Expansion microscopy reveals characteristic ultrastructural features of pathogenic budding yeast species.

Candida albicans is the most prevalent fungal pathogen associated with candidemia. Similar to other fungi, the complex life cycle of C. albicans has been challenging to study with high-resolution microscopy due to its small size. We employed ultrastructure expansion microscopy (U-ExM) to directly visualise sub-cellular structures at high resolution in the yeast and during its transition to hyphal growth. NHS-ester pan-labelling in combination with immunofluorescence (IF) via snapshots of various mitotic stages provided a comprehensive map of nucleolar and mitochondrial segregation dynamics and enabled the resolution of inner and outer plaque of spindle pole bodies (SPBs). Analyses of microtubules (MTs) and SPBs suggest that C. albicans displays side-by-side SPB arrangement with a short mitotic spindle and longer astral MTs (aMTs) at the pre-anaphase stage. Modifications to the established U-ExM protocol enabled the expansion of six other human fungal pathogens, revealing that the side-by-side SPB configuration is a plausible conserved feature shared by many fungal species. We highlight the power of U-ExM to investigate sub-cellular organisation at high resolution and low cost in poorly studied and medically relevant microbial pathogens.

Frequent transitions in mating-type locus chromosomal organization in Malassezia and early steps in sexual reproduction.

Fungi in the basidiomycete genus Malassezia are the most prevalent eukaryotic microbes resident on the skin of human and other warm-blooded animals and have been implicated in skin diseases and systemic disorders. Analysis of Malassezia genomes revealed that key adaptations to the skin microenvironment have a direct genomic basis, and the identification of mating/meiotic genes suggests a capacity to reproduce sexually, even though no sexual cycle has yet been observed. In contrast to other bipolar or tetrapolar basidiomycetes that have either two linked mating-type-determining (MAT) loci or two MAT loci on separate chromosomes, in Malassezia species studied thus far the two MAT loci are arranged in a pseudobipolar configuration (linked on the same chromosome but capable of recombining). By generating additional chromosome-level genome assemblies, and an improved Malassezia phylogeny, we infer that the pseudobipolar arrangement was the ancestral state of this group and revealed six independent transitions to tetrapolarity, seemingly driven by centromere fission or translocations in centromere-flanking regions. Additionally, in an approach to uncover a sexual cycle, Malassezia furfur strains were engineered to express different MAT alleles in the same cell. The resulting strains produce hyphae reminiscent of early steps in sexual development and display upregulation of genes associated with sexual development as well as others encoding lipases and a protease potentially relevant for pathogenesis of the fungus. Our study reveals a previously unseen genomic relocation of mating-type loci in fungi and provides insight toward the identification of a sexual cycle in Malassezia, with possible implications for pathogenicity.

Rates of Recurrent Intestinal Metaplasia and Dysplasia After Successful Endoscopic Therapy of Barrett's Neoplasia by Endoscopic Mucosal Resection vs Endoscopic Submucosal Dissection and Ablation: A Large North American Multicenter Cohort.

INTRODUCTION: Endoscopic eradication therapy (EET) combining endoscopic resection (ER) with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) followed by ablation is the standard of care for the treatment of dysplastic Barrett's esophagus (BE). We have previously shown comparable rates of complete remission of intestinal metaplasia (CRIM) with both approaches. However, data comparing recurrence after CRIM are lacking. We compared rates of recurrence after CRIM with both techniques in a multicenter cohort. METHODS: Patients undergoing EET achieving CRIM at 3 academic institutions were included. Demographic and clinical data were abstracted. Outcomes included rates and predictors of any BE and dysplastic BE recurrence in the 2 groups. Cox-proportional hazards models and inverse probability treatment weighting (IPTW) analysis were used for analysis. RESULTS: A total of 621 patients (514 EMR and 107 ESD) achieving CRIM were included in the recurrence analysis. The incidence of any BE (15.7, 5.7 per 100 patient-years) and dysplastic BE recurrence (7.3, 5.3 per 100 patient-years) were comparable in the EMR and ESD groups, respectively. On multivariable analyses, the chances of BE recurrence were not influenced by ER technique (hazard ratio 0.87; 95% confidence interval 0.51-1.49; P = 0.62), which was also confirmed by IPTW analysis (ESD vs EMR: hazard ratio 0.98; 95% confidence interval 0.56-1.73; P = 0.94). BE length, lesion size, and history of cigarette smoking were independent predictors of BE recurrence. DISCUSSION: Patients with BE dysplasia/neoplasia achieving CRIM, initially treated with EMR/ablation, had comparable recurrence rates to ESD/ablation. Randomized trials are needed to confirm these outcomes between the 2 ER techniques.

