Inconsequential role for chemerin-like receptor 1 in the manifestation of ozone-induced lung pathophysiology in male mice.

We executed this study to determine if chemerin-like receptor 1 (CMKLR1), a Gi/o protein-coupled receptor expressed by leukocytes and non-leukocytes, contributes to the development of phenotypic features of non-atopic asthma, including airway hyperresponsiveness (AHR) to acetyl-ß-methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non-atopic asthma in wild-type mice and mice incapable of expressing CMKLR1 (CMKLR1-deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3), a criteria pollutant and non-atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi-functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1-deficient as compared to wild-type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype-related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype-related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3.

Role of Endoscopic Ultrasound in Staging and Vascular Assessment of Pancreatic Cancer.

Introduction Computed tomography (CT) of the abdomen with contrast stands as the gold standard for assessing pancreatic cancer, encompassing both staging and vascular analysis. However, not all patients are suitable candidates for contrast-enhanced CT (CECT) scans due to factors such as contrast agent allergies, pregnancy, renal impairment, radiation risks, and limited tissue sampling capability in CECT scans of the abdomen. In light of these challenges, this study evaluated the diagnostic capabilities of endoscopic ultrasound (EUS) compared to CECT for staging and vascular assessment of pancreatic cancer. Methods Fifty patients diagnosed with pancreatic cancer underwent evaluations using both CECT scans and EUS, focusing on staging and vascular invasion assessment. Vascular evaluation was carried out using a categorization system based on EUS findings, classifying them into three types based on the tumor-vessel relationship: Type 1 indicating clear invasion or encasement of a vessel by a tumor or contact with a vessel wall exceeding 180 degrees, Type 2 representing abutment, wherein a tumor contacts a vessel wall but at an angle less than 180 degrees, and Type 3 implying clear non-invasion, where a discernible distance exists between a tumor and a vessel. In this categorization, Type 1 and Type 2 indicated signs of vascular invasion, while Type 3 indicated vascular non-invasion. These findings were subsequently compared to the results from CECT scans. The endoscopist performing EUS was blinded to the CT outcomes prior to the examination. Results Regarding pancreatic cancer staging, EUS exhibited remarkable sensitivity, specificity, and accuracy rates of 100% according to the T criterion.As for vascular invasion assessment, EUS demonstrated sensitivity, specificity, and accuracy of 100%, 95.93%, and 96%, respectively, for venous invasion. For arterial invasion, the figures were 95.65% sensitivity, 100% specificity, and an overall accuracy of 99.5%. Conclusion EUS is an effective modality for evaluating both staging and vascular invasion in pancreatic cancer, boasting exceptional sensitivity, specificity, and accuracy rates. The findings are robust enough to consider EUS a viable alternative to CT scans in evaluation, with the added advantage of EUS offering tissue sampling capability.

Pembrolizumab-induced myocarditis with complete atrioventricular block and concomitant myositis in a metastatic bladder cancer patient: a case report and review of the literature.

BACKGROUND: The cardiovascular system is among the least systems affected by immune-related adverse events. We report a rare life-threatening case of pembrolizumab-induced myocarditis with complete atrioventricular block and concomitant myositis in a metastatic bladder cancer patient. CASE PRESENTATION: An 82-year-old Caucasian female with invasive urothelial carcinoma, started on first-line pembrolizumab, was admitted four days after receiving her second dose for severe asthenia, diffuse muscle aches, neck pain, and lethargy. In the emergency department, she had several episodes of bradycardia reaching 40 beats per minute associated with general discomfort and fatigue. Electrocardiography showed a third-degree atrioventricular heart block, while the patient remained normotensive. Cardiac damage parameters were altered with elevated levels of creatine phosphokinase of 8930 U/L, suggestive of immune checkpoint inhibitor-induced myositis, and troponin T of 1.060 ng/mL. Transthoracic echocardiography showed a preserved ejection fraction. Pembrolizumab-induced myocarditis was suspected. Therefore, treatment was initiated with high-dose glucocorticoids for 5 days, followed by a long oral steroid taper. A pacemaker was also implanted. Treatment resulted in the resolution of heart block and a decrease in creatine phosphokinase to the normal range. CONCLUSION: Life-threatening cardiac adverse events in the form of myocarditis may occur with pembrolizumab use, warranting vigilant cardiac monitoring. Troponin monitoring in high-risk patients, along with baseline echocardiography may help identify this complication promptly to prevent life-threatening consequences.

