Hypoxia-inducible factor: role in cell survival in superoxide dismutase overexpressing mice after neonatal hypoxia-ischemia.

BackgroundSixty percent of infants with severe neonatal hypoxic-ischemic encephalopathy die, while most survivors have permanent disabilities. Treatment for neonatal hypoxic-ischemic encephalopathy is limited to therapeutic hypothermia, but it does not offer complete protection. Here, we investigated whether hypoxia-inducible factor (HIF) promotes cell survival and suggested neuroprotective strategies.PurposeHIF-1α-deficient mice have increased brain injury after neonatal hypoxia-ischemia (HI), and the role of HIF-2α in HI is not well characterized. Copper-zinc superoxide dismutase (SOD)1 overexpression is not beneficial in neonatal HI. The expression of HIF-1α and HIF-2α was measured in SOD1 overexpressing mice and compared to wild-type littermates to see if alteration in expression explains this lack of benefit.MethodsOn postnatal day 9, C57Bl/6 mice were subjected to HI, and protein expression was measured by western blotting in the ipsilateral cortex of wild-type and SOD1 overexpressing mice to quantify HIF-1α and HIF-2α. Spectrin expression was also measured to characterize the mechanism of cell death.ResultsHIF-1α protein expression did not significantly change after HI injury in the SOD1-overexpressing or wild-type mouse cortex. However, HIF-2α protein expression increased 30 minutes after HI injury in the wild-type and SOD1-overexpressing mouse cortex and decreased to baseline value at 24 hours after HI injury. Spectrin 145/150 expression did not significantly change after HI injury in the SOD1- overexpressing or wild-type mouse cortex. However, spectrin 120 expression increased in both wild-type and SOD1-overexpressing mouse at 4 hours after HI, which decreased by 24 hours, indicating a greater role of apoptotic cell death.ConclusionHIF-1α and HIF-2α may promote cell survival in neonatal HI in a cell-specific and regional fashion. Our findings suggest that early HIF-2α upregulation precedes apoptotic cell death and limits necrotic cell death. However, the influence of SOD was not clarified; it remains an intriguing factor in neonatal HI

Effects of therapeutic hypothermia on white matter injury from murine neonatal hypoxia-ischemia.

BackgroundTherapeutic hypothermia (TH) is the standard of care for neonates with hypoxic-ischemic encephalopathy, but it is not fully protective in the clinical setting. Hypoxia-ischemia (HI) may cause white matter injury (WMI), leading to neurological and cognitive dysfunction.MethodsP9 mice were subjected to HI as previously described. Pups underwent 3.5 h of systemic hypothermia or normothermia. Cresyl violet and Perl's iron staining for histopathological scoring of brain sections was completed blindly on all brains. Immunocytochemical (ICC) staining for myelin basic protein (MBP), microglia (Iba1), and astrocytes (glia fibrillary acidic protein (GFAP)) was performed on adjacent sections. Volumetric measurements of MBP coverage were used for quantitative analysis of white matter.ResultsTH provided neuroprotection by injury scoring for the entire group (n=44; P<0.0002). ICC analysis of a subset of brains showed that the lateral caudate was protected from WMI (P<0.05). Analysis revealed decreased GFAP and Iba1 staining in hippocampal regions, mostly CA2/CA3. GFAP and Iba1 directly correlated with injury scores of normothermic brains.ConclusionTH reduced injury, and qualitative data suggest that hippocampus and lateral caudate are protected from HI. Mildly injured brains may better show the benefits of TH. Overall, these data indicate regional differences in WMI susceptibility and inflammation in a P9 murine HI model

Variations, approximation, and low regularity in one dimension

We investigate the properties of minimizers of one-dimensional variational problems when the Lagrangian has no higher smoothness than continuity. An elementary approximation result is proved, but it is shown that this cannot be in general of the form of a standard Lipschitz "variation". Part of this investigation, but of interest in its own right, is an example of a nowhere locally Lipschitz minimizer which serves as a counter-example to any putative Tonelli partial regularity statement. Under these low assumptions we find it nonetheless remains possible to derive necessary conditions for minimizers, in terms of approximate continuity and equality of the one-sided derivatives.Comment: v3, 60 pages. To appear in CoVPDE. Minor cosmetic correction

Trust/untrust is not the same as true/false. lessons learned and ethical questions on the application of untrustworthiness scales to judge individuals

This special paper reflects on trustworthiness and its implications for scientific medical journals and all the communities they serve: health professionals, policymakers, the public, and a specific discipline, in our case, Physical and Rehabilitation Medicine. We start from a recent episode: a paper claimed the untrustworthiness of two randomised controlled trials (RCTs) published in the European Journal of Physical and Rehabilitation Medicine based on a newly developed trustworthiness scale, used until now only in systematic reviews. This likely represents the first case of applying such a scale focusing on a single leading author. Developing a proper answer to this case led us to present some insights from the perspective of a Journal editor. We discuss the impact of false research results, why trust is needed in science and medicine, the difference between untrust and false results, the problems in judging trustworthiness, the unfortunately weak capacity of the peer review system in preventing these issues, the problems of "post-hoc" judgements and the emerging ethical issues. We conclude with some suggestions for the future based on prevention at the system level

Late complications of robot-assisted radical cystectomy with totally intracorporeal urinary diversion

