Underlying Disease State Research Articles

Microbiome and metabolome patterns after lung transplantation reflect underlying disease and chronic lung allograft dysfunction

BackgroundProgression of chronic lung disease may lead to the requirement for lung transplant (LTx). Despite improvements in short-term survival after LTx, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the molecular and microbial relationships between underlying lung disease and the development of CLAD in bronchoalveolar lavage fluid (BALF) from subjects post-LTx, which is crucial for tailoring treatment strategies specific to allograft dysfunctions.MethodsPaired 16S rRNA gene amplicon sequencing and untargeted LC–MS/MS metabolomics were performed on 856 BALF samples collected over 10 years from LTx recipients (n = 195) with alpha-1-antitrypsin disease (AATD, n = 23), cystic fibrosis (CF, n = 47), chronic obstructive pulmonary disease (COPD, n = 78), or pulmonary fibrosis (PF, n = 47). Data were analyzed using random forest (RF) machine learning and multivariate statistics for associations with underlying disease and CLAD development.ResultsThe BALF microbiome and metabolome after LTx differed significantly according to the underlying disease state (PERMANOVA, p = 0.001), with CF and AATD demonstrating distinct microbiome and metabolome profiles, respectively. Uniqueness in CF was mainly driven by Pseudomonas abundance and its metabolites, whereas AATD had elevated levels of phenylalanine and a lack of shared metabolites with the other underlying diseases. BALF microbiome and metabolome composition were also distinct between those who did or did not develop CLAD during the sample collection period (PERMANOVA, p = 0.001). An increase in the average abundance of Veillonella (AATD, COPD) and Streptococcus (CF, PF) was associated with CLAD development, and decreases in the abundance of phenylalanine-derivative alkaloids (CF, COPD) and glycerophosphorylcholines (CF, COPD, PF) were signatures of the CLAD metabolome. Although the relative abundance of Pseudomonas was not associated with CLAD, the abundance of its virulence metabolites, including siderophores, quorum-sensing quinolones, and phenazines, were elevated in those with CF who developed CLAD. There was a positive correlation between the abundance of these molecules and the abundance of Pseudomonas in the microbiome, but there was no correlation between their abundance and the time in which BALF samples were collected post-LTx.ConclusionsThe BALF microbiome and metabolome after LTx are particularly distinct in those with underlying CF and AATD. These data reflect those who developed CLAD, with increased virulence metabolite production from Pseudomonas, an aspect of CF CLAD cases. These findings shed light on disease-specific microbial and metabolic signatures in LTx recipients, offering valuable insights into the underlying causes of allograft rejection.9jCt4jk1gKgtvTcVFjuR9mVideo

6728 Bilateral Adrenal Hemorrhage: Cause Or Consequence?

Abstract Disclosure: M.N. Rayan: None. R. Horner: None. A. Valenciaga: None. L.E. Ryan: None. Introduction: Before the advent of the CT scan, bilateral adrenal hemorrhage was primarily discovered post-mortem in patients who had succumbed to sepsis, burns, or anticoagulant therapy. Today, non-traumatic hemorrhage is recognized as an infrequent, yet potentially lethal diagnosis causing clinical deterioration in acutely ill patients. Clinical Case: Our patient is a 64-year-old-male with a medical history of Myelodysplastic Syndrome initially presented to an external ED with abdominal pain. CT abdomen revealed hepatomegaly, splenomegaly, and new bilateral adrenal masses—absent in an MRI conducted a year earlier. He was treated conservatively and subsequently discharged. Two weeks later, he returned to the hospital with severe right sided flank pain. His hemoglobin and platelet counts dropped from 11.5 g/dL and 309 K/uL during the previous ED visit to 7.7 g/dL and 80 K/uL, respectively. Additionally, his PT/INR, PTT, fibrinogen, and D-Dimer levels were elevated. A repeat CT scan indicated a significant enlargement of the right adrenal mass, raising suspicion of adrenal hemorrhage. He was appropriately transfused, and a BM biopsy was performed to evaluate for acute transformation of underlying MDS. Cortisol levels were monitored daily for adrenal insufficiency. A complicated hospital course ensued marked by worsening anemia, thrombocytopenia, and coagulopathy, accompanied by high fevers and new-onset atrial fibrillation. Mixing studies showed absence of a factor inhibitor ruling out acquired forms of Hemophilia. Infectious workup including fungal and viral serologies returned negative. A PET scan revealed several small hypermetabolic hypodense liver lesions, and hypermetabolic activity diffusely in the spleen, and adrenal glands leading to suspicion of metastasis. Results of the BM biopsy returned revealing hypercellularity, with aggregates of hemosiderin-laden macrophages replacing the bone marrow space with associated necrosis. Worsening abdominal pain with hematochezia prompted an endoscopy, confirming a diagnosis of metastatic melanoma. Concurrently, seizure activity and altered mentation led to a head CT, revealing new metastatic lesions that confirmed the rapid progression of the disease. Subsequently, the patient was transitioned to comfort care and passed away. Clinical Lesson: It is crucial to review the various causes of adrenal hemorrhage, understand the challenges associated with interpreting adrenal imaging, emphasize the need to monitor adrenal function, and consider the occasional necessity for tissue sampling. In this clinical scenario, metastases with hemorrhage were the most likely etiology. The causes of adrenal hemorrhage are not always apparent; in this presentation, the consequence of the underlying disease state ultimately led to the initial presenting symptom of abdominal pain. Presentation: 6/2/2024

