Neuroprotective effects of flavonoids: endoplasmic reticulum as the target.

The incidence of neurological disorders, particularly age-related neurodegenerative pathologies, exhibits an alarming upward trend, while current pharmacological interventions seldom achieve curative outcomes. Despite their diverse clinical presentations, neurological diseases often share a common pathological thread: the aberrant accumulation of misfolded proteins within the endoplasmic reticulum (ER). This phenomenon, known as ER stress, arises when the cell's intrinsic quality control mechanisms fail to cope with the protein-folding burden. Consequently, misfolded proteins accumulate in the ER lumen, triggering a cascade of cellular stress responses. Recognizing this challenge, researchers have intensified their efforts over the past two decades to explore natural compounds that could potentially slow or even reverse these devastating pathologies. Flavonoids constitute a vast and heterogeneous class of plant polyphenols, with over 10,000 identified from diverse natural sources such as wines, vegetables, medicinal plants, and organic products. Flavonoids are generally divided into six different subclasses: anthocyanidins, flavanones, flavones, flavonols, isoflavones, and flavonols. The diverse family of flavonoids, featuring a common phenolic ring backbone adorned with varying hydroxyl groups and additional modifications, exerts its antioxidant activity by inhibiting the formation of ROS, as evidenced by research. Also, studies suggest that polyphenols such as flavonoids can regulate ER stress through apoptosis and autophagy. By understanding these mechanisms, we can unlock the potential of flavonoids as novel therapeutic agents for neurodegenerative disorders. Therefore, this review critically examines the literature exploring the modulatory effects of flavonoids on various steps of the ER stress in neurological disorders.

Don't Ask Us to Stop Cycling: A Surgical Perspective.

MINI ABSTRACT: In this surgical perspective, we argue that counseling avoidance of bicycle commuting is not the right approach to cycling injury prevention or to overall urban health. Instead, we propose surgeons should take a more holistic approach that includes mitigating individual risk factors as well as creating an equitable environment of safety.

Circulating levels of C1q/TNF-α-related protein 6 (CTRP6) in coronary artery disease and its correlation with inflammatory markers.

Introduction: Circulating levels of C1q/TNF-α-related protein 6 (CTRP6) is an adipokine that is involved in regulation of glucose and lipid metabolism, inflammation, and insulin sensitivity. However, the exact role of CTRP6 in metabolic processes remains unclear due to conflicting findings. To address current gap, we aimed to investigate the serum levels of CTRP6 in patients with coronary artery disease (CAD) and its association with inflammatory cytokines. Method: In this case-control study, the serum levels of CTRP6, interlukin-6 (IL-6), tumor necrosis factor- α (TNF-α), adiponectin, and fasting insulin were measured using enzyme-linked immunosorbent assay (ELISA) kits in a total of 176 participants, consisting of 88 CAD patients and 88 control subjects. Additionally, various anthropometric and biochemical measurements were measured and compared between cases and controls. Results: The present study found that serum levels of CTRP6 were significantly higher in the CAD group (561.3 ± 15.14) compared to the control group (429.3 ± 12.85, p < 0.001). After adjusting for age, sex, and body mass index (BMI), CTRP6 levels were found to be positively associated with the risk of CAD (p < 0.001). Correlation analysis in CAD subjects revealed a positive correlation between CTRP6 levels and BMI, systolic blood pressure (SBP), malondialdehyde (MDA), TNF-α, and IL-6, as well as a negative correlation with creatinine and total anti-oxidant capacity. Conclusion: The findings of this study provide novel evidence that elevated serum levels of CTRP6 are significantly associated with an increased risk of developing CAD. Moreover, our results indicate a correlation between CTRP6 and various risk factors for atherosclerosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-024-01415-5.

Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases.

