Tetraalkylammonium salts (TAS) in solar energy applications - A review on in vitro and in vivo toxicity.

Tetraalkylammonium salt (TAS) is an organic salt widely employed as a precursor, additive or electrolyte in solar cell applications, such as perovskite or dye-sensitized solar cells. Notably, Perovskite solar cells (PSCs) have garnered acclaim for their exceptional efficiency. However, PSCs have been associated with environmental and health concerns due to the presence of lead (Pb) content, the use of hazardous solvents, and the incorporation of TAS in their fabrication processes, which significantly contributes to environmental and human health toxicity. As a response, there is a growing trend towards transitioning to safer and biobased materials in PSC fabrication to address these concerns. However, the potential health hazards associated with TAS necessitate a thorough evaluation, considering the widespread use of this substance. Nevertheless, the overexploitation of TAS could potentially increase the disposal of TAS in the ecosystem, thus, posing a major health risk and severe pollution. Therefore, this review article presents a comprehensive discussion on the in vitro and in vivo toxicity assays of TAS as a potential material in solar energy applications, including cytotoxicity, genotoxicity, in vivo dermal, and systemic toxicity. In addition, this review emphasizes the toxicity of TAS compounds, particularly the linear tetraalkyl chain structures, and summarizes essential findings from past studies as a point of reference for the development of non-toxic and environmentally friendly TAS derivatives in future studies. The effects of the TAS alkyl chain length, polar head and hydrophobicity, cation and anion, and other properties are also included in this review.

Early-Onset Hearing Loss in Mouse Models of Alzheimer's Disease and Increased DNA Damage in the Cochlea.

There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polß+/-. The 3xTgAD/Polß+/- mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polß+/- mice than in 3xTgAD mice at 16 kHz, and distortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factor underlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex. Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner hair cells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulated in the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findings provide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damage in the cochlea might contribute to the development of early hearing loss in AD.

Prevalence and antimicrobial resistance profile of Salmonella typhi infection in Iraq, 2019-2021.

INTRODUCTION: Salmonella typhi could infect the intestinal tract and the bloodstream or invade body organs and secrete endotoxins. It is endemic in developing countries. It is increasingly evolving antimicrobial resistance to several commonly used antimicrobial agents. MATERIALS AND METHODS: A cross-sectional study was done at Iraqi Communicable Disease Control Center, where all confirmed cases of Salmonella typhi are reported, for a period 2019-2021. All demographic, epidemiological and clinical characteristics of patients, comorbidities, type of samples, distribution of S. typhi by age and gender, time distribution in each year and profile of bacterial resistance and sensitivity to antibiotics were gathered and analysed. RESULTS: Most samples were taken from blood. The mean age of cases during 2019, 2020 and 2021 was 18.7 ± 6.5, 17.7 ± 14.1 and 17.3 ± 12.8. Males constituted 56.7%, 58.5% and 39.8%, respectively. Some cases had comorbidities. Most cases had headache and fever. Some of them had nausea, diarrhoea, vomiting and epigastric pain. The age and sex were significantly associated with years of reporting. The most months of case reporting were June-July (2019 and 2021), Jan. -Feb. (2020). There was an obvious increase in S. typhi resistance to ceftriaxone (92.2%, 86.1%, 88.8%) and ampicillin (77.1%, 76.9%, 81.27%). There was a gradual increase in sensitivity to tetracycline (83.1%, 88.1%, 94%), cotrimoxazole (86.7%, 86.1%, 92.2%), ciprofloxacin (78.3%, 90.1%, 87.8%) and cefixime (77.7%, 72.3%, 72.7%). CONCLUSIONS: There was a sharp rise in resistance rates of the S. typhi in Iraq (during 2019-2021) to ceftriaxone and ampicillin, while there were highest sensitivity rates to imipenem, aztreonam and chloramphenicol. The following recommendations were made: (1) Improvement of general hygiene and food safety measures. (2) Emphasis on vaccination and surveillance of Salmonella infection. (3) Rational use of appropriate antibiotics through implementation of treatment guidelines. (5) Educate communities and travelers about the risks of S. typhi and its preventive measures.

