Reduction of β-cell mass and function is central to the pathogenesis of type 2 diabetes. The terms glucotoxicity, lipotoxicity, and glucolipotoxicity are used to describe potentially responsible ...processes. The premise is that chronically elevated glucose levels are toxic to β-cells, that elevated lipid levels in the form of circulating free fatty acids (FFA) also have toxic effects, and that the combination of the two, glucolipotoxicity, is particularly harmful. Much work has shown that high concentrations of FFA can be very damaging to β-cells when used for in vitro experiments, and when infused in large amounts in humans and rodents they produce suppression of insulin secretion. The purpose of this Perspective is to raise doubts about whether the FFA levels found in real-life situations are ever high enough to cause problems. Evidence supporting the importance of glucotoxicity is strong because there is such a tight correlation between defective insulin secretion and rising glucose levels. However, there is virtually no convincing evidence that the alterations in FFA levels occurring during progression to diabetes are pathogenic. Thus, the terms lipotoxicity and glucolipotoxicity should be used with great caution, if at all, because evidence supporting their importance has not yet emerged.
Summary Angiogenesis, the formation of new blood vessels from pre-existing vessels, has been validated as a target in several tumour types through randomised trials, incorporating vascular ...endothelial growth factor (VEGF) pathway inhibitors into the therapeutic armoury. Although some tumours such as renal cell carcinoma, ovarian and cervical cancers, and pancreatic neuroendocrine tumours are sensitive to these drugs, others such as prostate cancer, pancreatic adenocarcinoma, and melanoma are resistant. Even when drugs have yielded significant results, improvements in progression-free survival, and, in some cases, overall survival, are modest. Thus, a crucial issue in development of these drugs is the search for predictive biomarkers—tests that predict which patients will, and will not, benefit before initiation of therapy. Development of biomarkers is important because of the need to balance efficacy, toxicity, and cost. Novel combinations of these drugs with other antiangiogenics or other classes of drugs are being developed, and the appreciation that these drugs have immunomodulatory and other modes of action will lead to combination regimens that capitalise on these newly understood mechanisms.
There has been evidence that mitochondrial fragmentation is required for apoptosis, but the molecular links between the machinery regulating dynamics and cell death have been controversial. Indeed, ...activated BAX and BAK can form functional channels in liposomes, bringing into question the contribution of mitochondrial dynamics in apoptosis. We now demonstrate that the activation of apoptosis triggers MAPL/MUL1-dependent SUMOylation of the fission GTPase Drp1, a process requisite for cytochrome c release. SUMOylated Drp1 functionally stabilizes ER/mitochondrial contact sites that act as hotspots for mitochondrial constriction, calcium flux, cristae remodeling, and cytochrome c release. The loss of MAPL does not alter the activation and assembly of BAX/BAK oligomers, indicating that MAPL is activated downstream of BAX/BAK. This work demonstrates how interorganellar contacts are dynamically regulated through active SUMOylation during apoptosis, creating a stabilized platform that signals cytochrome c release.
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•MAPL and mitochondrial SUMOylation are required for an efficient cell death•MAPL SUMOylates Drp1 at the ER/mitochondria interface during apoptosis•SUMOylated Drp1 functionally stabilizes an ER/mitochondrial signaling platform•Ca2+ transfer from ER is required for cristae remodeling and cytochrome c release
Prudent et al. show that MAPL SUMOylates Drp1 at the ER/mitochondria contact sites during cell death. This mitochondrial SUMOylation is involved in the stabilization of an ER/mitochondrial signaling platform required for mitochondrial constriction, calcium flux, cristae remodeling, and an efficient cytochrome c release downstream of BAX/BAK activation.
Staphylococcus aureus is one of the most frequent worldwide causes of morbidity and mortality due to an infectious agent. This pathogen can cause a wide variety of diseases, ranging from moderately ...severe skin infections to fatal pneumonia and sepsis. Treatment of S. aureus infections is complicated by antibiotic resistance and a working vaccine is not available. There has been ongoing and increasing interest in the extraordinarily high number of toxins and other virulence determinants that S. aureus produces and how they impact disease. In this review, we will give an overview of how S. aureus initiates and maintains infection and discuss the main determinants involved. A more in-depth understanding of the function and contribution of S. aureus virulence determinants to S. aureus infection will enable us to develop anti-virulence strategies to counteract the lack of an anti-S. aureus vaccine and the ever-increasing shortage of working antibiotics against this important pathogen.
