Overexpression of mouse prion protein in transgenic mice causes a non-transmissible spongiform encephalopathy

Transgenic mice over-expressing human PRNP or murine Prnp transgenes on a mouse prion protein knockout background have made key contributions to the understanding of human prion diseases and have provided the basis for many of the fundamental advances in prion biology, including the first report of synthetic mammalian prions. In this regard, the prion paradigm is increasingly guiding the exploration of seeded protein misfolding in the pathogenesis of other neurodegenerative diseases. Here we report that a well-established and widely used line of such mice (Tg20 or tga20), which overexpress wild-type mouse prion protein, exhibit spontaneous aggregation and accumulation of misfolded prion protein in a strongly age-dependent manner, which is accompanied by focal spongiosis and occasional neuronal loss. In some cases a clinical syndrome developed with phenotypic features that closely resemble those seen in prion disease. However, passage of brain homogenate from affected, aged mice failed to transmit this syndrome when inoculated intracerebrally into further recipient animals. We conclude that overexpression of the wild-type mouse prion protein can cause an age-dependent protein misfolding disorder or proteinopathy that is not associated with the production of an infectious agent but can produce a phenotype closely similar to authentic prion disease

Social Networks in Limbo. The Experiences of Older Adults During COVID-19 in Ghana

While studies exploring COVID-19 and its global influence have begun, social networks and support among older adults in low-and middle-income countries, such as Ghana have been inadequate despite its enormous relevance. Thus, the study presents the voices of older adults in Jamestown, Accra and their social networks during the COVID-19 pandemic in Ghana. Using a phenomenological approach, data were collected from 15 older adults through in-depth interviews on older adults' social network experiences during COVID-19 pandemic situation. Older adults generally struggled to maintain connections with their family members, friends, neighbors, and the community, especially during the lockdown. They ascribed their limited interaction to COVID-19 preventive measures, such as social distancing and the limitation of face-to-face meetings imposed by the government. Loneliness, stress, and depression are also linked to the breakdown of social networks. The findings provide a deeper understanding of the impact of COVID-19 on older adults' quality of life. It emerged that the Ghanaian society could reconsider the professional services of gerontologists, social workers, community outreach workers, and philanthropists in mitigating loneliness, stress, and depression among older adults in current and future pandemics

Effect of xylopic acid on alloxan-induced diabetic neuropathy in rats

Background: Neuropathic pain is a very disturbing condition commonly found in diabetic patients. This study investigated xylopic acid (XA), the major constituent of Xylopia aethiopica in diabetic neuropathy as well as established possible toxicity of the compound on some selected tissues.Methods: Diabetes was induced in six groups of male rats with 120 mg/kg alloxan monohydrate. Diabetes was confirmed as a blood glucose level >15 mmol/dl. Neuropathic pain was confirmed on day three post-diabetes induction and treatment with 10 mg/kg, 30 mg/kg or 100 mg/kg xylopic acid, 10 mg/kg glibenclamide, 10 mg/kg morphine, and 10 ml/kg normal saline were initiated and continued for the next 15 days. The effects of the treatments on cold allodynia (cold water at 4°C) and thermal hyperalgesia (hot water at 55 ± 1°C) were evaluated within the duration of treatments. Histology of the liver and kidney, as well as haematological, serum biochemical, and semen analyses, were done after the fifteenth day of the experiment.Results: Xylopic acid produced significant anti-hyperglycaemic and analgesic effects in the cold allodynia and thermal hyperalgesia tests. Sperm motility, viability and count were significantly restored at 10 mg/kg XA as compared higher doses and negative control. The outcome of haematological analysis revealed a protective effect of XA although histological damage liver and kidney due to alloxan treatment was observable.Conclusions: Xylopic acid ameliorates diabetic neuropathy in rats and does not exert detrimental effects at low doses

Predictors of abortions in Rural Ghana: a cross-sectional study.

BACKGROUND: Abortion continues to be used as a method of family planning by many women. The complications of unsafe abortions are a major contributor to maternal mortality in sub-Saharan Africa, including Ghana. This study explored the influence of socio-demographic characteristics on abortions in 156 communities within the Kintampo Health and Demographic Surveillance System (KHDSS) area located in the middle part of Ghana. METHODS: A survey on Sexual and Reproductive Health among a representative sample of females aged 15-49 years was conducted in 2011. They were asked about the outcome of pregnancies that occurred between January 2008 and December 2011. Data on their socio-demographic characteristics including household assets were accessed from the database of the KHDSS. Univariate and multivariate random effects logistic regression models were used to explore the predictors of all reported cases of abortion (induced or spontaneous) and cases of induced abortion respectively. RESULTS: A total of 3554 women were interviewed. Of this total, 2197 women reported on the outcomes of 2723 pregnancies that occurred over the period. The number of all reported cases of abortions (induced and spontaneous) and induced abortions were 370 (13.6%) and 101 (3.7%) respectively. Unmarried women were more likely to have abortion as compared to married women (aOR = 1.77, 95% CI [1.21-2.58], p = 0.003). Women aged 20-29 years were 43% less likely to have abortion in comparison with those within the ages 13-19 years (aOR = 0.57, 95% CI [0.34-0.95], p = 0.030). Women with primary, middle/junior high school (JHS) and at least secondary education had higher odds of having abortion as compared to women without education. Compared with the most poor women, wealthiest women were three-fold likely to have abortion. Unmarried women had higher odds of having induced abortion as compared to married women (aOR = 7.73, 95% CI [2.79-21.44], p < 0.001). Women aged 20-29 years, 30-39 years and 40-49 years were less likely to have induced abortion as compared to those 13-19 years of age. CONCLUSION: Extra efforts are needed to ensure that family planning services, educational programs on abortion and abortion care reach the target groups identified in this study

