Kinin B1 receptor and TLR4 interaction in inflammatory response.

OBJECTIVE: We aimed to broaden our understanding of a potential interaction between B1R and TLR4, considering earlier studies suggesting that lipopolysaccharide (LPS) may trigger B1R stimulation. METHODS: We assessed the impact of DBK and LPS on the membrane potential of thoracic aortas from C57BL/6, B1R, or TLR4 knockout mice. Additionally, we examined the staining patterns of these receptors in the thoracic aortas of C57BL/6 and in endothelial cells (HBMEC). RESULTS: DBK does not affect the resting membrane potential of aortic rings in C57BL/6 mice, but it hyperpolarizes preparations in B1KO and TLR4KO mice. The hyperpolarization mechanism in B1KO mice involves B2R, and the TLR4KO response is independent of cytoplasmic calcium influx but relies on potassium channels. Conversely, LPS hyperpolarizes thoracic aorta rings in both C57BL/6 and B1KO mice, with the response unaffected by a B1R antagonist. Interestingly, the absence of B1R alters the LPS response to potassium channels. These activities are independent of nitric oxide synthase (NOS). While exposure to DBK and LPS does not alter B1R and TLR4 mRNA expression, treatment with these agonists increases B1R staining in endothelial cells of thoracic aortic rings and modifies the staining pattern of B1R and TLR4 in endothelial cells. Proximity ligation assay suggests a interaction between the receptors. CONCLUSION: Our findings provide additional support for a putative connection between B1R and TLR4 signaling. Given the involvement of these receptors and their agonists in inflammation, it suggests that drugs and therapies targeting their effects could be promising therapeutic avenues worth exploring.

Intraoperative Angle Measurement of Anatomical Structures: A Systematic Review.

Ensuring precise angle measurement during surgical correction of orientation-related deformities is crucial for optimal postoperative outcomes, yet there is a lack of an ideal commercial solution. Current measurement sensors and instrumentation have limitations that make their use context-specific, demanding a methodical evaluation of the field. A systematic review was carried out in March 2023. Studies reporting technologies and validation methods for intraoperative angular measurement of anatomical structures were analyzed. A total of 32 studies were included, 17 focused on image-based technologies (6 fluoroscopy, 4 camera-based tracking, and 7 CT-based), while 15 explored non-image-based technologies (6 manual instruments and 9 inertial sensor-based instruments). Image-based technologies offer better accuracy and 3D capabilities but pose challenges like additional equipment, increased radiation exposure, time, and cost. Non-image-based technologies are cost-effective but may be influenced by the surgeon's perception and require careful calibration. Nevertheless, the choice of the proper technology should take into consideration the influence of the expected error in the surgery, surgery type, and radiation dose limit. This comprehensive review serves as a valuable guide for surgeons seeking precise angle measurements intraoperatively. It not only explores the performance and application of existing technologies but also aids in the future development of innovative solutions.

Comparison of endothelial cell loss in diabetic patients after conventional phacoemulsification and femtosecond laser-assisted cataract surgery.

PURPOSE: This study aims to comparatively evaluate the morphological changes of the cornea after phacoemulsification (PHACO) and femtosecond laser-assisted cataract surgery (FLACS) without intercurrences in patients with type 2 diabetes mellitus. METHODS: A total of 95 diabetic patients with moderate cataracts (N2 + and N3+), 47 undergoing PHACO and 48 undergoing FLACS, were selected randomly for the study. Surgeries were performed by a single surgeon between July 2021 and December 2021. Cumulative dissipated energy (CDE) and total balanced saline solution (BSS) data were obtained at the end of each surgery. Changes in corneal endothelial cell density (ECD) and central corneal thickness (CCT) at three months postoperatively were investigated. RESULTS: After three months, evidence is lacking between groups in the CCT measures; the difference was neither statistically nor clinically relevant. However, for ECD, a significant and clinically significant difference was found; if all patients were treated with laser, the mean ECD would be 423.55 greater (RSE: 86.09; p-value < 0.001; 95% CI: 254.81-592.29) than the ECD potential means of 1656.423 among the conventional group (RSE: 74.90; p-value < 0.001; 95% CI: 1509.62-1803.23). CONCLUSIONS: Diabetic patients under treatment with moderate cataracts may predispose themselves to a more significant loss of endothelial cells after conventional phacoemulsification than femtosecond laser-assisted cataract surgery. TRIAL REGISTRATION: It was registered at The Brazilian Registry of Clinical Trials (ReBEC) with the code RBR-6d8whb5 (UTN code: U1111-1277-6020) on 17/05/2022.

