Exercise in patients with multiple sclerosis Motl, Robert W; Sandroff, Brian M; Kwakkel, Gert ...
Lancet neurology,
October 2017, 2017-10-00, 20171001, Letnik:
16, Številka:
10
Journal Article
Recenzirano
Exercise can be a beneficial rehabilitation strategy for people with multiple sclerosis to manage symptoms, restore function, optimise quality of life, promote wellness, and boost participation in ...activities of daily living. However, this population typically engages in low levels of health-promoting physical activity compared with adults from the general population, a fact which has not changed in the past 25 years despite growing evidence of the benefits of exercise. To overcome this challenge, the main limitations to promoting exercise through the patient–clinician interaction must be addressed. These limitations are the inadequate quality and scope of existing evidence, incomplete understanding of the mechanisms underlying the beneficial effects of exercise in people with multiple sclerosis, and the absence of a conceptual framework and toolkit for translating the evidence into practice. Future research to address those limitations will be essential to inform decisions about the inclusion of exercise in the clinical care of people with multiple sclerosis.
Context:
Hürthle cell cancer (HCC) of the thyroid remains the subject of controversy with respect to natural course, treatment, and follow-up.
Objective:
The objective of the study was to evaluate ...the clinical and molecular features associated with outcome in HCC.
Design:
The study was a review of 173 HCC cases treated at Mayo Clinic over 11 years with a median 5.8-year follow-up.
Results:
None of the patients with minimally invasive histology had persistent disease, clinical recurrence, or disease-related death. Male gender and TNM stage were independently associated with increased risk of clinical recurrence or death in widely invasive patients. The 5-year cumulative probability of clinical recurrence or death was higher in patients with TNM stage III–IV (females, 74%; males, 91%) compared with patients with TNM stage I–II (females, 0%; males, 17%). Pulmonary metastases were best identified by computed tomography, whereas radioactive iodine scans were positive in only two of 27 cases. Thyroglobulin was detectable in patients with clinical disease, with the notable exception of five patients with distant metastases. The common TERT C228T promoter mutation was detected in both widely invasive and minimally invasive tumors. TERT mRNA was below the limit of detection in all samples.
Conclusion:
Widely invasive HCC with TNM stage III–IV is aggressive, with low probability of recurrence-free survival. Males have worse outcomes than females. Minimally invasive HCC appears to be considerably less aggressive. Radioactive iodine scan performs poorly in detecting distant disease. Although the TERT gene is mutated in HCC, the role of this mutation remains to be demonstrated.
Episodic radiations in the fly tree of life Wiegmann, Brian M; Trautwein, Michelle D; Winkler, Isaac S ...
Proceedings of the National Academy of Sciences - PNAS,
04/2011, Letnik:
108, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Flies are one of four superradiations of insects (along with beetles, wasps, and moths) that account for the majority of animal life on Earth. Diptera includes species known for their ubiquity (Musca ...domestica house fly), their role as pests (Anopheles gambiae malaria mosquito), and their value as model organisms across the biological sciences (Drosophila melanogaster). A resolved phylogeny for flies provides a framework for genomic, developmental, and evolutionary studies by facilitating comparisons across model organisms, yet recent research has suggested that fly relationships have been obscured by multiple episodes of rapid diversification. We provide a phylogenomic estimate of fly relationships based on molecules and morphology from 149 of 157 families, including 30 kb from 14 nuclear loci and complete mitochondrial genomes combined with 371 morphological characters. Multiple analyses show support for traditional groups (Brachycera, Cyclorrhapha, and Schizophora) and corroborate contentious findings, such as the anomalous Deuterophlebiidae as the sister group to all remaining Diptera. Our findings reveal that the closest relatives of the Drosophilidae are highly modified parasites (including the wingless Braulidae) of bees and other insects. Furthermore, we use micro-RNAs to resolve a node with implications for the evolution of embryonic development in Diptera. We demonstrate that flies experienced three episodes of rapid radiation--lower Diptera (220 Ma), lower Brachycera (180 Ma), and Schizophora (65 Ma)--and a number of life history transitions to hematophagy, phytophagy, and parasitism in the history of fly evolution over 260 million y.
Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in ...breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We hypothesize that intrauterine hypoxia (HPX) alters the mitochondrial phenotype in fetal hearts contributing to developmental programming. Pregnant guinea pigs were exposed to normoxia (NMX) or ...hypoxia (HPX, 10.5% O
), starting at early 25 days (25d), 39d duration or late gestation (50d, 14d duration). Near-term (64d) male and female fetuses were delivered by hysterotomy from anesthetized sows, and body/organ weights were measured. Left ventricles of fetal hearts were excised and frozen for measurement of expression of complex (I-V) subunits, fusion (Mfn2/OPA1) and fission (DRP1/Fis1) proteins, and enzymatic rates of I and IV from isolated mitochondrial proteins. Chronic HPX decreased fetal body weight and increased relative placenta weight regardless of timing. Early-onset HPX increased I, III, and V subunit levels, increased complex I but decreased IV activities in males but not females (all
< 0.05). Late-onset HPX decreased (
< 0.05) I, III, and V levels in both sexes but increased I and decreased IV activities in males only. Both HPX conditions decreased cardiac mitochondrial DNA content in males only. Neither early- nor late-onset HPX had any effect on Mfn2 levels but increased OPA1 in both sexes. Both HPX treatments increased DRP1/Fis1 levels in males. In females, early-onset HPX increased DRP1 with no effect on Fis1, whereas late-onset HPX increased Fis1 with no effect on DRP1. We conclude that both early- and late-onset HPX disrupts the expression/activities of select complexes that could reduce respiratory efficiency and shifts dynamics toward fission in fetal hearts. Thus, intrauterine HPX disrupts the mitochondrial phenotype predominantly in male fetal hearts, potentially altering cardiac metabolism and predisposing the offspring to heart dysfunction.
The concept of trophic levels is one of the oldest in ecology and informs our understanding of energy flow and top-down control within food webs, but it has been criticized for ignoring omnivory. We ...tested whether trophic levels were apparent in 58 real food webs in four habitat types by examining patterns of trophic position. A large proportion of taxa (64.4%) occupied integer trophic positions, suggesting that discrete trophic levels do exist. Importantly however, the majority of those trophic positions were aggregated around integer values of 0 and 1, representing plants and herbivores. For the majority of the real food webs considered here, secondary consumers were no more likely to occupy an integer trophic position than in randomized food webs. This means that, above the herbivore trophic level, food webs are better characterized as a tangled web of omnivores. Omnivory was most common in marine systems, rarest in streams, and intermediate in lakes and terrestrial food webs. Trophic-level-based concepts such as trophic cascades may apply to systems with short food chains, but they become less valid as food chains lengthen.
Chronic inflammation associated with ulcerative colitis predisposes individuals to increased colon cancer risk. The aim of these studies was to identify microRNAs that are aberrantly regulated during ...inflammation and may participate in transformation of colonic epithelial cells in the inflammatory setting.
We have use quantitative PCR arrays to compare microRNA (miRNA) expression in tumors and control colonic epithelial cells isolated from distal colons of chronically inflamed mice and APC(Min/+) mice. Rank order statistics was utilized to identify differentially regulated miRNAs in tumors that arose due to chronic inflammation and/or to germline APC mutation. Eight high priority miRNAs were identified: miR-215, miR-137, miR-708, miR-31, and miR-135b were differentially expressed in APC tumors and miR-215, miR-133a, miR-467d, miR-218, miR-708, miR-31, and miR-135b in colitis-associated tumors. Four of these (miR-215, miR-708, miR-31, and miR-135b) were common to both tumors types, and dysregulation of these miRNAs was confirmed in an independent sample set. Target prediction and pathway analysis suggests that these microRNAs, in the aggregate, regulate signaling pathways related to MAPK, PI3K, WNT, and TGF-β, all of which are known to be involved in transformation.
We conclude that these four miRNAs are dysregulated at some very early stage in transformation of colonic epithelial cells. This response is not dependent on the mechanism of initiation of transformation (inflammation versus germline mutation), suggesting that the miRNAs that we have identified are likely to regulate critical signaling pathways that are central to early events in transformation of colonic epithelial cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A New Global Definition of Acute Respiratory Distress Syndrome Matthay, Michael A; Arabi, Yaseen; Arroliga, Alejandro C ...