The Development of Gout Treat-To-Target booklet.

INTRODUCTION: The treat-to-target serum uric acid approach is recommended in local and international guidelines on gout management. Instruction for initiation and dose escalation for urate lowering therapy may cause confusion to the patient. Our aim was to develop and validate Gout Treat-To- Target booklet to aid in patient education. MATERIALS AND METHODS: A content development team which consisted of three consultant rheumatologists developed the booklet. Content validation was performed by a panel of evaluators consisted of eleven physicians (four consultant rheumatologists, two clinical specialists, and five medical officers), who were involved in gout management. Face validation was performed by ten patients with gout. RESULTS: Item-Content Validity Index ranged from 0.9 to 1 with regards to relevancy, clarity, ambiguity and simplicity. Side effects of uricosuric agents were added to the draft based on an evaluator's comment. Item-Face Validity Index was 1, which indicated that all patients were in 100% agreement with all items. CONCLUSION: We developed and validated our Gout Treat-to- Target booklet. There was high agreement in I-FVI and I-CVI among physicians and patients.

Incidence, Presentation, and Natural History of Adrenal Hemorrhage: An Institutional Analysis.

INTRODUCTION: Adrenal hemorrhage (AH) can occur due to multiple etiologies with variable radiographic appearance, often indistinguishable from underlying adrenal neoplasms. There is a lack of AH literature and evidence-based guidelines. Our study aimed to understand the prevalence and etiology of AH, follow-up, and incidence of underlying neoplasm. METHODS: An institutional database was queried from January 2006 to October 2021 for patients with AH on imaging, excluding patients with known malignancies, adrenal masses, or prior adrenal surgery. Demographics, medical history, hematoma size, laterality, biochemical evaluation, intervention, and additional imaging were reviewed. RESULTS: Of 490,301 imaging reports queried, 530 (0.11%) with AH met inclusion criteria. Most imaging (n = 485, 91.5%) was performed during trauma evaluation. Two patients underwent dedicated intervention at presentation. Interval imaging was performed in 114 (21.5%) patients at a median of 2.6 (interquartile range 0.99-13.4) mo, with resolution (n = 84, 73.7%) or decreased size of AH (n = 21, 18.4%) in most patients. Only 10 patients (1.9%) saw an outpatient provider in our system to address AH or evaluate for underlying mass, and 9 (1.7%) underwent biochemical screening. Thirteen patients (11% of 118 patients with any follow-up) had evidence of an adrenal mass, confirmed on serial imaging (n = 10) or adrenalectomy (n = 3). Scans performed for nontrauma indications were significantly more likely to have an underlying mass (n = 6/26 [23.1%]) than those performed for trauma evaluation (n = 7/92 [7.6%], P = 0.04). CONCLUSIONS: AH is a rare finding associated with an increased rate of underlying adrenal mass, particularly when unrelated to trauma. Most AH resolves spontaneously without intervention. Follow-up imaging at 6 mo can help distinguish mass-associated AH from simple hemorrhage.

Reusability of Discarded Tubular Ceramic Membranes for CO2 Removal: A Case Study for Membrane Circularity.

Discarded polymeric or ceramic membranes are currently in need of appropriate and sustainable management. In the present study, the direct reuse of discarded ceramic membranes in membrane contactor (MC) systems for CO2 removal was investigated for the first time. The hydrophobic surface modification of the discarded ceramic membrane was done by using macromolecule additive coating. The influence of operational parameters (absorbent liquid flow rate (QL), feed gas flow rate (Qg), and different NaOH concentrations) of the MC on CO2 removal was investigated to prove the technical feasibility of reused ceramic membranes. The CO2 absorption flux was 7.9 × 10-4 mol/m2 s at optimal conditions of 2 M NaOH, QL (20 mL/min), and Qg (300 mL/min) with a removal efficiency of 98%, which lasted for 8 h. This study demonstrates a potential alternative for the reuse of discarded ceramic membranes and avoids their disposal in landfills. The proposed approach will also bring membrane technology into the circular economy and achieve sustainability goals by reducing the amount of waste from discarded ceramic membranes in the future and combating global warming by absorbing CO2.

Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice.

Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimer's and Parkinson's disease. It has also been beneficial against noise-induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.

Eos Promotes TH2 Differentiation by Interacting with and Propagating the Activity of STAT5.

The Ikaros zinc-finger transcription factor Eos has largely been associated with sustaining the immunosuppressive functions of regulatory T cells. Paradoxically, Eos has more recently been implicated in promoting proinflammatory responses in the dysregulated setting of autoimmunity. However, the precise role of Eos in regulating the differentiation and function of effector CD4+ T cell subsets remains unclear. In this study, we find that Eos is a positive regulator of the differentiation of murine CD4+ TH2 cells, an effector population that has been implicated in both immunity against helminthic parasites and the induction of allergic asthma. Using murine in vitro TH2 polarization and an in vivo house dust mite asthma model, we find that EosKO T cells exhibit reduced expression of key TH2 transcription factors, effector cytokines, and cytokine receptors. Mechanistically, we find that the IL-2/STAT5 axis and its downstream TH2 gene targets are one of the most significantly downregulated pathways in Eos-deficient cells. Consistent with these observations, we find that Eos forms, to our knowledge, a novel complex with and supports the tyrosine phosphorylation of STAT5. Collectively, these data define a regulatory mechanism whereby Eos propagates STAT5 activity to facilitate TH2 cell differentiation.

The CNS-penetrating taxane drug TPI 287 potentiates antiglioma activity of the AURKA inhibitor alisertib in vivo.

INTRODUCTION: Glioblastoma (GBM) has a very poor prognosis despite current treatment. We previously found cytotoxic synergy between the AURKA inhibitor alisertib and the CNS-penetrating taxane TPI 287 against GBM tumor cells in vitro. METHODS: We used an orthotopic human GBM xenograft mouse model to test if TPI 287 potentiates alisertib in vivo. Western blotting, immunohistochemistry, siRNA knockdown, annexin V binding, and 3-dimensional Matrigel invasion assays were used to investigate potential mechanisms of alisertib and TPI 287 treatment interactions. RESULTS: Alisertib + TPI 287 combination therapy significantly prolonged animal survival compared to vehicle (p = 0.011), but only marginally compared to alisertib alone. Alisertib, TPI 287, and combined alisertib + TPI 287 reduced animal tumor volume compared to vehicle-treated controls. This was statistically significant for the combination therapy at 4 weeks (p < 0.0001). Alisertib + TPI 287 treatment decreased anti-apoptotic Bcl-2 protein levels in vivo and in vitro. Expression of the pro-apoptotic protein Bak was significantly increased by combination treatment (p < 0.0001). Pro-apoptotic Bim and Bak knockdown by siRNA decreased apoptosis by alisertib + TPI 287 in GB9, GB30, and U87 cells (p = 0.0005 to 0.0381). Although alisertib and TPI 287 significantly reduced GBM cell invasion (p < 0.0001), their combination was no more effective than TPI 287 alone. CONCLUSIONS: Results suggest that apoptosis is the dominant mechanism of potentiation of GBM growth inhibition by alisertib + TPI 287, in part through effects on Bcl-2 family proteins, providing a rationale for further laboratory testing of an AURKA inhibitor plus TPI 287 as a potential therapy against GBM.

Olfactory impairment in patients with coronavirus disease 2019 self-perceived as asymptomatic.

BACKGROUND: Olfactory impairment may be present among patients with coronavirus disease 2019 self-perceived as asymptomatic. This study aimed to assess olfactory function among these individuals. METHODS: A cross-sectional study involving patients with coronavirus disease 2019 self-perceived as asymptomatic was conducted. Assessments included the subjective Malaysian Smell and Taste Questionnaire and the culturally adapted Malaysian version of the objective Sniffin' Sticks Identification smell test. RESULTS: In 81 participants (mean age of 31.59 ± 12.04 years), with mean time from diagnosis to smell test of 7.47 ± 3.79 days, subjective assessment showed that 80.2 per cent were asymptomatic (questionnaire score of 6) and 19 per cent had mild symptoms (questionnaire score of 7 and 8). The mean objective smell test score was 10.89 ± 2.11. The prevalence of olfactory impairment was 76.6 per cent among patients with coronavirus disease 2019 self-perceived as asymptomatic. There was no association between the questionnaire and the smell test scores (p = 0.25). There was a correlation between the smell test score and the duration from diagnosis to smell test (p = 0.04). CONCLUSION: The objective assessment demonstrated that coronavirus disease 2019 patients who perceived themselves as asymptomatic showed olfactory impairment.