Discovery of new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof.

New thymol-3,4-disubstitutedthiazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 6b, 6d, 6e, and 6f displayed in vitro inhibitory activity against COX-2 (IC50= 0.037, 0.042, 0.046, and 0.039 µM) nearly equal to celecoxib (IC50= 0.045 µM). 6b, 6d, and 6f showed SI (379, 341, and 374, respectively) higher than that of celecoxib (327). 6a-l elicited in vitro 5-LOX inhibitory activity higher than quercetin. 6a-f, 6i-l, 7a, and 7c possessed in vivo inhibition of formalin induced paw edoema higher than celecoxib. 6a, 6b, 6f, 6h-l, and 7b showed gastrointestinal safety profile as celecoxib and diclofenac sodium in the population of fasted rats. Induced fit docking and molecular dynamics simulation predicted good fitting of 6b and 6f without changing the packing and globularity of the apo protein. In conclusion, 6b and 6f achieved the target goal as multitarget inhibitors of inflammation.

Retraction: Ruptured Isolated Common Iliac Artery Aneurysm Masquerading as Renal Colic.

[This retracts the article DOI: 10.7759/cureus.19752.].

Compact, portable, automatic sample changer stick for cryostats and closed-cycle refrigerators.

Beamlines are facilities that produce and deliver highly focused and intense beams of radiation, typically x rays, synchrotron radiation, or neutrons, for scientific research purposes. Millions of dollars are spent annually to maintain and operate these scientific beamlines, oftentimes running continuously between cycles. To reduce human intervention and improve productivity, mechanical sample changers are often commissioned for use. Designing sample changers is difficult because mechanical parts can be bulky, expensive, and challenging to design for instruments with low volume access, high radiation, and cryogenic environments. We present a portable and inexpensive sample changer stick that can hold and manipulate up to four samples, specifically designed for use with cryogenic closed-cycle refrigerators. The sample changer stick enables rapid and efficient exchange of samples without manual intervention, and is compatible with standard sample mounts such as vanadium cans. The sample changer stick includes a motorized rotation and lancing mechanism, which enables the precise positioning of each sample in the neutron beam, while ensuring compatibility with the operating temperatures and vacuum conditions required for closed-cycle refrigerators. The design has been successfully tested at the VISION beamline at the Spallation Neutron Source. The mechanical action and software controls are detailed. The sample changer stick is a valuable tool for scientists working with cryogenic closed-cycle refrigerators.

Interaction between gut microbiota metabolites and dietary components in lipid metabolism and metabolic diseases.

Gut microbiota composition has caused perplexity in developing precision therapy to cure metabolic disorders. However, recent research has focused on using daily diet and natural bioactive compounds to correct gut microbiota dysbiosis and regulate host metabolism. Complex interactions between the gut microbiota and dietary compounds disrupt or integrate the gut barrier and lipid metabolism. In this review, we investigate the role of diet and bioactive natural compounds in gut microbiota dysbiosis and also the modulation of lipid metabolism by their metabolites. Recent studies have revealed that diet, natural compounds and phytochemicals impact significantly on lipid metabolism in animals and humans. These findings suggest that dietary components or natural bioactive compounds have a significant impact on microbial dysbiosis linked to metabolic diseases. The interaction between dietary components or natural bioactive compounds and gut microbiota metabolites can regulate lipid metabolism. Additionally, natural products can shape the gut microbiota and improve barrier integrity by interacting with gut metabolites and their precursors, even in unfavourable conditions, potentially contributing to the alignment of host physiology.

Effect of Ajwa date pits powder (Phoenix dactylifera L.) on body composition, lipid profile and blood pressure in patients with hyperlipidemia: A randomized clinical trial.

Objective: To evaluate the effect of Ajwa dates pit powder (ADP) on lipid profile, body composition and blood pressure in patients with hyperlipidemia. Materials and Methods: This randomized controlled clinical study was carried out on 40 patients with total cholesterol >200 mg/dl, triglycerides >150 mg/dl and BMI >25, of either sex, aged 30-50 years, who were recruited through written consent. The patients were divided into two groups (n=20 each): the ADP and the control group (CG). All patients received the doctor's prescribed class A statin (Rosuvastatin/ Atorvastatin) 10 mg/day, while 2.7 g ADP was given on daily basis before breakfast with lukewarm water for 40 days and the control group received the same amount of wheat flour. Body composition, blood pressure and lipid profile were determined at baseline, and after 20 and 40 days. Data were analyzed by using SPSS and GraphPad Prism. Results: ADP significantly reduced body weight (p<0.001), BMI (p<0.001), fat mass, body fat percentage, visceral fat area and waist circumference compared to the control group. Similarly, ADP significantly (p=0.000) decreased the serum level of total cholesterol and low-density lipoprotein. Conclusion: ADP may have the potential to improve dyslipidemia and obesity.

