Objectives This study sought to examine whether exenatide is capable of reducing myocardial infarct size. Background Exenatide is a glucagon-like peptide (GLP)-1 analogue with insulinotropic and ...insulinomimetic properties. Because insulin and GLP-1 have been described as reducing apoptosis, exenatide might confer cardioprotection after acute myocardial infarction (MI). Methods Pigs were randomized to exenatide or phosphate-buffered saline (PBS) treatment after 75 min of coronary artery ligation and subsequent reperfusion. Infarct size was assessed with Evans Blue (Sigma-Aldrich, St. Louis, Missouri) and triphenyltetrazolium chloride. Cardiac function was measured with epicardial ultrasound and conductance catheter-based pressure-volume loops. Western blotting, histology, and activity assays were performed to determine markers of apoptosis/survival and oxidative stress. Results Exenatide reduced myocardial infarct size (32.7 ± 6.4% vs. 53.6 ± 3.9%; p = 0.031) and prevented deterioration of systolic and diastolic cardiac function (systolic wall thickening: 47.3 ± 6.3% vs. 8.1 ± 1.9%, p < 0.001; myocardial stiffness: 0.12 ± 0.06 mm Hg/ml vs. 0.22 ± 0.07 mm Hg/ml; p = 0.004). After exenatide treatment, myocardial phosphorylated Akt and Bcl-2 expression levels were higher compared with those after PBS treatment, and active caspase 3 expression was lower. In addition, fewer cells were terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling-positive. In addition, nuclear oxidative stress as assessed with an 8-hydroxydeoxyguanosine staining was reduced in the exenatide treatment arm, and superoxide dismutase activity and catalase activity were increased. Serum insulin levels increased after exenatide treatment, without affecting glucose levels. Conclusions These data identify exenatide as a potentially effective compound to reduce infarct size in adjunction to reperfusion therapy in patients with acute MI.
Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic condition characterized by the ossification and calcification of ligaments and entheses. DISH is observed on all continents and in all ...races, but most commonly in men over 50 years of age. Although DISH is asymptomatic in most individuals, the condition is often an indicator of underlying metabolic disease, and the presence of spinal or extraspinal ossifications can sometimes lead to symptoms including pain, stiffness, a reduced range of articular motion, and dysphagia, as well as increasing the risk of unstable spinal fractures. The aetiology of DISH is poorly understood, and the roles of the many factors that might be involved in the development of excess bone are not well delineated. The study of pathophysiological aspects of DISH is made difficult by the formal diagnosis requiring the presence of multiple contiguous fully formed bridging ossifications, which probably represent advanced stages of DISH. In this Review, the reader is provided with an up-to-date discussion of the epidemiological, aetiological and clinical aspects of DISH. Existing classification criteria (which, in the absence of diagnostic criteria, are used to establish a diagnosis of DISH) are also considered, together with the need for modified criteria that enable timely identification of early phases in the development of DISH.
This study critically appraises the measurement properties of tools to measure muscle mass, strength, and physical performance in community-dwelling older people. This can support the selection of a ...valid and reliable set of tools that is feasible for future screening and identification of sarcopenia.
The databases PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane were systematically searched (January 11, 2012). Studies were included if they investigated the measurement properties or feasibility, or both, of tools to measure muscle mass, strength, and physical performance in community-dwelling older people aged ≥60 years. The consensus-based standards for the selection of health status measurement instruments (COSMIN) checklist was used for quality appraisal of the studies.
Sixty-two publications were deemed eligible, including tools for muscle mass (n = 16), muscle strength (n = 15), and physical performance (n = 31). Magnetic resonance imaging, computed tomography, and a 4-compartment model were used as gold standards for muscle mass assessment. Other frequently used measures of muscle mass are dual-energy x-ray and the bioelectrical impedance (BIA); however, reliability data of the BIA are lacking. Handheld dynamometry and gait speed or a short physical performance battery provide a valid and reliable measurement of muscle strength and physical performance, respectively.
It can be concluded that several tools are available for valid and reliable measurements of muscle mass, strength, and performance in clinical settings. For a home-setting BIA, handheld dynamometry and gait speed or a short physical performance battery are the most valid, reliable, and feasible. The combination of selected instruments and its use for the screening and identification of sarcopenia in community-dwelling older people need further evaluation.
