The use of oral sedatives in dental care

Oral administration of tranquillizing and anxiety-suppressing drugs has long been the commonest method of achieving light sedation. The benzodiazepines are the drugs of first choice. Benzodiazepines given orally may be indicated to avoid 'treatment stress', alleviate mild anxiety before dental treatment, and facilitate sleep on the night before the treatment. Furthermore, they could be used for the dental treatment of medically poor risk patients, particularly those with cardiovascular disease. The drug can be given either in a fractionated dose or a single dose. The recommended doses for diazepam vary from 0.1–0.8 mg/kg body weight, depending on age, with higher doses in children and lower doses in elderly patients. Few side effects are reported.     

The program for phenotyping of genetically modified animals at AstraZeneca

Genetically modified mice offer a wide range of possibilities in preclinical drug discovery, e.g. for use in target identification, target validation and disease model generation. However, genomic modification and alteration in gene expression may cause unpredicted phenotypic alterations in the organism other than the intended ones. The aim of this study was to determine the importance of establishing the phenotype of transgenic and knockout mice models for use in pharmaceutical research.

A total number of 51 mouse models (transgenic and knockout) produced at AstraZeneca during a 4 year period were subjected to a thorough phenotyping package covering clinical as well as morphological aspects. Phenotype abnormalities were recorded in 36 (70.6%) of the mouse models. The majority of findings were considered to be minor in magnitude. Histopathological changes related to the genotype of the animals were observed in 33% of the mouse models, underlining the importance of pathology in the phenotyping program.     

Neutralization assay using a modified vaccinia virus Ankara vector expressing the green fluorescent protein is a high-throughput method to monitor the humoral immune response against vaccinia virus

Vaccination against smallpox is again considered in order to face a possible bioterrorist threat, but the nature and the level of the immune response needed to protect a person from smallpox after vaccination are not totally understood. Therefore, simple, rapid, and accurate assays to evaluate the immune response to vaccinia virus need to be developed. Neutralization assays are usually considered good predictors of vaccine efficacy and more informative with regard to protection than binding assays. Currently, the presence of neutralizing antibodies to vaccinia virus is measured using a plaque reduction neutralization test, but this method is time-consuming and labor-intensive and has a subjective readout. Here, we describe an innovative neutralization assay based on a modified vaccinia virus Ankara (MVA) vector expressing the green fluorescent protein (MVA-gfp). This MVA-gfp neutralization assay is rapid and sensitive and has a high-throughput potential. Thus, it is suitable to monitor the immune response and eventually the efficacy of a large campaign of vaccination against smallpox and to study the vector-specific immune response in clinical trials that use genetically engineered vaccinia viruses. Most importantly, application of the highly attenuated MVA eliminates the safety concern in using the replication-competent vaccinia virus in the standard clinical laboratory.     

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

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CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin

Background  

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is associated with local activation of microglia and astroglia, infiltration of activated macrophages and T cells, active degradation of myelin and damage to axons and neurons. The proposed role for CX₃CL1 (fractalkine) in the control of microglia activation and leukocyte infiltration places this chemokine and its receptor CX₃CR1 in a potentially strategic position to control key aspects in the pathological events that are associated with development of brain lesions in MS. In this study, we examine this hypothesis by analyzing the distribution, kinetics, regulation and cellular origin of CX₃CL1 and CX₃CR1 mRNA expression in the CNS of rats with an experimentally induced MS-like disease, myelin oligodendrocyte glycoprotein (MOG)-induced autoimmune encephalomyelitis (EAE).     

Temporal expression and cellular origin of CC chemokine receptors CCR1, CCR2 and CCR5 in the central nervous system: insight into mechanisms of MOG-induced EAE

Background  

The CC chemokine receptors CCR1, CCR2 and CCR5 are critical for the recruitment of mononuclear phagocytes to the central nervous system (CNS) in multiple sclerosis (MS) and other neuroinflammatory diseases. Mononuclear phagocytes are effector cells capable of phagocytosing myelin and damaging axons. In this study, we characterize the regional, temporal and cellular expression of CCR1, CCR2 and CCR5 mRNA in the spinal cord of rats with myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE). While resembling human MS, this animal model allows unique access to CNS-tissue from various time-points of relapsing neuroinflammation and from various lesional stages: early active, late active, and inactive completely demyelinated lesions.     