American journal of respiratory and critical care medicine,
2024-Jan-01, 2024-01-01, 20240101, Letnik:
209, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of ...high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings.
A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would
) identify patients with the currently accepted conceptual framework for ARDS,
) facilitate rapid ARDS diagnosis for clinical care and research,
) be applicable in resource-limited settings,
) be useful for testing specific therapies, and
) be practical for communication to patients and caregivers.
The committee made four main recommendations:
) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min;
) use Pa
:Fi
⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry Sp
:Fi
⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia;
) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and
) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices.
We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.
•Juvenile rats consumed prebiotic, lactoferrin and milk fat globule membrane diet.•Diet altered gene expression in brain circuits important for emotion regulation.•Diet decreased anxiety in the open ...field task.•This diet, fed in early life, can alter brain plasticity and behavior.
Early life nutrition is critical for brain development. Dietary prebiotics and bioactive milk fractions support brain development by increasing plasticity and altering activity in brain regions important for cognition and emotion regulation, perhaps through the gut-microbiome-brain axis. Here we examined the impact of a diet containing prebiotics, lactoferrin, and milk fat globule membrane (test diet) on beneficial gut bacteria, basal gene expression for activity and plasticity markers within brain circuits important for cognition and anxiety, and anxiety-related behavior in the open field. Juvenile male F344 rats were fed the test diet or a calorically matched control diet beginning postnatal day 24. After 4 weeks on diets, rats were sacrificed and brains were removed. Test diet significantly increased mRNA expression for cfos, brain derived neurotropic factor, and the GluN1 subunit of the NMDA receptor in the prefrontal cortex and reduced cfos mRNA within the amygdala. Diet-induced increases in fecal Lactobacillus spp., measured using selective bacterial culture, positively correlated with altered gene expression for cfos and serotonin receptors within multiple brain regions. In a separate cohort of juvenile rats, 4 weeks of the test diet increased time spent in the center of the open field, a behavior indicative of reduced anxiety. These data demonstrate that early life diets containing prebiotics and bioactive milk fractions can adaptively alter genes in neural circuits underlying emotion regulation and impact anxiety-related behavior.
Adverse intrauterine conditions cause fetal growth restriction and increase the risk of adult cardiovascular disease. We hypothesize that intrauterine hypoxia impairs fetal heart function, is ...sustained after birth, and manifests as both cardiac and mitochondrial dysfunction in offspring guinea pigs (GPs). Pregnant GPs were exposed to 10.5% O
(HPX) at 50 days of gestation (full term = 65 days) or normoxia (NMX) for the duration of the pregnancy. Pups were allowed to deliver vaginally and raised in a NMX environment. At 90 days of age, mean arterial pressure (MAP) was measured in anesthetized GPs. NMX and prenatally HPX offspring underwent echocardiographic imaging for in vivo measurement of left ventricular cardiac morphology and function, and O
consumption rates and complex IV enzyme activity were measured from isolated cardiomyocytes and mitochondria, respectively. Prenatal HPX increased ( P < 0.01) MAP (52.3 ± 1.3 and 58.4 ± 1.1 mmHg in NMX and HPX, respectively) and decreased ( P < 0.05) stroke volume (439.8 ± 54.5 and 289.4 ± 15.8 μl in NMX and HPX, respectively), cardiac output (94.4 ± 11.2 and 67.3 ± 3.8 ml/min in NMX and HPX, respectively), ejection fraction, and fractional shortening in male, but not female, GPs. HPX had no effect on left ventricular wall thickness or end-diastolic volume in either sex. HPX reduced mitochondrial maximal respiration and respiratory reserve capacity and complex IV activity rates in hearts of male, but not female, GPs. Prenatal HPX is a programming stimulus that increases MAP and decreases cardiac and mitochondrial function in male offspring. Sex-related differences in the contractile and mitochondrial responses suggest that female GPs are protected from cardiovascular programming of prenatal HPX.
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