When benign leiomyomas metastasize to the lungs - a case report.

Benign metastasizing leiomyoma is a rare disease that primarily affects premenopausal women who have a history of uterine leiomyoma, which is characterized by pulmonary metastases. The pathogenesis of this condition is unknown. Patients are usually asymptomatic or have vague symptoms. Pathological examination in conjunction with immunohistochemistry is required for diagno-sis. Treatment is determined by the patient's age, hormonal status, symptoms, and the extent of the lesions (number, size, and location of nodules), with surgical resection being the most effective. We present the case of a 72-year-old woman who had a total hysterec-tomy 30 years earlier due to myomas and developed a persistent dry cough. Her computed tomography of the chest revealed several small nodules in the pulmonary parenchyma. Because of the nod-ules' small size and difficult accessibility, a surgical biopsy was per-formed for histopathological examination and immunohistochemi-cal staining, which revealed metastasizing leiomyoma. Letrozole treatment was started and was well tolerated.

Inflammatory myofibroblastic tumor presenting as a subepithelial lesion of the colon.

We present the case of a 42-year-old male admitted to the emergency department for a 15-day history of diarrhea, with bloody stools in the past 7 days. The patient denied abdominal pain or distension as well as any constitutional symptoms. On physical examination he presented good general health condition, with abdomen slightly tender in the lower quadrants; digital rectal examination was remarkable for the presence of dark blood. Laboratory evaluation revealed new onset normocytic anemia (Hb 10.8 g/dL, MCV 89 fL) and RCP of 3.3 mg/dL. Colonoscopy was performed, which showed a large cecal subepithelial lesion, with surface ulcerations. Histology reported mixed inflammatory infiltrate but no malignancy. Further investigation was carried out with an abdominal and pelvic computerized tomography that, other than the cecal mass, showed multiple infracentimetric mesenteric lymph nodes. A right laparoscopic hemicolectomy was performed. Pathological analysis led to the unusual diagnosis of inflammatory myofibroblastic tumor (IMT) of the colon. There was no sign of recurrence after 6 months of follow-up.

The pan-genome of the emerging multidrug-resistant pathogen Corynebacterium striatum.

Corynebacterium striatum, a common constituent of the human skin microbiome, is now considered an emerging multidrug-resistant pathogen of immunocompromised and chronically ill patients. However, little is known about the molecular mechanisms in the transition from colonization to the multidrug-resistant (MDR) invasive phenotype in clinical isolates. This study performed a comprehensive pan-genomic analysis of C. striatum, including isolates from "normal skin microbiome" and from MDR infections, to gain insights into genetic factors contributing to pathogenicity and multidrug resistance in this species. For this, three novel genome sequences were obtained from clinical isolates of C. striatum of patients from Brazil, and other 24 complete or draft C. striatum genomes were retrieved from GenBank, including the ATCC6940 isolate from the Human Microbiome Project. Analysis of C. striatum strains demonstrated the presence of an open pan-genome (α = 0.852803) containing 3816 gene families, including 15 antimicrobial resistance (AMR) genes and 32 putative virulence factors. The core and accessory genomes included 1297 and 1307 genes, respectively. The identified AMR genes are primarily associated with resistance to aminoglycosides and tetracyclines. Of these, 66.6% are present in genomic islands, and four AMR genes, including aac(6')-ib7, are located in a class 1-integron. In conclusion, our data indicated that C. striatum possesses genomic characteristics favorable to the invasive phenotype, with high genomic plasticity, a robust genetic arsenal for iron acquisition, and important virulence determinants and AMR genes present in mobile genetic elements.

Spontaneous Adverse Event Reporting by COVID-19 Vaccinated Healthcare Professionals Through an Electronic Form Implemented by the Hospital Pharmacy.

