A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-ß, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders.

Tracking the therapeutic efficacy of a ketone mono ester and ß-hydroxybutyrate for ulcerative colitis in rats: New perspectives.

Ulcerative colitis (UC) is an inflammatory condition that affects the colon's lining and increases the risk of colon cancer. Despite ongoing research, there is no identified cure for UC. The recognition of NLRP3 inflammasome activation in the pathogenesis of UC has gained widespread acceptance. Notably, the ketone body ß-hydroxybutyrate inhibits NLRP3 demonstrating its anti-inflammatory properties. Additionally, BD-AcAc 2 is ketone mono ester that increases ß-hydroxybutyrate blood levels. It has the potential to address the constraints associated with exogenous ß-hydroxybutyrate as a therapeutic agent, including issues related to stability and short duration of action. However, the effects of ß-hydroxybutyrate and BD-AcAc 2 on colitis have not been fully investigated. This study found that while both exogenous ß-hydroxybutyrate and BD-AcAc 2 produced the same levels of plasma ß-hydroxybutyrate, BD-AcAc 2 demonstrated superior effectiveness in mitigating dextran sodium sulfate-induced UC in rats. The mechanism of action involves modulating the NF-κB signaling, inhibiting the NLRP3 inflammasome, regulating antioxidant capacity, controlling tight junction protein expression and a potential to inhibit apoptosis and pyroptosis. Certainly, BD-AcAc 2's anti-inflammatory effects require more than just increasing plasma ß-hydroxybutyrate levels and other factors contribute to its efficacy. Local ketone concentrations in the gastrointestinal tract, as well as the combined effect of specific ketone bodies, are likely to have contributed to the stronger protective effect observed with ketone mono ester ingestion in our experiment. As a result, further investigations are necessary to fully understand the mechanisms of BD-AcAc 2 and optimize its use.

miRNAs dysregulation in ankylosing spondylitis: A review of implications for disease mechanisms, and diagnostic markers.

Epigenetic processes, including non-coding RNA, histone modifications, and DNA methylation, play a vital role in connecting the environment to the development of a disorder, especially when there is a favorable genetic background. Ankylosing Spondylitis (AS) is a chronic type of spinal arthritis that highlights the significance of epigenetics in diseases related to autoimmunity and inflammation. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in both normal and aberrant pathological and physiological gene expression. This study focuses on the pathophysiological pathways to clarify the role of miRNAs in AS. We have conducted a thorough investigation of the involvement of miRNAs in several processes, including inflammation, the production of new bone, T-cell activity, and the regulation of pathways such as BMP, Wnt, and TGFß signaling. Undoubtedly, miRNAs play a crucial role in enhancing our comprehension of the pathophysiology of AS, and their promise as a therapeutic strategy is quickly expanding.

Item analysis: the impact of distractor efficiency on the difficulty index and discrimination power of multiple-choice items.

