Raphe-striatal serotonergic system in the AS/AGU mutant rat

The AS/AGU rat is a spontaneous recessive mutation which arose in a closed colony of Albino Swiss (AS) rats. It is characterised by disordered locomotion including a wide gait, whole body tremor and frequent falling over in continuous locomotion. It has been demonstrated that there is a substantial dysfunction of the nigro-striatal dopaminergic system which begins with a marked reduction in dopamine release in the striatum, followed by a reduction in whole tissue dopamine levels and, finally, a loss of dopaminergic cells. The mutation has recently been shown to be a stop codon in the gene responsible for the activity of protein kinase C (PKC)-gamma. Although few specific functions are known for this particular isoform (and those that are appear to cover widely disparate types of CNS activity), the PKC family in general has a role in transmitter packaging and release, as well as in ion channel modulation and receptor sensitivity. It is very likely, therefore, that the mutation will affect other transmitter systems in addition to the dopaminergic system already investigated. Furthermore, all human neurodegenerative conditions which combine disordered locomotion with basal ganglia and aminergic dysfunction have shown evidence of effects on several transmitter systems. This study was undertaken, therefore, to look at the integrity and functioning of the raphe-striatal serotonergic system in the mutant, using the parent strain as a control. This is an exciting model, since any differences found must stem directly or indirectly from a single point mutation. Initial experiments were carried out to verify a) the nature of the mutation and b) the connectivity of the dorsal and median raphe nuclei to the striatum in these strains. Immunocytochemical investigations of the AS wild-type showed positive staining for PKC-gamma in many parts of the brain, including cerebral and cerebellar cortices, striatum, substantia nigra and raphe regions; no staining could be found in the AS/AGU mutant. This confirms the identification of the gene mutation. Injections of the tracer cholera toxin-B were made into the dorsal caudate-putamen (a region of the basal ganglia found to be particularly affected in previous work on the dopaminergic system). Cells of the dorsal raphe nucleus (but not the median raphe nucleus) were found to be retrogradely labelled. Labelling occurred throughout the dorsal raphe nucleus, with peak cell numbers occurring in the centre of the rostral-caudal distribution of the nucleus. Approximately a third of the cell bodies were positively stained for CB-T. This confirms that the dorsal caudate putamen receives a strong afferent input from the dorsal raphe nucleus, but that the median raphe does not project to the striatum. (Abstract shortened by ProQuest.)

Hepatoprotective Role of α-Lipoic acid and Thymoquinone in Acetaminophen- Induced Liver Injury: Down-Regulation of COX-2 and flt-1 Expression

ABSTRACT Acetaminophen (APAP) is a widely-used analgesic, while toxic doses of which induce liver injury. Inducible cyclooxygenase-2 (COX-2) is derived prostaglandins which play an anti-inflammatory role in acetaminophen-induced hepatotoxicity. Selective activation of vascular endothelial growth factor (VEGFR1, flt -1) on endothelial cells increased mRNA levels of hepatocyte mitogens (IL-6) and hepatocyte growth factor leading to prosurvival effects on hepatocytes. The aim of this study was to compare the hepatoprotective effect of N-acetylcysteine (NAC; the antidote for APAP) with that of α-Lipoic acid (ALA) and/or Thymoquinone (THQ) either alone or in combination on liver injury induced by APAP. APAP administration elevated most of the previously measured parameters and decreased GSH, SOD, and total protein levels compared with the control group. Liver sections of H&E demonstrate liver injury characterized by centrilobular hepatocellular necrosis, COX-2, and flt-1 expressions were also increased. Treatment with all fore mentioned antioxidants ameliorated most of the altered parameters compared to APAP-treated group. Treatment with the combination of ALA and THQ was the most effective therapy in the attenuation of liver injury assessed by a decrease in ALT and ALP activities and down-regulation of COX-2 and flt-1 expression. Section of liver from rat received APAP, ALA and THQ shows a marked improvement of hepatic degeneration which restricted to few hepatocytes with mild vacuolation of their cytoplasm while the nuclei appear normal mimic to control cells. It was concluded that the natural antioxidants such as ALA and THQ, may be considered as a potential antidote in combating liver injury induced by APAP

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population