Clinical Outcomes After Endoscopic Management of Low-Risk and High-Risk T1a Esophageal Adenocarcinoma: A Multicenter Study.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Sustained exposure to high glucose induces differential expression of cellular senescence markers in murine macrophages but impairs immunosurveillance response to senescent cells secretome.

The influence of chronic diseases on various facets of macrophage cellular senescence is poorly understood. This study evaluated the impact of chronic hyperglycemia on the induction of cellular senescence and subsequent immunosurveillance functions in RAW264.7 macrophages. Macrophages were cultured under normal glucose (NG; 5 mM), high glucose (HG; 20 mM), and very high glucose (VHG; 40 mM) conditions and assessed for markers of cellular senescence. Hyperglycemia induced strong upregulation of SA-ß-gal activity, and loss of PCNA and Lamin B1 gene expression while markers of cell cycle arrest generally decreased. Non-significant changes in SASP-related proteins were observed while ROS levels slightly decreased and mitochondrial membrane potential increased. Protein concentration on the exosome membrane surface and their stability appeared to increase under hyperglycemic conditions. However, when macrophages were exposed to the secretory media (SM) of senescent preadipocytes, a dramatic increase in the levels of all inflammatory proteins was recorded especially in the VHG group that was also accompanied by upregulation of NF-κB and NLRP3 gene expression. SM treatment to hyperglycemic macrophages activated the TLR-2/Myd88 pathway but decreased the expression of scavenger receptors RAGE, CD36, and Olr-1 while CD44 and CXCL16 expression increased. On exposure to LPS, a strong upregulation in NO, ROS, and inflammatory cytokines was observed. Together, these results suggest that primary markers of cellular senescence are aberrantly expressed under chronic hyperglycemic conditions in macrophages with no significant SASP activation. Nonetheless, hyperglycemia strongly deregulates macrophage functions leading to impaired immunosurveillance of senescent cells and aggravation of inflamm-aging. This work provides novel insights into how hyperglycemia-induced dysfunctions can impact the potency of macrophages to manage senescent cell burden in aging tissues.

A Review of the Ethnobotany, Biological Activity, and Phytochemistry of the Plants in the Gundelia Genus.

A comprehensive literature search was conducted in PubMed, Cochrane Library, Web of Science, Scopus, the National Library of Medicine (NLM) catalog, and Google Scholar from January 1980 up until October 2023 on plants in the Gundelia genus. Gundelia L. (Asteraceae) has been treated as a monospecific genus with Gundelia tournefortii L. (1753: 814) in most recent floras with wide variation in corolla color, but nowadays, the genus consists of 17 species. The unripe inflorescences of these species, especially G. tournefortii L., are consumed in many ways. 'Akkoub' or 'akko' in Arabic, "Kangar" in Persian, and "Silifa" in Greek are the common names of G. tournefortii L., also known as tumble thistle in English. They have been used in traditional medicine to treat bronchitis, kidney stones, diarrhea, stomach pain, inflammation, liver and blood diseases, bacterial and fungal infections, and mumps. Based on recent studies, their extracts have exhibited hepatoprotective, hypolipidemic, antioxidant, anti-inflammatory, and antimicrobial effects. Moreover, a variety of phytochemicals, including terpenoids, sterols, and fatty acids, as well as vitamins and minerals, have been identified in this genus. This study reviewed the ethnobotany, phytochemicals, and biological activities of the plants in the Gundelia genus as functional foods and herbal remedies.