Phase 3 Study of Subcutaneous Versus Intravenous Ravulizumab in Eculizumab-Experienced Adult Patients with PNH: Primary Analysis and 1-Year Follow-Up.

INTRODUCTION: This study compared the pharmacokinetics (PK) of the ravulizumab on-body delivery system for subcutaneous (SUBQ) administration with intravenous (IV) ravulizumab in eculizumab-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: Patients with PNH received SUBQ ravulizumab (n = 90) or IV ravulizumab (n = 46) during the 10-week randomized treatment period; all patients then received SUBQ ravulizumab during an extension period (< 172 weeks; data cutoff 1 year). Primary endpoint was day 71 serum ravulizumab trough concentration (Ctrough). Secondary endpoints were ravulizumab Ctrough and free C5 over time. Efficacy endpoints included change in lactate dehydrogenase (LDH), breakthrough hemolysis (BTH), transfusion avoidance, stabilized hemoglobin, and Treatment Administration Satisfaction Questionnaire (TASQ) score. Safety, including adverse events (AEs) and adverse device effects (ADEs), was assessed until data cutoff. RESULTS: SUBQ ravulizumab demonstrated PK non-inferiority with IV ravulizumab (day 71 SUBQ/IV geometric least-squares means ratio 1.257 [90% confidence interval 1.160-1.361; p < 0.0001]). Through 1 year of SUBQ administration, ravulizumab Ctrough values were > 175 µg/mL (PK threshold) and free C5 < 0.5 µg/mL (PD threshold). Efficacy endpoints remained stable: mean (standard deviation, SD) LDH percentage change was 0.9% (20.5%); BTH events, 5/128 patients (3.9%); 83.6% achieved transfusion avoidance; 79.7% achieved stabilized hemoglobin. Total TASQ score showed improved satisfaction with SUBQ ravulizumab compared with IV eculizumab (mean [SD] change at SUBQ day 351, - 69.3 [80.1]). The most common AEs during SUBQ treatment (excluding ADEs) were headache (14.1%), COVID-19 (14.1%), and pyrexia (10.9%); the most common ADE unrelated to a device product issue was injection site reaction (4.7%). Although many patients had ≥ 1 device issue-related ADE, full SUBQ dose administration was achieved in 99.9% of attempts. CONCLUSIONS: SUBQ ravulizumab provides an additional treatment choice for patients with PNH. Patients may switch to SUBQ ravulizumab from IV eculizumab or ravulizumab without loss of efficacy. TRIAL REGISTRATION: NCT03748823.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by the destruction of red blood cells (hemolysis) within blood vessels. In addition to hemolysis, patients with PNH are susceptible to life-threatening blood clots (thromboses). Eculizumab and ravulizumab are types of treatments for PNH, called C5 inhibitors. In the blood, these treatments bind to C5 protein and prevent the destruction of red blood cells, reducing the symptoms and complications of PNH. Both treatments are approved for use via intravenous (through the vein) administration. Ravulizumab is also approved in the USA for use via subcutaneous (under the skin) administration. This study compared subcutaneous ravulizumab with intravenous ravulizumab in patients with PNH who had previously been treated with eculizumab. During the initial treatment period of 71 days, 90 patients received subcutaneous ravulizumab and 46 received intravenous ravulizumab. Following this period, all patients received subcutaneous ravulizumab. At day 71, the amount of ravulizumab in the blood of patients taking subcutaneous ravulizumab was no less than in patients taking intravenous ravulizumab and was maintained over 1 year of treatment. Efficacy measures (how well it works) remained stable in patients taking subcutaneous ravulizumab for 1 year and side effects were comparable with those of intravenous ravulizumab. Patients reported more satisfaction with subcutaneous ravulizumab than intravenous eculizumab, as assessed by the Treatment Administration Satisfaction Questionnaire. This study showed that patients with PNH can switch from intravenous eculizumab or ravulizumab to subcutaneous ravulizumab without loss of efficacy. Subcutaneous ravulizumab provides an additional treatment choice for patients with PNH.