The rapid evolution and dissemination of antibiotic resistance among bacterial pathogens are outpacing the development of new antibiotics, but antivirulence agents provide an alternative. These ...agents can circumvent antibiotic resistance by disarming pathogens of virulence factors that facilitate human disease while leaving bacterial growth pathways - the target of traditional antibiotics - intact. Either as stand-alone medications or together with antibiotics, these drugs are intended to treat bacterial infections in a largely pathogen-specific manner. Notably, development of antivirulence drugs requires an in-depth understanding of the roles that diverse virulence factors have in disease processes. In this Review, we outline the theory behind antivirulence strategies and provide examples of bacterial features that can be targeted by antivirulence approaches. Furthermore, we discuss the recent successes and failures of this paradigm, and new developments that are in the pipeline.
Summary Background Fetal growth restriction is a major determinant of adverse perinatal outcome. Screening procedures for fetal growth restriction need to identify small babies and then differentiate ...between those that are healthy and those that are pathologically small. We sought to determine the diagnostic effectiveness of universal ultrasonic fetal biometry in the third trimester as a screening test for small-for-gestational-age (SGA) infants, and whether the risk of morbidity associated with being small differed in the presence or absence of ultrasonic markers of fetal growth restriction. Methods The Pregnancy Outcome Prediction (POP) study was a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan. Women participating had clinically indicated ultrasonography in the third trimester as per routine clinical care and these results were reported as usual (selective ultrasonography). Additionally, all participants had research ultrasonography, including fetal biometry at 28 and 36 weeks' gestational age. These results were not made available to participants or treating clinicians (universal ultrasonography). We regarded SGA as a birthweight of less than the 10th percentile for gestational age and screen positive for SGA an ultrasonographic estimated fetal weight of less than the 10th percentile for gestational age. Markers of fetal growth restriction included biometric ratios, utero-placental Doppler, and fetal growth velocity. We assessed outcomes for consenting participants who attended research scans and had a livebirth at the Rosie Hospital (Cambridge, UK) after the 28 weeks' research scan. Findings Between Jan 14, 2008, and July 31, 2012, 4512 women provided written informed consent of whom 3977 (88%) were eligible for analysis. Sensitivity for detection of SGA infants was 20% (95% CI 15–24; 69 of 352 fetuses) for selective ultrasonography and 57% (51–62; 199 of 352 fetuses) for universal ultrasonography (relative sensitivity 2·9, 95% CI 2·4–3·5, p<0·0001). Of the 3977 fetuses, 562 (14·1%) were identified by universal ultrasonography with an estimated fetal weight of less than the 10th percentile and were at an increased risk of neonatal morbidity (relative risk RR 1·60, 95% CI 1·22–2·09, p=0·0012). However, estimated fetal weight of less than the 10th percentile was only associated with the risk of neonatal morbidity (pinteraction =0·005) if the fetal abdominal circumference growth velocity was in the lowest decile (RR 3·9, 95% CI 1·9–8·1, p=0·0001). 172 (4%) of 3977 pregnancies had both an estimated fetal weight of less than the 10th percentile and abdominal circumference growth velocity in the lowest decile, and had a relative risk of delivering an SGA infant with neonatal morbidity of 17·6 (9·2–34·0, p<0·0001). Interpretation Screening of nulliparous women with universal third trimester fetal biometry roughly tripled detection of SGA infants. Combined analysis of fetal biometry and fetal growth velocity identified a subset of SGA fetuses that were at increased risk of neonatal morbidity. Funding National Institute for Health Research, Medical Research Council, Sands, and GE Healthcare.
There is limited evidence to support the use of customised centile charts to identify those at risk of stillbirth and infant death at term. We sought to determine birth weight thresholds at which ...mortality and morbidity increased and the predictive ability of noncustomised (accounting for gestational age and sex) and partially customised centiles (additionally accounting for maternal height and parity) to identify fetuses at risk.
This is a population-based linkage study of 979,912 term singleton pregnancies in Scotland, United Kingdom, between 1992 and 2010. The main exposures were noncustomised and partially customised birth weight centiles. The primary outcomes were infant death, stillbirth, overall mortality (infant and stillbirth), Apgar score <7 at 5 min, and admission to the neonatal unit. Optimal thresholds that predicted outcomes for both non- and partially customised birth weight centiles were calculated. Prediction of mortality between non- and partially customised birth weight centiles was compared using area under the receiver operator characteristic curve (AUROC) and net reclassification index (NRI).