Prevalence of Barrett's Esophagus and Esophageal Adenocarcinoma With and Without Gastroesophageal Reflux: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Although gastroesophageal reflux disease (GERD) symptoms are an essential criterion for Barrett's esophagus (BE) screening in most gastroenterology society guidelines, a significant proportion of BE and esophageal adenocarcinoma (EAC) cases do not endorse them. In a systematic review and meta-analysis, we aimed to study the prevalence of BE/EAC in those with and without GERD. METHODS: A systematic search was conducted through 5 major databases for studies reporting prevalence of BE/EAC in patients with and without GERD. Pooled proportions and odds ratios (ORs) of BE, long-segment BE, short-segment BE, dysplasia, and EAC in patients with and without GERD were synthesized. RESULTS: Forty-three articles (12,883 patients with GERD; 51,350 patients without GERD) were included in the final analysis. BE prevalence was 7% (95% confidence interval [CI], 5.8%-8.5%) and 2.2% (95% CI, 1.6%-3%) among individuals with and without GERD, respectively. EAC prevalence was 0.6% (95% CI, 0.4%-1%) and 0.1% (95% CI, 0%-0.2%) in those with and without GERD, respectively. The overall risks for BE (OR, 2.91; 95% CI, 2.06-4.11) and long-segment BE (OR,4.17; 95% CI, 1.78-9.77) were higher in patients with GERD, but the risk for short-segment BE (OR, 1.77; 95% CI, 0.89-3.52) did not differ between the two groups. In 9 population-based high-quality studies (2244 patients with GERD; 3724 patients without GERD), BE prevalence in patients without GERD was 4.9% (95% CI, 2.6%-9%). BE prevalence was highest in North American studies (10.6% [GERD] and 4.8% [non-GERD]). CONCLUSIONS: BE prevalence in those without GERD is substantial, particularly in large high-quality population-based studies. These data are important to factor in future BE/EAC early detection guidelines.

Nanomaterials and Their Impact on the Immune System.

Nanomaterials have been the focus of intensive development and research in the medical and industrial sectors over the past several decades. Some studies have found that these compounds can have a detrimental impact on living organisms, including their cellular components. Despite the obvious advantages of using nanomaterials in a wide range of applications, there is sometimes skepticism caused by the lack of substantial proof that evaluates potential toxicities. The interactions of nanoparticles (NPs) with cells of the immune system and their biomolecule pathways are an area of interest for researchers. It is possible to modify NPs so that they are not recognized by the immune system or so that they suppress or stimulate the immune system in a targeted manner. In this review, we look at the literature on nanomaterials for immunostimulation and immunosuppression and their impact on how changing the physicochemical features of the particles could alter their interactions with immune cells for the better or for the worse (immunotoxicity). We also look into whether the NPs have a unique or unexpected (but desired) effect on the immune system, and whether the surface grafting of polymers or surface coatings makes stealth nanomaterials that the immune system cannot find and get rid of.

Exploring the role of antibiotics and steroids in managing respiratory diseases.

Respiratory diseases (RDs), such as chronic obstructive pulmonary disease, cystic fibrosis, asthma, and pneumonia, are associated with significant morbidity and mortality. Treatment usually consists of antibiotics and steroids. Relevant published literature reviews, studies, and clinical trials were accessed from institutional and electronic databases. The keywords used were respiratory diseases, steroids, antibiotics, and combination of steroids and antibiotics. Selected articles and literature were carefully reviewed. Antibiotics are often prescribed as the standard therapy to manage RDs. Types of causative respiratory pathogens, spectrum of antibiotics activity, route of administration, and course of therapy determine the type of antibiotics that are prescribed. Despite being associated with good clinical outcome, treatment failure and recurrence rate are still high. In addition, antibiotic resistance has been widely reported due to bacterial mutations in response to the use of antibiotics, which render them ineffective. Nevertheless, there has been a growing demand for corticosteroids (CS) and antibiotics to treat a wide variety of diseases, including various airway diseases, due to their immunosuppressive and anti-inflammatory properties. The use of CS is well established and there are different formulations based on the diseases, such as topical administration, tablets, intravenous injections, and inhaled preparations. Both antibiotics and CS possess similar properties in terms of their anti-inflammatory effects, especially regulating cytokine release. Thus, the current review examines and discusses the different applications of antibiotics, CS, and their combination in managing various RDs. Drawbacks of these interventions are also discussed.

