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This article is linked to Pai et al papers. To view these articles, visit https://doi.org/10.1111/apt.16142 and https://doi.org/10.1111/apt.16245
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Although there have been a multitude of studies, the mechanisms of angiogenesis remain incompletely understood. Increasing evidence suggests that cellular redox homeostasis is an important regulator ...of angiogenesis. The thioredoxin (TRX) system functions as an endogenous antioxidant that can exert influence over endothelial cell function via modulation of cellular redox status. It has become apparent that the cytosolic TRX1 isoform participates in both canonical and novel angiogenic signaling pathways and may represent an avenue for therapeutic exploitation. Recent studies have further identified a role for the mitochondrial isoform TRX2 in ischemia-induced angiogenesis. TRX-interacting protein (TXNIP) is the endogenous inhibitor of TRX redox activity that has been implicated in growth factor-mediated angiogenesis. As TXNIP is strongly induced by glucose, this molecule could be of consequence to disordered angiogenesis manifest in diabetes mellitus. This review will focus on data implicating the TRX system in endothelial cell homeostasis and angiogenesis.
Transcription factors play a crucial role in regulation of cardiac biology. FOG-2 is indispensable in this setting, predominantly functioning through a physical interaction with GATA-4. This study ...aimed to identify novel co-regulators of FOG-2 to further elaborate on its inhibitory activity on GATA-4. The Art27 transcription factor was identified by a yeast-2-hybrid library screen to be a novel FOG-2 protein partner. Characterisation revealed that Art27 is co-expressed with FOG-2 and GATA-4 throughout cardiac myocyte differentiation and in multiple structures of the adult heart. Art27 physically interacts with GATA-4, FOG-2 and other cardiac transcription factors and by this means, down-regulates their activity on cardiac specific promoters α-myosin heavy chain, atrial natriuretic peptide and B-type natriuretic peptide. Regulation of endogenous cardiac genes by Art27 was shown using microarray analysis of P19CL6-Mlc2v-GFP cardiomyocytes. Together these results suggest that Art27 is a novel transcription factor that is involved in downregulation of cardiac specific genes by physically interacting and inhibiting the activity of crucial transcriptions factors involved in cardiac biology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Aim
Marked elevations of alanine aminotransferase (ALT) are caused by a limited number of underlying pathologies, including hepatic ischemia, drugs/toxins, viral hepatitis, ...and—rarely—autoimmune hepatitis. The aim of this study was to determine the relative incidence of pathologies resulting in ALT greater than 1000 IU/L and factors predicting clinical outcomes in an Australian cohort.
Methods
A retrospective cohort study of all adult patients with ALT levels greater than 1000 IU/L between January 2013 and December 2015 was conducted at a large teaching hospital network in Australia. Multivariable logistic regression analysis was used to determine predictors of etiology and mortality.
Results
There were 287 patients identified with ALT levels greater than 1000 IU/L. The most common causes were ischemia (44%), drugs/toxins (19%), biliary obstruction (16%), and viral hepatitis (7%). Independent predictors of a diagnosis of ischemic hepatitis included (adjusted odds ratio; 95% confidence interval): hypotension (29.2; 8.2–104.7), chronic obstructive pulmonary disease (COPD) (20.2; 2.8–145.3), coronary artery disease (12.9; 1.7–98.9), congestive cardiac failure (7.8; 1.2–49.2), diabetes mellitus (7.4; 1.6–33.9), metabolic acidosis (6.2; 2.0–19.4), gamma‐glutamyltransferase < 135 IU/L (5.1; 1.5–17.6), and albumin <34 g/L (3.4; 1.1–11.0). Independent risk factors for all‐cause 28‐day mortality included: septic shock (14.7; 4.3–50.7), metabolic acidosis (7.3; 2.5–21.3), history of COPD (5.4; 1.6–17.8), cardiogenic shock (4.3; 1.6–11.7), prothrombin time ≥ 20 s (3.7; 1.5–9.2), and age ≥ 65 years (3.0; 1.3–7.2).
Conclusions
Ischemic hepatitis was the most common cause of ALT levels greater than 1000 IU/L and was associated with high mortality.
Common causes of marked alanine aminotransferase derangement include liver ischemia, drugs/toxins, biliary obstruction, and viral hepatitis. Determination of etiology and outcomes of patients with severe liver injury can be guided by clinical and biochemical parameters.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background & Aims: Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by heterozygous germline sequence mutations of DNA mismatch repair genes, most frequently MLH1 or MSH2. A novel ...molecular mechanism for HNPCC has recently been suggested by the finding of individuals with soma-wide monoallelic hypermethylation of the MLH1 gene promoter. In this study, we determined the frequency and role of germline epimutations of MLH1 in HNPCC. Methods: A cohort of 160 probands from HNPCC families who did not harbor germline sequence mutations in the mismatch repair genes were screened for methylation of the MLH1 and EPM2AIP1 promoters by combined bisulfite and restriction analyses. Allelic expression and family transmission of MLH1 were determined using polymorphisms in intron 4 and the 3′ untranslated region. Results: One of 160 individuals had monoallelic MLH1 hypermethylation in peripheral blood, hair follicles, and buccal mucosa, indicative of a soma-wide alteration. Monoallelic transcription of the paternal MLH1 allele was shown using a heterozygous expressed polymorphism within the 3′ untranslated region. The hypermethylated allele was maternally transmitted, however, the mother and siblings who inherited the same maternal homologue were unmethylated at MLH1, suggesting the epimutation arose as a de novo event. Conclusions: Germline MLH1 epimutations are functionally equivalent to an inactivating mutation and produce a clinical phenotype that resembles HNPCC. Inheritance of epimutations is weak, so family history is not a useful guide for screening. Germline epimutations should be suspected in younger individuals without a family history who present with a microsatellite unstable tumor showing loss of MLH1 expression.