Birth weight ≤25th centile was associated with higher risk for all mortality and morbidity outcomes. For stillbirth, low Apgar score, and neonatal unit admission, risk also increased from the 85th centile. Similar patterns and magnitude of associations were observed for both non- and partially customised birth weight centiles. Partially customised birth weight centiles did not improve the discrimination of mortality (AUROC 0.61 95%CI 0.60, 0.62) compared with noncustomised birth weight centiles (AUROC 0.62 95%CI 0.60, 0.63) and slightly underperformed in reclassifying pregnancies to different risk categories for both fatal and non-fatal adverse outcomes (NRI -0.027 95% CI -0.039, -0.016, p < 0.001). We were unable to fully customise centile charts because we lacked data on maternal weight and ethnicity. Additional analyses in an independent UK cohort (n = 10,515) suggested that lack of data on ethnicity in this population (in which national statistics show 98% are white British) and maternal weight would have misclassified ~15% of the large-for-gestation fetuses.
At term, birth weight remains strongly associated with the risk of stillbirth and infant death and neonatal morbidity. Partial customisation does not improve prediction performance. Consideration of early term delivery or closer surveillance for those with a predicted birth weight ≤25th or ≥85th centile may reduce adverse outcomes. Replication of the analysis with fully customised centiles accounting for ethnicity is warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ovarian cancer Jayson, Gordon C, Prof; Kohn, Elise C, MD; Kitchener, Henry C, Prof ...
The Lancet (British edition),
10/2014, Letnik:
384, Številka:
9951
Journal Article
Recenzirano
Summary Epithelial ovarian cancer is the commonest cause of gynaecological cancer-associated death. The disease typically presents in postmenopausal women, with a few months of abdominal pain and ...distension. Most women have advanced disease (International Federation of Gynecology and Obstetrics FIGO stage III), for which the standard of care remains surgery and platinum-based cytotoxic chemotherapy. Although this treatment can be curative for most patients with early stage disease, most women with advanced disease will develop many episodes of recurrent disease with progressively shorter disease-free intervals. These episodes culminate in chemoresistance and ultimately bowel obstruction, the most frequent cause of death. For women whose disease continues to respond to platinum-based drugs, the disease can often be controlled for 5 years or more. Targeted treatments such as antiangiogenic drugs or poly (ADP-ribose) polymerase inhibitors offer potential for improved survival. The efficacy of screening, designed to detect the disease at an earlier and curable stage remains unproven, with key results expected in 2015.
Summary Background Stillbirth rates in high-income countries have shown little or no improvement over the past two decades. Prevention strategies that target risk factors could be important in rate ...reduction. This systematic review and meta-analysis was done to identify priority areas for stillbirth prevention relevant to those countries. Methods Population-based studies addressing risk factors for stillbirth were identified through database searches. The factors most frequently reported were identified and selected according to whether they could potentially be reduced through lifestyle or medical intervention. The numbers attributable to modifiable risk factors were calculated from data relating to the five high-income countries with the highest numbers of stillbirths and where all the data required for analysis were available. Odds ratios were calculated for selected risk factors, from which population-attributable risk (PAR) values were calculated. Findings Of 6963 studies initially identified, 96 population-based studies were included. Maternal overweight and obesity (body-mass index >25 kg/m2 ) was the highest ranking modifiable risk factor, with PARs of 8–18% across the five countries and contributing to around 8000 stillbirths (≥22 weeks' gestation) annually across all high-income countries. Advanced maternal age (>35 years) and maternal smoking yielded PARs of 7–11% and 4–7%, respectively, and each year contribute to more than 4200 and 2800 stillbirths, respectively, across all high-income countries. In disadvantaged populations maternal smoking could contribute to 20% of stillbirths. Primiparity contributes to around 15% of stillbirths. Of the pregnancy disorders, small size for gestational age and abruption are the highest PARs (23% and 15%, respectively), which highlights the notable role of placental pathology in stillbirth. Pre-existing diabetes and hypertension remain important contributors to stillbirth in such countries. Interpretation The raising of awareness and implementation of effective interventions for modifiable risk factors, such as overweight, obesity, maternal age, and smoking, are priorities for stillbirth prevention in high-income countries. Funding The Stillbirth Foundation Australia, the Department of Health and Ageing, Canberra, Australia, and the Mater Foundation, Brisbane, Australia.
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