A combination Alzheimer’s therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice

BACKGROUND: Accumulating evidence indicates that partial inhibition of β-site APP-cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, mitigates Alzheimer’s disease (AD)-like pathologies and memory deficits in a battery of transgenic mouse models. However, our previous investigations suggest that therapeutic BACE1 suppression may be beneficial only if targeted on earlier stages of AD and encounter dramatic reductions in efficacy during disease progression. This study was designed to test the possibility that a combination approach, aimed at inhibiting BACE1 and boosting neprilysin (a major Aβ-degrading enzyme) activities, may be able to mechanistically overcome the limited efficacy of anti-Aβ therapy in advanced AD. RESULTS: After crossbreeding between BACE1 heterozygous knockout (BACE1(+/−)), neprilysin transgenic (NEP) and 5XFAD mice, we analyzed the resultant mice at 12 months of age when 5XFAD controls showed robust amyloid-β (Aβ) accumulation and elevation of BACE1 expression (~2 folds). Although haploinsufficiency lowered BACE1 expression by ~50% in concordance with reduction in gene copy number, profound β-amyloidosis, memory deficits and cholinergic neuron death were no longer rescued in BACE1(+/−) · 5XFAD mice concomitant with their persistently upregulated BACE1 (i.e., equivalent to wild-type control levels). Notably, neprilysin overexpression not only prevented Aβ accumulation but also suppressed the translation initiation factor eIF2α-associated elevation of BACE1 and lowered levels of the β-secretase-cleaved C-terminal fragment of APP (C99) in NEP · 5XFAD mice. Interestingly, these markers for β-amyloidogenesis in BACE1(+/−) · NEP · 5XFAD mice were further reduced to the levels reflecting a combination of single BACE1 allele ablation and the abolishment of translational BACE1 upregulation. However, since neprilysin overexpression was striking (~8-fold relative to wild-type controls), memory impairments, cholinergic neuronal loss and β-amyloidosis were similarly prevented in NEP · 5XFAD and BACE1(+/−) · NEP · 5XFAD mice. CONCLUSIONS: Our findings indicate that robust overexpression of neprilysin is sufficient to ameliorate AD-like phenotypes in aged 5XFAD mice. We also found that Aβ-degrading effects of overexpressed neprilysin can block deleterious BACE1-elevating mechanisms that accelerate Aβ production, warranting further study to test whether interventions moderately activating neprilysin may be useful for boosting the limited efficacy of therapeutic BACE1 inhibition in treating AD with established Aβ pathology

COMPARATIVE STUDY OF PERCENTAGE PURITY AND COST OF SOME GENERIC AND BRANDED MARKETED TABLETS OF DIFFERENT CLASSES M.Gayathri Devi*, M.Savitri, P.Uma Devi, P.V.Madhavi Latha, B. Nagamani, G.Anand Rao, R.Triveni, Y.Krishnaveni

The present work describes about the comparative study of percentage purity and cost of some generic and branded marketed tablets of different categories like Anti-diabetic , Diuretic, Anti-pyretic and Vitamin B formulations. Branded formulations are at high cost, so that the poor can’t afford them. Therapeutic efficacy of Generics is almost identical to that of branded drugs. But one of the major differences is Generics are 80% cheaper on average when compared to branded drugs. In fact FDA estimates that 50% of generic drug production is by brand-name companies. So the consumption of generic and branded medicines depends on this un-popularized fact. Therefore the generic drugs of various pharmaceutical companies are sold at low cost .The present study is about comparison of Percentage purity and cost of the different generics and branded formulations. Our experimental results of generic and branded tablets were compared by statistical analysis which gave an important conclusion that the percentage purity of both generic and branded drugs are similar whereas the cost of branded drugs is more. Key Words: Branded drugs, Generic drugs, Percentage purity, T-value