BACKGROUND: Distractor efficiency (DE) of multiple-choice questions (MCQs) responses is a component of the psychometric analysis used by the examiners to evaluate the distractors' credibility and functionality. This study was conducted to evaluate the impact of the DE on the difficulty and discrimination indices. METHODS: This cross-sectional study was conducted from April to June 2023. It utilizes the final exam of the Principles of Diseases Course with 45 s-year students. The exam consisted of 60 type A MCQs. Item analysis (IA) was generated to evaluate KR20, difficulty index (DIF), discrimination index (DIS), and distractor efficiency (DE). DIF was calculated as the percentage of examinees who scored the item correctly. DIS is an item's ability to discriminate between higher and lower 27% of examinees. For DE, any distractor selected by less than 5% is considered nonfunctional, and items were classified according to the non-functional distractors. The correlation and significance of variance between DIF, DI, and DE were evaluated. RESULTS: The total number of examinees was 45. The KR-20 of the exam was 0.91. The mean (M), and standard deviation (SD) of the DIF of the exam was 37.5(19.1), and the majority (69.5%) were of acceptable difficulty. The M (SD) of the DIS was 0.46 (0.22), which is excellent. Most items were excellent in discrimination (69.5%), only two were not discriminating (13.6%), and the rest were of acceptable power (16.9%). Items with excellent and good efficiency represent 37.3% each, while only 3.4% were of poor efficiency. The correlation between DE and DIF (p = 0.000, r= -0.548) indicates that items with efficient distractors (low number of NFD) are associated with those having a low difficulty index (difficult items) and vice versa. The correlation between DE and DIS is significantly negative (P = 0.0476, r=-0.259). In such a correlation, items with efficient distractors are associated with low-discriminating items. CONCLUSIONS: There is a significant moderate negative correlation between DE and DIF (P = 0.00, r = -0.548) and a significant weak negative correlation between DE and DIS (P = 0.0476, r = -0.259). DIF has a non-significant negative correlation with DIS (P = 0.7124, r = -0.0492). DE impacts both DIF and DIS. Items with efficient distractors (low number of NFD) are associated with those having a low difficulty index (difficult items) and discriminating items. Improving the quality of DE will decrease the number of NFDs and result in items with acceptable levels of difficulty index and discrimination power.

AI in medical education: uses of AI in construction type A MCQs.

BACKGROUND: The introduction of competency-based education models, student centers, and the increased use of formative assessments have led to demands for high-quality test items to be used in assessments. This study aimed to assess the use of an AI tool to generate MCQs type A and evaluate its quality. METHODS: The study design was cross-sectional analytics conducted from June 2023 to August 2023. This study utilized formative TBL. The AI tool (ChatPdf.com) was selected to generate MCQs type A. The generated items were evaluated using a questionnaire for subject experts and an item (psychometric) analysis. The questionnaire to the subject experts about items was formed based on item quality and rating of item difficulty. RESULTS: The total number of recurrent staff members as experts was 25, and the questionnaire response rate was 68%. The quality of the items ranged from good to excellent. None of the items had scenarios or vignettes and were direct. According to the expert's rating, easy items represented 80%, and only two had moderate difficulty (20%). Only one item out of the two moderate difficulties had the same difficulty index. The total number of students participating in TBL was 48. The mean mark was 4.8 ± 1.7 out of 10. The KR20 is 0.68. Most items were of moderately difficult (90%) and only one was difficult (10%). The discrimination index of the items ranged from 0.77 to 0.15. Items with excellent discrimination represented 50% (5), items with good discrimination were 3 (30%), and only one time was poor (10%), and one was none discriminating. The non-functional distractors were 26 (86.7%), and the number of non-functional distractors was four (13.3%). According to distractor analysis, 60% of the items were excellent, and 40% were good. A significant correlation (p = 0.4, r = 0.30) was found between the difficulty and discrimination indices. CONCLUSION: Items constructed using AI had good psychometric properties and quality, measuring higher-order domains. AI allows the construction of many items within a short time. We hope this paper brings the use of AI in item generation and the associated challenges into a multi-layered discussion that will eventually lead to improvements in item generation and assessment in general.

The role of matrix metalloproteinase-2 and miR-196a2 in bronchial asthma pathogenesis and diagnosis.