B-BIND: Biophysical Bayesian Inference for Neurodegenerative Dynamics.

Throughout an organism's life, a multitude of complex and interdependent biological systems transition through biophysical processes that serve as indicators of the underlying biological states. Inferring these latent, unobserved states is a goal of modern biology and neuroscience. However, in many experimental setups, we can at best obtain discrete snapshots of the system at different times and for different individuals. This challenge is particularly relevant in the study of Alzheimer's Disease (AD) progression, where we observe the aggregation of pathology in brain donors, but the underlying disease state is unknown. This paper proposes a biophysically motivated Bayesian framework (B-BIND: Biophysical Bayesian Inference for Neurodegenerative Dynamics), where the disease state is modeled and continuously inferred from observed quantifications of multiple AD pathological proteins. Inspired by biophysical models, we describe pathological burden as an exponential process. The progression of AD is modeled by assigning a latent score, termed pseudotime, to each pathological state, creating a pseudotemporal order of donors based on their pathological burden. We study the theoretical properties of the model using linearization to reveal convergence and identifiability properties. We provide Markov chain Monte Carlo estimation algorithms, illustrating the effectiveness of our approach with multiple simulation studies across various data conditions. Applying this methodology to data from the Seattle Alzheimer's Disease Brain Cell Atlas, we infer the pseudotime ordering of donors. Finally, we analyze the information within each pathological feature to refine the model, focusing on the most informative pathologies. This framework lays the groundwork for continuous pseudotime modeling in the analysis of neurodegenerative diseases.

The role of the gut microbiome in disorders of gut–brain interaction

Disorders of Gut‐Brain Interaction (DGBI) are widely prevalent and commonly encountered in gastroenterology practice. While several peripheral and central mechanisms have been implicated in the pathogenesis of DGBI, a recent body of work suggests an important role for the gut microbiome. In this review, we highlight how gut microbiota and their metabolites affect physiologic changes underlying symptoms in DGBI, with a particular focus on their mechanistic influence on GI transit, visceral sensitivity, intestinal barrier function and secretion, and CNS processing. This review emphasizes the complexity of local and distant effects of microbial metabolites on physiological function, influenced by factors such as metabolite concentration, duration of metabolite exposure, receptor location, host genetics, and underlying disease state. Large‐scale in vitro work has elucidated interactions between host receptors and the microbial metabolome but there is a need for future research to integrate such preclinical findings with clinical studies. The development of novel, targeted therapeutic strategies for DGBI hinges on a deeper understanding of these metabolite‐host interactions, offering exciting possibilities for the future of treatment of DGBI.

A structure-based computational model of IP3R1 incorporating Ca and IP3 regulation