Sex- and brain region-specific acceleration of β-amyloidogenesis following behavioral stress in a mouse model of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>It is hypothesized that complex interactions between multiple environmental factors and genetic factors are implicated in sporadic Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. Importantly, recent evidence reveals that expression and activity levels of the β-site APP cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, are elevated in AD brains. In this study, we investigated a molecular mechanism by which sex and stress interactions may accelerate β-amyloidogenesis and contribute to sporadic AD.</p> <p>Results</p> <p>We applied 5-day restraint stress (6 h/day) to the male and female 5XFAD transgenic mouse model of AD at the pre-pathological stage of disease, which showed little amyloid deposition under non-stressed control conditions. Exposure to the relatively brief behavioral stress increased levels of neurotoxic Aβ42 peptides, the β-secretase-cleaved C-terminal fragment (C99) and plaque burden in the hippocampus of female 5XFAD mice but not in that of male 5XFAD mice. In contrast, significant changes in the parameters of β-amyloidosis were not observed in the cerebral cortex of stressed male or female 5XFAD mice. We found that this sex- and brain region-specific acceleration of β-amyloidosis was accounted for by elevations in BACE1 and APP levels in response to adverse stress. Furthermore, not only BACE1 mRNA but also phosphorylation of the translation initiation factor eIF2α (a proposed mediator of the post-transcriptional upregulation of BACE1) was elevated in the hippocampus of stressed female 5XFAD mice.</p> <p>Conclusions</p> <p>Our results suggest that the higher prevalence of sporadic AD in women may be attributable to the vulnerability of female brains (especially, the hippocampus) to stressful events, which alter APP processing to favor the β-amyloidogenesis through the transcriptional and translational upregulation of BACE1 combined with elevations in its substrate APP.</p

ANTICANCER AND FREE RADICAL SCAVENGING POTENTIAL OF THE MARINE ALGICOLOUS ENDOPHYTIC FUNGUS CLADOSPORIUM UREDINICOLA

Objective: The objective was to study the antioxidant and anticancer potential of the endophytic fungus Cladosporium uredinicola, isolated from the marine brown alga Dictyota dichotoma. Methods: Anticancer effect of the endophytic fungal extract was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay using MDA-MB-231 human mammary adenocarcinoma cells as in vitro cancer models. 3T3-L1 pancreatic adipocytes were used as in vitro models for the evaluation of cytotoxic activity against normal cells using MTT assay. Free radical scavenging activity was assessed by 2, 2-diphenyl-1- picrylhydrazyl (DPPH) assay. Results: The ethyl acetate extract of the endophytic fungus showed potent cytotoxic activity against MDA-MB-231 human breast adenocarcinoma cell lines with an inhibitory concentration (IC50) value of 373 μg/ml and a very mild cytotoxic effect on 3T3-L1 Cells with an IC50 value of 2403 μg/ml. DPPH free radical scavenging assay of the extract showed an IC50 value of 359 μg/ml indicating its potential free radical scavenging activity. Conclusion: The results indicated that the endophytic fungus C. uredinicola, isolated from the marine brown alga D. dichotoma, acts as a potential source for anticancer and antioxidant metabolites. Moreover, these anticancer metabolites were observed to be less toxic to the normal cells, which make them prospective therapeutic agents

Consumer Preferences in Choosing OTT Provider and Satisfaction

The selection of an Over-The-Top (OTT) service provider is significantly influenced by consumer preferences, which have a substantial impact on both the initial decision-making process and the subsequent level of satisfaction. The content library is a significant determinant influencing customer decision-making. Individuals are attracted to platforms that provide a diverse selection of superior material, including well-known films, television series, and unique original creations. The presence of a wide range of genres and the accessibility of material tailored to individual preferences greatly influence the appeal of an over-the-top (OTT) service. Ease of use and accessibility are also critical considerations. Consumers prefer platforms with user-friendly interfaces, intuitive navigation, and seamless cross-device compatibility. The ability to access content across various devices, such as smart TVs, smartphones, and tablets, enhances the overall user experience and contributes to higher satisfaction. Subscription pricing and flexibility in payment models are paramount in the decision-making process. Consumers appreciate transparent pricing structures and a variety of subscription plans that cater to different budgets and preferences. Additionally, the availability of free trial periods allows users to assess the platform\u27s offerings before committing to a subscription, contributing to overall satisfaction. Customer support and responsiveness are factors that significantly impact user satisfaction over time.. Users appreciate platforms that understand their tastes and deliver content suggestions tailored to their individual preferences, creating a more enjoyable and immersive streaming experience. In summary, consumer preferences encompass content variety, ease of use, pricing models, customer support, and personalized recommendations, all of which contribute to the selection of an OTT provider and the ongoing satisfaction of users in an increasingly competitive digital streaming landscape

MRSA: the leading pathogen of orthopedic infection in a tertiary care hospital, South India