Towards safer anti-inflammatory therapy: synthesis of new thymol-pyrazole hybrids as dual COX-2/5-LOX inhibitors.

New thymol - 1,5-disubstitutedpyrazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 8b, 8g, 8c, and 4a displayed in vitro inhibitory activity against COX-2 (IC50 = 0.043, 0.045, 0.063, and 0.068 µM) nearly equal to celecoxib (IC50 = 0.045 µM) with high SI (316, 268, 204, and 151, respectively) comparable to celecoxib (327). All target compounds, 4a-c and 8a-i, showed in vitro 5-LOX inhibitory activity higher than reference quercetin. Besides, they possessed in vivo inhibition of formalin-induced paw oedema higher than celecoxib. In addition, compounds 4a, 4b, 8b, and 8g showed superior gastrointestinal safety profile (no ulceration) as celecoxib and diclofenac sodium in the population of fasted rats. In conclusion, compounds 4a, 8b, and 8g achieved the target goal. They elicited in vitro dual inhibition of COX-2/5-LOX higher than celecoxib and quercetin, in vivo potent anti-inflammatory activity higher than celecoxib and in vivo superior gastrointestinal safety profile (no ulceration) as celecoxib.

Hypothesis and Holistic Knowledge of Testicular Torsion Among the General Population of the Kingdom of Saudi Arabia.

Background Testicular torsion is a serious condition that requires immediate medical attention. It occurs when the spermatic cord, which carries blood to the testicles, twists, reducing blood flow and oxygen to the testicle. This can lead to tissue death and loss of the testis if not treated promptly. It is important to seek medical attention immediately when symptoms of testicular torsion arise, as prompt treatment can help prevent permanent damage to the testicle. This study aimed to explore the level of knowledge about testicular torsion among the general population in the Kingdom of Saudi Arabia. Methodology A descriptive cross-sectional study was conducted using a convenience sample recruited from the general population who fulfilled the inclusion criteria. The data were collected from participants using an electronic pre-structured questionnaire. The researchers developed the questionnaire through expert consultation and after an intensive literature review. The questionnaire was reviewed by a panel of three experts for validation and applicability. After a pilot study, the reliability coefficient (Cronbach's alpha) was 0.74. The data were analyzed using SSPS version 25 (IBM Corp., Armonk, NY, USA) and presented as percentages and frequencies. Chi-square and logistic regression were conducted. P-values ≤0.05 were considered statistically significant. Results A total of 732 participants were recruited, most of whom were male (486, 66.4%), with ages ranging between 18 and 30 years (452, 61.7%). Regarding testicular torsion knowledge, more than half of the participants had good knowledge (406, 55.5%) and knew about the signs, symptoms, and risk factors of testicular torsion. There was a statistically significant relationship between age and knowledge (p < 0.001) and an insignificant relationship between sex and knowledge (p > 0.05). Conclusions The study participants were found to have good knowledge. Fortunately, most participants knew that testicular torsion is an emergency and they must immediately visit the hospital. With further awareness programs, the overall knowledge level can be improved.

Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone.

Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O3), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O3, we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O3-exposed IL-11Rα1-deficient as compared with O3-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O3-exposed mice. However, airway responsiveness to acetyl-ß-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O3 exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.

Painless Left Scrotal Mass: A Rare Case of Paratesticular Angiofibroma.

Angiofibromas, also known as angiomyofibroblastoma-like tumors or AMF-like tumors, refer to a collection of rare, benign yet highly cellular tumors of the vulva, scrotum, perineum, or inguinal region. In this paper, we present a 34-year-old Saudi man who presented with findings of a testicular tumor on physical examination and imaging and tested negative for all the markers associated with testicular tumors.

Cerebral Venous Sinus Thrombosis in Closed Head Injury: Systematic Review and Meta-analysis.