Abstract Background context The clinical outcome of patients with ankylosing spinal disorders (ASDs) sustaining a spinal fracture has been described to be worse compared with the general trauma ...population. Purpose To investigate clinical outcome (neurologic deficits, complications, and mortality) after spinal injury in patients with ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH) compared with control patients. Study design Retrospective cohort study. Patient sample All patients older than 50 years and admitted with a traumatic spinal fracture to the Emergency Department of the University Medical Center Utrecht, the Netherlands, a regional level-1 trauma center and tertiary referral spine center. Outcome measures Data on comorbidity (Charlson comorbidity score), mechanism of trauma, fracture characteristics, neurologic deficit, complications, and in-hospital mortality were collected from medical records. Methods With logistic regression analysis, the association between the presence of an ASD and mortality was investigated in relation to other known risk factors for mortality. Results A total of 165 patients met the inclusion criteria; 14 patients were diagnosed with AS (8.5%), 40 patients had DISH (24.2%), and 111 patients were control patients (67.3%). Ankylosing spinal disorder patients were approximately five years older than control patients and predominantly of male gender. The Charlson comorbidity score did not significantly differ among the groups, but Type 2 diabetes mellitus and obesity were more prevalent among DISH patients. In many AS and DISH cases, fractures resulted from low-energy trauma and showed a hyperextension configuration. Patients with AS and DISH were frequently admitted with a neurologic deficit (57.1% and 30.0%, respectively) compared with controls (12.6%; p=.002), which did not improve in the majority of cases. In AS and DISH patients, complication and mortality rates were significantly higher than in controls. Logistic regression analysis showed the parameters age and presence of DISH to be independently, statistically significantly related to mortality. Conclusions Many patients with AS and DISH showed unstable (hyperextension) fracture configurations and neurologic deficits. Complication and mortality rates were higher in patients with ASD compared with control patients. Increasing age and presence of DISH are predictors of mortality after a spinal fracture.
We assess the suitability of ECMWF Integrated Forecasting System (IFS) data for the global modeling of tropical cyclone (TC) storm surges. We extract meteorological forcing from the IFS at a 0.225° ...horizontal resolution for eight historical TCs and simulate the corresponding surges using the global tide and surge model. Maximum surge heights for Hurricanes Irma and Sandy are compared with tide gauge observations, with R
2
-values of 0.86 and 0.74 respectively. Maximum surge heights for the other TCs are in line with literature. Our case studies demonstrate that a horizontal resolution of 0.225° is sufficient for the large-scale modeling of TC surges. By upscaling the meteorological forcing to coarser resolutions as low as 1.0°, we assess the effects of horizontal resolution on the performance of surge modeling. We demonstrate that coarser resolutions result in lower-modeled surges for all case studies, with modeled surges up to 1 m lower for Irma and Nargis. The largest differences in surges between the different resolutions are found for the TCs with the highest surges. We discuss possible drivers of maximum surge heights (TC size, intensity, and coastal slope and complexity), and find that coastal complexity and slope play a more profound role than TC size and intensity alone. The highest surges are found in areas with complex coastlines (fractal dimension > 1.10) and, in general, shallow coastlines. Our findings show that using high-resolution meteorological forcing is particularly beneficial for areas prone to high TC surges, since these surges are reduced the most in coarse-resolution datasets.
Abstract Introduction Comprehensive geriatric assessment (CGA) gives useful information on the functional status of older cancer patients. However, its meaning for a proper selection of elderly ...patients before chemotherapy and, even more important, the influence of chemotherapy on the outcome of geriatric assessment is unknown. Methods 202 cancer patients, for whom an indication for chemotherapy was made by the medical oncologist, underwent a GA before start of chemotherapy by Mini Nutritional Assessment (MNA), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Groningen Frailty Index (GFI) and Mini Mental State Examination (MMSE). After completion of a minimum of four cycles of chemotherapy or at 6 months after the start of chemotherapy the GFI and MMSE assessment was repeated. Results Frailty was shown in 10% of patients by means of MMSE, 32% by MNA, 37% by GFI and in 15% by IQCODE. Compared to patients who received 4 or more cycles of chemotherapy, the MNA and MMSE scores were significantly lower for patients treated with less than 4 cycles ( p = 0.001 and p = 0.04 respectively). The mortality rate after start of chemotherapy was increased for patients with low MNA and high GFI scores with hazard ratios of 2.19 (95% confidence interval CI: 1.42–3.39; p < 0.001) and 1.80 (95% CI: 1.17–2.78; p = 0.007), respectively. After adjusting for sex, age, purpose of chemotherapy and type of malignancy these hazard ratios remained significant ( p < 0.001 and p = 0.004), respectively. Finally, for the 51 patients who underwent repeated post-chemotherapy evaluation by GFI and MMSE, a statistically significant deterioration for the MMSE ( p = 0.041) was found but not for the GFI. Conclusions Both inferior MNA and MMSE scores increased the probability not to complete chemotherapy. Also, an inferior score for MNA and GFI showed an increased mortality risk after the start of chemotherapy. The mean MMSE score worsened significantly during chemotherapy.
Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of ...chemotherapy and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC.
We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the small ubiquitin like modifier (SUMO) activating enzyme E1 could be used to treat a preclinical syngeneic PDAC mouse model and we have studied the mode of action of TAK-981.
We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared with normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumour burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and natural killer (NK) cells but transiently decreased B cell numbers in tumour, peripheral blood, spleen and lymph nodes. Single cell RNA sequencing revealed activation of the interferon response on TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes.
Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumour immunity by inducing interferon signalling.
SUMOylation is a reversible post-translational modification essential for genome stability. Using high-resolution MS, we have studied global SUMOylation in human cells in a site-specific manner, ...identifying a total of >4,300 SUMOylation sites in >1,600 proteins. To our knowledge, this is the first time that >1,000 SUMOylation sites have been identified under standard growth conditions. We quantitatively studied SUMOylation dynamics in response to SUMO protease inhibition, proteasome inhibition and heat shock. Many SUMOylated lysines have previously been reported to be ubiquitinated, acetylated or methylated, thus indicating cross-talk between SUMO and other post-translational modifications. We identified 70 phosphorylation and four acetylation events in proximity to SUMOylation sites, and we provide evidence for acetylation-dependent SUMOylation of endogenous histone H3. SUMOylation regulates target proteins involved in all nuclear processes including transcription, DNA repair, chromatin remodeling, precursor-mRNA splicing and ribosome assembly.
Extreme sea levels, caused by storm surges and high tides, can have devastating societal impacts. To effectively protect our coasts, global information on coastal flooding is needed. Here we present ...the first global reanalysis of storm surges and extreme sea levels (GTSR data set) based on hydrodynamic modelling. GTSR covers the entire world's coastline and consists of time series of tides and surges, and estimates of extreme sea levels. Validation shows that there is good agreement between modelled and observed sea levels, and that the performance of GTSR is similar to that of many regional hydrodynamic models. Due to the limited resolution of the meteorological forcing, extremes are slightly underestimated. This particularly affects tropical cyclones, which requires further research. We foresee applications in assessing flood risk and impacts of climate change. As a first application of GTSR, we estimate that 1.3% of the global population is exposed to a 1 in 100-year flood.
Background context
Patients with multiple myeloma (MM) are at increased risk of infections and suffer from poor bone quality due to their disseminated malignant bone disease. Therefore, postoperative ...complications may occur following surgical treatment of MM lesions.
Purpose
In this study, we aimed to determine the incidence of postoperative complications and retreatments after spinal surgery in MM patients. Additionally, we sought to identify risk factors associated with complications and retreatments.
Study design
Retrospective cohort study.
Patient sample.
In total, 270 patients with MM who received surgical treatment for spinal involvement between 2008 and 2021 were included.
Outcome measures.
The incidence of perioperative complications within 6 weeks and reoperations within 2.5 years and individual odds ratios for factors associated with these complications and reoperations.
Methods
Data were collected through manual chart review. Hosmer and Lemeshow’s purposeful regression method was used to identify risk factors for complications and reoperations.
Results
The median age of our cohort was 65 years (SD = 10.8), and 58% were male (
n
= 57). Intraoperative complications were present in 24 patients (8.9%). The overall 6-week complication rate after surgery was 35% (
n
= 95). The following variables were independently associated with 6-week complications: higher Genant grading of a present vertebral fracture (OR 1.41; 95% CI 1.04–1.95;
p
= .031), receiving intramuscular or intravenous steroids within a week prior to surgery (OR 3.97; 95% CI 1.79–9.06;
p
= .001), decompression surgery without fusion (OR 6.53; 95% CI 1.30–36.86;
p
= .026), higher creatinine levels (OR 2.18; 95% CI 1.19–5.60;
p
= .014), and lower calcium levels (OR 0.58; 95% CI 0.37–0.88;
p
= .013). A secondary surgery was indicated for 53 patients (20%), of which 13 (4.8%) took place within two weeks after the initial surgery. We additionally discovered factors associated with retreatments, which are elucidated within the manuscript.
Conclusion
The goal of surgical treatment for MM bone disease is to enhance patient quality of life and reduce symptom burden. However, postoperative complication rates remain relatively high after spine surgery in patients with MM, likely attributable to both inherent characteristics of the disease and patient comorbidities. The risk for complications and secondary surgeries should be explored and a multidisciplinary approach is crucial.
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