Background: Bronchial asthma is a persistent inflammatory respiratory condition that restricts the passage of air and causes hyperresponsiveness. Chronic asthma can be classified into three categories: mild, moderate, and severe. Remodeling took place as the extracellular matrix accumulated in the walls of the airways. Inflammation occurs as a result of the damage caused by matrix metalloproteinase-2 (MMP-2) to basement membrane type IV collagen. The severity of asthma may be associated with miR-196a2. The objective of our study was to investigate the underlying mechanisms and clinical relevance of miR-196a2 and MMP-2 serum levels in relation to the severity of asthma. Methods: This study recruited 85 controls and 95 asthmatics classified as mild, moderate, or severe. Expression of miR-196a2 was measured by quantitative reverse transcriptase PCR. Using the enzyme-linked immunosorbent assay (ELISA), MMP-2, IL-6, and total immunoglobulin E (IgE) levels in the serum of asthmatics of various grades were compared to a control group. MMP-2's diagnostic and prognostic potential was determined using ROC curve analysis. This study also measured blood Eosinophils and PFTs. We examined MMP-2's connections with IgE, blood Eosinophils, and PFTs. Results: The current investigation found that miR-196a2 expression was significantly higher in the control group than in asthmatic patients as a whole. The study found that severe asthmatics had higher MMP-2, IL-6, and IgE serum levels than healthy controls. We identified the MMP-2 serum concentration cutoff with great sensitivity and specificity. Significant relationships between MMP-2 serum level and miR-196a2 expression in the patient group with severe asthmatics were found. The MMP-2, IL-6, and IgE serum levels were considerably higher in mild, moderate, and severe asthmatics than controls. The miR-196a2 expression and MMP-2 serum concentration correlated positively with IgE and blood eosinophils % and negatively with all lung function tests in the asthmatic patient group.Conclusion: the study revealed that the elevated miR-196a2 expression and serum concentration of MMP-2, IL-6, and IgE associated with elevated blood eosinophils % is associated with pathophysiology and degree of asthma severity. The miR-196a2 expression and MMP-2 serum concentration have a promising diagnostic and prognostic ability in bronchial asthma.

Morphological Correlation between the Diameters of the Left Main Coronary Artery and its Branches Measured by QCA and Derived by Finet's Law.

BACKGROUND: Coronary artery diseases are the leading cause of death worldwide. Stenting or angioplasty of coronary arteries as interventional management requires knowledge about the morphology of the coronary tree, including luminal diameters. OBJECTIVE: This work aimed to study the diameters of the left main coronary artery and its branches measured by QCA in relation to the diameters derived by Finet's law. METHODS: This was a cross-sectional, retrospective, hospital-based study. The number of angiograms used was 357. The diameters of the left main coronary artery (LM1), left anterior interventricular artery (LAD1), and left circumflex artery (LCx1) were measured by QCA. The diameter of LM1 was measured by 5 mm before its termination, and the diameters of LAD1 and LCx1 were obtained by 5 mm from their origins. Finet's law was used to calculate the diameters of LM2, LAD2 and LCx2 using the QCA measurements. RESULTS: The mean age of participants was 53.3±8.8 years. Female patients represented 58.9%. The mean diameter of the left main coronary using QCA was 3.75±0.85 mm, and the diameter calculated using Finet's law was 3.89±0.80 mm. The diameters of LAD1 and LCx1 were larger than those calculated with Finet's law. The Z-test showed a significant difference between the diameter of the LM1 calculated by Finet's law; both diameters were positively associated. The diameters of LAD1 and LAD2 showed a non-significant correlation (r = 0.0653, P = 0.259526) and a negative correlation between LCx1 and LCX2 (r = -0.2659, P = 0.00001). The Z-test showed a significant difference in the diameter of LAD and LCx measured by QCA and Finet's law. CONCLUSION: An association was found between the diameter of LM measured by QCA and calculated with Finet's law; the diameter calculated by Finet's law was larger. The diameters of LAD and LCx measured by QCA were larger than those calculated by Finet's law. A positive correlation existed between the diameters measured by QCA and Finet's law, and they had significant differences. Finet's law can assist in the selection of stent size. Despite the literature about Finet's law, generalising its use requires more studies on different ethnicities.

Itraconazole halts hepatocellular carcinoma progression by modulating sonic hedgehog signaling in rats: A novel therapeutic approach.

