Decreased axonal transport rates in the Tg2576 APP transgenic mouse: improvement with the gamma‐secretase inhibitor MRK‐560 as detected by manganese‐enhanced MRI

Neuropil deposition of beta‐amyloid (Aβ) peptides is believed to be a key event in the neurodegenerative process of Alzheimer’s disease (AD). An early and consistent clinical finding in AD is olfactory dysfunction with associated pathology. Interestingly, transgenic amyloid precursor protein (Tg2576) mice also show early amyloid pathology in olfactory regions. Moreover, a recent study indicates that axonal transport is compromised in the olfactory system of Tg2576 mice, as measured by manganese‐enhanced magnetic resonance imaging (MEMRI). Here we tested whether the putative axonal transport deficit in the Tg2576 mouse model improves in response to a selective gamma‐secretase inhibitor, N‐[cis‐4‐[(4‐chlorophenyl)‐sulfonyl]‐4‐(2,5‐difluorophenyl)cyclohexyl]‐1,1,1‐trifluoromethanesulfonamide (MRK‐560). Tg2576 mice or wild‐type (WT) littermates were treated daily with MRK‐560 (30 μmol/kg) or vehicle for 4 (acute) or 29 days (chronic). The subsequent MEMRI analysis revealed a distinct axonal transport dysfunction in the Tg2576 mice compared with its littermate controls. Interestingly, the impairment of axonal transport could be fully reversed by chronic administration of MRK‐560, in line with the significantly lowered levels of both soluble and insoluble forms of Aβ found in the brain and olfactory bulbs (OBs) following treatment. However, no improvement of axonal transport was observed after acute treatment with MRK‐560, where soluble but not insoluble forms of Aβ were reduced in the brain and OBs. The present results show that axonal transport is impaired in Tg2576 mice compared with WT controls, as measured by MEMRI. Chronic treatment in vivo with a gamma‐secretase inhibitor, MRK‐560, significantly reduces soluble and insoluble forms of Aβ, and fully reverses the axonal transport dysfunction.     

Alternative lengthening of telomeres--an enhanced chromosomal instability in aggressive non-MYCN amplified and telomere elongated neuroblastomas

Telomere length alterations are known to cause genomic instability and influence clinical course in several tumor types, but have been little investigated in neuroblastoma (NB), one of the most common childhood tumors. In the present study, telomere-dependent chromosomal instability and telomere length were determined in six NB cell lines and fifty tumor biopsies. The alternative lengthening of telomeres (ALT) pathway was assayed by scoring ALT-associated promyelocytic leukemia (PML) bodies (APBs). We found a reduced probability of overall survival for tumors with increased telomere length compared to cases with reduced or unchanged telomere length. In non-MYCN amplified tumors, a reduced or unchanged telomere length was associated with 100% overall survival. Tumor cells with increased telomere length had an elevated frequency of APBs, consistent with activation of the ALT pathway. The vast majority of tumor biopsies and cell lines exhibited an elevated rate of anaphase bridges, suggesting telomere-dependent chromosomal instability. This was more pronounced in tumors with increased telomere length. In cell lines, there was a close correlation between lack of telomere-protective TTAGGG-repeats, anaphase bridging, and remodeling of oncogene sequences. Thus, telomere-dependent chromosomal instability is highly prevalent in NB, and may contribute to the complexity of genomic alterations as well as therapy resistance in the absence of MYCN amplification and in this tumor type.     

Length of Nutritional Transition Associates Negatively with Postnatal Growth in Very Low Birthweight Infants

Very low birthweight (VLBW, <1500 g) infants may be predisposed to undernutrition during the nutritional transition phase from parenteral to enteral nutrition. We studied the associations among the length of the transition phase, postnatal macronutrient intake, and growth from birth to term equivalent age in VLBW infants. This retrospective cohort study included 248 VLBW infants born before 32 weeks of gestation and admitted to the Children’s Hospital, Helsinki, Finland during 2005–2013. Daily nutrient intakes were obtained from computerized medication administration records. The length of the transition phase correlated negatively with cumulative energy, protein, fat, and carbohydrate intake at 28 days of age. It also associated negatively with weight and head circumference growth from birth to term equivalent age. For infants with a long transition phase (over 12 d), the estimates (95% CI) for weight and head circumference z-score change from birth to term equivalent age were −0.3 (−0.56, −0.04) and −0.44 (−0.81, −0.07), respectively, in comparison to those with a short transition phase (ad 7 d). For VLBW infants, rapid transition to full enteral feeding might be beneficial. However, if enteral nutrition cannot be advanced, well-planned parenteral nutrition during the transition phase is necessary to promote adequate growth.     