The etiology of prostate cancer, the second most common cancer in men globally, has a strong heritable component. While rare coding germline variants in several genes have been identified as risk factors from candidate gene and linkage studies, the exome-wide spectrum of causal rare variants remains to be fully explored. To more comprehensively address their contribution, we analysed data from 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline exome/genome sequencing and one cohort with imputed array data from a population enriched in low-frequency deleterious variants. Our gene-level collapsing analysis revealed that rare damaging variants in SAMHD1 as well as genes in the DNA damage response pathway (BRCA2, ATM and CHEK2) are associated with the risk of overall prostate cancer. We also found that rare damaging variants in AOX1 and BRCA2 were associated with increased severity of prostate cancer in a case-only analysis of aggressive versus non-aggressive prostate cancer. At the single-variant level, we found rare non-synonymous variants in three genes (HOXB13, CHEK2, BIK) significantly associated with increased risk of overall prostate cancer and in four genes (ANO7, SPDL1, AR, TERT) with decreased risk. Altogether, this study provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity.

Health Literacy Among University Students in the COVID-19 Pandemic: A Systematic Review.

BACKGROUND: The purpose of this systematic review was to assess different studies that worked on university students' health literacy during covid19 pandemic and to make an overview of this issue to recognize possible determinants associated with health literacy. METHODS: This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Four databases (Google Scholar, Web of Science, Pubmed, and Scopus) were used for searching cross-sectional works that assessed the health literacy of university students. We searched papers from December 1st, 2019 up to June 10th, 2022. English language articles were used. Studies were done in countries including; Iran, Pakistan, the USA, Vietnam, China, Colombia, Germany, and Indonesia. RESULTS: The systematic review contains 12 research studies involving 17773 students. There was a relationship between health literacy and some determinants. Positive determinants included age, female gender, Urban background, cognitive maturity, Higher educational qualification, information source (Health workers), number of semesters, and parental education. Some negative determinants were male gender, Rural background, smoking, drinking, being able to pay for medication, lower conspiracy beliefs, and higher fear of COVID-19. CONCLUSION: University students around the world should have courses about health literacy according to university disciplines. These courses should be available for students of different fields to enhance their effectiveness, and training should be associated with students' needs and their subgroup traits.

Precision Oncology in Breast Cancer Surgery.

Outcomes for patients with breast cancer have improved over time due to increased screening and the availability of more effective therapies. It is important to recognize that breast cancer is a heterogeneous disease that requires treatment based on molecular characteristics. Early endpoints such as pathologic complete response correlate with event-free survival, allowing the opportunity to consider de-escalation of certain cancer treatments to avoid overtreatment. This article discusses clinical trials of tailoring treatment (eg, I-SPY2) and screening (eg, WISDOM) to individual patients based on their unique risk features.

Mini review: human clinical studies of stem cell therapy in keratoconus.

Treatment of keratoconus is one of the most interesting research fields for researchers in the world. Regenerative medicine based on human stem cells in the treatment of keratoconus has recently received attention. Despite extensive laboratory and animal studies in regenerative medicine of cornea, there are limited clinical studies in keratoconus. These studies showed promising results of stem cell therapy. In initial studies, the transplantation of these cells into stroma was associated with increased vision and improved corneal parameters without side effects. In this article, we tried to review different aspects of keratoconus stem cell therapy, including cell extraction and culture, surgical procedure, effectiveness and safety of this method in human clinical studies.

Why some Patients Benefit from Participating in a Sham Surgery Trial.

OBJECTIVE: We analyze the ethics of sham surgical trials from a utilitarian perspective and explore whether patients can benefit from participating in these trials. BACKGROUND: Sham-controlled randomized trials are an essential tool to evaluate the risks and benefits of some surgical procedures. However, sham trials are controversial because they expose patients to the harms of a sham procedure without the possibility of benefit. We argue that ethical analyses of sham trials have focused only on the harms of sham surgery and neglected to account for the harms of the procedure being studied. METHODS: We develop a theoretical model to estimate the harms and benefits experienced by patients who enter a sham surgery trial, taking into account the harms and benefits of the sham and intervention. RESULTS: When the procedure in question is found to be ineffective, sham trials typically result in a net benefit to participants because some participants are only exposed to the harms of the sham procedure, which are much lower than the harms of the full procedure. When the procedure is found to be beneficial, the primary harm to patients who underwent the sham is not due to the sham itself but because they suffer a delay in receiving an effective intervention. CONCLUSIONS: Patients often benefit from participating in sham surgery trials because the harms of the sham procedure are lower than the harms of the full procedure, which may turn out to be ineffective. Our results call for re-thinking the ethics of sham surgery trials.

Fatal peritonitis due to gastric perforation in a male heroin addict: A case report and literature review.

INTRODUCTION AND IMPORTANCE: Perforation of hollow organs, such as the stomach, within the abdomen can lead to the development of acute abdomen, a critical and potentially life-threatening condition. It is important to note that there is currently insufficient information available regarding the specific effects of heroin, an illegal substance commonly abused, in causing this particular complication. CASE PRESENTATION: We present the case of a 32-year-old male who is addicted to heroin and was admitted to an addiction rehabilitation center with the aim of overcoming his addiction. After a few days of admission, the patient developed symptoms of abdominal pain, anorexia, and subsequent neurological manifestations, such as drowsiness, confusion, and a decreased level of consciousness. Tragically, the patient suffered a cardiorespiratory arrest upon arrival at the emergency room and despite efforts to resuscitate him, he unfortunately passed away. CLINICAL DISCUSSION: During the autopsy of the aforementioned case, an observation was made of a perforation in the stomach, which ultimately led to the cause of death being identified as peritonitis. Acute peritonitis is recognized as one of the potential causes of acute abdomen, often resulting from the rupture of hollow organs within the abdominal region. It is characterized by inflammation of the serous membrane that lines the abdominal cavity. CONCLUSIONS: Indeed, conducting original and coherent studies to investigate the potential effects of heroin on gastric perforation could prove to be highly valuable in facilitating the timely diagnosis and treatment of this fatal complication.

Characterization of microplastics in digestive tract of commercial fish species from the Oman Sea.

Microplastics (MPs) content of the digestive tract of two commercial fish from the northern shores of the Oman Sea were investigated. The MPs were characterized by optical microscopy, fluorescent microscopy, and SEM-EDX for their number, shape, size, and color. Polymer composition was analyzes using micro-Raman spectroscopy (RMS). MPs were recovered in all fish samples (100 %), with an average of 43.16 ± 8.23 items/individual in Otolithes ruber, and 29.9 ± 2.73 items/individual in Acanthopagrus latus. The predominant shape of MPs in both fishes was fiber (46 %) with black, transparent, and white colors. The majority of MPs were <1000 µm (75 %), and half of the MPs were smaller than 300 µm in size. Their synthetic nature was confirmed by Nile Red staining and determination of the elemental composition of selected items. Polypropylene (PP) and polyethylene (PE) were the dominant plastic polymers in the fish digestive tracts. This study reveals abundance distribution of MPs in digestive tract of commercial marine fish. High number of ingested MPs can alarm the accumulation of MPs in the northern of Oman Sea ecosystem with anthropogenic activities and raises issues in public health.

CCN3/NOV serum levels in coronary artery disease (CAD) patients and its correlation with TNF-α and IL-6.

