Histomorphological effects of sodium arsenite on uterus of rats

Background: Arsenic is highly toxic agent and a risk factor for disease and disability. Arsenic is present in drinking water of many developing and developed countries including Pakistan and due to rapid industrialization its quantity in soil and water is increasing day by day.Methods: In an 18 month study in which we took two principal groups, labelled as control group A and experimental group B. The animals of experimental group B were administered 4 µg of sodium arsenite dissolved in 10 ml of distilled water by oral gavage daily for 14 days. The uterus was removed and processed for paraffin embedding and stained with hematoxylin and eosin (H and E). The histological parameters; uterine luminal diameter, height of uterine luminal epithelium, area occupied by epithelial component of uterine glands and the thickness of myometrium were measured and evaluated by civil AutoCAD 2013 software. The data was analyzed statistically with the statistical package for social sciences (SPSS).Results: Histological results showed the degenerative effects. The luminal diameter of uterine horns was reduced in experimental animals. The height of uterine epithelium was reduced. Area occupied by epithelial component of uterine glands was reduced along the reduction in the thickness of myometrium.Conclusions: The histological abnormalities observed in uterus showed that the degenerative effects may be due to oxidative stress produced by the exposure to sodium arsenite. As sodium arsenite produces the oxidative stress by the formation of free radicals and by the denaturation of proteins

Characterization of oligomers from methylglyoxal under dark conditions : a pathway to produce secondary organic aerosol through cloud processing during nighttime

Aqueous-phase oligomer formation from methylglyoxal, a major atmospheric photooxidation product, has been investigated in a simulated cloud matrix under dark conditions. The aim of this study was to explore an additional pathway producing secondary organic aerosol (SOA) through cloud processes without participation of photochemistry during nighttime. Indeed, atmospheric models still underestimate SOA formation, as field measurements have revealed more SOA than predicted. Soluble oligomers (n = 1-8) formed in the course of acid-catalyzed aldol condensation and acid-catalyzed hydration followed by acetal formation have been detected and characterized by positive and negative ion electrospray ionization mass spectrometry. Aldol condensation proved to be a favorable mechanism under simulated cloud conditions, while hydration/acetal formation was found to strongly depend on the pH of the system and only occurred at a pH < 3.5. No evidence was found for formation of organosulfates. The aldol oligomer series starts with a beta-hydroxy ketone via aldol condensation, where oligomers are formed by multiple additions of C3H4O2 units (72 Da) to the parent beta-hydroxy ketone. Ion trap mass spectrometry experiments were performed to structurally characterize the major oligomer species. A mechanistic pathway for the growth of oligomers under cloud conditions and in the absence of UV-light and OH radicals, which could substantially enhance in-cloud SOA yields, is proposed here for the first time

COVID-19 Vaccination Uptake, Infection Rates, and Seropositivity Among Youth Experiencing Homelessness in the United States.

People experiencing homelessness are at greater risk of exposure and poor health outcomes from COVID-19. Yet, little data exists on the prevalence and correlates of COVID-19 among homeless populations. To mitigate the spread and severity, uptake of the COVID-19 vaccine is needed. This can be challenging among youth experiencing homelessness who are more likely to be unvaccinated when compared to stably housed youth

Anatomical Variations of Rhinogenic Headache and Its Relation with Sinusitis: A Computerized Tomography (CT) Scan Study

Background: Variable anatomy, hallmark of sinonasal region is the reason for the etiology of sinonasal symptoms such as rhinogenic headache. This study aimed to investigate the incidence of anatomical variations of the nasal cavity and paranasal sinuses in sinusitis patients with complaint of rhinogenic headache on computed tomography of paranasal sinuses, and the correlation of these variants with a rhinogenic headache. Methods: A prospective cross-sectional study (n=50) of 18-60 years having sinusitis with rhinogenic headache was steered at the Department of Radiology in the PNS Shifa Hospital of Karachi, Pakistan, between June-December 2021. After obtaining written informed consent, all subjects were investigated for various anatomical variants of the sinonasal region detected on computed tomographic scans of paranasal sinuses and were correlated with a rhinogenic headache. The Chi-square test and Pearson correlation were applied for statistical analysis and the level of significance was set at p≤ 0.05. Results:  The most common anatomical variant of sinonasal region detected was agger nasi cells 32(64%) (Right: r/r -0.24, p =0.09; Left: r/r -0.28, p = 0.04), followed by deviated nasal septum 28(56%) (r/r 0.04, p= 0.75), concha bullosa 23(46%) (r/r 0.07, p=0.59), deviated nasal septum with bony spur (r/r 0.07, p=0.62) and other variants. The overall, study found male (68%) predominance. Significant association existed between rhinogenic headache and some of the anatomical variants along with sinus mucosal thickening (p<0.05). Conclusion: The significant association (p<0.05) was found between rhinogenic headache and different anatomical variants like agger nasi cells, left-sided agger nasi cells, right-sided Haller’s cells, left-sided maxillary and ethmoid sinusitis. Keywords: Rhinogenic Headache; CT-PNS; Sinonasal Region; Anatomical Variants

Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers

PURPOSE: Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy. EXPERIMENTAL DESIGN: Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array. RESULTS: Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd-treated colon cancer model. CONCLUSIONS: We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications. See related commentary by Rolfo et al., p. 4317

Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts

Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.7% take rate) from 17 patients. Established PDXs represented a broad range of HER2-expressing cancers, and in vivo testing demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab and demonstrated that MET inhibitors have single-agent activity and can enhance zanidatamab activity in vitro and in vivo. These findings provide evidence that PDXs can be developed from pretreatment biopsies in clinical trials and may provide insight into mechanisms of resistance

Caso atípico de Sarna Crostosa em paciente jovem imunocompetente: um relato de caso

A sarna crostosa é uma infecção comum que afeta indivíduos de qualquer idade e nível socioeconômico,&nbsp; sendo majoritariamente descrita em pacientes que apresentam má nutrição ou imunossupressão. O agente causador é o ácaro Sarcoptes scabiei var hominis, que é um parasita obrigatório que vive em túneis escavados no estrato córneo. Na sarna crostosa, o número de ácaros aumenta para milhões devido à multiplicação não inibida, causando um quadro clínico mais exuberante e com lesões marcadas por hiperceratoses maciças locais ou difusas de fundo eritematoso, com crostas e fissuras nas mãos, pés, cotovelos, cabeça e pescoço. Neste trabalho objetivamos demonstrar um quadro clínico atípico de um paciente do Hospital Santa Casa de Misericórdia de Vitória – ES, Brasil, acometido por esta entidade, além de evidenciar um método diagnóstico simples porém incomum de ser utilizado no dia a dia e também pouco evidenciado na literatura. O paciente relatado teve seu diagnóstico realizado de forma relativamente tardia devido ao quadro atípico. Seu tratamento foi realizado com medicação tópica e oral com obtenção de ótima resposta clínica. A discussão baseia-se em apontar as principais formas de transmissão, como evitá-las, como fazer um melhor diagnóstico clínico para manejo precoce do paciente, evitando complicações

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension