TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1ß-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1ß were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1ß-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.

Allosteric regulation of thioesterase superfamily member 1 by lipid sensor domain binding fatty acids and lysophosphatidylcholine.

Nonshivering thermogenesis occurs in brown adipose tissue to generate heat in response to cold ambient temperatures. Thioesterase superfamily member 1 (Them1) is transcriptionally up-regulated in brown adipose tissue upon exposure to the cold and suppresses thermogenesis in order to conserve energy reserves. It hydrolyzes long-chain fatty acyl-CoAs that are derived from lipid droplets, preventing their use as fuel for thermogenesis. In addition to its enzymatic domains, Them1 contains a C-terminal StAR-related lipid transfer (START) domain with unknown ligand or function. By complementary biophysical approaches, we show that the START domain binds to long-chain fatty acids, products of Them1's enzymatic reaction, as well as lysophosphatidylcholine (LPC), lipids shown to activate thermogenesis in brown adipocytes. Certain fatty acids stabilize the START domain and allosterically enhance Them1 catalysis of acyl-CoA, whereas 18:1 LPC destabilizes and inhibits activity, which we verify in cell culture. Additionally, we demonstrate that the START domain functions to localize Them1 near lipid droplets. These findings define the role of the START domain as a lipid sensor that allosterically regulates Them1 activity and spatially localizes it in proximity to the lipid droplet.

Colchicine for Patients With Coronary Artery Disease: A Systematic Review and Meta-analysis.

ABSTRACT: Several randomized controlled trials have studied the role of colchicine, a potent anti-inflammatory drug, to prevent adverse cardiovascular events in patients with coronary artery disease (CAD). In this meta-analysis, we aimed to determine the role of colchicine in patients with CAD in clinical outcomes and mortality. We searched PubMed, PubMed Central, Scopus, and Embase for randomized controlled trials/experimental studies evaluating the role of colchicine in patients with CAD. After assessing the eligibility for inclusion, risk-of-bias assessment, and data extraction from the included studies, a narrative synthesis was conducted. Of 17 studies included for the qualitative analysis, 11 studies reported that inflammatory markers such as C-reactive protein and cytokines were reduced in the colchicine group, suggesting an anti-inflammatory role of colchicine in CAD. Quantitative analysis with pooling of data from 9 studies using a fixed-effect model showed 28% lower odds of acute myocardial infarction [odds ratio (OR) 0.72, 95% CI 0.59-0.86; n = 11,712], 52% lower occurrence of stroke (OR 0.48, 95% CI 0.30-0.76), and 37% reduction in odds of coronary revascularization procedure in the colchicine group (OR 0.63, 95% CI 0.52-0.76; n= 11,258). However, the odds of gastrointestinal adverse events were 50% higher in the colchicine group (OR 1.50, 95% CI 1.01-2.23; n = 12,214). In conclusion, colchicine is associated with a lower risk of acute myocardial infarction, stroke, and coronary revascularization. However, there is some increased risk of gastrointestinal adverse events with the use of colchicine.

Sterol Composition and Biosynthetic Genes of Vitrella brassicaformis, a Recently Discovered Chromerid: Comparison to Chromera velia and Phylogenetic Relationship with Apicomplexan Parasites.

Vitrella brassicaformis is the second discovered species in the Chromerida, and first in the family Vitrellaceae. Chromera velia, the first discovered species, forms an independent photosynthetic lineage with V. brassicaformis, and both are closely related to peridinin-containing dinoflagellates and nonphotosynthetic apicomplexans; both also show phylogenetic closeness with red algal plastids. We have utilized gas chromatography/mass spectrometry to identify two free sterols, 24-ethylcholest-5-en-3ß-ol, and a minor unknown sterol which appeared to be a C(28:4) compound. We have also used RNA Seq analysis to identify seven genes found in the nonmevalonate/methylerythritol pathway (MEP) for sterol biosynthesis. Subsequent genome analysis of V. brassicaformis showed the presence of two mevalonate (MVA) pathway genes, though the genes were not observed in the transcriptome analysis. Transcripts from four genes (dxr, ispf, ispd, and idi) were selected and translated into proteins to study the phylogenetic relationship of sterol biosynthesis in V. brassicaformis and C. velia to other groups of algae and apicomplexans. On the basis of our genomic and transcriptomic analyses, we hypothesize that the MEP pathway was the primary pathway that apicomplexans used for sterol biosynthesis before they lost their sterol biosynthesis ability, although contribution of the MVA pathway cannot be discounted.

Prevalence and clinical characteristics of hyperuricemia among patients with chronic kidney disease under haemodialysis in a tertiary care center: a cross-sectional study.