The effect of microglia on embryonic dopaminergic neuronal survival in vitro: diffusible signals from neurons and glia change microglia from neurotoxic to neuroprotective

When embryonic dopaminergic neurons are transplanted into the adult brain, approximately 95% die within a few days. To assess whether microglia activated during transplantation might be responsible for this rapid death, we examined the effect of microglia on rat embryonic dopaminergic neurons in vitro. Conditioned medium from 7-day-old microglia was found to decrease the number of dopamine neurons surviving in primary culture, but activation of the microglia with N-formyl-methionyl-leucyl-phenylalanine (FMLP) or Zymosan A did not increase the toxicity of the conditioned medium. We next tested the effect of coculturing microglia and dopaminergic neurons by placing microglia in semipermeable well inserts over the neuronal cultures. The presence of microglia now increased dopaminergic neuronal survival, microglial activation again having no effect. To increase yet further the possible interactions between microglia and neurons, the mesencephalic cells and microglia were mixed together and placed as a tissue in three-dimensional culture, and here again the presence of microglia increased dopaminergic neuronal survival with no effect of activation. Contact of microglia with the mesencephalic cells therefore converted them from being toxic to dopaminergic neurons to promoting their survival. The change in microglial effect from toxic to protective was caused by soluble molecules secreted by cells in the neuronal cultures, as conditioned medium derived from microglia-neuronal cocultures also had a dopaminergic neuron survival effect, indicating that microglia in cocultures behave differently from microglia removed from neuronal and glial influence. Microglia cocultured with either neurons or astrocytes downregulated inducible nitric oxide synthase (iNOS), indicating a decrease in the production of nitric oxide and possibly other toxic molecules. These findings indicate that in their natural environment, microglia are likely to be beneficial for the survival of embryonic dopaminergic grafts.     

Outcome after major renovascular injuries: a Western trauma association multicenter report

BACKGROUND: Major renal vascular injuries are uncommon and are frequently associated with a poor outcome. In addition to renal dysfunction, posttraumatic renovascular hypertension may result, although the true incidence of this complication is unknown. The objective of this study was to describe the factors contributing to outcome after major renovascular trauma. We hypothesized that the highest percentage of renal salvage would be achieved by minimizing the time from injury to repair. METHODS: This was a retrospective chart review over a 16-year period conducted at six university trauma centers of patients with American Association for the Surgery of Trauma grade IV/V renal injuries surviving longer than 24 hours. Postinjury renal function with poor outcome was defined as renal failure requiring dialysis, serum creatinine greater than or equal to 2 mg/dL, renal scan showing less than 25% function of the injured kidney, postinjury hypertension requiring treatment, or delayed nephrectomy. Data collected for analysis included demographics, mechanism of injury, presence of shock, presence of hematuria, associated injuries, type of renal injury (major artery, renal vein, segmental artery), type of repair (primary vascular repair, revascularization, observation, nephrectomy), time from injury to definitive renal surgery, and type of surgeon performing the operation (urologist, vascular surgeon, trauma surgeon). RESULTS: Eighty-nine patients met inclusion criteria; 49% were injured from blunt mechanisms. Patients with blunt injuries were 2.29 times more likely to have a poor outcome compared with those with penetrating injuries. Similarly, the odds ratio of having a poor outcome with a grade V injury (n = 32) versus grade IV (n = 57) was 2.2 (p = 0.085). Arterial repairs had significantly worse outcomes than vein repairs (p = 0.005). Neither the time to definitive surgery nor the operating surgeon's specialty significantly affected outcome. Ten percent (nine patients) developed hypertension or renal failure postoperatively: three had immediate nephrectomies, four had arterial repairs with one intraoperative failure requiring nephrectomy, and two were observed. Of the 20 good outcomes for grade V injuries, 15 had immediate nephrectomy, 1 had a renal artery repair, 1 had a bypass graft, 1 underwent a partial nephrectomy, and 2 were observed. CONCLUSION: Factors associated with a poor outcome following renovascular injuries include blunt trauma, the presence of a grade V injury, and an attempted arterial repair. Patients with blunt major vascular injuries (grade V) are likely to have associated major parenchymal disruption, which contributes to the poor function of the revascularized kidney. These patients may be best served by immediate nephrectomy, provided that there is a functioning contralateral kidney.     

Guardianship: A medicolegal review for clinicians

Guardianship may pose an ethical dilemma for physicians, who must balance protecting vulnerable patients from potential safety concerns with respecting their autonomy. Older adults with dementia are particularly susceptible to loss of independence and the ability to participate in medical decision making. To have the capacity for medical decision making, individuals must understand relevant information, appreciate their circumstances, demonstrate reasoning, and express a consistent choice free from coercion. Although capacity assessments are usually task-specific, geriatricians and other specialists may be asked to comment on capacity more globally. These determinations may be used to support a Petition for the Appointment of a Guardian of a Legally Incapacitated Adult, the legal process of pursuing guardianship in probate court. Assigned guardians may be known to the incapacitated individual (e.g., a family member or friend) or may be professional guardians with no prior relationship to the ward. Guardians are encouraged to use substituted decision-making, taking into account the ward's previously expressed values and preferences. Although a number of viable alternatives to guardianship exist, numerous systemic barriers may prevent these from being fully explored. The ongoing need for guardianship should be periodically revisited and reassessed. Data about guardians and wards is shockingly sparse, as there are no centralized databases. Laws and regulations for guardianships vary significantly between states. Physicians can serve as important allies and advocates for patients with cognitive impairment at risk of incapacity, can help preserve their autonomy for as long as possible, and ensure appropriate protections are in place if the patient does lose their decision-making ability.