Genetic analysis of heterogeneous subsets of circulating tumour cells from high grade serous ovarian carcinoma patients

Circulating tumour cells (CTCs) are heterogenous and contain genetic information from the tumour of origin. They bear specific intra- and extra-cellular protein markers aiding in their detection. However, since these markers may be shared with other rare cells in the blood, only genetic testing can confirm their malignancy. Herein, we analyse different CTC subsets using single cell whole genome DNA sequencing to validate their malignant origin. We randomly selected putative CTCs identified by immunostaining that were isolated from 4 patients with high grade serous ovarian cancer (HGSOC) and one with benign cystadenoma. We specifically targeted CTCs positive for epithelial (CK/EpCAMpos), mesenchymal (vimentinpos), and pseudoendothelial (CK/EpCAMpos plus CD31pos) markers. We isolated these cells and performed whole genome amplification (WGA) and low-pass whole-genome sequencing (LP-WGS) for analysis of copy number alterations (CNA). Of the CK/EpCAMpos cells analysed from the HGSOC patients, 2 of 3 cells showed diverse chromosomal CNAs. However, the 4 pseudoendothelial cells (CK/EpCAMpos plus CD31pos) observed in the HGSOC cases did not carry any CNA. Lastly, two of the clusters of vimentin positive cells sequenced from those found in the benign cystadenoma case had CNA. Despite the low number of cells analysed, our results underscore the importance of genetic analysis of putative CTCs to confirm their neoplastic origin. In particular, it highlights the presence of a population of CK/EpCAMpos cells that are not tumour cells in patients with HGSOC, which otherwise would be counted as CTCs

Multi-marker immunofluorescent staining and pd-l1 detection on circulating tumour cells from ovarian cancer patients

Detection of ovarian cancer (OC) circulating tumour cells (CTCs) is primarily based on targeting epithelial markers, thus failing to detect mesenchymal tumour cells. More importantly, the immune checkpoint inhibitor marker PD-L1 has not been demonstrated on CTCs from OC patients. An antibody staining protocol was developed and tested using SKOV-3 and OVCA432 OC cell lines. We targeted epithelial (cytokeratin (CK) and EpCAM), mesenchymal (vimentin), and OC-specific (PAX8) markers for detection of CTCs, and CD45/16 and CD31 were used for the exclusion of white blood and vascular endothelial cells, respectively. PD-L1 was used for CTC characterisation. CTCs were enriched using the Parsortix™ system from 16 OC patients. Results revealed the presence of CTCs in 10 (63%) cases. CTCs were heterogeneous, with 113/157 (72%) cells positive for CK/EpCAM (epithelial marker), 58/157 (37%) positive for vimentin (mesenchymal marker), and 17/157 (11%) for both (hybrid). PAX8 was only found in 11/157 (7%) CTCs. In addition, 62/157 (39%) CTCs were positive for PD-L1. Positivity for PD-L1 was significantly associated with the hybrid phenotype when compared with the epithelial (p = 0.007) and mesenchymal (p = 0.0009) expressing CTCs. Characterisation of CTC phenotypes in relation to clinical outcomes is needed to provide insight into the role that epithelial to mesenchymal plasticity plays in OC and its relationship with PD-L1

Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology.

Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immuno- gold labelling confirmed that they are derived from the endolysosomal system. Consistent with these findings, CHMP2B mutation patient brains contain morphologically similar autofluorescent aggregates. These aggregates occur significantly more frequently in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is a major degenerative pathway in FTD

Vitamin A status and body pool size of infants before and after consuming fortified home-based complementary foods.

BACKGROUND: Home fortification using sachets of micronutrient powder (e.g. "Sprinkles") is a food-based approach offering an alternative to high dose vitamin A (VA) supplements for infants. The primary objective was to investigate the impact of VA-home fortification on infant VA pool size. The secondary objective was to compare VA status of infants assessed by the modified relative dose response (MRDR) test before and the (13)C-retinol isotope dilution ((13)C-RID) test in the same infants after vitamin A supplementation. METHODS: A randomized-controlled trial was conducted in 7-9 month old infants in Ghana. Eligible children were randomly allocated to receive a daily sachet of "Sprinkles" with or without VA for 5 months added to complementary foods. The MRDR test indirectly determined VA liver reserves at baseline and the (13)C-RID determined VA body pool at follow-up in the same cohort of children. RESULTS: At baseline, the MRDR values (95 % CI) for infants were comparable in the intervention and control groups: normal at 0·032 (SD 0·018) (0·025-0·038) and 0·031 (SD 0·018) (0·024-0·038), respectively. After intervention, total body stores (TBS) and liver retinol concentrations did not differ between intervention and control groups; TBS were 436 (SD 303) and 434 (SD 186) μmol, respectively, and estimated liver concentrations were 0·82 (SD 0·53) and 0·79 (SD 0·36) μmol/g liver, indicating adequate reserves in all children. CONCLUSIONS: Both the MRDR and (3)C-RID tests confirmed that the infants had adequate VA status before and after home fortification of their complementary foods. These tests offered more information than serum retinol concentrations alone, which predicted VA deficiency using current suggested cutoffs not corrected for inflammation status

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

We analyse the process of conversion of near-field thermal radiation into usable work by considering the radiation emitted between two planar sources supporting surface phonon-polaritons. The maximum work flux that can be extracted from the radiation is obtained taking into account that the spectral flux of modes is mainly dominated by these surface modes. The thermodynamic efficiencies are discussed and an upper bound for the first law efficiency is obtained for this process