Explore the vast range of titles available.

BackgroundPrimary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, characterized by mononuclear cell infiltrates in the salivary and lacrimal glands, leading to glandular atrophy and dryness. Patient heterogeneity and lack of knowledge regarding its pathogenesis makes pSS a difficult disease to manage.MethodsAn exploratory analysis using mass cytometry was conducted of MAPK/ERK and JAK/STAT signaling pathways in peripheral blood mononuclear cells (PBMC) from 16 female medication free pSS patients (8 anti-Sjögren’s syndrome-related antigen A negative/SSA- and 8 SSA+) and 8 female age-matched healthy donors after stimulation with interferons (IFNs).ResultsWe found significant differences in the frequencies of memory B cells, CD8+ T central and effector memory cells and terminally differentiated CD4+ T cells among the healthy donors and patient subgroups. In addition, we observed an upregulation of HLA-DR and CD38 in many cell subsets in the patients. Upon IFNα2b stimulation, slightly increased signaling through pSTAT1 Y701 was observed in most cell types in pSS patients compared to controls, while phosphorylation of STAT3 Y705 and STAT5 Y694 were slightly reduced. IFNγ stimulation resulted in significantly increased pSTAT1 Y701 induction in conventional dendritic cells (cDCs) and classical and non-classical monocytes in the patients. Most of the observed differences were more prominent in the SSA+ subgroup, indicating greater disease severity in them.ConclusionsAugmented activation status of certain cell types along with potentiated pSTAT1 Y701 signaling and reduced pSTAT3 Y705 and pSTAT5 Y694 induction may predispose pSS patients, especially the SSA+ subgroup, to upregulated expression of IFN-induced genes and production of autoantibodies. These patients may benefit from therapies targeting these pathways.

This research introduces a thorough analytical technique for measuring Fulvestrant, an estrogen receptor antagonist utilized in the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women. Fulvestrant functions by competing with natural estrogen for attachment to estrogen receptors, leading to the downregulation and degradation of these receptors, thereby inhibiting the growth of cancer cells. Although it holds clinical importance, there are only few reported analytical methods for its measurement. This research fills that void by creating and validating a dependable stability-indicating HPLC method for the precise and sensitive quantification of Fulvestrant, including the characterization of its degradants through LC-MS. The method development adhered to ICH Q1A (R2) guidelines, including degradation studies conducted under acidic, basic, oxidative, UV light and thermal stress conditions to guarantee the effective separation of Fulvestrant from its degradation products. The optimized chromatographic conditions utilized a JASCO PU2080 plus HPLC system equipped with a HiQSil C18 Column (250mm  4.6mm, 5µm), with detection performed at 225nm. The method displayed excellent linearity across the 2-12µg/ml range, achieving a correlation coefficient of 0.9983. High precision was observed in the method (%RSD< 2), along with accuracy reflected by mean recoveries ranging from 99.98% to 100.485%, with LOD and LOQ values recorded at 0.210µg/ml and 0.636 µg/ml, respectively. Fulvestrant was found to be vulnerable to acid and alkaline hydrolysis, oxidation, and thermal stress but remained stable when exposed to photodegradation.

Tubulocystic anomalies of the mesonephric duct (MND) are a rare group of related entities with a perplexing clinical presentation. Ultrasound is a useful screening investigation, which can help identify a dysplastic kidney or point to renal agenesis and identify cystic or tubulocystic changes in the structures derived from the ureteric bud or MND. Further evaluation with MRI can help in characterisation and direct management. The presence of a dysplastic kidney or absence of a kidney should prompt further evaluation for associated ureteric abnormalities such as ectopic insertion or ureterocoele, which could lead to a diagnosis of tubulocystic anomaly of the MND.ContributionThe authors describe two cases, briefly outline the diagnostic approach and summarise the literature on management. Reporting radiologists should be aware of these entities.

