Advancing Prostate Cancer Staging: A Single-Step Approach With Bi-parametric and Whole-Body Diffusion MRI in an African Cohort.

OBJECTIVES:  To document our initial experience using whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) and bi-parametric magnetic resonance imaging (bpMRI) as a single exam in the staging of biopsy-proven prostate cancers. METHODS: This retrospective study involved 120 African men with biopsy-confirmed prostate cancer (PCa). All the participants had a single exam that included both a bpMRI and a WB-DWI/MRI. The results were analyzed based on the American Urological Association's risk stratification system and evaluated using descriptive statistics. RESULTS: The combined imaging approach confirmed PCa in all cases, identifying pelvic lymph node metastases in 21 (17.5%) patients. Among 72 high-risk patients, bpMRI+WB-DWI/MRI detected pelvic lymph node metastases in 18 (25.0%), bone metastases in 15 (20.8%), retroperitoneal lymph node metastases in six (8.3%), and extraprostatic extension in 18 (25%), with no solid organ metastases observed. CONCLUSION: The combination of WB-DWI/MRI and bpMRI in a single-step approach demonstrates diagnostic potential in primary prostate cancer staging for high-risk groups, with the added advantage of shorter examination times, lower patients' costs, and elimination of the risks of adverse events associated with the use of contrast agents and exposure to radiation.

Analysis, treatment modality and demographic characteristics of urolithiasis patients visiting Korle-Bu Teaching Hospital in Ghana.

Background: Globally urolithiasis is on the rise and gradually becoming a public health concern due to the associated complications. This study reviewed the demographic characteristics, the chemical composition of stones, treatment modality and duration of hospitalisation of urolithiasis patients at Korle-Bu Teaching Hospital, Accra, Ghana. Materials and Methods: This was a retrospective study conducted between March 2019 and April 2022. Data from consecutive patients treated for urolithiasis were used for this study. Data on demographic characteristics, stones chemical composition, urine factors, urolithiasis treatment modality and duration of hospital stay after therapy were collated and analysed using descriptive and inferential approaches. Results: The age of the patients ranged from 2 to 75 years with a mean of 45 (±13.4). The predominant age group for stone formation was 30-39 years - 52(26.3%). Urolithiasis was common among patients in the formal employment sector: 81(40.9%). All stones had two or more chemical compositions, with the combination of calcium oxalate monohydrate, calcium oxalate dihydrate and uric acid being the predominant stone type: 88(57.5%). Ureteroscopy with semi-rigid and Percutaneous nephrolithotomy were the predominant treatment modalities: 105(53.0%) and 74(37.4%), respectively. Escherichia coli was responsible for most urinary tract infections in urolithiasis patients 8(4.0%) and the least duration of hospital stay after the procedure was associated with the use of semi-rigid ureteroscope as the treatment modality with a median duration of 2 days (1-2 days) with P < 0.0001. Conclusions: Urolithiasis was predominant among professionals in the formal sector. All stones were mixed with Calcium oxalate monohydrate, calcium oxalate dihydrate, and uric acid combination being the majority. Ureteroscopy with semi-rigid and percutaneous nephrolithotomy were the common treatment modality.

Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6.

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.

Formulation and Evaluation of Herbal-Based Antiacne Gel Preparations.

Acne vulgaris is an inflammatory skin condition that affects virtually everyone at some point. Papules, comedones, pustules, scarring, and nodules are standard features of the disease and can have a detrimental social and psychological impact on an individual. Although allopathic acne treatments are available, they have adverse side effects, are expensive, and are prone to cause antibiotic resistance. The present study is aimed at formulating and evaluating topical gels containing Aloe vera, Allium cepa, and Eucalyptus globulus extracts as potential antiacne drugs. Six formulations containing the herbal extracts were prepared using 1% Carbopol 940 as a gelling agent. The phytochemical composition of the plant extracts was determined. The extracts and gels' minimum inhibitory concentration (MIC) was assessed using the microbroth dilution method. The physicochemical properties of the formulated gels, such as homogeneity, colour, texture, odour, grittiness, spreadability, extrudability, viscosity, pH, and drug content, were evaluated. All the plant extracts contained alkaloids, flavonoids, tannins, triterpenoids, and coumarins. The gel formulations showed varying activity against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Candida albicans, and Pseudomonas aeruginosa at various concentrations. The phytochemical components of the plant extracts are probably responsible for the antimicrobial activity of the gel formulations. The 5% Aloe vera-Allium cepa (1 : 1) combination gel formulation showed excellent activity against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans, with MICs of 12.50, 25.00, 6.25, 25.00, and 12.50 mg/mL, respectively. The gels generally had good physicochemical and antimicrobial properties and could be used as antiacne remedies.