Aim: Implementation of a web-form based pharmacovigilance plan for the spontaneous notification of adverse events to the Comirnaty® COVID-19 vaccine during its administration to hospital healthcare professionals. Methods: An electronic pharmacovigilance form was developed containing 8 pre-defined event options, an open answer option for the description of other events and/or symptoms, and a question about the overall intensity of symptoms. The adverse events reports were standardized according to physiological and pathological condition. Results: A total of 4119 adverse events notifications were obtained with a 45% rate of electronic notification. The most clinically relevant events reported were:tachycardia (n = 19), dyspnea (n = 7), chest pain (n = 6), facial/labial edema (n = 6), lipothymia (n = 5), bronchospasm (n = 2), herpetic infection (n = 2), vasculitis (n = 2), arrhythmia (n = 1), difficult to control arterial hypertension (n = 1), gastritis (n = 1), and spontaneous abortion (n = 1). Regarding the intensity of symptoms (n = 2928), 70.0% were reported as mild, 25.8% as moderate, and 4.27% as severe, with higher intensity in the second dose compared to first dose. The highest frequency of severe events were reported in the groups from 40 to 59 years in both vaccination periods. During the vaccination process, no hospitalizations and no deaths were notified and/or recorded. Conclusion: In this real world study, comparing with Comirnaty clinical trials program, it was observed a higher frequency of adenomegaly and gastrointestinal disorders. Noteworthy, the notification of a case of miscarriage. The use of hospital pharmacy pharmacovigilance electronic forms, seemed to be relevant to notification adherence and to obtain a greater and faster knowledge of COVID-19 vaccine safety profile.

Cardiovascular and cerebrovascular risk markers in Parkinson's disease: Results from a case-control study.

BACKGROUND: The relationship between Parkinson's disease (PD) and cardiovascular and cerebrovascular disease is not yet well established. Recent data suggest an increased risk of myocardial infarction and stroke in PD patients. Therefore, we designed a study to assess surrogate markers of cardiovascular and cerebrovascular risk in PD. METHODS: We conducted a case-control study comparing PD patients recruited from a Movement Disorders Unit with controls randomly invited from a primary healthcare center. All participants underwent a detailed clinical evaluation, including medical history, physical assessment, carotid ultrasound, blood and urine analysis, and 24-h ambulatory blood pressure monitoring. The primary outcome was the carotid intima-media thickness (CIMT). RESULTS: We included 102 participants in each study arm. No significant difference was found in the CIMT among groups (MD: 0.01, 95% CI: -0.02, 0.04). Carotid plaques were more frequent in PD patients (OR: 1.90, 95% CI: 1.02, 3.55), although the lipid profile was more favorable in this group (LDL MD: -18.75; 95% CI: -10.69, -26.81). Nocturnal systolic blood pressure was significantly higher in PD patients (MD: 4.37, 95% CI: 0.27, 8.47) and more than half of the PD patients were non-dippers or reverse dippers (OR: 1.83, 95% CI: 1.04, 3.20). CONCLUSION: We did not find a difference in CIMT between PD and controls. A higher frequency of carotid plaques and abnormal dipper profile supports the hypothesis that PD patients are not protected from cardiovascular and cerebrovascular disease.

Biomonitoring of children and adolescents using orthodontic appliances made of acrylic resins through micronucleus testing of exfoliated buccal and palatal mucosa cells.

INTRODUCTION: The present study aimed to investigate the occurrence of micronuclei and the degenerative nuclear alterations indicative of apoptosis and necrosis in the exfoliated buccal and palatal mucosa cells of children and adolescents using orthodontic appliances made of self-curing acrylic resins. METHODS: The micronuclei and nuclear alterations were evaluated in a minimum of 2000 cells collected from the cheeks and palates of 30 patients of both sexes, aged between 6 and 12 years. The cell evaluations were performed before appliance installation and 15 to 21 days after installation. A conditional test was used. In all analyses, the significance level was 5%. RESULTS: No differences in the occurrence of micronuclei or the nuclear degenerative changes indicative of apoptosis and necrosis were observed in the cheek cells between the 2 time points (P > 0.05). However, evaluation of the palate cells revealed a significant increase in the occurrence of micronuclei and the nuclear alterations indicative of apoptosis (P < 0.01) but not of karyolysis (P > 0.05). CONCLUSIONS: Direct contact of orthodontic appliances made of acrylic resins with the oral mucosa increases the incidence of chromosomal damage and degenerative nuclear alterations.

