CRC COVID: Colorectal cancer services during COVID-19 pandemic. Study protocol for service evaluation

COVID-19 has had an impact on the provision of colorectal cancer care. The aim of the CRC COVID study is to describe the changes in colorectal cancer services in the UK and USA in response to the pandemic and to understand the long-term impact

Analysis of mitochondrial haemoglobin in Parkinson's disease brain

Mitochondrial dysfunction is an early feature of neurodegeneration. We have shown there are mitochondrial haemoglobin changes with age and neurodegeneration. We hypothesised that altered physiological processes are associated with recruitment and localisation of haemoglobin to these organelles. To confirm a dynamic localisation of haemoglobin we exposed Drosophila melanogaster to cyclical hypoxia with recovery. With a single cycle of hypoxia and recovery we found a relative accumulation of haemoglobin in the mitochondria compared with the cytosol. An additional cycle of hypoxia and recovery led to a significant increase of mitochondrial haemoglobin (p b 0.05). We quantified ratios of human mitochondrial haemoglobin in 30 Parkinson's and matched control human post-mortem brains. Relative mitochondrial/cytosolic quantities of haemoglobin were obtained for the cortical region, substantia nigra and cerebellum. In age matched postmortem brain mitochondrial haemoglobin ratios change, decreasing with disease duration in female cerebellum samples (n = 7). The change is less discernible in male cerebellum (n = 18). In cerebellar mitochondria, haemoglobin localisation in males with long disease duration shifts from the intermembrane space to the outer membrane of the organelle. These new data illustrate dynamic localisation of mitochondrial haemoglobin within the cell. Mitochondrial haemoglobin should be considered in the context of gender differences characterised in Parkinson's disease. It has been postulated that cerebellar circuitry may be activated to play a protective role in individuals with Parkinson's. The changing localisation of intracellular haemoglobin in response to hypoxia presents a novel pathway to delineate the role of the cerebellum in Parkinson's disease

Exploring the association between Alzheimer’s disease, oral health, microbial endocrinology and nutrition

Longitudinal monitoring of patients suggests a causal link between chronic periodontitis and the development of Alzheimer’s disease (AD). However, the explanation of how periodontitis can lead to dementia remains unclear. A working hypothesis links extrinsic inflammation as a secondary cause of AD. This hypothesis suggests a compromised oral hygiene leads to a dysbiotic oral microbiome whereby Porphyromonas gingivalis, a keystone periodontal pathogen, with its companion species, orchestrates immune subversion in the host. Brushing and chewing on teeth supported by already injured soft tissues leads to bacteraemias. As a result, a persistent systemic inflammatory response develops to periodontal pathogens. The pathogens, and the host’s inflammatory response, subsequently lead to the initiation and progression of multiple metabolic and inflammatory co-morbidities, including AD. Insufficient levels of essential micronutrients can lead to microbial dysbiosis through the growth of periodontal pathogens such as demonstrated for P. gingivalis under low hemin bioavailability. An individual’s diet also defines the consortium of microbial communities that take up residency in the oral and gastrointestinal (GI) tract microbiomes. Their imbalance can lead to behavioural changes. For example, probiotics enriched in Lactobacillus genus of bacteria, when ingested, exert some anti-inflammatory influence through common host/bacterial neurochemicals, both locally, and through sensory signalling back to the brain. Early life dietary behaviours may cause an imbalance in the host/microbial endocrinology through a dietary intake incompatible with a healthy GI tract microbiome later in life. This imbalance in host/microbial endocrinology may have a lasting impact on mental health. This observation opens up an opportunity to explore the mechanisms, which may underlie the previously detected relationship between diet, oral/GI microbial communities, to anxiety, cognition and sleep patterns. This review suggests healthy diet based interventions that together with improved life style/behavioural changes may reduce and/or delay the incidence of AD

Selective Cholinergic Depletion in Medial Septum Leads to Impaired Long Term Potentiation and Glutamatergic Synaptic Currents in the Hippocampus

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning

Dysregulation of neuronal iron homeostasis as an alternative unifying effect of mutations causing familial Alzheimer's disease

The overwhelming majority of dominant mutations causing early onset familial Alzheimer's disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid ß (Aß). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer's disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship - the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer's disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a "Stress Threshold Change of State" model of Alzheimer's disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeostasis in EOfAD may be a profitable way forward in our struggle to understand this form of dementia

Pathogenesis of cognitive dysfunction in patients with obstructive sleep apnea: a hypothesis with emphasis on the nucleus tractus solitarius.