Introduction and objectives: To evaluate late complications in a large cohort of patients undergoing robot-assisted radical cystectomy (RARC) with totally intracorporeal urinary diversion (ICUD). Materials and methods: We prospectively enrolled patients who underwent RARC and ICUD between August 2012 and June 2019. We excluded patients with Ejection fraction < 36%, retinal vasculopathy, ventriculoperitoneal shunts, and those treated without curative intent. All complications and their onset date have been recorded, defined, and graded according to Clavien classification adapted for radical cystectomy. Results: 210 patients were included, 76% of whom were men, with a mean age of 62 years. Urinary diversions used were Padua Ileal Bladder (PIB) in 80% of cases, and ileal conduit (IC) in 20% of patients (generally older and with more comorbidity). The mean follow-up was 30 ± 22 months. The stenosis rate of uretero-ileal anastomosis was 14%, while a reduction in eGFR (≥ 20%) was observed in about half of the cases. UTIs occurred in 37% of the patients, especially in the first 12 months. Only 2% of patients had bowel occlusion, whereas incisional hernia, lymphocele, and systemic events (metabolic acidosis and major cardiovascular events) occurred respectively in 20%, 10%, and 1% of cases. Conclusions: Our study evaluates first late complications in a cohort of patients who underwent RARC with ICUD. These data are encouraging and in line with findings from a historical series of open radical cystectomy (ORC). This study is a further step in supporting RARC as a safe and effective surgical option for the treatment of muscle-invasive bladder cancer (MIBC) in tertiary referral centers

Accuracy of elastic fusion biopsy in daily practice: results of a multicenter study of 2115 patients

OBJECTIVES: To assess the accuracy of Koelis fusion biopsy for the detection of prostate cancer and clinically significant prostate cancer in the everyday practice. METHODS: We retrospectively enrolled 2115 patients from 15 institutions in four European countries undergoing transrectal Koelis fusion biopsy from 2010 to 2017. A variable number of target (usually 2-4) and random cores (usually 10-14) were carried out, depending on the clinical case and institution habits. The overall and clinically significant prostate cancer detection rates were assessed, evaluating the diagnostic role of additional random biopsies. The cancer detection rate was correlated to multiparametric magnetic resonance imaging features and clinical variables. RESULTS: The mean number of targeted and random cores taken were 3.9 (standard deviation 2.1) and 10.5 (standard deviation 5.0), respectively. The cancer detection rate of Koelis biopsies was 58% for all cancers and 43% for clinically significant prostate cancer. The performance of additional, random cores improved the cancer detection rate of 13% for all cancers (P < 0.001) and 9% for clinically significant prostate cancer (P < 0.001). Prostate cancer was detected in 31%, 66% and 89% of patients with lesions scored as Prostate Imaging Reporting and Data System 3, 4 and 5, respectively. Clinical stage and Prostate Imaging Reporting and Data System score were predictors of prostate cancer detection in multivariate analyses. Prostate-specific antigen was associated with prostate cancer detection only for clinically significant prostate cancer. CONCLUSIONS: Koelis fusion biopsy offers a good cancer detection rate, which is increased in patients with a high Prostate Imaging Reporting and Data System score and clinical stage. The performance of additional, random cores seems unavoidable for correct sampling. In our experience, the Prostate Imaging Reporting and Data System score and clinical stage are predictors of prostate cancer and clinically significant prostate cancer detection; prostate-specific antigen is associated only with clinically significant prostate cancer detection, and a higher number of biopsy cores are not associated with a higher cancer detection rate

Head to Head Impact of Margin, Ischemia, Complications, Score Versus a Novel Trifecta Score on Oncologic and Functional Outcomes After Robotic-assisted Partial Nephrectomy: Results of a Multicenter Series

BACKGROUND: There is a paucity of data describing the ability of margin, ischemia, complications, score (MIC) and trifecta in predicting long-term outcomes of robotic-assisted partial nephrectomy (RAPN).OBJECTIVE: To compare a novel trifecta (negative margins, no significant complications, and perioperative estimated glomerular filtration rate [eGFR] decrease 6430%) versus standard MIC as predictors of oncologic and functional results in a large series of RAPNs.DESIGN, SETTING, AND PARTICIPANTS: Between 2009 and 2019, a multicenter dataset was queried for patients with nonmetastatic renal masses who underwent RAPN at eight participating institutions.INTERVENTION: RAPN.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MIC and trifecta achievement were determined for the overall cohort and a subgroup undergoing off-clamp RAPN (ocRAPN), respectively. The overall survival (OS), recurrence-free survival (RFS), and new onset of end-stage renal disease (ESRD; defined as eGFR &lt;30 ml/min) probabilities were assessed by the Kaplan-Meier method. Cox regression analyses were used to identify predictors of OS, RFS, and ESRD. For all analyses, two-sided p &lt; 0.05 was considered significant.RESULTS AND LIMITATIONS: Out of 1807 patients, MIC and trifecta were achieved in 71.1% (n = 1285) and 82.6% (n = 1492), respectively, and once restricted to the ocRAPN cohort, in 95.6% (n = 625) and 81.6% (n = 534), respectively. On Kaplan-Meier analysis, both MIC and trifecta achievement predicted higher OS and lower ESRD probabilities (all p &lt; 0.014), while only trifecta achievement was a predictor of RFS probabilities (p = 0.009). On multivariable Cox regression, MIC did not predict any of the endpoints independently, while trifecta achievement was an independent predictor of higher OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.18-0.86; p = 0.019) and lower ESRD development probabilities (HR 0.32, 95% CI 0.15-0.72; p = 0.005).CONCLUSIONS: Trifecta, initially described as comprehensive measures of perioperative outcomes, needs to stand the test of time. Compared with MIC, the recent trifecta was an independent predictor of clinically significant endpoints, namely, survival and ESRD development probabilities.PATIENT SUMMARY: Our novel trifecta represents a reliable method for estimating survival and development of end-stage renal disease after robotic-assisted partial nephrectomy