CUB domain-containing protein 1 (CDCP1) binds transforming growth factor beta family members and increase TGF-ß1 signaling pathway.

CUB domains are most exclusively found in secreted proteins and in a few transmembrane proteins. These domains are approximately 110 amino acids long and have four conserved cysteines that form a ß-sandwich fold. CUB domains proteins are involved in a wide range of biological functions. We have shown that CUB domains from Tolloid/BMP1 can bind BMP4 and block BMP signaling in the developing frog embryo. CUB domain-containing protein 1 (CDCP1) is one of the few transmembrane glycoprotein that contains three extracellular CUB domains and regulates anchorage-independent growth and cancer cell migration through activation of Src kinases. In the extracellular space, only a few proteins were found to interact with CDCP1 and at the moment no ligand was found. We demonstrate by using real time protein interaction on BIAcore chip that CDCP1 CUB domains bind directly to TGF-ß1 and BMP4. CDCP1 enhances TGF-ß1 signaling reporter activity and phosphorylated Smad2 levels but does not modulate BMP signaling pathway. CDCP1 actions on TGF-ß/Smad2 signaling are dependent on Smad2 and TGFRI and do not require Src or PKCδ binding. Our findings uncover a new co-receptor for TGF-ß1 and bring up new questions on whether CDCP1 cooperates with TGF-ß1 to promote cancer progression.

Anaerobic and Agility Parameters of Salonists in Laboratory and Field Tests.

This study aimed to investigate the relationship between mechanical parameters from the Running-based Anaerobic Sprint Test (RAST2×17.5), agility performance from the Illinois Agility Test (IAT) and all-out 30-second tethered running (AO30) in college futsal athletes. It also investigates whether these protocols are capable of identifying differences between sexes. Twenty subjects were evaluated. The IAT was applied on a specific course and performance was considered as the total time (T.T). The RAST2×17.5 consisted of six maximum efforts in a shuttle exercise of 2x17.5 m per bout. The AO30 was conducted under maximal effort on a non-motorized treadmill. Maximum, mean and minimum power were determined for RAST2×17.5 and AO30. Mean power from RAST2×17.5 was inversely and significantly correlated to T.T regardless of sex (male: r=-0.76; p=0.010; female: r=-0.89; p=0.010). A similar association was noticed for maximum power for females (r=-0.94; p=0.001). The AO30 maximum and mean power were significantly correlated with T.T (male: r=-0.67; p=0.031 and r=-0.66; p=0.035, respectively; female: r=-0.64; p=0.046 and r=0.66; p=0.035, respectively). Maximum power from RAST2×17.5 and AO30 were significantly correlated (male: r=0.68; p=0.030; female: r=0.72; p=0.019). Our results reinforce the adoption of field-based tests like RAST2×17.5 and IAT for futsal, since significant relationships among these parameters and AO30 results were obtained. Moreover, these protocols differentiated male and female athletes by mechanical and agility parameters, proving their application under specific field evaluation.

Paroxysmal atrial fibrillation detection in patients with acute ischemic stroke through prolonged Holter: prospective study.