BACKGROUND: Cerebral venous sinus thrombosis (CSVT) is a rare condition, causing 0.5% of all strokes only, several mechanisms might be involved in forming the thrombosis, including closed head injury. METHODS: Systematic review was done by using the following databases: PubMed, Google Scholar, Microsoft Academic, Clinical Trials, Cochrane Library, and Web of Science. RESULTS: 25 articles met our criteria out of 152 articles, average and standard deviation of the age was 38.2 ± 16.8 years with an age range of 18-82. The majority of cases presented with loss of consciousness or decreased GCS (41%), followed by headache (26%), scalp abrasions/lacerations (21%), paralysis (18%), visual disturbance (18%), nystagmus (15%), and agitation (15%). The most commonly used diagnostic method was angiography. Thrombosis was the most frequently reported radiological finding among all the cases (26/34, 76%). Comparisons of outcomes between patients who underwent surgical intervention and those who did not undergo surgery revealed a significant difference in outcome favoring non-surgical treatment (p < 0.005, odds ratio (OR) 0.04, (95% CI) 0.003 - 0.30). CONCLUSION: Non-surgical outcomes were better than the surgical outcomes. However, no significant difference was seen comparing anti-coagulation versus conservative management (supportive without anticoagulation), single versus multi-sinuses (≥2 sinuses) involvement, and between any of the sinuses involved.

Fracture risk following bariatric surgery: a systematic review and meta-analysis.

Bariatric surgery may negatively impact bone health. We aimed to compare fracture risk following bariatric surgery by type (malabsorptive, restrictive), or to non-surgical weight loss, or to controls with obesity. We systematically searched four databases from inception until October 2020. We included observational and interventional studies on adults. We screened articles and abstracted data in duplicate and independently and assessed the risk of bias. We conducted random-effects model meta-analyses (Review Manager v5.3), to calculate the relative risk of any or site-specific fracture (CRD42019128536). We identified four trials of unclear-to-high risk of bias and 15 observational studies of fair-to-good quality. Data on fracture risk following bariatric surgery compared to medical weight loss is scarce and limited by the small number of participants. In observational studies, at a mean/median post-operative follow-up > 2 years, the relative risk of any fracture was 45% (p < 0.001) and 61% (p = 0.04) higher following malabsorptive procedures compared to obese controls and restrictive procedures, respectively, with moderate to high heterogeneity. Site-specific relative fracture risk (hip and wrist) was one- to two-folds higher post malabsorptive procedures compared to obese controls or restrictive procedures. The risks of any and of site-specific fracture were not increased following restrictive procedures compared to obese controls. Fracture risk seems to increase following malabsorptive bariatric surgeries, at a mean/median follow-up > 2 years. The risk is not increased with restrictive surgeries. The available evidence has several limitations. A prospective and rigorous long-term follow-up of patients following bariatric surgery is needed for a better assessment of their fracture risk with aging.

Ruptured Isolated Common Iliac Artery Aneurysm Masquerading as Renal Colic.

Urinary stone disease is a common problem globally. Ureteric colic typically presents with flank pain and hematuria. However, several conditions may give a similar clinical picture. Hence, imaging studies are essential to make the diagnosis of urinary stone disease and evaluate for possible complications. We present the case of a 64-year-old man who presented with severe left flank pain radiating to the groin for two days. In his first visit to the emergency department, he was prescribed conservative treatment, but it failed to give any clinical improvement. The patient does not have a previous history of urinary stone disease. He had a long-standing history of hypertension, diabetes mellitus, dyslipidemia, and coronary artery disease. Further, he had a 30 pack-years history of smoking. Upon examination, the abdomen was soft and lax with generalized tenderness. Subsequently, a non-contrast computed tomography scan for the kidneys, ureters, and bladder was performed, which demonstrated a large high attenuation fluid seen in the left side of the retroperitoneum. The scan was then repeated after the administration of intravenous contrast and showed an aneurysmal dilatation of the left common iliac artery with surrounding hematoma. The patient was taken for an emergency laparotomy for evacuation of the hematoma and graft repair of the aneurysm. The patient tolerated the operation without complications. The present case highlights the importance of considering the wide differential diagnoses of flank pain in emergency settings. Physicians should keep a high index of suspicion for aneurysmal disease when they encounter patients with risk factors for arterial wall degeneration.

Discovery of small molecule acting as multitarget inhibitor of colorectal cancer by simultaneous blocking of the key COX-2, 5-LOX and PIM-1 kinase enzymes.