INTRODUCTION: Dysregulation in the secretion of adipokines or adipocytokines plays a significant role in triggering a pro-inflammatory state, leading to endothelial dysfunction and insulin resistance, and ultimately elevating the risk of atherosclerosis and coronary artery disease (CAD). Previous studies have shown a link between NOV/CCN3 (an adipokine) and obesity, insulin resistance, and inflammation. However, no research has explored the relationship between CCN3 serum levels and CAD. Therefore, we conducted the first investigation to examine the correlation between CCN3 and CAD risk factors in patients. METHODS: In a case-control study, we measured the serum levels of CCN3, IL-6, adiponectin, and TNF-α in 88 angiography-confirmed CAD patients and 88 control individuals using ELISA kits. Additionally, we used an auto analyzer and commercial kits to measure the biochemical parameters. RESULTS: In patients with CAD, the serum levels of CCN3, TNF-α, and IL-6 were significantly higher compared to the control group, whereas lower levels of adiponectin were observed in the CAD group (P < 0.0001). A positive correlation was found between CCN3 and IL-6 and TNF-α in the CAD group ([r = 0.38, P < 0.0001], [r = 0.39, P < 0.0001], respectively). A binary logistic regression analysis showed the risk of CAD in the model adjusted (OR [95% CI] = 1.29 [1.19 - 1.41]), (P < 0.0001). We determined a cut-off value of CCN3 (3169.6 pg/mL) to distinguish CAD patients from the control group, with good sensitivity and specificity obtained for this finding (83.8% and 87.5%, respectively). CONCLUSION: This study provides evidence of a positive association between CCN3 serum levels and CAD, as well as inflammation markers such as IL-6 and TNF-α. These findings suggest that CCN3 may serve as a potential biomarker for CAD, and further investigations are necessary to validate this association and explore its potential use in clinical settings.

Comparison of the effect of pressure control and volume control ventilation on endotracheal tube cuff pressure in patients undergoing general anesthesia and mechanical ventilation: a parallel randomized clinical trial.

BACKGROUND: Endotracheal intubation and mechanical ventilation are prevalent interventions in the operating room and intensive care unit. Recently, the complications of endotracheal tube cuff pressure have been a topic of interest. Therefore, this study compared the effect of pressure control and volume control ventilation modes on the endotracheal cuff pressure rate in patients undergoing general anesthesia and mechanical ventilation. METHODS: In this triple-blinded randomized clinical trial, 50 patients undergoing open limb surgery and inguinal hernia were allocated to two groups of 25 based on inclusion criteria. After intubation, one group underwent ventilation on the pressure control ventilation mode, and the other underwent ventilation on the volume control ventilation mode. In both groups, using a manometer, the cuff's pressure was first adjusted in the range of 25-30 cm of water. Then, the cuff pressure was measured at 10, 20, and 30 min intervals. The data were statistically analyzed using independent t-test, and two-way repeated measures ANOVA. RESULTS: The present study's findings showed that cuff pressure has significantly decreased over time in both study groups (F = 117.7, P < 0.001). However, a repeated measures ANOVA with a Greenhouse-Geisser correction showed no interaction between time and groups (F = 0.019, P = 0.98). The two groups had no significant difference in cuff pressure (F = 0.56, P = 0.458). CONCLUSION: Since the cuff pressure has been significantly reduced in both groups over time, continuous monitoring of endotracheal tube cuff pressure in patients undergoing mechanical ventilation is essential. Therefore, it is suggested to keep the cuff pressure within the recommended range to prevent complications resulting from cuff pressure reduction, such as aspiration and ventilation decrease. TRIAL REGISTRATION: The study was registered in the Iranian Registry of Clinical Trial on 23/02/2019 (trial registration number: IRCT20181018041376N1).

Assessment of the effects of intrastromal injection of adipose-derived stem cells in keratoconus patients.

