Nicorandil treatment improves survival and spatial learning in aged granulin knockout mice.

Mutations in the human granulin (GRN) gene are associated with multiple diseases, including dementia disorders such as frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). We studied a Grn knockout (Grn-KO) mouse model in order to evaluate a potential therapeutic strategy for these diseases using nicorandil, a commercially available agonist for the ABCC9/Abcc9-encoded regulatory subunit of the "KATP" channel that is well-tolerated in humans. Aged (13 months) Grn-KO and wild-type (WT) mice were treated as controls or with nicorandil (15 mg/kg/day) in drinking water for 7 months, then tested for neurobehavioral performance, neuropathology, and gene expression.

A small molecule p38α MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model of mixed amyloid and vascular pathologies.

Background: Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in "pure" models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage.

A high-throughput single-cell RNA expression profiling method identifies human pericyte markers.

Aims: We sought to identify and optimise a universally available histological marker for pericytes in the human brain. Such a marker could be a useful tool for researchers. Further, identifying a gene expressed relatively specifically in human pericytes could provide new insights into the biological functions of this fascinating cell type.

Atorvastatin rescues hyperhomocysteinemia-induced cognitive deficits and neuroinflammatory gene changes.

Background: Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia.

Early chronic suppression of microglial p38α in a model of Alzheimer's disease does not significantly alter amyloid-associated neuropathology.

The p38 alpha mitogen-activated protein kinase (p38α) is linked to both innate and adaptive immune responses and is under investigation as a target for drug development in the context of Alzheimer's disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38α inhibition can protect against AD-associated neuropathology, the underlying mechanisms are not fully elucidated. Inhibitors of p38α may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to AD pathology.

Association between APOE genotype and microglial cell morphology.

APOE is the largest genetic risk factor for late-onset Alzheimer disease (AD) with E4 conferring an increased risk for AD compared to E3. The ApoE protein can impact diverse pathways in the brain including neuroinflammation but the precise impact of ApoE isoforms on inflammation remains unknown. As microglia are a primary source of neuroinflammation, this study determined whether ApoE isoforms have an impact on microglial morphology and activation using immunohistochemistry and digital analyses.

Targeting Astrocyte Signaling Alleviates Cerebrovascular and Synaptic Function Deficits in a Diet-Based Mouse Model of Small Cerebral Vessel Disease.

Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice.

Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue.

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking.

Entomological determinants of insecticide-treated bed net effectiveness in Western Myanmar.

Background: In a large cluster randomized control trial of insecticide-treated bed nets (ITN) in Western Myanmar the malaria protective effect of ITN was found to be highly variable and, in aggregate, the effect was not statistically significant. A coincident entomological investigation measured malaria vector abundance and biting behaviour and the human population sleeping habits, factors relevant to ITN effectiveness.

Methods: Entomological surveys were carried out using different catching methods to identify potential malaria vector species and characterise their biting habits.

The effect of insecticide-treated bed nets on the incidence and prevalence of malaria in children in an area of unstable seasonal transmission in western Myanmar.

Background: Insecticide-treated bed nets (ITN) reduce malaria morbidity and mortality consistently in Africa, but their benefits have been less consistent in Asia. This study's objective was to evaluate the malaria protective efficacy of village-wide usage of ITN in Western Myanmar and estimate the cost-effectiveness of ITN compared with extending early diagnosis and treatment services.

Methods: A cluster-randomized controlled trial was conducted in Rakhine State to assess the efficacy of ITNs in preventing malaria and anaemia in children and their secondary effects on nutrition and development.

Preoperative axillary staging in breast cancer-saving time and resources.

This study was performed to assess the feasibility and accuracy of ultrasound guided fine needle aspiration biopsy for axillary staging in invasive breast cancer. Data were collected prospectively from June 2005 to June 2006. In all, 197 patients with invasive breast cancer and clinically nonsuspicious axillary lymph nodes were included.

Venous gangrene and cancer: a cool look at a burning issue.

Venous gangrene (VG) is defined as a clinical triad of skin necrosis and discolouration, documented evidence of venous thromboembolism (VTE) and presence of palpable or doppler-identifiable arterial pulsation. Venous gangrene is rare condition which is associated with poor prognosis in cancer patients. The pathogenesis of VG is multifactorial and could paradoxically be due to warfarin treatment.

Typhaphthalide and typharin, two phenolic compounds from Typha capensis.

Two new phenolics, named typhaphthalide (a benzylphthalide) and typharin (an isocoumarin) plus sitosterol were isolated and identified from the hexane extract of the rhizomes of Typha capensis. The acetone extract yielded afzelechin, epiafzelechin, and catechin.

Methyl gardenolate A, a novel cycloartenoid ester from the leaves of Combretum woodii (Combretaceae).

Isolation of the novel cycloartenoid ester methyl gardenolate A (3a), together with gardenolic acid A (2a) and the unusual triterpenoid xi-glutinol (D:B-friedoolean-5-en-3xi-ol) (1a) from the leaves of Combretum woodii support its differentiation from the closely related C. krausii.