Waste-derived volatile fatty acid production and ammonium removal from it by ion exchange process with natural zeolite.

Volatile fatty acids (VFAs) produced during anaerobic digestion (AD) of organic waste are a promising alternative carbon source for various biological processes; however, their applications are limited due to the presence of impurities such as ammonium (NH4+). This study investigates the potential for removal of ammonium using a naturally occurring zeolite (clinoptilolite) from chicken manure (CKM) derived VFA effluent recovered from an anaerobic membrane bioreactor (MBR). Experiments were conducted for both synthetic and actual VFA (AD-VFA) solutions, and the effects of different parameters were investigated with batch and continuous studies. It was observed that the Langmuir-type isotherm provided the best fit to the equilibrium data in the isotherm investigations carried out with the AD-VFA solution. The maximum adsorption capacity (qm) was found as 15.7 mg NH4+/g clinoptilolite. The effect of some operational parameters on process performance such as pH, initial NH4+ loading and potassium ion (K+) concentration was investigated. The pH had a negligible effect on ammonium removal for a pH range of 3-7, while the removal efficiency of ammonium decreased with the increase of initial NH4+ loading and K+ concentration. At the optimum conditions determined in batch experiments, the ammonium removal from synthetic and AD-VFA solutions were compared and average ammonium removal efficiencies of 93 and 94% were found in 12 h equilibrium time for synthetic and AD-VFA solutions, respectively. Overall findings indicated that clinoptilolite has excellent potential for ion exchange when combined with biological processes such as acidogenic fermentation of VFAs to purify the solution from high-ammonium content.

Multiparametric MRI with MR elastography findings in patients with sinusoidal obstruction syndrome after oxaliplatin-based chemotherapy.

OBJECTIVE: To evaluate the magnetic resonance elastography (MRE)-derived liver stiffness measurement (LSM), T1 and T2 relaxation times, and hepatobiliary phase images in patients, who developed sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. METHODS: Thirty-four patients (M/F:22/12) who underwent liver MRI-MRE and received oxaliplatin for colorectal, gastric, and pancreas cancer were included in the study. SOS was diagnosed by Gd-EOB-DTPA-enhanced MRI in 18 patients. MRE-LSM and T1-T2 maps were evaluated. Patients with SOS were grouped according to the amount of reticular hypointensity on the hepatobiliary phase images. RESULTS: The mean MRE-LSM in the patients with SOS was 3.14 ± 0.45 kPa, and the control group was 2.6 ± 0.5 kPa (p = 0.01). The mean-corrected T1 (cT1) relaxation time was 1181 ± 151 ms in the SOS group and 1032 ± 129 ms in the control group (p = 0.005). The mean T2 relaxation time was 50.29 ± 3.6 ms in the SOS group and 44 ± 3.9 ms in the control group (p = 0.01). Parenchymal stiffness values were 2.8 ± 0.22 kPa, 3 ± 0.33 kPa, and 3.65 ± 0.28 kPa in patients with mild, moderate, and advanced SOS findings, respectively (p = 0.002). Although cT1 and T2 relaxation times increased with increasing SOS severity, no statistical significance was found. CONCLUSIONS: We observed increased MRE-LSM in patients with SOS after chemotherapy compared to control group. T1 and T2 relaxation times were also useful in diagnosing SOS but were found inadequate in determining SOS severity. MRE is effective in diagnosing SOS and determining SOS severity in patients who cannot receive contrast agents, and it may be useful in the follow-up evaluation of these patients.

Proton density fat fraction: magnetic resonance imaging applications beyond the liver.

Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) is an emerging quantitative imaging biomarker that accurately measures the fat fraction of tissue by correcting factors influencing magnetic resonance signal intensity. Beyond fat quantification, it also measures R2* which is a direct measure of iron concentration. The utilization of MRI-PDFF in liver diseases is well established. In the present review, we focused on applications of MRI-PDFF in different body areas including pancreas, bone, muscle, spleen, testis, visceral, and subcutaneous adipose tissue. Future studies can enable tracking of quantitative fat fraction changes in different organs simultaneously, which can be critical in understanding fat metabolism.

A first attempt for using of combined sorption and anaerobic processes for handling source separated human urine.

Processing human urine with clinoptilolite results in a solid phase upon which majority of nutrients are concentrated, which may be used as fertilizer; in addition to a liquid residue to be disposed of which is saline, rich in organics and contains residual nutrients. Despite several work regarding nutrients recovery from human urine, the fate of organic matter in the liquid residue is yet to be revealed. This study aims to investigate the combination of sorption and anaerobic processing (ANA) to accomplish concurrent nutrient recovery, and organic matter removal from hydrolyzed human urine (HHU) for environmental protection. Fixed bed clinoptilolite columns were used for nutrient recovery from HHU and an anaerobic expanded granular sludge bed reactor (AnEGSB) was used for removal of organic matter from residue of the former process. Furthermore, the effluent of AnEGSB was subjected to post treatment using stage-wise sorption to enhance the effluent quality before disposal. Majority of nutrients were removed by the sorption process with 80% of ammonium and almost all of phosphorus. Sorption removed 35% of orgnic matter while ANA was responsible for the rest. Post treatment helped to polish the quality of the AnEGSB effluent to the permissible level of domestic wastewater discharge standards of EU.With the proposed combination, almost 100% of nitrogen and phosphorus were recovered for further use as fertilizer providing benefits for sustainability. Also, 97% of organic matter could be removed from HHU to provide environmental protection, which was accompanied by methane (CH4) production of 0.4 L CH4/day which is equivalent to 0.113 L CH4/g COD removed. Successful implementation of the proposed combination helps improve management of domestic wastewater.

Advances in Deep Neuropathological Phenotyping of Alzheimer Disease: Past, Present, and Future.

Alzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the presence of neurofibrillary tangles and amyloid beta (Aß) plaques in the brain. The disease was first described in 1906 by Alois Alzheimer, and since then, there have been many advancements in technologies that have aided in unlocking the secrets of this devastating disease. Such advancements include improving microscopy and staining techniques, refining diagnostic criteria for the disease, and increased appreciation for disease heterogeneity both in neuroanatomic location of abnormalities as well as overlap with other brain diseases; for example, Lewy body disease and vascular dementia. Despite numerous advancements, there is still much to achieve as there is not a cure for AD and postmortem histological analyses is still the gold standard for appreciating AD neuropathologic changes. Recent technological advances such as in-vivo biomarkers and machine learning algorithms permit great strides in disease understanding, and pave the way for potential new therapies and precision medicine approaches. Here, we review the history of human AD neuropathology research to include the notable advancements in understanding common co-pathologies in the setting of AD, and microscopy and staining methods. We also discuss future approaches with a specific focus on deep phenotyping using machine learning.

Influence of photobiomodulation and tricalcium silicate-based cement on viability and dentinogenic activity of cultured human dental pulp stem cells / Influência da fotobiomodulação e cimento de silicato tricálcio na viabilidade e atividade dentinogênica de células tronco cultivadas da polpa de dente humano