AIM: To evaluate the efficacy and safety of intrastromal transplantation of adipose-derived stem cells (ASCs) in keratoconus patients. METHODS: This study was conducted on 8 eyes of 8 patients with moderate to severe keratoconus. In the patients, ophthalmic assessments including visual acuity, refraction, slit lamp examination, fundoscopy, corneal topography, and confocal microscopy were performed. Autologous stem cells were used. The isolated stem cells were injected into the corneal stroma by using femtosecond laser. Surgical procedure was similar to intracorneal ring implantation. All patients were re-assessed 1, 3, and 6mo after surgery. RESULTS: The baseline mean visual acuity was 0.48±0.18 and improved to 0.66±0.17 after surgery and final acuity increased by 1.85±0.80 lines (P=0.001). The mean spherical refraction of patients improved 0.34±0.35 D (P=0.039), and the mean cylindrical refraction of patients improved 0.84±0.23 D (P=0.016). The mean flat keratometry decreased 0.78±0.71 D (P=0.017), and the mean steep keratometry decreased 0.59±0.68 D (P=0.023). The mean central corneal thickness of patients improved of 6.29±4.47 µm (P=0.03). The mean keratocyte density at the anterior and middle stroma of cornea increased (P<0.05) but remained stable at the posterior stroma after 6mo. All patients had no complications and their corneas remained transparent. CONCLUSION: Intrastromal transplantation of ASCs has positive effects on vision and refractive parameters in most patients with keratoconus. After six months, visual acuity improved moderately, corneal parameters reduced slightly, and stromal keratocytes density increased. This modality is safe, and patients do not have any complications.

Assessment of bone-targeting agents use in patients with bone metastasis from breast, lung or prostate cancer using structured and unstructured electronic health records from a regional UK-based hospital.

ObjectiveTo assess use of bone-targeting agents (BTA) in patients with confirmed bone metastases (BM) from breast cancer (BC), non-small cell lung cancer (NSCLC) or prostate cancer (PC). DESIGN: Retrospective cohort study. SETTING: Regional hospital-based oncology database of approximately 2 million patients in England. PARTICIPANTS: Patients aged ≥18 years with a diagnosis of BC, NSCLC or PC as well as BM between 1 January 2007 and 31 December 2018, with follow-up to 30 June 2020 or death; BM diagnosis ascertained from recorded medical codes and unstructured data using natural language processing (NLP). MAIN OUTCOMES MEASURES: Initiation or non-initiation of BTA following BM diagnosis, time from BM diagnosis to BTA initiation, time from first to last BTA, time from last BTA to death. RESULTS: This study included 559 BC, 894 NSCLC and 1013 PC with BM; median age (Q1-Q3) was 65 (52-76), 69 (62-77) and 75 (62-77) years, respectively. NLP identified BM diagnosis from unstructured data for 92% patients with BC, 92% patients with NSCLC and 95% patients with PC. Among patients with BC, NSCLC and PC with BM, 47%, 87% and 88% did not receive a BTA, and 53%, 13% and 12% received at least one BTA, starting a median 65 (27-167), 60 (28-162) and 610 (295-980) days after BM, respectively. Median (Q1-Q3) duration of BTA treatment was 481 (188-816), 89 (49-195) and 115 (53-193) days for patients with BC, NSCLC and PC. For those with a death record, median time from last BTA to death was 54 (26-109) for BC, 38 (17-98) for NSCLC and 112 (44-218) days for PC. CONCLUSION: In this study identifying BM diagnosis from both structured and unstructured data, a high proportion of patients did not receive a BTA. Unstructured data provide new insights on the real-world use of BTA.

Recent advances in gene therapy-based cancer monotherapy and synergistic bimodal therapy using upconversion nanoparticles: Structural and biological aspects.

In accordance with human genetics and genomics advances over the past years, it can be found that cancer is created through a somatic aberration in the host genome. Accordingly, researchers use therapeutic methods in genetic manipulation to discover the possible cure for the disease. In combination with traditional cancer treatments, gene therapy (GT) is essential in future cancer therapy. The development of powerful nanocarriers for targeted, controlled, and efficient intracellular delivery of therapeutic biomolecules that increase pharmacokinetics indicates that the development of GT is highly dependent on nanotechnology. Among nanocarriers, upconversion nanoparticles (UCNPs) have become the focus of great attention in the realm of inorganic nanomedicines following the strategy of "diagnosis for treatment" due to their outstanding features including safety, deep penetration of near-infrared (NIR) light into tissue, and reduction of unfavorable side effects of NIR-triggered therapies. Moreover, various individual therapies can be intelligently combined into a single nanotranostic system based on a UCNP platform for multimodal synergistic treatment. Given that the preparation of multifunctional nanomaterials is a prerequisite for the realization of cancer treatment, especially synergistic therapies, the recognition of the main components of advanced nanoparticles can help researchers in choosing the proper platform for cancer treatment. In view of this, the main goal of this review is to highlight the latest advances in the construction and application of upconversion nanoparticles as carriers for gene delivery and gene editing in cancer monotherapy and bimodal synergistic therapy, with an emphasis on the structural and biological aspects of these studies.