Targeting LIN28: a new hope in prostate cancer theranostics.

The mortality and morbidity rates for prostate cancer have recently increased to alarming levels, rising higher than lung cancer. Due to a lack of drug targets and molecular probes, existing theranostic techniques are limited. Human LIN28A and its paralog LIN28B overexpression are associated with a number of tumors resulting in a remarkable increase in cancer aggression and poor prognoses. The current review aims to highlight recent work identifying the key roles of LIN28A and LIN28B in prostate cancer, and to instigate further preclinical and clinical research in this important area.

Role of the Serine/Threonine Kinase 11 (STK11) or Liver Kinase B1 (LKB1) Gene in Peutz-Jeghers Syndrome.

Peutz-Jeghers syndrome (PJS) is a well-described inherited syndrome, characterized by the development of gastrointestinal polyps and characteristic mucocutaneous freckling. PJS is an autosomal prevailing disease, due to genetic mutation on chromosome 19p, manifested by restricted mucocutaneous melanosis in association with gastrointestinal (GI) polyposis. The gene for PJS has recently been shown to be a serine/threonine kinase, known as LKB1 or STK11, which maps to chromosome subband 19p13.3. This gene has a putative coding region of 1302 bp, divided into nine exons, and acts as a tumor suppressor in the hamartomatous polyps of PJS patients and in the other neoplasms that develop in PJS patients. It is probable that these neoplasms develop from hamartomas, but it remains possible that the LKB1 or STK11 locus plays a role in a different genetic pathway of tumor growth in the cancers of PJS patients. This article focuses on the role of LKB1 or STK11 gene expression in PJS and related cancers.

Severe Manifestations of Chikungunya Fever in Children, India, 2016.

Chikungunya is a relatively benign disease, and a paucity of literature on severe manifestations in children exits. We describe a cohort of pediatric chikungunya fever patients in New Delhi, India, who had severe sepsis and septic shock, which can develop during the acute phase of illness.

In-vitro osteoblast proliferation and in-vivo anti-osteoporotic activity of Bombax ceiba with quantification of Lupeol, gallic acid and ß-sitosterol by HPTLC and HPLC.

BACKGROUND: Bombax ceiba is used traditionally to treat bone disorders, rheumatism, and joint pain. The aim of the study is to carry out osteogenic activity in-vitro and anti-osteoporotic activity in-vivo of stem bark of B. ceiba in surgical ovariectomy model in female rats. METHODS: Plant drug: B. ceiba stem bark was extracted with solvents petroleum ether and methanol using Soxhlet extraction. In-vitro osteoblastic proliferation study was performed using UMR-106 cell lines. Both the extracts were undergone to acute toxicity study as per OECD423 guidelines. Female Wistar albino rats 180-240 g were used (n = 6). Surgical ovariectomy was performed under anesthesia to induce bone porosity and loss in all animals except normal control and sham control. Each extract was administered at two dose level: 100 and 200 mg/kg and the standard Raloxifene was given at 1 mg/kg orally for 28 days. The phytochemical study of both the extracts was performed using HPLC and HPTLC. RESULTS: A significant osteoblast cell proliferation and alkaline phosphatase activity were observed with B. ceiba extracts in UMR-106 cell lines. Surgical removal of ovaries produced significant (p < 0.05) decline in bone mineral density, bone breaking strength, serum ALP, calcium, phosphorus, and estradiol level and marked bone tissue destruction in histology. Administration of petroleum ether and methanolic extract for 28 days significantly (p < 0.05) ameliorated the consequences of ovariectomy induced bone porosity and restored the normal architecture of bone, as compared to OVX control. The phytochemical screening of both the extracts were also carried out. The quantification of phytoconstituents showed the presence of ß-sitosterol and lupeol in petroleum ether extract, whereas the lupeol is also quantified in the methanolic extract. The presence of gallic acid was quantified in methanolic extract using HPLC. CONCLUSION: B. ceiba: stem bark ameliorated the state of bone fragility and fracture possibly due to estrogenic modulation, as also confirmed by in-vitro osteogenic activity which may be due to the presence of lupeol, gallic acid and ß-sitosterol constituents of the plant.

Association Between Parenting Stress and Functional Impairment Among Children Diagnosed with Neurodevelopmental Disorders.

The objective of this study was to examine the association between parenting stress and functional impairment among children with Neurodevelopmental Disorder (NDD). A sample of 150 parents of children diagnosed with NDD were recruited from schools that offer special education services. Parents completed a self-administered survey containing the parenting stress index-short form (PSI-SF) scale and the Columbia Impairment Scale. The multiple logistic regression conducted to compare those with clinically significant PSI-SF scores indicated that the risk of parents with clinically significant scores of parenting stress increased 5.5 times with functionally impaired children with NDD. Further the risk of stress increased 4.6 times when these parents reported having their own disorder/disease. The risk of stress was reduced by 57% for those who had higher than a college level education compared to those with a college level education or below. These findings might help health care providers to initiate early intervention strategies such as peer support and education that can prevent parenting stress and reduce the risk of potential incidence of depression.

Potential biological efficacy of Pinus plant species against oxidative, inflammatory and microbial disorders.

BACKGROUND: Traditionally, Pine has been used to treat oxidative and inflammatory disorders. The study was aimed to investigate biological potential of phytoconstituents of Pinus plant species: Pinus roxburghii, Pinus wallichiana and Pinus gerardiana using in-vitro antioxidant, anti-inflammatory and antimicrobial methods. METHOD: The hydro-alcoholic extraction of dried plant: stem bark was done and the antioxidant activity was evaluated using free radical scavenging methods for 1,1-diphenyl-2-picrylhydrazyl, (DPPH), nitric oxide and hydrogen peroxide radicals, reducing power assays, and total antioxidant capacity. Anti-inflammatory activity was carried out using albumin denaturation and HRBC membrane stabilization assays. Antimicrobial and antifungal activities were also conducted using agar well diffusion method. RESULTS: The qualitative phytochemical analysis of hydro-alcoholic stem bark extracts of three plant species revealed the presence of various biochemical compounds such as alkaloids, flavonoids, glycosides, triterpenoids and saponins. Quantitative phytochemical analysis of plant extracts showed the presence of phenolics, flavonoids, tannins, beta-carotene and lycopene. Plant extracts of three pinus species showed significant antioxidant activity against DPPH, nitric oxide and H2O2 radicals. In in-vitro anti-inflammatory investigation, Pinus roxburghii exhibited highest protection against albumin denaturation 86.54 ± 1.85 whereas Pinus gerardiana showed 82.03 ± 2.67. Moreover, plant extracts were found to prevent the growth of microorganisms Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Candida albicans showing promising antibacterial and antifungal activities againstCandida albicans. CONCLUSION: The findings of the present study derived the rational for the therapeutic usage of Pinus which is a highly timber yielding plant from Himalayan region, against oxidative, inflammatory and microbial diseases.

Do Circadian Rhythms Draw the Patterns of Sustained Mental Vigor and Ailment?