INTRODUCTION: The detection of paroxysmal atrial fibrillation (PAF) is crucial in the etiological study of an acute ischemic stroke (AIS), although this type of arrhythmia is often under-diagnosed. This prospective study aims to (1) evaluate the new-onset PAF detection rate among elderly patients with AIS in an acute setting, and (2) to assess the applicability of the STAF score (Score for the Targeting of Atrial Fibrillation) for such patients. METHODOLOGY: An observational and prospective study was performed over a period of 11 months. Patients with acute ischemic stroke who had been admitted to the stroke unit were included. Exclusion criteria included prior AF, AF readings on ECG during admission, or stroke mimic. The patients were monitored with a bedside ECG monitor throughout the first 48 h, then simultaneously with an extended Holter recorder for a maximum of 6 days. The occurrence and duration of PAF events was evaluated. The STAF risk score for PAF was calculated and compared to the detection rate of PAF for each patient. RESULTS: The sample population consisted of 67 patients, whose median age was 76 years (IQR 71-84) and who were 57% males. The median duration of Holter recording was 3.5 days per patient (IQR 2-5). We detected new PAF cases in 16% of patients, and a total of 31% had supraventricular arrhythmia episodes lasting 10 s or longer. Among the patients in which this arrhythmia was detected, 10% had it detected by the bedside ECG monitor in the first 48 h. The median risk score was 5 (IQR 4-6). There was no association between the risk score used and PAF. CONCLUSION: In elderly patients with AIS, the use of an extended Holter recorder led to the detection of more cases of PAF, offering them the chance to initiate hypocoagulant therapy. Among this population, the STAF score was non-discriminative and did not prove useful in predicting PAF.

Adult thigh muscle injuries-from diagnosis to treatment: what the radiologist should know.

Muscle injuries are one of the major problems facing elite athletes, representing a significant source of time lost from competition, with substantial consequences for teams and athletes. There are considerable pressures for a rapid return, but players who return to competition too soon have an increased risk of recurrent muscle injuries, which are associated with longer lay-offs. Imaging plays a key role in achieving the correct diagnosis, and magnetic resonance imaging (MRI) has emerged as the method of choice for skeletal muscle imaging. Several authors have reported prognostic MRI features, but it is difficult to predict the exact length of time to return to full training afterwards due to considerable discrepancy and overlap between different injuries. Therefore, development of a universally applicable classification and grading system is challenging. This paper aims to: (a) review the contemporary role of imaging in the setting of muscle injuries, with special focus on thigh muscles; (b) list the most accepted terminology used to describe muscle injuries;

Antibacterial Paramagnetic Quinones from Actinoallomurus.

Four metabolites, designated paramagnetoquinone A, B, C, and D (1-4), were isolated from three strains belonging to the actinomycete genus Actinoallomurus. Compounds 1 and 2 showed potent antibacterial activity with MIC values lower than 0.015 µg/mL against Gram-positive pathogens, including antibiotic-resistant strains. Since compounds 1 and 2 were NMR-silent due to the presence of an oxygen radical, structure elucidation was achieved through a combination of derivatizations, oxidations, and analysis of 13C-labeled compounds. The paramagnetoquinones share the same carbon scaffold as tetracenomycin but carry two quinones and a five-membered lactone fused to the aromatic system. Compounds 2 and 1 are identical except for an unprecedented replacement of a methoxy in 2 by a methylamino group in 1. Related compounds devoid of methyl group(s) and of antibacterial activity were isolated from a different Actinoallomurus strain. The likely pmq biosynthetic gene cluster was identified from strain ID145113. While the cluster encodes many of the expected enzymes involved in the formation of aromatic polyketides, it also encodes a dedicated ketoacid dehydrogenase complex and an unusual acyl carrier protein transacylase, suggesting that an unusual starter unit might prime the polyketide synthase.

The Lantibiotic NAI-107 Efficiently Rescues Drosophila melanogaster from Infection with Methicillin-Resistant Staphylococcus aureus USA300.

We used the fruit fly Drosophila melanogaster as a cost-effective in vivo model to evaluate the efficacy of novel antibacterial peptides and peptoids for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. A panel of peptides with known antibacterial activity in vitro and/or in vivo was tested in Drosophila Although most peptides and peptoids that were effective in vitro failed to rescue lethal effects of S. aureus infections in vivo, we found that two lantibiotics, nisin and NAI-107, rescued adult flies from fatal infections. Furthermore, NAI-107 rescued mortality of infection with the MRSA strain USA300 with an efficacy equivalent to that of vancomycin, a widely applied antibiotic for the treatment of serious MRSA infections. These results establish Drosophila as a useful model for in vivo drug evaluation of antibacterial peptides.

Advancing cell wall inhibitors towards clinical applications.