Short- and long-term outcome after surgical aortic valve replacement in patients on dialysis

BackgroundThere is no consensus on the choice of aortic valve prosthesis for patients with end-stage renal failure. We analyzed short- and long-term complications in dialysis patients who underwent aortic valve replacement (AVR) with either a biological (bAVR) or a mechanical (mAVR) prosthesis.MethodsAll patients on dialysis who underwent bAVR or mAVR in Sweden from 1995 to 2017 (n=335) were included in a nationwide, population-based, observational, cohort study. Short and long-term complications were compared. Long-term mortality was compared with multivariable Cox regression analysis adjusted for age, sex, comorbidities, and a propensity score-matched model. Median follow-up was 2.8 (range, 0–16) years.ResultsBiological and mechanical valves were implanted in 253 (75.5%) and 82 (24.5%) patients, respectively. The bAVR patients were older and had more comorbidities. There was no significant difference in early complication rate. Thirty-day mortality was 9.1% in bAVR and 7.3% in mAVR patients (P=0.62). The multivariable Cox regression model did not show significant difference in mortality risk between bAVR and mAVR patients [adjusted hazard ratio (aHR) 1.33; 95% CI: 0.84–2.13; P=0.22]. The results were confirmed in the propensity-score matched model. The rate of aortic valve reoperations did not differ significantly between the bAVR and mAVR group.ConclusionsThe short- and long-term complication rate is high, and the expected life expectancy limited, in dialysis patients undergoing AVR, without significant difference between biological and mechanical prostheses. The results suggest that biological valve prosthesis, avoiding systemic anticoagulation, is appropriate in most dialysis patients.     

Molecular and genetic diversity in the metastatic process of melanoma

Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene‐expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene‐expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk     

Adverse effects of an aldosterone synthase (CYP11B2) inhibitor,fadrozole (FAD286), on inflamed rat colon

Recently, we described local aldosterone production in the murine large intestine. Upregulated local aldosterone synthesis in different tissues has been linked with inflammatory conditions, which have been attenuated by the aldosterone synthase (CYP11B2) inhibitor, fadrozole (FAD286). Therefore, we investigated the effect of inhibition of intestinal aldosterone synthesis on the development of intestinal inflammation. Sprague-Dawley rats were administered 5% (v/w) dextran sodium sulphate (DSS) for 7 days with or without daily FAD286 (30 mg/kg/d) subcutaneous injections on 3 days before, during and one day after DSS. Tissue aldosterone concentrations were evaluated by ELISA, CYP11B2 by Western blot and RT-qPCR. FAD286 halved adrenal aldosterone production but, intriguingly, increased the colonic aldosterone concentration. The lack of inhibitory effect of FAD286 in the colon might have been affected by the smaller size of colonic vs. adrenal CYP11B2, as seen in Western blot. When combined with DSS, FAD286 aggravated the macroscopic and histological signs of intestinal inflammation, lowered the animals' body weight gain and increased the incidence of gastrointestinal bleeding and the permeability to iohexol in comparison to DSS-animals. To conclude, FAD286 exerted harmful effects during intestinal inflammation. Local intestinal aldosterone did not seem to play any role in the inflammatory pathogenesis occurring in the intestine.     

Inter- and intra-observer variability in the echocardiographic evaluation of wall motion abnormality in patients with ST-elevation myocardial infarction or takotsubo syndrome – A novel approach

Introduction and Objectives

Using existing transthoracic echocardiographic indices to quantify left ventricular wall motion abnormalities (WMAs) can be difficult due to the variations in the location of the abnormalities within the left ventricle, the quality of examinations, and the inter-/intra-observer variability of available indices. This study aimed to evaluate a new approach for measuring the extent of WMA by calculating the percentage of abnormal wall motion and comparing it to the wall motion score index (WMSI). The study also sought to assess inter- and intra-observer variability.

Methods

The study included 140 echocardiograms from 54 patients presenting with ST-elevation myocardial infarction or Takotsubo syndrome. All patients underwent an echocardiographic examination according to a standard protocol and the images were used to measure the extent of akinesia (proportion akinesia, PrA), akinesia and hypokinesia (proportion akinesia/hypokinesia, PrAH), and WMSI. The inter-observer variability between the two operators was analyzed. The intra-observer analysis was performed by one observer using the same images at least 1 month after the first measurement. The agreement was analyzed using the Pearson correlation coefficient and Bland-Altman plots.

Results

Inter- and intra-observer variability for PrA and PrAH were low and comparable to those for WMSI.

Conclusion

PrA and PrAH are reliable and reproducible echocardiographic methods for the evaluation of left ventricular wall motion.