The PTW-Linacheck was assessed for its ability to monitor linear accelerator radiation output constancy. The key issues that were considered were the setup for daily output measurements, e.g., ...requirements for build-up and backscatter material, and the reproducibility and linearity of the device with linear accelerator output. An appropriate measurement setup includes a 10 × 10 cm field at 100 cm FSD, 5 cm backscatter, and no added build-up for 4 MeV electron beams, 1 cm added build-up for 6-16 MeV electron beams and 5 cm added build-up for 6-15 MV photon beams. Using this measurement setup, the dose linearity and short-term reproducibility were acceptable; however, the Linacheck should be recalibrated on a monthly basis to ensure acceptable long-term reproducibility.
Background
Caustic ingestion is relatively common in developing countries and can result in life‐threatening sequelae. There is limited understanding of the epidemiology and incidence in Australia.
...Aims
This statewide 10‐year audit aims to document the rate of caustic injury in a defined Australian pouplation.
Methods
A retrospective review was conducted over 10 years (2007–2016), including all admissions to hospitals in Victoria. This includes a population of 5.9 million people and 22 hospitals.
Results
Three hundred and eighty‐four cases of caustic ingestion were admitted to hospital between January 2007 and December 2016. The overall incidence was 7 cases/million/year. This cohort included 217 (56.5%) females, 193 (50.2%) overseas born patients and 196 (51%) people with a history of mental illness. The countries of birth with the highest incidence of caustic ingestion were Ethiopia (11 patients; 227 cases/million/year; relative risk (RR) 31.7; P < 0.0001), Sudan (11 patients; 161 cases/million/year; RR 22.6; P < 0.0001) and India (38 patients; 27 cases/million/year; RR 3.9; P < 0.0001). All had a significantly higher incidence than the Australian‐born population of only 6.5 cases/million/year (RR 0.4; P < 0.0001). Of those born in India, Sudan and Ethiopia, rates of females (72%) were considerably higher than males. The overall mortality rate in this cohort was 2.3%.
Conclusions
Caustic ingestion remains a significant cause of morbidity and health expenditure in Victoria, particularly among vulnerable groups such as recent female migrants from areas in Africa and India. The high frequency of events seen in migrant populations highlights the significant need for awareness of risks in these groups for the development of possible prevention strategies that are required.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background Caustic ingestion is relatively common in developing countries and can result in life‐threatening sequelae. There is limited understanding of the epidemiology and incidence in Australia. ...Aims This statewide 10‐year audit aims to document the rate of caustic injury in a defined Australian pouplation. Methods A retrospective review was conducted over 10 years (2007–2016), including all admissions to hospitals in Victoria. This includes a population of 5.9 million people and 22 hospitals. Results Three hundred and eighty‐four cases of caustic ingestion were admitted to hospital between January 2007 and December 2016. The overall incidence was 7 cases/million/year. This cohort included 217 (56.5%) females, 193 (50.2%) overseas born patients and 196 (51%) people with a history of mental illness. The countries of birth with the highest incidence of caustic ingestion were Ethiopia (11 patients; 227 cases/million/year; relative risk (RR) 31.7; P < 0.0001), Sudan (11 patients; 161 cases/million/year; RR 22.6; P < 0.0001) and India (38 patients; 27 cases/million/year; RR 3.9; P < 0.0001). All had a significantly higher incidence than the Australian‐born population of only 6.5 cases/million/year (RR 0.4; P < 0.0001). Of those born in India, Sudan and Ethiopia, rates of females (72%) were considerably higher than males. The overall mortality rate in this cohort was 2.3%. Conclusions Caustic ingestion remains a significant cause of morbidity and health expenditure in Victoria, particularly among vulnerable groups such as recent female migrants from areas in Africa and India. The high frequency of events seen in migrant populations highlights the significant need for awareness of risks in these groups for the development of possible prevention strategies that are required.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Over the last two decades there has been a broad paradigm shift in our understanding of gastric cancer (GC) and its premalignant states from gross histological models to increasingly precise ...molecular descriptions. In this review we reflect upon the historic approaches to describing premalignant lesions and GC, highlight the current molecular landscape and how this could inform future risk assessment prevention strategies.
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