NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis.

Background: Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients, highlighting sex differences. Methods: We included 38 IBM patients and 22 age- and sex-matched controls without myopathy. Bulk RNA sequencing, Meso Scale Discovery ELISA, western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants. Results: We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated. On muscle histopathology, there is increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction-NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy, most significantly in males, with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction. NLRP3 RNA levels correlated with p-S65-Ubiquitin levels in both sexes but with loss of in muscle strength only in males. Finally, we identified sex-specific molecular pathways in IBM, with females having activation of pathways that could offset some of the pathomechanisms of IBM. Conclusions: NLRP3 inflammasome is activated in IBM, along with altered mitophagy particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice.

Alzheimer's disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aß and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aß and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.

Enhanced Degradation of Rhodamine B by Metallic Organic Frameworks Based on NH2-MIL-125(Ti) under Visible Light.

Samples of the bimetallic-based NH2-MIL-125(Ti) at a ratio of Mn+/Ti4+ is 0.15 (Mn+: Ni2+, Co2+ and Fe3+) were first synthesized using the solvothermal method. Their fundamental properties were analyzed by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Raman spectra, scanning electron microscopy (SEM), N2 adsorption-desorption measurements, and UV-Vis diffuse reflectance spectroscopy (UV-Vis DRS). The as-acquired materials were used as high-efficiency heterogeneous photocatalysts to remove Rhodamine B (RhB) dye under visible light. The results verified that 82.4% of the RhB (3 × 10-5 M) was degraded within 120 min by 15% Fe/Ti-MOFs. Furthermore, in the purpose of degrading Rhodamine B (RhB), the rate constant for the 15% Fe/Ti-MOFs was found to be 2.6 times as fast as that of NH2-MIL-125(Ti). Moreover, the 15% Fe/Ti-MOFs photocatalysts remained stable after three consecutive cycles. The trapping test demonstrated that the major active species in the degradation of the RhB process were hydroxyl radicals (HO∙) and holes (h+).

Advances in developing therapeutic strategies for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive deterioration of brain function, initially characterized by cognitive deficits, with loss of recent memory and language ability, impairment of orientation, problem solving, and abstract thinking. While existing drug treatments help reduce the symptoms of AD and improve people's quality of life, they neither slow its progression nor cure it. Currently, targeted drug delivery to the central nervous system (CNS), for therapy of AD, is confined by the challenges posed by blood-brain interfaces surrounding the CNS, limiting the bioavailability of therapeutics. Among new strategies to overcome these limitations and successfully deliver drugs to the CNS, nanoparticles (NPs) are able to overcome these limitations, offering new therapeutic designations in term of driving drugs to cross the BBB and enter the brain more effectively. The current article aimed to summary and highlight advances in recent research on the development of nanotechnology-based therapeutics for their implications in therapy of AD.

Facilitators and barriers to a family empowerment strategy to improve healthcare worker hand hygiene in a resource-limited setting.

OBJECTIVES: The World Health Organization recommends empowering patients/families to remind healthcare workers (HCWs) to perform hand hygiene (HH). We sought to understand acceptability of a family empowerment strategy in a Vietnamese pediatric intensive care unit (PICU). METHODS: With end-user input, we designed a tool to help families in a PICU in Vietnam to remind HCWs to perform HH. We conducted 3 preliminary focus group discussions (FGDs) with patients' family members (n = 8), physicians (n = 9), and nurses (n = 8) to understand acceptability of preliminary tools, attitudes towards HH and barriers to HH. Tools were then modified and implemented in a 5-week intervention study. We then conducted 3 more FGDs with families (n = 7), physicians (n = 7), and nurses (n = 8). Discussions were analyzed using qualitative directed content analysis. Families who used the tool were asked to complete written surveys. FINDINGS: Both family members and HCWs felt that HCWs had a responsibility to perform HH. Barriers to performing HH were identified, including forgetfulness and time constraints. Family members felt shy reminding HCWs to perform HH. However, the HH reminder tool was acceptable, and some felt it could overcome barriers to reminding HCWs to perform HH. HCWs felt embarrassed when reminded to perform HH, but felt that the reminder was useful. Nearly all (99%) survey respondents felt that family members should speak up if they noticed HCWs omitting HH. CONCLUSIONS: A tool given to families to remind HCWs to perform HH was largely acceptable in a pediatric ICU in Vietnam. Perceived benefits of improving HH were felt to surmount barriers to tool use.

Role of Body-Fluid Biomarkers in Alzheimer's Disease Diagnosis.