Arteriovenous malformation of the ear optimized with cinematic rendering images: A case presentation and review of literature.

Arteriovenous malformations (AVMs) define rare aberrations in vascular morphogenesis. AVMs are typically present at birth, and unless they are stimulated to grow quickly by trauma, illness, or hormonal effects, they enlarge in proportion to an individual's growth. Clinical manifestations of AVMs are often linked to abnormal mass effects and blood perfusion. In this report, we describe a unique case of AVM of the left ear in a 24-year-old male, employing cinematic rendering along with a review of differential diagnosis and treatment options.

Stories of restitution: Family experiences of diagnosis and help-seeking for a child with cerebral palsy.

BACKGROUND: The experience of living with children with CP is dominated by the voice of the mother while others are rarely reported. Incorporation of the voices of other family members is important for a holistic understanding. METHODS: Drawing on the philosophical perspectives of pragmatism, generic qualitative methodology, and Frank's narratives, this article highlights how restitution was constructed by 30 family members. FINDINGS: They constructed restitution by hoping for a cure through either biomedical and/or alternative models of treatment, followed by intransitive and transcendent restitution. DISCUSSION: This appears to be the first time that restitution has been extended to families living with children with chronic illnesses. APPLICATION TO PRACTICE: This would mean that paediatric nursing professionals and other health professionals dealing with family members living with children with CP could attend to their stories in an open and focused manner to honour and validate their stories as well as their experiences.

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.

Three-Dimensional Co-Culture Method for Studying Interactions Between Adipocytes, Extracellular Matrix, and Cancer Cells.

Three-dimensional (D) culture models are increasingly becoming the model of choice for studying different biological phenomena such as cell-cell interaction, drug resistance, and gene expression. These models include extracellular matrix (ECM) proteins that better model the in vivo conditions as it allows cells to have both cell-cell and cell-ECM contacts. In the context of the tumor microenvironment, there are additional types of cells present in addition to the ECM. Thus, an intermediate between 2D cell culture and in vivo mouse models can be desired to interrogate the interactions between multiple cell types under the influence of the ECM. Here we describe a 3D co-culture technique for studying breast cancer-adipocyte interactions. This technique could easily be modified to analyze interactions between other cancer cell types and different fibroblast-like cells.

Pharmaceutical Assessment of Melia azedarach Gum as a Binder and Disintegrant in Immediate-Release Tablets.

Excipients are components other than active ingredients that are added to pharmaceutical formulations. Naturally sourced excipients are gradually gaining preeminence over synthetically sourced excipients due to local availability and continuous supply. This study aimed to investigate the binding and disintegrating characteristics of gum extracted from the bark of Melia azedarach tree. The bark of Melia azedarach was harvested from Kwahu Asasraka in Ghana. The gum was extracted with ethanol (96%), and the percentage yield, phytochemical constituents, and flow characteristics were assessed. As a disintegrant, the gum was utilized to formulate granules at varying concentrations of 5% w/w and 10% w/w using starch as the standard. The gum was also utilized to prepare granules at varying concentrations of 10% w/v and 20% w/v as a binder, with tragacanth gum serving as the reference. Eight batches of tablets were produced from the granules. The formulated tablets from each batch were then subjected to quality control testing, which included uniformity of weight, friability, disintegration, hardness, drug content, and dissolution tests, respectively. Tannins, saponins, alkaloids, and glycosides were identified in the Melia azedarach gum. The gum had a percentage yield of 67.75% and also exhibited good flow properties. All tablets passed the uniformity of weight, friability, disintegration, hardness, dissolution, and drug content tests, respectively. According to the findings of the study, Melia azedarach gum can be utilized as an excipient in place of tragacanth and starch as a binder and disintegrant, respectively, in immediate-release tablets.