Background: The rate of infection is high and heterogeneous in developing countries. This study aimed to find the rate and pattern of infection in a tertiary care hospital with a goal to improve the infection control practices.Methods: The study was conducted in the orthopedic units of a multispecialty teaching hospital. Medical records of major orthopedic surgery adult patients without immunosuppression state were included. The bacterial culture report of the wound swabs were noted over a period of one year. The bacterial culture testing was performed by a recommended method.Results: Among 2,249 orthopedic surgery patients, 83.7% were males, 49.1% had open wounds during admission and 32.2% patients were infected. Majority (64.2%) of the injuries were in the lower limb with 19.4% patients having undergone multiple surgeries during hospitalization. A total of 946 pathogens were grown from 725 specimens. Staphylococcus aureus was the max- imum (48.4%) followed by Pseudomonas aeruginosa (26.3%) and E coli (16.7%). Among them, 57.3% were Methicillin Resistant Staphylococcus aureus (MRSA) and was the leading pathogen causing infection among orthopedic patients.Conclusion: MRSA infection was high. Consequent to this, an interventional program entitled ‘Extended Infection Control Measures' was designed to reduce the burden of infection.Keywords: MRSA, orthopedic, infection, South India

Multiple control policy in unreliable two-phase bulk queueing system with active Bernoulli feedback and vacation

In this paper, a bulk arrival and two-phase bulk service with active Bernoulli feedback, vacation, and breakdown is considered. The server provides service in two phases as mandatory according to the general bulk service rule, with minimum bulk size ' a ' and maximum bulk size ' b '. In the first essential service (FES) completion epoch, if the server fails, with probability 'delta ' , then the renewal of the service station is considered. On the other hand, if there is no server failure, with a probability ' 1 - delta ' , then the server switches to a second essential service (SES) in succession. A customer who requires further service as feedback is given priority, and they join the head of the queue with probability beta. On the contrary, a customer who does not require feedback leaves the system with a probability ' 1- beta '. If the queue length is less than ' a ' after SES, the server may leave for a single vacation with probability ' 1 - beta '. When the server finds an inadequate number of customers in the queue after vacation completion, the server becomes dormant. After vacation completion, the server requires some time to start service, which is attained by including setup time. The setup time is initiated only when the queue length is at least ' a '. Even after setup time completion, the service process begins only with a queue length 'N' (N > b). The novelty of this paper is that it introduces an essential two-phase bulk service, immediate Bernoulli feedback for customers, and renewal service time of the first essential service for the bulk arrival and bulk service queueing model. We aim to develop a model that investigates the probability-generating function of the queue size at any time. Additionally, we analyzed various performance characteristics using numerical examples to demonstrate the model's effectiveness. An optimum cost analysis was also carried out to minimize the total average cost with appropriate practical applications in existing data transmission and data processing in LTE-A networks using the DRX mechanism.Web of Science121art. no. 7

Workplace misconduct and the requirement of due inquiry: with reference to the practice in Malaysia

This paper discusses the concept of workplace misconduct and the requirement of a domestic or due inquiry to establish the alleged act and with reference to the practice in Malaysia. The issues considered herein are as follows: (a) whether the disciplinary or domestic inquiry is essential in an impending dismissal for alleged gross misconduct; and (b) whether the dismissal carried out without convening a disciplinary inquiry violates the principles of natural justice thereby rendering the dismissal unfair

MRSA: the leading pathogen of orthopedic infection in a tertiary care hospital, South India

Background: The rate of infection is high and heterogeneous in developing countries. This study aimed to find the rate and pattern of infection in a tertiary care hospital with a goal to improve the infection control practices. Methods: The study was conducted in the orthopedic units of a multispecialty teaching hospital. Medical records of major orthopedic surgery adult patients without immunosuppression state were included. The bacterial culture report of the wound swabs were noted over a period of one year. The bacterial culture testing was performed by a recommended method. Results: Among 2,249 orthopedic surgery patients, 83.7% were males, 49.1% had open wounds during admission and 32.2% patients were infected. Majority (64.2%) of the injuries were in the lower limb with 19.4% patients having undergone multiple surgeries during hospitalization. A total of 946 pathogens were grown from 725 specimens. Staphylococcus aureus was the maximum (48.4%) followed by Pseudomonas aeruginosa (26.3%) and E coli (16.7%). Among them, 57.3% were Methicillin Resistant Staphylococcus aureus (MRSA) and was the leading pathogen causing infection among orthopedic patients. Conclusion: MRSA infection was high. Consequent to this, an interventional program entitled \u2018Extended Infection Control Measures' was designed to reduce the burden of infection. DOI: https://dx.doi.org/10.4314/ahs.v19i1.12 Cite as: Latha T, Anil B, Manjunatha H, Chiranjay M, Elsa D, Baby N, et al. MRSA: the leading pathogen of orthopedic infection in a tertiary care hospital, South India. Afri Health Sci. 2019;19(1). 1393-1401. https://dx.doi.org/10.4314/ahs.v19i1.1