Medication adherence with denosumab in patients with bone metastases from solid tumors treated in routine clinical settings: a retrospective study.

PURPOSE: To describe (non)adherence with denosumab among patients with solid tumors and bone metastases. METHODS: This retrospective, observational study pooled data from two completed prospective, multicenter cohort studies (X-TREME; Study 240) in adult patients with bone metastases from primary breast, prostate, lung, kidney, or other solid cancer types and administered denosumab 120 mg in routine clinical practice in Germany and Central and Eastern Europe. The studies were conducted between May 2012 and May 2017; pooled analysis was completed in August 2021. Medication adherence was described according to a three-component consensus taxonomy: initiation (first-ever administration ≤ 90 days from bone metastasis diagnosis), implementation (actual vs prescribed dosing; optimal implementation = regular/consistent dosing), and persistence (≤ 60-day gap between administrations at 3, 6, 9, and 12 months). Descriptive analyses were conducted for each cancer type. RESULTS: The analysis included 1748 patients with solid tumors and bone metastases. Adherence with denosumab was generally high across the initiation, implementation, and persistence phases. Most patients experienced timely initiation (from 64.4% [kidney cancer] to 81.2% [breast cancer]) and optimal implementation (from 62.4% [lung cancer] to 72.5% [breast cancer]). The proportion of patients who were persistent with treatment at 6 months ranged from 41.4% (lung cancer) to 77.8% (prostate cancer). CONCLUSIONS: This study revealed variations by cancer type in the initiation, implementation, and persistence of denosumab in patients with solid tumors and bone metastases in routine clinical practice. Further cancer-specific studies are warranted to examine the determinants of (non)adherence with denosumab, and potential ways to improve medication adherence.

To compare on-axis measurements of the axial length with off-axis measurements in the paracentral horizontal and vertical positions.

PURPOSE: To compare on-axis measurements of the axial length (AL) with off-axis measurements in the paracentral horizontal and vertical positions using the Lenstar LS 900 biometer. METHODS: In this, the samples were selected from patients scheduled for cataract surgery using a systematic randomization method. After applying the exclusion criteria, all subjects underwent optometric examinations and AL measurement using the Lenstar. Five consecutive, non-cycloplegic measurements were done on the right eye centrally, 10° temporally, 10° nasally, 10° superiorly and 10° inferiorly on the retina by the same examiner. RESULTS: Two hundred and seven eyes were examined in this study, of which 126 (60%) were for female patients. The mean age of the participants was 64.32 ± 10.77 years (range: 34-91 years). The mean central, superior, inferior, temporal, and nasal axial AL was 23.22 ± 1.02, 23.21 ± 1.02, 23.21 ± 1.02, 23.21 ± 1.02, 23.20 ± 1.03, respectively. Comparison of these readings using repeated measures ANOVA showed a statistically significant difference in the AL value among these positions. According to the post-hoc results, superior and nasal AL was statistically significantly lower compared to the central AL. CONCLUSION: If on-axis biometry is not available, AL can be measured in an off-axis manner in the paracentral temporal, superior and inferior positions. Considering the marked difference in AL measurement between central and nasal positions, off-axis measurement is not recommended in the nasal part because it may be associated with a marked hyperopic shift after cataract surgery.