Profile of suicide within the northern part of Ghana: A decade under review.

BACKGROUND: Several reports show that suicide is the second and third leading cause of untimely death in young people below the age of 30. Little, however, is known about the profile and trend of suicide in this country due to lack of systematic studies and a lack of national statistics on suicide. This study seeks to examine the profile and pattern of suicide cases recorded within northern Ghana for the past decade. AIM: This study aimed to report the prevalence of suicide as an independent cause of death; the choice of suicide method and the alleged reasons for suicide within the northern part of Ghana. SETTING: Retrospective review of coroners' reports within the northern part of Ghana. METHOD: In this descriptive study, 309 completed suicides as archived by the office of the coroner were examined. The coroners' reports of 309 individuals, whose deaths received a suicide verdict or an open verdict in which the cause of death was likely to be suicide from 2008 to 2017, were examined. Student's t-test was used to ascertain significant age differences between the genders involved. RESULTS: Amongst the 309 decedents examined, approximately, 61% were male, with ages ranging from 5 to 81 years. Hanging and poisoning were the most commonly used methods to complete suicide accounting for 124 (40.1%) and 102 (33.0%) deaths, respectively. Regarding the reasons for completed suicide, 78 (25.2%) were because of unknown reasons and 66 (21.4%) were because of social stigma. There was a notable decline in the prevalence of suicide from 2014 to 2017 compared with the years from 2010 to 2013. CONCLUSION: Suicide was highest in the 30-39 year age group with hanging and poisoning being the most common method employed. Stigmatisation and psychosocial problems arising from chronic illness and economic hardship were significant triggers of suicide amongst the suicide decedents in the northern part of Ghana.

Humanized Transgenic Mice Are Resistant to Chronic Wasting Disease Prions From Norwegian Reindeer and Moose.

Chronic wasting disease (CWD) is the transmissible spongiform encephalopathy or prion disease affecting cervids. In 2016, the first cases of CWD were reported in Europe in Norwegian wild reindeer and moose. The origin and zoonotic potential of these new prion isolates remain unknown. In this study to investigate zoonotic potential we inoculated brain tissue from CWD-infected Norwegian reindeer and moose into transgenic mice overexpressing human prion protein. After prolonged postinoculation survival periods no evidence for prion transmission was seen, suggesting that the zoonotic potential of these isolates is low.

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.

The Analysis of Human Epidermal Growth Receptor-2 (HER-2) in Gastric Cancer in a Tertiary Hospital in Sub-Saharan Africa.

Background: In Ghana, gastric cancer contributes significantly to cancer morbidity and mortality. However, the recent usage of HER-2 monoclonal antibody in combination with chemotherapy has greatly improved the overall survival of patients. This study, therefore, aims at evaluating the pattern of HER-2 over expression in gastric carcinomas in Kumasi, Ghana. Methodology: Demographic data and histological diagnosis were retrieved from the surgical daybook of the Department of Pathology, Komfo Anokye Teaching Hospital, Kumasi. The slides were retrieved and reviewed to confirm the diagnosis, grading and classification of gastric cancer and immunohistochemistry was done with anti-HER-2 antibody to confirm HER-2 over-expression. Results: Of the 99 cases of gastric cancer seen over the 8 years, there were 57 males and 42 females. There were 91 adenocarcinomas, 5 GIST and 3 Non-Hodgkin Lymphoma. The age range of the study population was 8-90 years with a modal age group in the 6th decade. Of the adenocarcinomas, 45 were poorly differentiated, 38 moderately differentiated and 8 well differentiated. The diffuse type was most common with 47 cases followed by intestinal-type with 41cases and mixed type with 3 cases. Three of the 4 patients under the age of 30 years had lymphoma. HER-2 over expression was seen in 14 out of the 47 tested and all were intestinal type. Conclusion: HER -2 over-expression was seen in 30% of patients with gastric carcinoma especially those with intestinal-type.

Treatment of localized prostate cancer and use of nomograms among urologists in the West Africa sub-region.

INTRODUCTION: there is a high incidence of prostate cancer among men of African descent. The disease tends to occur at an early age with a tendency to be aggressive. The objective was to determine the practice of urologists in the West African sub-region regarding treatment of localized prostate cancer, the use of nomograms and their perception of the usefulness of nomograms. METHODS: this was a cross-sectional study that involved urologists practicing in the West African sub-region attending urology and surgery conferences of the "Société Internationale d´Urologie", West African college of surgeons and the Ghana association of urological surgeons. A structured questionnaire was used that sort to ascertain the treatment modalities used for localized prostate cancer and the use of nomograms in the sub-region. The study period spanned the years 2018 and 2019. RESULTS: fifty-six urologists practicing in eleven West African countries responded. Fifty percent had been in practice for less than 5 years. Sixty eight percent (38/56) had been involved in the treatment of localized prostate cancer. Radical prostatectomy was widely available and the treatment modality most used 94.7% (36/38). Nomograms was used by 57.9% of them (22/38) with the Partin tables being the most commonly used nomogram (34.2%). No Locally developed nomogram for treatment of localized prostate cancer was identified. CONCLUSION: radical prostatectomy is the commonest treatment modality used for the management of localized prostate cancer in the West Africa sub-region. Majority of the urologists used nomograms with the Partin tables being the most used.

Adipose Tissue from Lean and Obese Mice Induces a Mesenchymal to Epithelial Transition-Like Effect in Triple Negative Breast Cancers Cells Grown in 3-Dimensional Culture.

Breast cancer is the second leading cause of cancer-related mortality among women globally with obesity being one risk factor. Obese breast cancer patients have at least a 30% increased risk of death from breast cancer compared to non-obese breast cancer patients because they present with larger tumors and generally have increased rates of metastasis. Moreover, obese breast cancer patients respond more poorly to treatment compared to non-obese patients, particularly pre-menopausal women diagnosed with triple negative breast cancer (TNBC). To help understand the molecular mechanisms underlying the increased metastasis associated with obesity, we previously established a three-dimensional culture system that permits the co-culture of adipocytes and TNBC cells in a manner that mimics an in vivo milieu. Using this system, we demonstrate that white adipose tissue from both lean and obese mice can induce a partial mesenchymal-to-epithelial transition (MET). Triple negative breast cancer cells adopt an epithelial morphology and have an increased expression of some epithelial markers, but they maintain the expression of mesenchymal markers, furnishing the breast cancer cells with hybrid properties that are associated with more aggressive tumors. Thus, these data suggest that adipose tissue has the potential to promote secondary tumor formation in lean and obese women. Further work is needed to determine if targeting the partial MET induced by adipose tissue could reduce metastasis.

Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS.

Inherited prion diseases are caused by autosomal dominant coding mutations in the human prion protein (PrP) gene (PRNP) and account for about 15% of human prion disease cases worldwide. The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis, to-date spontaneous formation of disease-relevant, transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Here, we report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which model the PRNP A117V mutation causing inherited prion disease (IPD) including Gerstmann-Sträussler-Scheinker (GSS) disease phenotypes in humans. By studying brain samples from uninoculated groups of mice, we discovered that some mice (≥475 days old) spontaneously generated abnormal PrP assemblies, which after inoculation into further groups of 117VV Tg30 mice, produced a molecular and neuropathological phenotype congruent with that seen after transmission of brain isolates from IPD A117V patients to the same mice. To the best of our knowledge, the 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited prion disease in humans.

The hydroxyl moiety on carbon one (C1) in the monoterpene nucleus of thymol is indispensable for anti-bacterial effect of thymol.