Importance The association between place of birth and hypothermic neuroprotection after hypoxic-ischemic encephalopathy (HIE) in low- and middle-income countries (LMICs) is unknown. Objective To ascertain the association between place of birth and the efficacy of whole-body hypothermia for protection against brain injury measured by magnetic resonance (MR) biomarkers among neonates born at a tertiary care center (inborn) or other facilities (outborn). Design, Setting, and Participants This nested cohort study within a randomized clinical trial involved neonates at 7 tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh between August 15, 2015, and February 15, 2019. A total of 408 neonates born at or after 36 weeks’ gestation with moderate or severe HIE were randomized to receive whole-body hypothermia (reduction of rectal temperatures to between 33.0 °C and 34.0 °C; hypothermia group) for 72 hours or no whole-body hypothermia (rectal temperatures maintained between 36.0 °C and 37.0 °C; control group) within 6 hours of birth, with follow-up until September 27, 2020. Exposure 3T MR imaging, MR spectroscopy, and diffusion tensor imaging. Main Outcomes and Measures ThalamicN-acetyl aspartate (NAA) mmol/kg wet weight, thalamic lactate to NAA peak area ratios, brain injury scores, and white matter fractional anisotropy at 1 to 2 weeks and death or moderate or severe disability at 18 to 22 months. Results Among 408 neonates, the mean (SD) gestational age was 38.7 (1.3) weeks; 267 (65.4%) were male. A total of 123 neonates were inborn and 285 were outborn. Inborn neonates were smaller (mean [SD], 2.8 [0.5] kg vs 2.9 [0.4] kg;P = .02), more likely to have instrumental or cesarean deliveries (43.1% vs 24.7%;P = .01), and more likely to be intubated at birth (78.9% vs 29.1%;P = .001) than outborn neonates, although the rate of severe HIE was not different (23.6% vs 17.9%;P = .22). Magnetic resonance data from 267 neonates (80 inborn and 187 outborn) were analyzed. In the hypothermia vs control groups, the mean (SD) thalamic NAA levels were 8.04 (1.98) vs 8.31 (1.13) among inborn neonates (odds ratio [OR], −0.28; 95% CI, −1.62 to 1.07;P = .68) and 8.03 (1.89) vs 7.99 (1.72) among outborn neonates (OR, 0.05; 95% CI, −0.62 to 0.71;P = .89); the median (IQR) thalamic lactate to NAA peak area ratios were 0.13 (0.10-0.20) vs 0.12 (0.09-0.18) among inborn neonates (OR, 1.02; 95% CI, 0.96-1.08;P = .59) and 0.14 (0.11-0.20) vs 0.14 (0.10-0.17) among outborn neonates (OR, 1.03; 95% CI, 0.98-1.09;P = .18). There was no difference in brain injury scores or white matter fractional anisotropy between the hypothermia and control groups among inborn or outborn neonates. Whole-body hypothermia was not associated with reductions in death or disability, either among 123 inborn neonates (hypothermia vs control group: 34 neonates [58.6%] vs 34 [56.7%]; risk ratio, 1.03; 95% CI, 0.76-1.41), or 285 outborn neonates (hypothermia vs control group: 64 neonates [46.7%] vs 60 [43.2%]; risk ratio, 1.08; 95% CI, 0.83-1.41). Conclusions and Relevance In this nested cohort study, whole-body hypothermia was not associated with reductions in brain injury after HIE among neonates in South Asia, irrespective of place of birth. These findings do not support the use of whole-body hypothermia for HIE among neonates in LMICs. Trial Registration ClinicalTrials.gov Identifier:NCT02387385

The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMA-like neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. Dysregulation of UBA1 and subsequent ubiquitination pathways led to β-catenin accumulation, and pharmacological inhibition of β-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of β-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of β-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent β-catenin signaling, highlighting ubiquitin homeostasis and β-catenin as potential therapeutic targets for SMA.