OSA is characterized by the quintessential triad of intermittent apnea, hypoxia, and hypoxemia due to pharyngeal collapse. This paper highlights the upstream mechanisms that may trigger cognitive decline in OSA. Three interrelated steps underpin cognitive dysfunction in OSA patients. First, several risk factors upregulate peripheral inflammation; these crucial factors promote neuroinflammation, cerebrovascular endothelial dysfunction, and oxidative stress in OSA. Secondly, the neuroinflammation exerts negative impact globally on the CNS, and thirdly, important foci in the neocortex and brainstem are rendered inflamed and dysfunctional. A strong link is known to exist between neuroinflammation and neurodegeneration. A unique perspective delineated here underscores the importance of dysfunctional brainstem nuclei in etiopathogenesis of cognitive decline in OSA patients. Nucleus tractus solitarius (NTS) is the central integration hub for afferents from upper airway (somatosensory/gustatory), respiratory, gastrointestinal, cardiovascular (baroreceptor and chemoreceptor) and other systems. The NTS has an essential role in sympathetic and parasympathetic systems also; it projects to most key brain regions and modulates numerous physiological functions. Inflamed and dysfunctional NTS and other key brainstem nuclei may play a pivotal role in triggering memory and cognitive dysfunction in OSA. Attenuation of upstream factors and amelioration of the NTS dysfunction remain important challenges

The aeitiopathogenesis of cutaneous wound failure in Crohn’s disease

Crohn’s disease (CD) is a multi-system condition with multiple cutaneous manifestations. Perineal wound failure is a common complication following surgery in CD. Despite advancements of our understanding of the underlying disease process in intestinal CD, our knowledge in the aetiopathogenesis of skin involvement is still lacking. Risk factors, which contribute to the development of an unhealed perineum following surgery was assessed. The rate for an unhealed perineum at 12 months following surgery was 23%. Poorer healing took place in patients with pre-existing perineal sepsis, but no significant difference was found between patients with IBD or cancer. Subsequent studies assessed immune cell function as a potential contributor to wound failure in CD. Dendritic cells (DC) are specialised antigen-presenting cells that play a central role in intestinal CD pathogenesis. DC dictate type of T-cell immunity and T-cell homing profiles, however wound DC have yet to be characterised. DC were successfully identified from all wound tissue. Expression of skin- homing molecule (CLA) was reduced on wound DC in CD compared with controls. Wound DC were found to stimulate dose-dependent allogeneic T-cell proliferation; both wound and blood DC from CD patients were significantly less stimulatory than their control DC counterparts. Furthermore, DC from CD patients generated T-cells with enhanced expression of CLA compared to T-cells stimulated by control DC in wound tissue and blood. Aberrant expression of skin-homing marker CLA on DC and T-cells that they stimulate may contribute to alterations in immune cell migration in CD. Taken with the restricted stimulatory capacity of DC in CD wounds, it is likely that a loss of DC function occurs contributing to wound failure. Histological assessment suggested an increase in plasma cells in CD wound tissue compared to non-CD wound tissue, further highlighting an immunological aetiology for the aberrant healing in CD. Finally, a randomised control study to assess quality of life benefits and effects on wound dimensions of regular wound digitation against current standard practice of community nurse-led dressings in the management of open perineal wounds was investigated. Wound digitation had a significant reduction in pain, restriction of daily activities and degree of induration, whilst having a comparable healing rate to regular dressings.Open Acces

Evidence of neurodegeneration in obstructive sleep apnea: Relationship between obstructive sleep apnea and cognitive dysfunction in the elderly

The incidence of dementia and obstructive sleep apnea (OSA) increases with age. Late-onset Alzheimer's disease (AD) is an irreversible neurodegenerative disease of the elderly characterized by amyloid β (Aβ) plaques and neurofibrillary tangles. The disease involves widespread synaptic loss in the neocortex and the hippocampus. Rodent and clinical studies suggest that OSA impairs the structural integrity of several brain regions, including the medial temporal lobe. Indeed, hypoxia, hypertension, hypoperfusion, endothelial dysfunction, inflammation, and oxidative stress noted in OSA patients also occur in AD patients. This Review highlights pathological commonality, showing that OSA upregulates Aβ, tau hyperphosphorylation, and synaptic dysfunction. Indeed, OSA and hypertension trigger hypoperfusion and hypometabolism of brain regions, including cortex and hippocampus. Several studies show that hypertension-driven brain damage and pathogenic mechanisms lead to an Aβ increase. The pathophysiological mechanism by which OSA enhances hypertension may be linked to sympathoexcitation, oxidative stress, and endothelial dysfunction. Strong pathophysiological similarities that exist between OSA and AD are underscored here. For example, the hippocampus is negatively impacted in both OSA and AD. OSA promotes hippocampal atrophy, which is associated with memory impairment. Cognitive impairment, even in the absence of manifest dementia, is an important independent predictor of mortality. However, several pathophysiological mechanisms in OSA are reversible with appropriate therapy. OSA, therefore, is a modifiable risk factor of cognitive dysfunction, and treating OSA prior to mild cognitive impairment may be an effective prevention strategy to reduce risk for cognitive decline and AD in middle-aged persons and the elderly