 weeks, under treatments where the seawater parameters Ω, pH, and DIC were manipulated to examine their differential effects on calcification rates and calcifying fluid chemistry (Ωcf , pHcf , and DICcf ). Here, using long duration experiments, we provide geochemical evidence that differing physiological controls on carbonate chemistry at the site of calcification, rather than seawater Ω, are the main determinants of calcification. We found that changes in seawater pH and DIC rather than Ω had the greatest effects on calcification and calcifying fluid chemistry, though the effects of seawater carbonate chemistry were limited. Our results demonstrate the capacity of organisms from taxa with vastly different calcification mechanisms to regulate their internal chemistry under extreme chemical conditions. These findings provide an explanation for the resistance of some species to OA, while also demonstrating how changes in seawater DIC and pH under OA influence calcification of key coral reef taxa.