BACKGROUND: Thymol, a natural monoterpene phenol is not only relevant clinically as an anti-microbial, anti-oxidant and anti-inflammatory agent but also holds the prospect as a natural template for pharmaceutical semi-synthesis of therapeutic agents. It is a major component of essential oils from many plants. Evidence abound linking overall bioactivity of thymol to its monoterpene nucleus, specifically, the hydroxyl (-OH) substituent on carbon number one (C1) on the monoterpene nucleus. Other studies have posited that the overall bioactivity of thymol is not substantially altered by chemical modification of - OH on the C1 of the monoterpene nucleus. In view of this, it is still unclear as to whether removal or modification of the -OH on C1 of the monoterpene nucleus relates generally or context-dependently to bioactivity of thymol. OBJECTIVE: The present study investigated anti-bacterial effects of ester-and-ether substituted derivatives of thymol on S. aureus, P. aeruginosa and E. coli. MATERIALS AND METHODS: twelve ester-and-ether substituted derivatives of thymol (6TM1s and 6TM2s) were synthesized and characterized by using HPLC, Mass spectrometry, and IR techniques. Anti-bacterial activity of the 12 thymol derivatives was evaluated using broth macrodilution and turbidimetric methods against pure clinical isolates (S. aureus, P. aeruginosa and E. coli). Standard anti-biotics used were Thymol Streptomycin and flucloxacillin, while DMSO was used as vehicle for thymol derivatives. MIC and MBC were determined. RESULTS: Thymol produced broad-spectrum growth inhibition on all isolates. At equimolar concentrations, thymol and reference drugs produced concentration-dependent growth inhibition against the isolates (Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli) compared to DMSO. Although the growth inhibitory effects of the ester-and-ether derivatives of thymol was significant (P ≤ 0.05) compared to DMSO, it was however insignificant (P ≥ 0.05) compared to thymol and reference antibiotics. Comparatively, at equimolar concentrations, ester-substituted derivatives of thymol, particularly the branched chain derivative (TM1C) produced more effective growth inhibition on the isolates than the ether-substituted derivatives of thymol. Thymol was twice as potent (MIC and MBC, 500 µg/ml) than both ester-and-ether substituted derivatives of thymol (MIC and MBC, > 1000 µg/ml) on all the three clinical isolates. Increase in side chain bulkiness of -OH moiety on the monoterpene nucleus of thymol decreased growth inhibition on isolates. CONCLUSION: Thymol has demonstrated broad-spectrum anti-bacterial effects attributable to the hydroxyl moiety on C1 of the monoterpene nucleus. Structural modification of the hydroxyl moiety on C1 of the monoterpene nucleus of thymol with either ether-or-ester substitutions yielded no significant anti-bacterial effects.

Experimental sheep BSE prions generate the vCJD phenotype when serially passaged in transgenic mice expressing human prion protein.

The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), causes variant Creutzfeldt-Jakob disease (vCJD) in humans following dietary exposure. While it is assumed that all cases of vCJD attributed to a dietary aetiology are related to cattle BSE, sheep and goats are susceptible to experimental oral challenge with cattle BSE prions and farmed animals in the UK were undoubtedly exposed to BSE-contaminated meat and bone meal during the late 1980s and early 1990s. Although no natural field cases of sheep BSE have been identified, it cannot be excluded that some BSE-infected sheep might have entered the European human food chain. Evaluation of the zoonotic potential of sheep BSE prions has been addressed by examining the transmission properties of experimental brain isolates in transgenic mice that express human prion protein, however to-date there have been relatively few studies. Here we report that serial passage of experimental sheep BSE prions in transgenic mice expressing human prion protein with methionine at residue 129 produces the vCJD phenotype that mirrors that seen when the same mice are challenged with vCJD prions from patient brain. These findings are congruent with those reported previously by another laboratory, and thereby strongly reinforce the view that sheep BSE prions could have acted as a causal agent of vCJD within Europe.

Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease.

Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP-positive humans with the emergence of new strain features.

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.