Objective: To assess the effect of application of Biodentine (BD), Photobiomodulation (PBM) using 810 nm diode laser and both on the proliferation and odontogenic differentiation of human dental pulp stem cells (HDPSCs). Material and Methods: HDPSCs were collected, isolated, and characterized and then divided into six groups: groups 1, control; groups 2, biodentine (BD); group 3, irradiation at 1 J/cm 2 of 810-nm diode laser; group 4, irradiation at 1 J/cm 2 and culture with BD; group 5, irradiation at 2 J/cm 2, and group 6, irradiation at 2 J/cm 2 and culture with BD. Viability assay was measured through MTT assay and Alkaline phosphatase (ALP) enzyme activity and mRNA levels of RUNX2, collagen 1 (Col-1) and BMP2 were also assessed. Results: Photobiomodulation at 1 and 2 J/cm 2 combined with biodentine significantly promoted HDPSCs proliferation (in MTT assay results) and odontogenic differentiation (through the gene expression of RUNX2, Col-1 and BMP2 levels (p < 0.05). Conclusion: Photobiomodulation at 2 J/cm 2 combined with biodentine enhanced proliferation and odontogenic differentiation of cultured HDPSCs and thus could further be beneficial for dentin regeneration (AU)

Objetivo: Avaliar o efeito da aplicação de Biodentina (BD), Fotobiomodulação (PBM) usando diodo de laser de 810 nm e ambos na proliferação e diferenciação odontogênica de células tronco cultivadas da polpa dental (HDPSCs). Material e Métodos: HDPSCs foram coletadas, isoladas, caracterizadas e então divididas em seis grupos: grupo 1, controle; grupo 2, biodentina (BD); grupo 3, irradiação com diodo de laser a 1 J/cm2 de 810- nm; grupo 4, irradiação a 1 J/cm 2 e cultivo com BD; grupo 5, irradiação a 2 J/cm2, e grupo 6, irradiação a 2 J/cm2 e cultivo com BD. A viabilidade foi mensurada através do teste MTT e a atividade da enzima Fosfatase alcalina (ALP), e níveis de RNAm de RUNX2, de colágeno 1 (Col-1) e de BMP2 foram também mensurados. Resultados: Fotobiomodulação a 1 e 2 J/cm 2 combinada com biodentina promoveu significativa proliferação de HDPSCs (nos resultados do teste MTT) e diferenciação odontogênica (através da expressão genética dos níveis de RUNX2, Col-1 e BMP2 (p < 0.05)). Conclusão: Fotobiomodulação a 2 J/cm2 combinada com biodentina aumentou a proliferação e diferenciação odontogênica de HDPSCs cultivadas e dessa forma poderia ser benéfica para a regeneração dentinária. (AU)

Special Considerations for Supportive Care and Management of Complications in Elderly Patients With Multiple Myeloma.

Multiple myeloma is a progressive and incurable hematologic malignancy. It is predominantly a disease of older individuals, with a third of these patients considered to be elderly. In recent years, there has been a focus and emphasis on identifying and stratifying patients based on their functional status and frailty. There are several hallmark complications of the disease-hypercalcemia, renal insufficiency, anemia, bone pain-along with thromboembolism and compromised immunity that are common in patients with multiple myeloma. Due to the wide range of patient ages and functional status, there are, accordingly, different considerations for management of the above complications based on numerous factors, including frailty status. This review focuses on considerations and management of common complications of multiple myeloma in elderly patients. These include renal failure, skeletal complications, anemia, thromboembolism, and infectious complications.

Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications.

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that 'fuel the fire' in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

Current and emerging roles of Cockayne syndrome group B (CSB) protein.

Cockayne syndrome (CS) is a segmental premature aging syndrome caused primarily by defects in the CSA or CSB genes. In addition to premature aging, CS patients typically exhibit microcephaly, progressive mental and sensorial retardation and cutaneous photosensitivity. Defects in the CSB gene were initially thought to primarily impair transcription-coupled nucleotide excision repair (TC-NER), predicting a relatively consistent phenotype among CS patients. In contrast, the phenotypes of CS patients are pleiotropic and variable. The latter is consistent with recent work that implicates CSB in multiple cellular systems and pathways, including DNA base excision repair, interstrand cross-link repair, transcription, chromatin remodeling, RNAPII processing, nucleolin regulation, rDNA transcription, redox homeostasis, and mitochondrial function. The discovery of additional functions for CSB could potentially explain the many clinical phenotypes of CSB patients. This review focuses on the diverse roles played by CSB in cellular pathways that enhance genome stability, providing insight into the molecular features of this complex premature aging disease.