The inositol 1,4,5-triphosphate receptor (IP3R) mediates Ca release in many cell types and is pivotal to a wide range of cellular processes. High-resolution cryoelectron microscopy studies have provided new structural details of IP3R type 1 (IP3R1), showing that channel function is determined by the movement of various domains within and between each of its four subunits. Channel properties are regulated by ligands, such as Ca and IP3, which bind at specific sites and control the interactions between these domains. However, it is not known how the various ligand-binding sites on IP3R1 interact to control the opening of the channel. In this study, we present a coarse-grained model of IP3R1 that accounts for the channel architecture and the location of specific Ca- and IP3-binding sites. This computational model accounts for the domain-domain interactions within and between the four subunits that form IP3R1, and it also describes how ligand binding regulates these interactions. Using a kinetic model, we explore how two Ca-binding sites on the cytosolic side of the channel interact with the IP3-binding site to regulate the channel open probability. Our primary finding is that the bell-shaped open probability of IP3R1 provides constraints on the relative strength of these regulatory binding sites. In particular, we argue that a specific Ca-binding site, whose function has not yet been established, is very likely a channel antagonist. Additionally, we apply our model to show that domain-domain interactions between neighboring subunits exert control over channel cooperativity and dictate the nonlinear response of the channel to Ca concentration. This suggests that specific domain-domain interactions play a pivotal role in maintaining the channel’s stability, and a disruption of these interactions may underlie disease states associated with Ca dysregulation.

Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.

To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling. We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale. A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes. Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.

Perceptions and Experiences of People with Obesity and Type 2 Diabetes Around Appetite and Eating Behaviors: A Qualitative Study.

Chronic weight management and treatments for type 2 diabetes (T2D) involve a combination of lifestyle-based (diet, exercise) and pharmaceutical interventions. In people with obesity or T2D, understanding the impact of drivers/triggers on appetite and eating behaviors can be crucial to successful medical management. This study aimed to characterize perceptions and experiences regarding appetite and eating behaviors among people with obesity or T2D and identify drivers/triggers of food choices. This non-interventional, cross-sectional, qualitative study utilized semi-structured concept elicitation interviews to explore the perceptions of people with obesity and/or T2D around appetite, eating behaviors and drivers/triggers of food choices. Adult US residents (≥ 18years) with stable body weight (± 5kg) in the 3months preceding participation were included in the study. Forty-five participants (obesity: n = 15; overweight: n = 10; T2D: n = 20) were interviewed. Interviews were audio-recorded and transcribed verbatim for analysis. A subset of participants described eating behaviors on smartphone-based app tasks over 5days. Most (> 96%) discussed the influence of hunger, cravings and satiety on food choices. Participants identified 22 drivers/triggers (including health, 95.6%; culture/heritage, 93.3%; location, 91.1%; stress, 88.8%). Participants also discussed associations between drivers/triggers and eating behavior concepts (appetite, hunger, cravings, satiety, motivation/determination). A conceptual model illustrating eating behavior concepts and related drivers/triggers was developed. The concept elicitation interviews identified a multitude of drivers and triggers and characterized the association of such drivers/triggers with seven core patient-reported concepts encompassing eating behaviors. The findings build upon existing models of factors influencing food choices. Findings confirm prior research regarding impact of drivers/triggers on food choice in people with obesity and T2D and indicate underlying disease state does not appear to influence eating behaviors in people with stable body weight.

Evaluation of Safety and Efficacy of Ruxolitinib in Patients with Pediatric Lymphoproliferative Disorders