Preclinical Research Circadian rhythms are fundamental processes in all cells that coordinate a variety of cellular functions related to a specific time of the day. Disruption of circadian rhythms markedly impacts homeostasis. In this Commentary, we present data that disruption of circadian rhythm may lead to the pathogenesis of neurodegenerative states. In this context, we further argue that there is an urgent need of developing new generations of compounds, chronobiotics, to modulate the molecular substrates of circadian timing system. Chronobiotics conceptually offer an effective way for restoration and protection from the consequences of the circadian disruption. We also briefly discuss whether dysfunctional circadian rhythms are a major driver of aging. Drug Dev Res 77 : 469-473, 2016. © 2016 Wiley Periodicals, Inc.

Mild alcohol intake exacerbates metabolic syndrome in rodents: a putative role of GSK-3ß.

Metabolic syndrome is characterized with abdominal obesity, insulin resistance, dyslipidemia and hepatic dysfunction. Glycogen synthase kinase-3ß (GSK-3ß) expression has been observed in adipose tissues in obese and diabetic humans, and in rodents. The aim of study was to investigate role of GSK-3ß in modulation of metabolic alterations in alcoholic fed rats. Male Wistar albino rats (180-220 g) were used. High fat diet (HFD) for 8 weeks and alcohol (2%) from third to eighth week were given. Lithium chloride (LiCl), a GSK-3ß inhibitor (60 mg/kg) was used orally from third to eighth week. HFD treatment caused significant (p < 0.05) increase in the percentage of body weight gain, BMI, Lee index, different fat pads, liver weights, serum glucose, leptin, triglyceride, LDL, VLDL, cholesterol, alanine transaminase, aspartate transaminase, tissue thio-barbituric acid reactive substances, nitrate/nitrite and significant decrease in food intake (g), serum HDL and tissue GSH in HFD control rats, as compared to normal control (NC). Administration of alcohol (2%) ad libitum potentiated the effect of normal and HFD, respectively, in NC and HFD control rats, respectively. Administration of LiCl produced significant amelioration in biochemical and pathological changes caused in the form of metabolic syndrome in HFD alone and HFD and alcohol-treated rats. The histological observations also showed similar findings in liver tissue. It may be concluded that inactivation of GSK-3ß consequently leads to increased leptin and insulin sensitivity as evidenced by the reversal of alterations caused due to metabolic syndrome in rodents fed with HFD and mild alcohol.

Preconditioning offers cardioprotection in hyperlipidemic rat hearts: possible role of Dopamine (D2) signaling.

BACKGROUND: Ischemic preconditioning (IPC) induced cardioprotection has been reported to be blunted in hyperlipidemic subjects. Dopamine, via its D2 receptor signaling, appears to mimic the signaling cascade involved in myocardial preconditioning and is also involved in the inhibition of hyperlipidemia induced mediators. The present study was designed to investigate the possible involvement of D2 receptors in IPC and to see whether dopamine preconditioning can offer cardioprotection in hyperlipidemic rat hearts. METHODS: Wistar albino rats were divided into 8 groups and fed on normal or high fat diet for 4 weeks. Hyperlipidemia was confirmed after 4 weeks by serum lipid estimations. Isolated perfused hearts were subjected to ischemic preconditioning or dopamine induced pharmacological preconditioning followed by 30-min ischemic insult and 60-min reperfusion. Clozapine was administered as D2 antagonist. Coronary perfusate (basal and post-ischemic) was collected for the estimations of LDH (Lactate dehydrogenase) and CKMB (Creatine kinase MB). Hearts were then removed and frozen for infarct size measurement. RESULTS: A significant increase body weight, serum lipids except HDL was noted in high fat diet fed rats, as compared to normal rats. The level of LDH, CKMB in coronary effluent and infarct size were found to be decreased in preconditioned normal hearts, as compared to hearts treated with ischemia reperfusion. This effect was found to be blunted in hyperlipidemic animals. Dopamine (10 µM) alone and in combination with ischemic preconditioning significantly reduced the levels of LDH, CKMB and infarct size in hyperlipidemic hearts, as compared to preconditioned and non-preconditioned hyperlipidemic hearts. This effect was abolished significantly by Clozapine (D2 antagonist). CONCLUSION: The present study reveals possible involvement of D2 receptors in ischemic preconditioning and suggests that dopamine preconditioning may offer significant cardioprotection in hyperlipidemic rat hearts.

