No Evidence of Sensory Neuropathy in a Traditional Mouse Model of Idiopathic Parkinson's Disease.

Parkinson's disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems are affected can contribute to the development of targeted therapies and deepen our understanding of the pathophysiology of PD. Although the cause of sporadic PD is unknown, chronic exposure to the pesticide rotenone in humans increases the risk of developing the disease. Here, we aimed to investigate whether peripheral neuropathy is present in a traditional model of PD. Mice receiving intrastriatal rotenone showed greatly reduced dopamine terminals in the striatum and a reduction in tyrosine hydroxylase-positive neurons in the Substantia nigra pars compacta and developed progressive motor impairments in hindlimb stepping and rotarod but no change in spontaneous activity. Interestingly, repeated testing using gold-standard protocols showed no change in gut motility, a well-known non-motor symptom of PD. Importantly, we did not observe any change in heat, cold, or touch sensitivity, again based upon repeated testing with well-validated protocols that were statistically well powered. Therefore, this traditional model fails to replicate PD, and our data again reiterate the importance of the periphery to the disorder.

Preclinical trials in Alzheimer's disease: Sample size and effect size for behavioural and neuropathological outcomes in 5xFAD mice.

5xFAD transgenic (TG) mice are used widely in AD preclinical trials; however, data on sample sizes are largely unaddressed. We therefore performed estimates of sample sizes and effect sizes for typical behavioural and neuropathological outcome measures in TG 5xFAD mice, based upon data from single-sex (female) groups. Group-size estimates to detect normalisation of TG body weight to WT littermate levels at 5.5m of age were N = 9-15 depending upon algorithm. However, by 1 year of age, group sizes were small (N = 1 -<6), likely reflecting the large difference between genotypes at this age. To detect normalisation of TG open-field hyperactivity to WT levels at 13-14m, group sizes were also small (N = 6-8). Cued learning in the Morris water maze (MWM) was normal in Young TG mice (5m of age). Mild deficits were noted during MWM spatial learning and memory. MWM reversal learning and memory revealed greater impairment, and groups of up to 22 TG mice were estimated to detect normalisation to WT performance. In contrast, Aged TG mice (tested between 13 and 14m) failed to complete the visual learning (non-spatial) phase of MWM learning, likely due to a failure to recognise the platform as an escape. Estimates of group size to detect normalisation of this severe impairment were small (N = 6-9, depending upon algorithm). Other cognitive tests including spontaneous and forced alternation and novel-object recognition either failed to reveal deficits in TG mice or deficits were negligible. For neuropathological outcomes, plaque load, astrocytosis and microgliosis in frontal cortex and hippocampus were quantified in TG mice aged 2m, 4m and 6m. Sample-size estimates were ≤9 to detect the equivalent of a reduction in plaque load to the level of 2m-old TG mice or the equivalent of normalisation of neuroinflammation outcomes. However, for a smaller effect size of 30%, larger groups of up to 21 mice were estimated. In light of published guidelines on preclinical trial design, these data may be used to provide provisional sample sizes and optimise preclinical trials in 5xFAD TG mice.

Outcomes of Conservative Management of Acute Appendicitis during COVID-19 Pandemic.

OBJECTIVE: To measure the outcomes of conservative treatment of acute appendicitis. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Fauji Foundation Hospital, Rawalpindi from April to July 2020. METHODOLOGY: All 58 patients (n=58) presenting with acute appendicitis (AA) were included. Assessment was done with Alvarado score (AS) and ultrasound. Treatment was initiated according to the algorithm corresponding with AS. Those with AS score of 4 or less were started on outpatient oral antibiotics. Patients with AS score of 5 or more were admitted for IV antibiotics. If the symptoms and signs resolved, they were sent home on oral antibiotics to complete a course of 5 days. If their condition did not improve in 72 hours or deteriorated at any time, appendectomy was done. Outcomes were recorded and analysed on SPSS. RESULTS: Out of 58 patients, 16 were treated with oral, while 42 with IV antibiotics. This yielded a statistically significant difference on the course of disease (p=0.028). Resolution of symptoms was seen in 27.6% (n=16) with conservative management; whereas, 72.4% (n=42) patients needed a subsequent appendectomy. The difference in operative findings between patients, who had been given oral or IV antibiotics was statistically insignificant (p=0.536). Diagnostic value of leukocyte count (TLC), ultrasound and AS was not found to be significant. CONCLUSION: Non-operative management is successful in about a quarter of the patients of AA. There is very limited value of sonography, laboratory parameters, or AS in confirming the diagnosis of AA. Key Words: Appendicitis, Conservative treatmen, COVID-19.

Outcomes of Conservative Management of Acute Appendicitis during COVID-19 Pandemic.

OBJECTIVE: To measure the outcomes of conservative treatment of acute appendicitis. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Fauji Foundation Hospital, Rawalpindi from April to July 2020.  Methodology: All 58 patients (n=58) presenting with acute appendicitis (AA) were included. Assessment was done with Alvarado score (AS) and ultrasound. Treatment was initiated according to the algorithm corresponding with AS. Those with AS score of 4 or less were started on outpatient oral antibiotics. Patients with AS score of 5 or more were admitted for IV antibiotics. If the symptoms and signs resolved, they were sent home on oral antibiotics to complete a course of 5 days. If their condition did not improve in 72 hours or deteriorated at any time, appendectomy was done. Outcomes were recorded and analysed on SPSS. RESULTS: Out of 58 patients, 16 were treated with oral, while 42 with IV antibiotics. This yielded a statistically significant difference on the course of disease (p=0.028). Resolution of symptoms was seen in 27.6% (n=16) with conservative management; whereas, 72.4% (n=42) patients needed a subsequent appendectomy. The difference in operative findings between patients, who had been given oral or IV antibiotics was statistically insignificant (p=0.536). Diagnostic value of leukocyte count (TLC), ultrasound and AS was not found to be significant. CONCLUSION: Non-operative management is successful in about a quarter of the patients of AA. There is very limited value of sonography, laboratory parameters, or AS in confirming the diagnosis of AA. Key Words: Appendicitis, Conservative treatmen, COVID-19.