Background: Hyperuricemia is common in chronic kidney disease patients. This study aimed to investigate the prevalence and clinical characteristics of hyperuricemia in patients with chronic kidney disease undergoing haemodialysis. Materials and methods: This cross-sectional study was conducted among 104 patients with chronic kidney disease who visited the haemodialysis unit of a tertiary centre hospital from 11 September 2022, to 11 November 2022. A convenience sampling technique was used. The data were collected using a proforma form, entered into, and analyzed using the Statistical Package for Social Sciences version 21. Results: The mean age group of the study participants was 54.02 ± 14.03 years, and around two-thirds were male (n=70, 67.3%). Almost half of the participants (50, 48.07%) had hyperuricemia with a mean uric acid level of 6.76 ± 2.62 mg/dl. The majority of the participants had associated hypertension (n=100, 96.2%). More than three-fourths of the respondents (83, 79.8%) had haemoglobin levels below the target range. Conclusion: Nearly half of the study participants had hyperuricemia.

Integrative brain omics approach reveals key role for sn-1 lysophosphatidylethanolamine in Alzheimer's dementia.

The biology of individual lipid species and their relevance in Alzheimer's disease (AD) remains incompletely understood. We utilized non-targeted mass spectrometry to examine brain lipids variations across 316 post-mortem brains from participants in the Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) cohorts classified as either control, asymptomatic AD (AAD), or symptomatic AD (SAD) and integrated the lipidomics data with untargeted proteomic characterization on the same individuals. Lipid enrichment analysis and analysis of variance identified significantly lower abundance of lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) species in SAD than controls or AAD. Lipid-protein co-expression network analyses revealed that lipid modules consisting of LPE and LPC exhibited a significant association to protein modules associated with MAPK/metabolism, post-synaptic density, and Cell-ECM interaction pathways and were associated with better antemortem cognition and with neuropathological changes seen in AD. Particularly, LPE 22:6 [sn-1] levels are significantly decreased across AD cases (SAD) and show the most influence on protein changes compared to other lysophospholipid species. LPE 22:6 may be a lipid signature for AD and could be leveraged as potential therapeutic or dietary targets for AD.

Kounis syndrome following multiple wasp stings: A case report.

This is a case of Kounis syndrome with chest tightness, lightheadedness, unconsciousness, and features of shock following multiple wasp stings. Despite cardiopulmonary resuscitation and management of allergic and cardiac symptoms, the patient died. Kounis syndrome should be suspected when a patient presents with allergic symptoms and acute coronary syndrome.

A rare case of an inflammatory myofibroblastic tumor of the appendix presenting as acute appendicitis: A case report.

INTRODUCTION AND IMPORTANCE: An inflammatory myofibroblastic tumor is commonly seen in the lungs but rarely in the appendix. It has a distinct inflammatory cell component and myofibroblastic component. The study presents an inflammatory myofibroblastic tumor of the appendix in an elderly who presented with acute appendicitis and was later found to have an appendicular mass intraoperatively. CASE PRESENTATION: Herein, we report a case of inflammatory myofibroblastic tumor of the appendix in a 59 years old female who presented with acute abdomen, features suggestive of acute appendicitis clinically. However, the intra-operative findings showed an appendicular mass involving the base of the appendix for which a right hemicolectomy was done. The histopathological examination of the resected specimen later confirmed it as an inflammatory myofibroblastic tumor of the appendix. CLINICAL DISCUSSION: An inflammatory myofibroblastic tumor is common in the lungs, whereas rare in the appendix. It primarily involves children and young adults. It can present as mimic appendicitis or appendicular mass and should thus be considered in the differentials of these. CONCLUSION: The rare presentation of inflammatory myofibroblastic tumor of the appendix makes it likely to be missed resulting in overzealous resection of the tumor. Thus, it is important to consider it in the differential diagnosis of acute appendicitis and manage it accordingly.

Meningococcemia in an 11 Months Old Infant.

Meningococcemia is the infection of the blood caused by Neisseria meningitidis. Herein, we report a case of meningococcemia in an 11 months old infant who had a high-grade fever, nonblanching purpuric rash over the face and limbs, low blood pressure, tachycardia, and prolonged capillary refill time, but without neck rigidity and focal neurologic signs. He recovered after supportive care and treatment with antibiotics (intravenous ceftriaxone, vancomycin, and teicoplanin). Therefore, in a febrile, ill-looking child in shock with a nonblanching rash, meningococcal disease should be suspected. The study shows the importance of vaccination against meningococcal disease.

Comparison of spirometric parameters in athletes engaged in aerobic and anaerobic sports: a cross-sectional study.

Pulmonary function tests are better among athletes than non-athletes. The spirometry parameters may vary among athletes involved in aerobic and anaerobic sports. This study aims to study the difference in spirometry parameters among aerobic and anaerobic sports athletes. Materials and methods: This cross-sectional study was conducted among 131 professional athletes. A convenience sampling technique was used. The data were collected from April to November 2022 using a proforma form, entered into Microsoft Excel, and analyzed using Statistical Package for Social Sciences version 16. Results: Out of 131 total participants, 65 were involved in aerobic sports, while 66 were in anaerobic sports. The mean age of the participants was 27.34±5 years, the majority being male (n=104). Aerobic athletes had higher differences in forced vital capacity (1.19%, P=0.726) and forced expiratory volume in the first second (3.08%, P=0.315), the difference was not statistically significant. Statistically significantly higher difference in forced expiratory flow at 25-75% (13.42%, P=0.001), forced expiratory flow at 0.2-1.2 l/s (7.47%, P=0.035), and maximum voluntary ventilation (8.58%, P=0.023) values were observed among aerobic athletes. Conclusion: Aerobic and anaerobic athletes had no statistically significant difference in forced vital capacity and forced expiratory volume in the first second; however, other spirometry parameters were comparatively better in aerobic athletes.

Proximal radioulnar synostosis following Monteggia fracture-dislocation: a case report.

Introduction and importance: Radioulnar synostosis is a rare complication of a forearm fracture that restricts pronation-supination. This study presents a case of proximal radioulnar synostosis in an adult male after Monteggia fracture-dislocation who had a loss of pronation and supination movements. Case presentation: Herein, we report a case of proximal radioulnar synostosis in a 43-year-old man who presented with loss of pronation and supination of the right forearm that restricted his daily activities. He had a history of Monteggia fracture-dislocation 9 months back, which was managed with open reduction and internal fixation with a dynamic compression plate. Plain radiography and computed tomography of the right forearm after 9 months of operation showed an implant in situ with proximal radioulnar synostosis. Implant removal was performed and the excess fibro-osseous connection in the proximal radius and ulna was removed. Clinical discussion: Forearm injuries that affect the interosseous membrane may result in radioulnar synostosis. Trauma and treatment-related factors increase the risk of radioulnar synostosis. The fibro-osseous fusion between the forearm bones restricts the pronation and supination movements. Conclusion: Loss of pronation-supination following forearm fracture should raise suspicion of radioulnar synostosis.

Chronic myelomonocytic leukemia in a 72-year-old male from Nepal: A case report.

Chronic myelomonocytic leukemia (CMML) is a rare disease of clonal hematopoietic stem cells with an inherent risk of leukemic transformation, seen in an elderly male. Case Presentation: Herein, the authors report a case of CMML in a 72-year-old male who presented with fever and abdominal pain for 2 days with a history of easy fatigability. Examination revealed pallor and palpable supraclavicular nodes. Investigations showed leukocytosis with a monocyte count of 22% of white blood cell count, 17% blast cells in bone marrow aspiration, increased blast/promonocytes, and positive markers in immunophenotyping. The patient is planned for injection of azacitidine, 7 days cycle for a total of six cycles. Clinical Discussion: CMML is classified as overlapping myelodysplastic/myeloproliferative neoplasms. It can be diagnosed based on a peripheral blood smear, bone marrow aspiration and biopsy, chromosomal analysis, and genetic tests. The commonly used treatment options are hypomethylating agents like azacitidine and decitabine, allogeneic hematopoietic stem cell transplant, and cytoreductive agents like hydroxyurea. Conclusion: Despite various treatment options, the treatment is still unsatisfactory, demanding standard management strategies.

Appendicular actinomycosis: The first reported case of an uncommon finding of a common ailment from Nepal.

Key Clinical Message: Actinomycosis is a rare cause of appendicitis with an incidence of 0.3-1 incident per year per 100,000 people. A significant preoperative diagnostic challenge exists and is usually diagnosed incidentally on histopathological examination. Abstract: Appendicular actinomycosis, a rare, chronic granulomatous infection caused by actinomyces species, holds a significant preoperative diagnostic summons and is often diagnosed serendipitously during the regular histopathological examination. Herein, we present a case of a 36-year-old female who presented with features suggestive of acute appendicitis, underwent laparoscopic appendicectomy, and was diagnosed with appendicular actinomycosis from the histopathological examination.

Prevalence of acute myeloid leukemia and its associated risk factors at a tertiary care center: a retrospective cross-sectional study.