ObjectiveTo examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE).DesignDouble-blind pilot randomised controlled trial.SettingEight neonatal units in South Asia.PatientsNeonates (≥36 weeks) with moderate or severe HIE admitted between 31 December 2022 and 3 May 2023.InterventionsErythropoietin (500 U/kg daily) or to the placebo (sham injections using a screen) within 6 hours of birth and continued for 9 days. MRI at 2 weeks of age.Main outcomes and measuresFeasibility of randomisation, drug administration and assessment of brain injury using MRI.ResultsOf the 154 neonates screened, 56 were eligible; 6 declined consent and 50 were recruited; 43 (86%) were inborn. Mean (SD) age at first dose was 4.4 (1.2) hours in erythropoietin and 4.1 (1.0) hours in placebo. Overall mortality at hospital discharge occurred in 5 (19%) vs 11 (46%) (p=0.06), and 3 (13%) vs 9 (40.9%) (p=0.04) among those with moderate encephalopathy in the erythropoietin and placebo groups. Moderate or severe injury to basal ganglia, white matter and cortex occurred in 5 (25%) vs 5 (38.5%); 14 (70%) vs 11 (85%); and 6 (30%) vs 2 (15.4%) in the erythropoietin and placebo group, respectively. Sinus venous thrombosis was seen in two (10%) neonates in the erythropoietin group and none in the control group.ConclusionsBrain injury and mortality after moderate or severe HIE are high in South Asia. Evaluation of erythropoietin monotherapy using MRI to examine treatment effects is feasible in these settings.Trial registration number NCT05395195.

Magnetic resonance elastography (MRE) is a promising non-invasive technique for the identification and quantification of hepatic fibrosis. This manuscript describes our early experience with MRE for the assessment of the presence and staging of liver fibrosis on a 3T magnetic resonance imaging (MRI) system. The purpose of this study was to describe the MRE physics, procedure, interpretation and drawbacks, along with a few recommendations as per our experience. Magnetic resonance elastography was performed on 85 patients with a 3T MRI and the images were analysed both qualitatively and quantitatively. Liver stiffness was assessed by drawing freehand geographic regions of interest on the elastograms to cover the maximum portion of the hepatic parenchyma within the 95% confidence maps on each slice. Correlation with histopathology was performed whenever available. Of the 80 patients who met the inclusion criteria, 41 patients displayed a normal liver stiffness measurement (LSM) and 39 patients had a raised LSM. In the patients who had a raised LSM, 14 patients had Stage I-II fibrosis, 8 patients had Stage II-III fibrosis, 6 patients had Stage III-IV fibrosis, 4 patients had Stage IV fibrosis or cirrhosis and 7 patients had non-alcoholic steatohepatitis. The mean thickness of the waves increased with increasing stages of fibrosis. The waves became gradually darker medially in patients with normal LSM as compared to the patients with raised LSM. Histopathology with METAVIR scoring was available in 46 patients, which agreed with the MRE findings in all except two patients. Magnetic resonance elastography is a suitable non-invasive modality for the identification and quantification of hepatic fibrosis.

Background: Teeth have always been known as stable tissue that can be preserved both physically and chemically for long periods of time. Blood group substances have been known to be present in both the hard and soft tissues of the teeth. Objectives: This study aimed at detection of ABO blood group substances from soft and hard tissues of teeth and also to evaluate the reliability of teeth stored for a relatively long period as a source of blood group substances by absorption-elution technique with some modifications. Results: Blood group obtained from the teeth was compared with those obtained from the blood sample. Pulp showed a very large correlation in both fresh and long-standing teeth though it decreased slightly in the latter. Hard tissue showed a large correlation in both the groups indicating that hard tissue is quite reliable to detect blood group and that there is no much difference in the reliability in both the groups. However, combining pulp and hard tissue, correlation is moderate. Correlation of blood grouping with the age, sex, and jaw distribution was carried out. Conclusion: Blood group identification from hard and soft tissues of teeth aids in the identification of an individual.

The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, the authors determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, they observed widespread perturbations in an ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMAlike neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. The data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent Β-catenin signaling, highlighting ubiquitin homeostasis and Β-catenin as potential therapeutic targets for SMA.