Liver cancer stands as the fourth leading global cause of death, and its prognosis remains grim due to the limited effectiveness of current medical interventions. Among the various pathways implicated in the development of hepatocellular carcinoma (HCC), the hedgehog signaling pathway has emerged as a crucial player. Itraconazole, a relatively safe and cost-effective antifungal medication, has gained attention for its potential as an anticancer agent. Its primary mode of action involves inhibiting the hedgehog pathway, yet its impact on HCC has not been elucidated. The main objective of this study was to investigate the effect of itraconazole on diethylnitrosamine-induced early-stage HCC in rats. Our findings revealed that itraconazole exhibited a multifaceted arsenal against HCC by downregulating the expression of key components of the hedgehog pathway, shh, smoothened (SMO), and GLI family zinc finger 1 (GLI1), and GLI2. Additionally, itraconazole extended survival and improved liver tissue structure, attributed mainly to its inhibitory effects on hedgehog signaling. Besides, itraconazole demonstrated a regulatory effect on Notch1, and Wnt/ß-catenin signaling molecules. Consequently, itraconazole displayed diverse anticancer properties, including anti-inflammatory, antiangiogenic, antiproliferative, and apoptotic effects, as well as the potential to induce autophagy. Moreover, itraconazole exhibited a promise to impede the transformation of epithelial cells into a more mesenchymal-like phenotype. Overall, this study emphasizes the significance of targeting the hedgehog pathway with itraconazole as a promising avenue for further exploration in clinical studies related to HCC treatment.

Diameter of the orifice of the left coronary artery: angiographic study / Diámetro del ostio de la arteria coronaria izquierda: estudio angiográfico

SUMMARY: The ongoing advances in the technology of coronary artery angiograms have put high demands on the basic knowledge of coronary arteries. This study describes the angiographic morphology of the ostium (orifice) of the left coronary artery among Sudanese with respect to sex, age, length, and BMI. The study design is a cross-sectional retrospective hospital-based conducted from 2014 to 2016. The inclusion criterion of participants is adult males and females presented to the cardiac centers for elective angiograms. The exclusion criteria are age below 18 years, documented congenital heart disease, and previous coronary bypass. Angiograms were done using a digital radiographic system. Data was collected through a predesigned data collection sheet. The data were entered and analyzed using SPSS v27. A test of correlation was done between the different variables. The data were presented in the form of tables. A P-value of <0.05 was considered statistically significant. The total number of participants was 441; males and females represent 42.9 % and 57,1 %, respectively. The mean age of participants was 56.24±8.68 years. The left coronary artery originated from the left aortic sinus. The mean diameter and length of the left coronary artery were 3.8±0.70 mm and 8.1576±4.32 mm, respectively. A significant negative correlation was reported between the diameter of the orifice and both age and length of the left coronary artery. A non-significant difference between males and females in the diameter of the left coronary artery at ostium (P=0.058) and a significant difference in the length (P=0.00). Sudanese have the smallest diameter of the orifice of the left coronary artery among Africans. Sudanese males have a smaller diameter of orifice than females; females have the longest arteries. A wider orifice of the left coronary artery is associated with a short arterial length.

RESUMEN: Los avances en la tecnología de los angiogramas de las arterias coronarias constituyen importantes exigencias al conocimiento básico de las arterias coronarias. Este estudio describe la morfología angiográfica del ostio de la arteria coronaria izquierda (ACI) entre los sudaneses respecto al sexo, la edad, la longitud y el IMC. El estudio es un diseño hospitalario retrospectivo transversal realizado entre 2014 y 2016. El criterio de inclusión de los participantes, hombres y mujeres adultos, fue aquellos que se realizaron angiografías electivas en los centros cardiológicos Los criterios de exclusión fueron: edad menor de 18 años, cardiopatía congénita documentada y bypass coronario previo. Los angiogramas se realizaron utilizando un sistema radiográfico digital. Los datos se obtuvieron a través de una ficha de datos prediseñada. Estos fueron ingresados y analizados con SPSS v27. Se realizó una prueba de correlación entre las diferentes variables. Los datos se presentaron en forma de tablas. Un valor P de <0,05 se consideró estadísticamente significativo. El número total de participantes fue de 441; Hombres y mujeres representanron el 42,9 % y 57,1 %, respectivamente. La edad media de los participantes fue de 56,24±8,68 años. La arteria coronaria izquierda se originaba en el seno aórtico izquierdo. El diámetro medio y la longitud de la arteria coronaria izquierda fueron 3,8±0,70 mm y 8,1576±4,32 mm, respectivamente. Se encontró una correlación negativa significativa entre el diámetro del ostio, la edad y la ACI. Además se encontró una diferencia no significativa entre hombres y mujeres en el diámetro del ostio de la ACI (P=0,058) y una diferencia significativa en la longitud (P=0,00). Los sudaneses tienen el diámetro del ostio de la arteria coronaria izquierda más pequeño entre los africanos. Los hombres sudaneses tienen un diámetro del ostio de la arteria coronaria izquierda más pequeña y las mujeres tienen las arterias más largas. Un ostio más ancho de la arteria coronaria izquierda se asocia con una longitud arterial corta.

Morphometry: assessing direct and indirect methods of measuring the diameters of tubular structures / Morfometría: evaluación de métodos directos e indirectos para medir los diámetros de las estructuras tubulares

SUMMARY: Knowledge of the diameter of a structure or particle is required for stereological calculations. However, there is no consensus on the methodology for its measurement. This study aims to assess the differences between direct and indirect methods of measuring diameter. It is hypothesised that kidneys were removed, fixed, processed, sectioned, and stained. The stained slides were imaged using a digital microscope. The images were processed using the ImageJ software. The diameters of the renal glomeruli and collecting tubules were measured using direct and indirect methods. The measured diameters were analysed using the SPSS software v20. The differences between the measurements were assessed using a Z-test and test of association, and P < 0.05 was considered significant. No significant differences were observed between the diameters of the glomeruli (P = 0.82) and proximal (P = 0.86) and distal (P = 0.55) convoluted tubules as measured via direct and indirect methods. There was a strong positive correlation between the diameters of glomeruli (P = 0.97) and proximal (P = 0.82) and distal (P = 0.93) convoluted tubules measured using the two methods, both of which are convenient, accurate and suitable. The P-values based on these measurements were more than 0.05. Therefore, the study hypothesis was rejected. There was no significant difference between the direct and indirect methods of measuring diameter, and the null hypothesis was rejected; thus, both methods can be applied either independently or jointly.

RESUMEN: Se requiere el conocimiento del diámetro de una estructura o partícula para los cálculos estereológicos. Sin embargo, no existe consenso sobre la metodología para su medición. Este estudio tuvo como objetivo evaluar las diferencias entre los métodos directos e indirectos de medición del diámetro de una estructura. Riñones de ratas Wistar fueron extirpados, fijados, procesados y seccionados, y luego se tiñeron con HE. Se tomaron imágenes de las muestras teñidas usando un microscopio digital. Las imágenes fueron procesadas utilizando el software ImageJ. Los diámetros de los glomérulos renales y túbulos colectores se midieron por métodos directos e indirectos. Los diámetros medidos se analizaron utilizando el software SPSS v20. Las diferencias entre las medidas se evaluaron mediante una prueba Z y una prueba de asociación, y se consideró significativa P < 0,05. No se observaron diferencias significativas entre los diámetros de los glomérulos (P = 0,82) y túbulos contorneados proximales (P = 0,86) y distales (P = 0,55) medidos mediante métodos directos e indirectos. Hubo una fuerte correlación positiva entre los diámetros de los glomérulos (P = 0,97) y los túbulos contorneados proximales (P = 0,82) y distales (P = 0,93) medidos con los dos métodos, ambos convenientes, precisos y adecuados. Los valores P basados en estas mediciones fueron superiores a 0,05. Por lo tanto, se rechazó la hipótesis del estudio. No hubo diferencia significativa entre los métodos directo e indirecto de medición del diámetro, y se rechazó la hipótesis nula; por lo tanto, ambos métodos se pueden aplicar de forma independiente o conjunta.