Eosinophilic Esophagitis: Clinical Pearls for Primary Care Providers and Gastroenterologists.

Eosinophilic esophagitis (EoE) is a chronic and progressive immune-mediated esophageal disorder. Given its increasing incidence, it is now a leading cause of dysphagia and food impaction in the United States. Eosinophilic esophagitis is most common in adult White men and has a high concurrence rate with other atopic conditions like allergic rhinitis, bronchial asthma, and eczema. The initial presentation includes symptoms of esophageal dysfunction, classically solid-food dysphagia. Without treatment, inflammation can progress to fibrosis with the formation of strictures, leading to complications such as food impaction. It is a clinicopathologic disease requiring compatible clinical symptoms and histologic evidence of eosinophil-predominant inflammation of the esophageal epithelium with more than 15 eosinophils per high-power field. The mainstay of management includes the 3 d's (diet, drugs, dilation): dietary modifications to eliminate trigger food groups; medications including proton pump inhibitors, swallowed topical glucocorticoids, and dupilumab; and esophageal dilation to manage strictures. Various elimination diets have been found to be effective, including 1-food, 2-food, 4-food, and 6-food elimination diets. Dupilumab, a humanized monoclonal antibody that regulates interleukin 4 and 13 signaling pathways, has shown promising results in clinical trials and was approved by the Food and Drug Administration in 2022 for use in EoE. Symptom alleviation, although important, is not the sole end point of treatment in EoE as persistent inflammation, even in the absence of symptoms, can lead to esophageal fibrosis and stricture formation over time. The chronic nature and high recurrence rates of EoE warrant maintenance therapy in patients with EoE after initial remission is achieved.

Emerging Burkholderia Musculoskeletal Infections With Delayed Diagnosis in Non-endemic Regions Affect Patient Morbidity: A Case Series of 10 Patients With a Review of the Literature.

INTRODUCTION:  Burkholderia infection commonly presents as bacteraemic pulmonary disease; however, it is notorious for its wide variety of presentations in chronic cases, including musculoskeletal manifestations. It is common in patients living in endemic areas with comorbidities such as diabetes and who have chronic alcoholism. It was previously under-reported due to a low index of suspicion. Now, there is an increasing trend of diagnosis of these infections in non-endemic areas because of various factors, such as MALDI-TOF, molecular tests, and PCR. MATERIALS AND METHODS: This is a single tertiary centre study of 10 patients, diagnosed with Burkholderia infection and treated at our institution between 2021 and 2023 and followed up for a minimum of six months. Information was collected from outpatient and inpatient records. RESULTS: In this study, the mean age of the patients was 45 years, with eight males and two females. Out of 10, seven patients had comorbidities. However, only one patient has a history of travelling to an endemic area. All our patients were treated operatively, and the course of intervention and the planning of the surgical procedure were decided according to clinico-radiological findings. Six out of 10 patients suffering from Burkholderia species infections have a history of prolonged ICU stay, four of them tested positive for Burkholderia pseudomallei and the remaining two tested positive for Burkholderia cepacia, with a mean average time of 24.6 days. Diabetes was the most common comorbidity in 70% of the patients. The knee was the most commonly affected joint, showing involvement in 60% of patients. We have done surgical intervention in all patients. In our study, we have given IV antibiotics for a minimum of six weeks to all patients, followed by oral antibiotic therapy for three to six months on the basis of regular follow-up of clinico-haematologic parameters. CONCLUSION: Infections caused by Burkholderia species should be considered a potential causative agent of musculoskeletal infections in non-endemic areas without prior history of travelling to endemic areas. It may present with a chronic, mild course; a high index of suspicion is required, and it is important that due suspicion translates to prompt diagnosis and appropriate treatment to mitigate the course of the disease and associated morbidities in patients.