Degenerative Myelopathy and Neuropathy in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) Mice Caused by Lactate Dehydrogenase-Elevating Virus (LDV).

Following implantation of patient-derived xenograft (PDX) breast carcinomas from three separate individuals, 33/51 female NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice presented with progressive, unilateral to bilateral, ascending hindlimb paresis to paralysis. Mice were mildly dehydrated, in thin to poor body condition, with reduced to absent hindlimb withdrawal reflex and deep pain sensation. Microscopically, there was variable axonal swelling, vacuolation, and dilation of myelin sheaths within the ventral spinal cord and spinal nerve roots of the thoracolumbar and sacral spinal cord, as well as within corresponding sciatic nerves. Results of PCR screening of PDX samples obtained at necropsy and pooled environmental swabs from the racks housing affected animals were positive for lactate dehydrogenase-elevating virus (LDV). LDV is transmitted through animal-animal contact or commonly as a contaminant of biologic materials of mouse origin. Infection is associated with progressive degenerative myelopathy and neuropathy in strains of mice harboring endogenous retrovirus (AKR, C58), or in immunosuppressed strains (NOD-SCID, Foxn1nu), and can interfere with normal immune responses and alter engraftment and growth of xenograft tumors in immunosuppressed mice. This is the first reported series of LDV-induced poliomyelitis in NSG mice and should be recognized as a potentially significant confounder to biomedical studies utilizing immunodeficient xenograft models.

Dental public health in action: The covid-19 restrictions on dentistry in England and their impact on access to dental care for high-risk patient groups in the North-East and North Cumbria.

The Covid-19 pandemic has significantly impacted dental practices with the initial response being a complete suspension of face to face care unless designated as an urgent care centre. Even with subsequent easing of restrictions, a significant change to the delivery of dental care is continuing to restrict patient access. The introduction of new Standard Operating Procedures, with a benchmark fallow time of 15 to 30 minutes after aerosol generating procedures, has also reduced capacity levels within dental practices. Triaging systems have been implemented within practices to ensure those with the highest oral health care needs are prioritised for face to face care. Altered patient attendance, due to the Covid-19 restrictions placed upon dental care, may also be compounded by patients avoiding dental care due to personal perceptions of risks associated with Covid-19 or due to a desire not to overburden health systems. With the additional Covid-19 restrictions in place the access to dental care for vulnerable populations may have been even further impacted, there is therefore a concern that the restrictions may have exacerbated inequalities in oral health for these groups. Public health competencies illustrated: Developing and monitoring the quality of dental services, Dental Public Health Intelligence, and Policy and Strategy Development are illustrated within this project.

Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Stress and hypertension--a critical review.

Recurrent psychosomatic stress has been popularly thought to cause permanent hypertension by repeated reactive blood pressure elevations. These are considered by some to be caused by various mechanisms, including an increased sympathetic outflow and a decreased parasympathetic inhibition, or possibly an inborn functional abnormality in the walls of the resistance vessels, which becomes a structural abnormality as a result of the elevated pressure. Recent work, however, has questioned some of these concepts. Many of the assumptions in the past concerning the ill-effects of elevated blood pressure have been based on clinic or office readings. With the more widespread use of ambulatory monitoring, first developed in the 1960s, information has accumulated which has helped to clarify the predictive value of such office readings. Ambulatory monitoring has also given much information about the relationship between daily activities, blood pressure reactivity and the mean daily blood pressure level. It appears that only the mean daily level is related to cardiovascular morbidity and mortality. Variations in blood pressure in response to bodily and mental activity are not so related. Nor has it been shown that variability is a precursor of fixed hypertension. The role of laboratory stressors is discussed to see whether they are predictive of future hypertension and whether they reflect real life situations. Clinical studies of the relationship between stress and hypertension and, in particular, specific causes of stress such as anxiety and hostility are considered. It is concluded that there is no satisfactory evidence that psychosocial stress leads to the elevation of the mean daily blood pressure with its pathogenic connotations.

Is type A behaviour a cause of coronary heart disease?

If claims that stress from work may cause coronary heart disease are true, then the medicolegal implications are serious. These claims may be derived from suggestions in the literature that factors in the environment can induce type A behaviour in individuals and thus increase an individual's risk of coronary heart disease. Type A behaviour has been described as the behaviour of an individual who is constantly struggling to reach poorly defined goals, in the shortest time possible, and with the added elements of hostility and aggression. Two major prospective, non-randomized studies which support this concept are examined and criticized. Another, the largest and most recent study that was both prospective and randomized (the Multiple Risk Factor Intervention Trial), did not confirm the results of studies which showed a higher incidence of myocardial infarction, recurrent infarction and mortality in patients with type A behaviour when compared with patients with type B behaviour. Methods of defining behavioural types are not consistent and there is no relationship between behavioural patterns, as defined by "type", and the extent of coronary disease as defined by coronary angiography. Pathophysiological pathways that have been postulated between type A behaviour and coronary heart disease are discussed and it is concluded that there is no scientific proof of a link that has been established between them. Recent suggestions of other psychosocial causes of coronary heart disease include outwardly directed hostility and inwardly directed anger. A genetic determinant has also been suggested, wherein both type A behaviour and coronary heart disease have a common but parallel course. The inability to prove that type A behaviour causes coronary heart disease does not rule out the possibility that other psychosocial causes may be related to coronary artery disease.