Learning style preferences among medical students in the College of Medicine, University of Bisha, Saudi Arabia (2018).

OBJECTIVES: This research aims to describe the learning styles among undergraduate medical students at the College of Medicine, University of Bisha. MATERIALS AND METHODS: Type of study is a cross-sectional. Students preference of learning styles was assessed through VARK (abbreviation stands for Visual, Aural, Read/Write, and Kinesthetic learning style) inventory questionnaire version 7.1. The questionnaire was bilingually translated. Data from the questionnaire were analyzed by SPSS (V20). Data were presented in the form of descriptive statistics. One-way ANOVA and Kruskal-Wallis test were used to assess the relations between study variables. RESULTS: One hundred and eighteen students (86.8%) were unimodal in their learning preference, and 18 students (13.3%) were multimodal. The dominant unimodal style was aural (55.9%), and the lowest was reading (5.1%). Among multimodal the commonest preference was AK (77.8%) followed by VR and VK equally (11.1%). The multimodal pattern is limited to students in level one. Visual style increases in percentage with the academic levels. CONCLUSION: Students in the College of Medicine, University of Bisha (UBCOM) have different patterns and types of learning style. Aural is the dominant unimodal style. The visual style is widely distributed among students of different levels. Planning and implementation of educational activities that satisfy all learning styles will support the learning process.

A morphological study of the dorsum sellae in human skull / Estudio morfológico del dorsum sellae en el cráneo humano

Anatomical variations in the shape and dimension of the dorsum sellae and posterior clinoid process are common. Most textbooks describe its shape as a median rectangular plate, a square plate, or a transverse ledge on a slope behind the sella turcica (hypophyseal fossa). This work aims to study the dorsum sellae of human skull. One hundred and twenty five dried adult human skulls, irrespective of age, were used for the study. Detailed features of the dorsum sellae were noted and classified into five types: crest like, thin plate, frail quadrilateral plate, heavy square plate, thick elongated plate. Fusion of the posterior and middle clinoid processes in one (unilateral) and all the clinoid processes (anterior, middle, and posterior) in three skulls (unilateral in one, bilateral in two) were also noticed. Findings are discussed in the light of the literature.

Son frecuentes las variaciones anatómicas de la forma y dimensión de dorsum sellae y de los procesos clinoides posteriores. La mayoría de los textos describen su forma como una placa rectangular mediana, una placa cuadrada, o un plano transversal en una pendiente detrás de la sella turcica (fosa hipofisaria). Este trabajo tiene como objetivo estudiar el dorsum sellae en cráneo humano. Para el estudio se utilizaron 125 cráneos humanos adultos secos, de diferentes edades. Se observaron características detalladas de dorsum sellae y se clasificaron en cinco tipos: cresta, al igual que la placa delgada, lámina cuadrilátera, placa cuadrada gruesa, placa alargada gruesa. En tres cráneos se observó fusión de la parte posterior y los procesos clinoides intermedios (unilateral) y los procesos clinoides (anterior, medio y posterior) (unilateral en uno de ellos, bilateral en dos). Los resultados se discuten en consideracion de la literatura.

Variations of the gallbladder in Sudanese subjects with literature review.

BACKGROUND: Advances in the use of laparoscopic surgery, especially in the biliary apparatus interference makes the need to revise the anatomical data of the gallbladder (GB) more important. Variations of the extra-hepatic biliary apparatus are characterized by large varieties of configurations. OBJECTIVE: The aim of this article was to study the morphology of the GB in Sudanese subjects and review the common variations. MATERIALS AND METHODS: Dissection of formalin-fixed cadavers' abdomens. RESULTS: GB is larger in Sudanese subjects than what is described in the standard text books. CONCLUSION: Congenital anomalies and anatomical variations of the extra-hepatic biliary tree, although not uncommon, can be of clinical importance. There are some differences in the only size of GB in Sudanese.