Alzheimer's disease (AD) is a complex neurodegenerative disease that requires extremely specific biomarkers for its diagnosis. For current diagnostics capable of identifying AD, the development and validation of early stage biomarkers is a top research priority. Body-fluid biomarkers might closely reflect synaptic dysfunction in the brain and, thereby, could contribute to improving diagnostic accuracy and monitoring disease progression, and serve as markers for assessing the response to disease-modifying therapies at early onset. Here, we highlight current advances in the research on the capabilities of body-fluid biomarkers and their role in AD pathology. Then, we describe and discuss current applications of the potential biomarkers in clinical diagnostics in AD.

Type 3 Diabetes and Its Role Implications in Alzheimer's Disease.

The exact connection between Alzheimer's disease (AD) and type 2 diabetes is still in debate. However, poorly controlled blood sugar may increase the risk of developing Alzheimer's. This relationship is so strong that some have called Alzheimer's "diabetes of the brain" or "type 3 diabetes (T3D)". Given more recent studies continue to indicate evidence linking T3D with AD, this review aims to demonstrate the relationship between T3D and AD based on the fact that both the processing of amyloid-ß (Aß) precursor protein toxicity and the clearance of Aß are attributed to impaired insulin signaling, and that insulin resistance mediates the dysregulation of bioenergetics and progress to AD. Furthermore, insulin-related therapeutic strategies are suggested to succeed in the development of therapies for AD by slowing down their progressive nature or even halting their future complications.

A family empowerment strategy is associated with increased healthcare worker hand hygiene in a resource-limited setting.

BACKGROUND: Guidelines recommend empowering patients and families to remind healthcare workers (HCWs) to perform hand hygiene (HH). The effectiveness of empowerment tools for patients and their families in Southeast Asia is unknown. METHODS: We performed a prospective study in a pediatric intensive care unit (PICU) of a Vietnamese pediatric referral hospital. With family and HCW input, we developed a visual tool for families to prompt HCW HH. We used direct observation to collect baseline HH data. We then enrolled families to receive the visual tool and education on its use while continuing prospective collection of HH data. Multivariable logistic regression was used to identify independent predictors of HH in baseline and implementation periods. RESULTS: In total, 2,014 baseline and 2,498 implementation-period HH opportunities were observed. During the implementation period, 73 families were enrolled. Overall, HCW HH was 46% preimplementation, which increased to 73% in the implementation period (P < .001). The lowest HH adherence in both periods occurred after HCW contact with patient surroundings: 16% at baseline increased to 24% after implementation. In multivariable analyses, the odds of HCW HH during the implementation period were significantly higher than baseline (adjusted odds ratio [aOR], 2.94; 95% confidence interval [CI], 2.54-3.41; P < .001) after adjusting for observation room, HCW type, time of observation (weekday business hours vs evening or weekend), and HH moment. CONCLUSIONS: The introduction of a visual empowerment tool was associated with significant improvement in HH adherence among HCWs in a Vietnamese PICU. Future research should explore acceptability and barriers to use of similar tools in low- and middle-income settings.

A novel multiplex PCR method for the detection of virulence-associated genes of Escherichia coli O157:H7 in food.

Shiga toxin-producing Escherichia coli O157:H7 (E. coli O157:H7) strains are foodborne infectious agents that cause a number of life-threatening diseases, including hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). Shiga toxin 1 (stx1), shiga toxin 2 (stx2), or a combination of both are responsible for most clinical symptoms of these diseases. Hence, various diagnostic methods have been developed so far to detect shiga toxins such as cell culture, ELISA, Rapid Latex Agglutination (RPLA) and hybridization, but due to high costs and labor time in addition to low sensitivity, they have not received much attention. The aim of this study was to develop a complete, rapid and reliable multiplex PCR (mPCR) method by using two pairs of specific primers to detect either the stx1 or the stx2 gene confirms the presence of E.coli O157:H7. The study results show that stx1F/stx1R primers are specific for stx1 and primers stx2F/stx2R are specific for stx2 genes in E. coli O157:H7. The mPCR method with two pairs of primers for amplifying the stx1, stx2 target genes to detect E. coli O157:H7 in food has been set up successfully. Complete method performed well in both types of food matrices with a detection limit of 3 CFU/25 g or mL of food samples. Tests on 180 food samples have shown a specificity value of 93.75 % (95 % confidence interval [CI], 82.83-100), a sensitivity of 100 % (95 % CI, 83.79-99.85 %), and an accuracy of 96.66 % (CI 95 %, 83.41-99.91 %). Interestingly, results indicate that the mPCR performed as well as the traditional culture methods and can reduce the diagnosis time to 2 days. Finally, complete mPCR method was applied to natural samples covering a wide variety of food types proving that the mPCR method was a rapid and reliable screening method for detection of E. coli O157:H7 in food and environmental samples.