Colorectal cancer (CRC) is the second cause of cancer death worldwide. Inhibitors of COX-2, 5-LOX and PIM-1 kinase were very effective in the treatment and prevention of CRC in mouse models in vivo. Furthermore, thymol was confirmed to inhibit CRC cell proliferation in cancer cell lines and inhibitory activity against COX-2 and 5-LOX. On the other hand, 4-thiazolidinone pharmacophore was incorporated in the structures of various reported COX-2, 5-LOX and PIM kinase inhibitors. Consequently, the aim of the present investigation was to combat CRC by synthesis and biological evaluation of new thymol - 4-thiazolidinone hybrids as multitarget anticancer agents that could inhibit the key COX-2, 5-LOX and PIM-1 kinase enzymes simultaneously. Compounds 5a-d and 5g displayed inhibitory activity against COX-2 nearly equal to Celecoxib with high selectivity index (SI). Moreover, compounds 5b-e showed 5-LOX inhibitory activity nearly equal to the reference Quercetin while compounds 5a, 5f and 5g elicited inhibitory activity slightly lower than Quercetin. Furthermore, in vivo formalin-induced paw edema test revealed that, compounds 5a, 5c, 5f and 5g showed higher % inhibition than Celecoxib and compounds 5a, 5f and 5g showed higher % inhibition than Diclofenac sodium. In addition, compounds 5a-c, 5e-g showed in vivo superior gastrointestinal safety profile as Celecoxib in fasted rats. Besides, compounds 5d, 5e and 5g exhibited the highest activity against human CRC cell lines (Caco-2 and HCT-116) at doses less than their EC100 on normal human cells. Furthermore, compounds 5e and 5g induced apoptosis-dependent death by above 50% in the treated CRC cell lines. Moreover, compounds 5e and 5g induced caspase activation by >50% in human CRC. Also, compounds 5d, 5e and 5g showed in vitro inhibitory activity against both PIM-1\2 kinases comparable to the reference Staurosporine. In silico docking studies were concordant with the biological results. In conclusion, compound 5g, of simple chemical structure, achieved the target goal of inhibiting three targets leading to inhibition of human CRC cell proliferation. It inhibited the target key enzymes COX-2, 5-LOX and PIM-1\2 kinase in vitro. Besides, it revealed in vitro inhibition of cell proliferation in cancer cell lines via activation of caspase 3\7 dependent-apoptosis in human CRC cell lines. In addition, it elicited in vivo anti-inflammatory activity in formalin-induced paw edema test and in vivo oral safety in gastric ulcerogenic activity test.

Design, microwave assisted synthesis, and molecular modeling study of some new 1,3,4-thiadiazole derivatives as potent anticancer agents and potential VEGFR-2 inhibitors.

A green and efficient method was developed for the synthesis of 1,3,4-thiadiazole based compounds under microwave (MW) activation. The nucleophile N-(5-amino-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide (3) was synthesized and reacted with different carbon electrophilic reagents to afford thiadiazolo-pyrimidine or imidazolo-thiadiazoline derivatives (4-6 and 8), respectively. Furthermore, a one-pot reaction of 3 with p-chlorobenzaldehyde and different carbon electrophile/ or nucleophiles under microwave irradiation yields the cyclic thiadiazolo-pyrimidine derivatives 10-15. Additionally, nucleophilic substitution of aromatic amines and/or potassium salts of some heterocyclic compounds with chloroacetamido-thiadiazole 6 yields derivatives 16-20. All the new derivatives were synthesized by both conventional and MW irradiation methods. All the new 1,3,4-thiadiazole derivatives were evaluated against four cancer cell lines, HepG-2, MCF-7, HCT-116, and PC-3. The anti-proliferative activity of most of the synthesized compounds exhibited excellent broad-spectrum cytotoxic activity against the cancer cell lines with IC50 values ranging from 3.97 to 9.62 µM. Moreover, the enzymatic assessment of five derivatives (2,4b, 6, 8, 9a) against VEGFR-2 tyrosine kinase showed significant inhibitory activities with IC50 of 11.5, 8.2, 10.3, 10.5 and 9.4 nM respectively. Further studies revealed the ability of compound 9a to have a strong DNA-binding affinity of 36.06 µM via DNA/methyl green assay. Moreover, molecular docking study was carried out to reveal the binding interactions of compounds in the binding site of VEGFR-2 enzyme explaining the significant inhibitory activity of these derivatives. Finally, ADME/Tox studies was performed to predict the pharmacokinetics of the synthesized compounds.