Natural products represent a major source of approved drugs and still play an important role in supplying chemical diversity. Consistently, 2014 has seen new, natural product-derived antibiotics approved for human use by the US Food and Drug Administration. One of the recently approved second-generation glycopeptides is dalbavancin, a semi-synthetic derivative of the natural product A40,926. This compound inhibits bacterial growth by binding to lipid intermediate II (Lipid II), a key intermediate in peptidoglycan biosynthesis. Like other recently approved antibiotics, dalbavancin has a complex history of preclinical and clinical development, with several companies contributing to different steps in different years. While our work on dalbavancin development stopped at the previous company, intriguingly our current pipeline includes two more Lipid II-binding natural products or derivatives thereof. In particular, we will focus on the properties of NAI-107 and related lantibiotics, which originated from recent screening and characterization efforts.

Brominated Variant of the Lantibiotic NAI-107 with Enhanced Antibacterial Potency.

We identified an Actinoallomurus strain producing NAI-107, a chlorinated lantibiotic effective against multidrug-resistant Gram-positive pathogens and previously reported from the distantly related genus Microbispora. Inclusion of KBr in the production medium of either the Actinoallomurus or the Microbispora producer readily afforded brominated variants of NAI-107, which were designated as NAI-108. The other post-translational modifications naturally occurring in this lantibiotic family (i.e., hydroxylation of Pro-14 and C-terminal decarboxylation) were unaffected by the presence of a brominated tryptophan. In addition to being the first example of a bromine-containing lantibiotic, NAI-108 displayed a small but consistent improvement in antibacterial activity against all tested strains. The brominated lantibiotic maintained the same rapid bactericidal activity as NAI-107 but at reduced concentrations, consistent with its increased potency and with the role played by the hydrophobicity of the first lanthionine ring. NAI-108 thus represents an interesting addition to a promising family of potent and effective lantibiotics.

Abdominal Wall Needle Tract Seeding: 15 Years After a Hepatocellular Carcinoma Biopsy.

Percutaneous liver biopsy, although considered a safe procedure, can lead to tumoral needle tract seeding. We describe a case of a 65-year-old woman with a history of hepatocellular carcinoma (HCC) who presented with a painless abdominal lump 15 years post-liver biopsy and left hepatectomy. An MRI revealed an abdominal wall mass suggestive of HCC metastasis from needle tract seeding. Surgical removal confirmed a well-differentiated HCC. Distinctive imaging features of HCC in specific clinical settings reduce the need for biopsy, which should be limited to exceptional cases.

Avian Haemosporidian Infection in Wildlife Rehabilitation Centres of Portugal: Causes, Consequences, and Genetic Diversity.

In the last decade, over 40% of bird species in Europe have experienced poor and bad conservation status, with more than 30% of bird species in mainland Portugal threatened with extinction. Along with anthropogenic factors, parasites and pathogens such as avian haemosporidians have been suggested to be responsible for these avian population declines. Wildlife rehabilitation centres play an essential role in species conservation and preservation. Moreover, animals admitted for rehabilitation can provide valuable information regarding transmission and pathogenicity of many diseases that affect wild birds that are rarely sampled in nature. However, reports of haemosporidians in captive birds are still limited. Here, we explored the prevalence and genetic diversity of avian haemosporidians in 89 birds from 29 species admitted to rehabilitation centres in Portugal, showing an overall infection prevalence of 30.3%. The prevalence of infection was higher in Strigiformes and in birds admitted to rehabilitation centres due to debilitating diseases. Remarkably, 30% of the infected bird species have not been found to harbour malaria parasites in preceding studies. We detected 15 different haemosporidian lineages infecting a third of bird species sampled. Notably, 2 out of these 15 detected haemosporidian lineages have not been obtained previously in other studies. Furthermore, we also identified nine new host-parasite interactions representing new host records for these haemosporidian parasites. Finally, our results revealed that birds infected with haemosporidians require longer rehabilitation treatments, which increase the economic costs for rehabilitation and may impair their survival prospects. These findings emphasise the importance of integrating haemosporidian infection considerations into rehabilitation protocols, highlighting the challenges posed by these infections in avian conservation and rehabilitation, including economic and logistical demands.