Introduction. Pediatric lymphoproliferative disorders (PLPD) encompass a wide spectrum of immune dysregulation conditions with heterogeneous clinical presentation and lab abnormalities. The underlying mechanisms of PLPD are diverse, including dysregulated differentiation of immune cell populations, aberrant recruitment of lymphocyte populations, and/or retention and pathologic survival of lymphocytes. Many PLPD are associated with inborn or acquired genetic factors impacting immune function. Standardized measures to characterize clinical and biological factors in PLPD patients and responses to therapy are lacking. One common feature in PLPD patients is activating IFNg signaling. Ruxolitinib is a drug that blocks hyperactivated IFNg signaling through the JAK-STAT pathway. The goal of this study is to describe the clinical responses of PLPD patients to ruxolitinib. Methods. Medical charts were reviewed to identify patients with PLPD treated with ruxolitnib at Texas Children's Hospital over a 7-year period. Clinical manifestations (recurrent fever, fatigue, lymphadenopathy, recurrent infections, pulmonary disease, endocrinopathy, enteropathy, hepatosplenomegaly, arthritis, CNS symptoms, atopy, dysphagia, underweight), lab values of complete blood count and pathologic inflammation markers (CXCL9, ferritin, sIL2R, IL-18, CD163, neopterin) were categorized with a severity system indicating: 0 no clinical signs and normal lab values; 1 mild to moderate symptoms and abnormal lab values; 2 severe symptoms, highly abnormal lab values (table 1). Total score was computed before and during the addition of ruxolitinib. Complete response (CR) represented a reduction of the total score to 0. Partial response (PR) signified reduction of criteria score ≥ 30% from the baseline with no progression or manifestation of new symptoms. Progression of the disease or improvement < 30% was marked as no response (NR). Results. Chart review identified 19 children and young adults with PLPD who received treatment with ruxolitinib (median age 8.5 years; range 1.2 to 21.6 years). Underlying disease states driving PLPD included HLH, inborn errors of immunity, juvenile rheumatoid arthritis, macrophage activation syndrome, malignant atrophic papulosis of Degos, Aicardi-Goutierres Syndrome, and T-cell large granular lymphocytic leukemia.Genetic variants known or predicted to be damaging were identified in 15 cases (79%), including STAT1, STAT3, TREX1, OFD1, NLRP12, NLRP4, UNC13, PRF1, AP3D1 and mosaic genome-wide paternal uniparental disomy. While 79% of patients received ruxolitinib in combination with other immune suppressants, 21% received only ruxolitinib out of which half received it as front-line therapy. Based on the PLPD Scoring System, overall response rate to ruxolitinib was 73.7%, with 5.3% achieving CR, and 68.4% PR. Overall survival on this study was 84.2% with median 11 months follow-up (range: 0.5 month to 7.1 years). Three patients died due to uncontrolled disease progression. Six patients in whom hematopoietic cell transplant was deemed essential for cure survived to conditioning. Toxicities potentially related to ruxolitinib included grades 1 to 4 cytopenias and grade 1 elevated liver enzymes. Conclusion. PLPD represents a population with overall poor outcomes. We developed standardized staging and response metrics to characterize extent of immune dysregulation and response to therapy. Ruxolitinib represents a potential “precision” therapeutic intervention for patients with pathologic IFNg pathway activation. Ruxolitinib was well-tolerated in this high risk population, and was associated with positive responses in the majority of patients. This study supports expansion of prospective studies to validate the PLPD Scoring System and to optimize therapeutic strategies to manage immune dysregulation, including ruxolitinib.

Environmental pollutants increase the risks of acute exacerbation in patients with chronic airway disease.

Respiratory infections are a common cause of acute exacerbations in patients with chronic airway disease, however, environmental factors such as air pollution can also contribute to these exacerbations. The study aimed to determine the correlation between pollutant levels and exacerbation risks in areas exposed to environmental pollution sources. From 2015 to 2016, a total of 788 patients with chronic airway diseases were enrolled in a study. Their medical records, including hospital visits due to acute exacerbations of varying severity were analyzed. Additionally, data on daily pollutant levels from the Air Quality Monitoring Network from 2014 to 2016 was also collected and analyzed. Patients with chronic airway disease and poor lung function (FEV1 < 50% or obstructive ventilatory defect) have a higher risk of severe acute exacerbations and are more likely to experience more than two severe acute exacerbations within a year. The study found that in areas exposed to environmental pollution sources, there is a significant correlation between NO2, O3, and humidity with the main causes of severe acute exacerbation. When the levels of NO2 were higher than 16.65 ppb, O3 higher than 35.65 ppb, or humidity higher than 76.95%, the risk of severe acute exacerbation in patients with chronic airway disease increased. Acute exacerbations of chronic airway disease can be triggered by both the underlying disease state and the presence of air pollution. Computer simulations and early warning systems should be developed to predict acute exacerbations of chronic airway disease based on dynamic changes in air pollution.

Interaction of admission platelet count with current medications and the risk for chronic subdural recurrence.

Chronic subdural hematoma (cSDH) has a reported 10%-24% rate of recurrence after surgery, and prognostic models for recurrence have produced equivocal results. The objective of this study was to leverage a data mining algorithm, chi-square automatic interaction detection (CHAID), which can incorporate continuous, nominal, and binary data into a decision tree, to identify the most robust predictors of repeat surgery for cSDH patients. This was a retrospective cohort study of all patients with SDH from two level 1 trauma centers at a single institution. All patients underwent cSDH evacuation performed by 15 neurosurgeons between 2011 and 2020. The primary outcome was the rate of repeat surgery for recurrent cSDH following the initial evacuation. The authors used CHAID to identify relevant predictors of repeat surgery, including age, sex, comorbidities, postsurgical complications, platelet count prior to the first procedure, midline shift prior to the first procedure, hematoma volume, and preoperative use of anticoagulants, antiplatelets, or statins. Sixty (13.8%) of 435 study-eligible patients (average age 74.0 years) had a cSDH recurrence. These patients had 2.0 times greater odds of having used anticoagulants. The final CHAID model had an overall accuracy of 87.4% and an area under the curve of 0.76. According to the model, the predictor with the strongest association with cSDH recurrence was admission platelet count. Approximately 26% of patients (n = 23/87) with an admission platelet count < 157 × 109/L had a cSDH recurrence, whereas none of the 44 patients with admission platelets > 313 × 109/L had a recurrence. Approximately 17% of patients in the 157-313 × 109/L platelet group who had used preoperative statins required a second procedure, which was associated with a 2.3 times increased risk for repeat surgery compared to those who had not used statins preoperatively. Among those who had not used preoperative statins, a platelet count ≤ 179 × 109/L on admission for the first procedure was the strongest differentiator for a second surgery (n = 5/22 [23%]), which increased the risk of recurrence by 4.5 times. Among the patients using preoperative statins, the use of anticoagulants was the strongest differentiator for requiring repeat surgery (n = 11/33 [33%]). The described model identified platelet count on admission as the most important predictor of repeat cSDH surgery, followed by preoperative statin use and anticoagulant use. Critical cutoffs for platelet count were identified, which future studies should evaluate to determine if they are modifiable or reflective of underlying disease states.

Genome-Wide Meta-Analysis of Cerebrospinal Fluid Biomarkers in Alzheimer's Disease and Parkinson's Disease Cohorts.

Amyloid-β, phosphorylated tau (p-tau), and total tau (t-tau) in cerebrospinal fluid are established biomarkers for Alzheimer's disease (AD). In other neurodegenerative diseases, such as Parkinson's disease (PD), these biomarkers have also been found to be altered, and the molecular mechanisms responsible for these alterations are still under investigation. Moreover, the interplay between these mechanisms and the diverse underlying disease states remains to be elucidated. To investigate genetic contributions to the AD biomarkers and assess the commonality and heterogeneity of the associations per underlying disease status. We conducted genome-wide association studies (GWASs) for the AD biomarkers on subjects from the Parkinson's Progression Markers Initiative, the Fox Investigation for New Discovery of Biomarkers, and the Alzheimer's Disease Neuroimaging Initiative, and meta-analyzed with the largest AD GWAS. We tested heterogeneity of associations of interest between different disease statuses (AD, PD, and control). We observed three GWAS signals: the APOE locus for amyloid-β, the 3q28 locus between GEMC1 and OSTN for p-tau and t-tau, and the 7p22 locus (top hit: rs60871478, an intronic variant for DNAAF5, also known as HEATR2) for p-tau. The 7p22 locus is novel and colocalized with the brain DNAAF5 expression. Although no heterogeneity from underlying disease status was observed for the earlier GWAS signals, some disease risk loci suggested disease-specific associations with these biomarkers. Our study identified a novel association at the intronic region of DNAAF5 associated with increased levels of p-tau across all diseases. We also observed some disease-specific genetic associations with these biomarkers. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Internal medicine intern performance on the gastrointestinal physical exam.

The gastrointestinal (GI) physical exam provides critical information about underlying disease states. However, since assessment of physical examination skills is rarely conducted as part of internal medicine residency training, little is known about resident performance on the GI physical exam. During a clinical skills assessment that took place between November 2019 and February 2020, internal medicine interns examined the same patient with chronic liver disease while being observed by faculty preceptors. We compared the exam maneuvers performed with those expected by the faculty evaluators. We noted which maneuvers were performed incorrectly, whether physical exam technique correlated with identification of physical exam findings, and if performance on the physical exam was associated with building an appropriate differential diagnosis. This four-hour assessment was required for internal medicine interns within two different residency programs in the Baltimore area. More than half of the 29 participating interns (n=17, 58.6 %) received a "needs improvement" score on their physical exam technique. Technique was highly correlated with identifying the correct physical signs (r=0.88, p<0.0001). The most commonly excluded maneuvers were assessing for splenomegaly and hepatomegaly. The most commonly missed findings were splenomegaly and hepatomegaly. Most interns included chronic liver disease as part of their differential diagnosis even if they received "needs improvement" scores on physical exam technique or identifying physical signs. Internal medicine interns would benefit from learning an organized approach to the gastrointestinal exam. This would likely lead to increased identification of important gastrointestinal findings.

ID: 213709 Use of LSS to Characterize and Quantify Blood Flow Changes in Patients During SCS

Spinal cord stimulation (SCS) has been reported to impact peripheral blood flow when used to treat pain from a variety of conditions.1-4 Peripheral blood flow measurements can be obtained via laser Doppler flowmetry (LDF), photo-plethysmography (PPG), and transcutaneous oxygen pressure (TcPO2); each having their own technology-specific drawbacks.5,6 Laser speckle spectroscopy (LSS) is an alternative way to measure peripheral blood flow that may overcome the limitations of previous technologies by quantitatively measuring blood flow through the full volume of a digit, and producing a blood flow waveform in real time. Real-time changes in blood flow in response to SCS could be useful in determining the impact of stimulation beyond pain relief by modifying the underlying disease state or improving circulation where blood flow in an affected limb is impaired. The aim of this study is to gain experience with perfusion measurements in SCS patients, and to characterize and quantify blood flow with stimulation on versus off.

Novel piperazine-based ionizable lipid nanoparticles allow the repeated dose of mRNA to fibrotic lungs with improved potency and safety.

mRNA-based protein replacement therapy has received much attention as a novel intervention in clinical disease treatment. Lipid nanoparticles (LNPs) are widely used for their therapeutic potential to efficiently deliver mRNA. However, clinical translation has been hampered by the immunogenicity of LNPs that may aggravate underlying disease states. Here, we report a novel ionizable LNP with enhanced potency and safety. The piperazine-based biodegradable ionizable lipid (244cis) was developed for LNP formulation and its level of protein expression and immunogenicity in the target tissue was evaluated. It was found that 244cis LNP enabled substantial expression of the target protein (human erythropoietin), while it minimally induced the secretion of monocyte chemoattractant protein 1 (MCP-1) as compared to other conventional LNPs. Selective lung targeting of 244cis LNP was further investigated in tdTomato transgenic mice with bleomycin-induced pulmonary fibrosis (PF). The repeated administration of 244cis LNP with Cre recombinase mRNA achieved complete transfection of lung endothelial cells (~80%) and over 40% transfection of Sca-1-positive fibroblasts. It was shown that 244cis LNP allows the repeated dose of mRNA without the loss of activity due to its low immunogenicity. Our results demonstrate that 244cis LNP has great potential for the treatment of chronic diseases in the lungs with improved potency and safety.

High-Energy, Whole-Body Proton Irradiation Differentially Alters Long-Term Brain Pathology and Behavior Dependent on Sex and Alzheimer’s Disease Mutations

Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer's-like and wildtype littermate mice 7-8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer's model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.

Idiopathic Granulomatous Mastitis and History of Hypothyroidism: Intervening Data of a Prospective Multicenter Trial and Meta-Analysis of the Existing Literature

Background: Idiopathic granulomatous mastitis (IGM) is a rare benign breast disease that mostly occurs in reproductive ages in parous women. Hormonal, autoimmune, and microbial causes have been implicated as causes. We carried out this prospective study to investigate the reproductive factors and underlying disease states in IGM. Methods: This study was conducted in two phases. In the first phase, we evaluated the reproductive factors, anthropometric parameters and past medical histories of participants of an ongoing multicentric clinical trial. In the second phase, we performed an extensive review of the literature for studies that had considered patients with a histologic-proven diagnosis of IGM without date limitations, and extracted the data about parity, breastfeeding, oral contraceptive pill use and past medical histories. We then carried out a meta-analysis. Results: Data of 123 patients were included. The mean age was 35.11±7.07 years, and the mean body mass index was 27.41±4.74. Overall, %93.8, 90.27% and 28.7% of patients were parous, had breastfed, and had used OCP, respectively. Hypothyroidism represented the most common (18.94%) previous medical disease. We included 89 studies in our search. Considering these studies and ours, the pooled prevalence of rates of parity, breastfeeding and oral contraceptive pill consumption were 96%, 89%, and 29%; and the pooled prevalence of hypothyroidism, diabetes and hypertension were 9%, 5% and 5%, respectively. Although not exactly comparable, these rates of hypothyroidism were higher than those reported in women in the general population (4.2% in one large study in Iran). Conclusion: Our study suggests a possible relation between a past history of hypothyroidism and IGM. We propose a study that investigates the occurrence of IGM in some large cohorts of healthy women, and the retrospective assessment of thyroid tests in the primary serum samples.

Dietary and nutrition considerations in caring for patients with nonalcoholic fatty liver disease: Updates for the practicing clinician.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide, affecting up to one-third of the global population. The disease is defined by excess fat deposition in the liver and has a strong correlation with metabolic syndrome, which, in turn, is also a risk factor for disease progression, including the development of steatohepatitis, advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Although a number of medications are being explored for disease mitigation, nothing is currently approved, and the mainstay of therapy remains dietary and lifestyle intervention that promotes weight loss as well as management of comorbid conditions. The landscape that guides care for patients with NAFLD continues to evolve. Clinicians caring for these patients need to consider underlying disease state and nutrition risk in addition to concurrent related diagnoses, such as insulin resistance and hyperlipidemia, when formulating treatment plans. The following is a comprehensive review of the current dietary and nutrition considerations in the management of patients with NAFLD, with a special emphasis on implications for the practicing clinician.

A case report of Scoliosis secondary to herniated lumbar disc in an adolescent: A case report

Background: Herniated nucleus pulposus is infrequent among children and adolescents. The first case of surgical intervention for disc herniation was reported in a 12-year-old child. Since then, very few cases or series of cases have been published. The current case report is of a 15-year-old girl with no history of spinal ailment, who presented with a large disc herniation in the L4–L5 region, associated with reactive secondary scoliosis and resolved following a successful surgical intervention.&#x0D; Case Description: A 15-year-old female with a known case of scoliosis and a history of lower back pain for nine months following a fall while playing football, without any past account of the spinal disease, was presented at the outpatient clinic. After a series of proper imaging, a large L4/5 HNP with positional secondary scoliosis was diagnosed. However, due to the persistence of symptoms for more than two months in radiculopathy and reactive scoliosis, the decision was made to proceed with L4/5 microscopic discectomy. After six months, the neurological examination was normal, with a significant improvement of scoliosis with the restoration of normal spine alignment seen in plain X-ray films. The right leg radiculopathy improved as well.&#x0D; Conclusion: Lumbar disc herniation in association with scoliosis needs a vigilant evaluation of signs and symptoms and appropriate diagnostic imaging. Imaging is vital in diagnosing underlying disease states and helps in clinical management and surgical planning. The appropriate treatment is a discectomy.

Role of the intensive care in allogeneic hematopoietic stem cell transplantation

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by life-threatening conditions.Aim — an analysis of the life-threatening complications in recipients of allogeneic hematopoietic stem cells (allo-HSCs)Main findings. From 10 to 50 % of allo-HSC recipients need to be admitted to the intensive care unit (ICU) due to the development of life-threatening complications. The reasons for ICU admission are acute respiratory failure, sepsis, graft-versus-host disease, veno-occlusive disease, thrombotic microangiopathy, cytokine release syndrome, engraftment syndrome, etc. Conditioning regimen, donor type, stem cell source, underlying disease state and patient comorbidity are the risk factors associated with development of life-threatening conditions. The main prognostic factors of unfavorable ICU outcomes in allo-HSC recipients are the severity of multiple organ dysfunction and the need for organ support.

An Update on Advancements and Challenges in Inhalational Drug Delivery for Pulmonary Arterial Hypertension.

A lethal condition at the arterial–alveolar juncture caused the exhaustive remodeling of pulmonary arterioles and persistent vasoconstriction, followed by a cumulative augmentation of resistance at the pulmonary vascular and, consequently, right-heart collapse. The selective dilation of the pulmonary endothelium and remodeled vasculature can be achieved by using targeted drug delivery in PAH. Although 12 therapeutics were approved by the FDA for PAH, because of traditional non-specific targeting, they suffered from inconsistent drug release. Despite available inhalation delivery platforms, drug particle deposition into the microenvironment of the pulmonary vasculature and the consequent efficacy of molecules are influenced by pathophysiological conditions, the characteristics of aerosolized mist, and formulations. Uncertainty exists in peripheral hemodynamics outside the pulmonary vasculature and extra-pulmonary side effects, which may be further exacerbated by underlying disease states. The speedy improvement of arterial pressure is possible via the inhalation route because it has direct access to pulmonary arterioles. Additionally, closed particle deposition and accumulation in diseased tissues benefit the restoration of remolded arterioles by reducing fallacious drug deposition in other organs. This review is designed to decipher the pathological changes that should be taken into account when targeting the underlying pulmonary endothelial vasculature, especially with regard to inhaled particle deposition in the alveolar vasculature and characteristic formulations.