Background: Acute myeloid leukemia (AML) is a common malignant disorder of the bone marrow, accounting for 23.1% of total leukemia cases globally in 2017. This study aimed to know the prevalence of AML in a tertiary hospital center in Nepal and assess the associated etiological factors in the causation of AML. Materials and methods: A hospital-based retrospective cross-sectional study was conducted among patients with acute leukemia admitted to a tertiary care center in Kathmandu from 1 April 2021 to 30 April 2022. Three hundred and ten participants with acute leukemia were selected via a convenience sampling technique. The data were entered into Microsoft Excel 365 and then analyzed using Statistical Packages for Social Sciences version 22.0. Results: One hundred and forty five (46.7%) out of 310 acute leukemia patients had AML. Most of the cases were male (104, 71.7%) and aged 40-49 years (36, 24.8%). The most common signs and symptoms were pallor (115, 79.3%), fever (n=92, 63.4%), and lethargy/weakness (78, 53.8%). Ninety one (62.8%) patients underwent multiple cycles of chemotherapy while 51 (35.2%) had supportive care only, and 3 (2.1%) went bone marrow transplants. Conclusion: The prevalence of AML was higher as compared to AML in other studies done in a similar setting. Early diagnosis and treatment are key to a good prognosis and cure in most cases.

Sterol composition and biosynthetic genes of the recently discovered photosynthetic alveolate, Chromera velia (chromerida), a close relative of apicomplexans.

Chromera velia is a recently discovered, photosynthetic, marine alveolate closely related to apicomplexan parasites, and more distantly to perkinsids and dinoflagellates. To date, there are no published studies on the sterols of C. velia. Because apicomplexans and perkinsids are not known to synthesize sterols de novo, but rather obtain them from their host organisms, our objective was to examine the composition of the sterols of C. velia to assess whether or not there is any commonality with dinoflagellates as the closest taxonomic group capable of synthesizing sterols de novo. Furthermore, knowledge of the sterols of C. velia may provide insight into the sterol biosynthetic capabilities of apicomplexans prior to loss of sterol biosynthesis. We have found that C. velia possesses two primary sterols, 24-ethylcholesta-5,22E-dien-3ß-ol, and 24-ethylcholest-5-en-3ß-ol, not common to dinoflagellates, but rather commonly found in other classes of algae and plants. In addition, we have identified computationally three genes, SMT1 (sterol-24C-methyltransferase), FDFT1 (farnesyl diphosphate farnesyl transferase, squalene synthase), and IDI1 (isopentenyl diphosphate Δ-isomerase), predicted to be involved in sterol biosynthesis by their similarity to analogous genes in other sterol-producing eukaryotes, including a number of algae.

Tuberous sclerosis in a 16 years old female: A case report.

INTRODUCTION: Tuberous sclerosis complex (TSC) is an uncommon multisystem disorder that can affect the lungs, skin, kidneys, and brain. The study highlights the importance of genetic and clinical diagnostic criteria in identifying this rare condition and the role of surveillance in preventing complications. CASE PRESENTATION: Herein, we report a case of 16 years old female presenting with right flank pain, hematuria, hypopigmented macule over the back, ash leaf spots over the right upper and lower limb, and a palpable mass over the right lumbar region. Laboratory tests showed low hemoglobin with plenty of red blood cells in urine. She was admitted for symptomatic management of pain and blood transfusion was done to manage anemia. After a diagnostic workup for tuberous sclerosis, she was diagnosed with the condition and is under regular follow-up. CLINICAL DISCUSSION: Tuberous sclerosis complex is one of the neurocutaneous syndromes, diagnosed based on the genetic or clinical diagnostic criteria as per the second International Tuberous Sclerosis Complex Consensus Conference 2012, which have been updated in 2021 with no changes in genetic diagnostic criteria and slight changes in clinical diagnostic criteria. After diagnosis, along with the management, surveillance is also crucial. CONCLUSION: Tuberous sclerosis runs a progressive course and can lead to various complications. Thus, early diagnosis with the help of genetic and clinical diagnostic criteria is important along with regular surveillance of different body systems to prevent debilitating complications.

Adenoid cystic carcinoma of maxillary antrum: A case report.

INTRODUCTION: Adenoid cystic carcinoma rarely involves the nose and paranasal sinuses. It is a slowly growing, aggressive malignant tumor with a predisposition for perineural invasion. The study highlights the importance of timely diagnosis and management of adenoid cystic carcinoma. PRESENTATION OF CASE: Herein, we report a case of adenoid cystic carcinoma of maxillary antrum in a 69 years old female, who presented with an insidious onset of painful right cheek swelling for three months. Biopsy showed the glandular pattern of tumor cells with perineural invasion, suggestive of adenoid cystic carcinoma. Contrast-enhanced computed tomography of paranasal sinuses showed a well-differentiated, irregularly outlined, non-enhancing heterogeneous lesion in the right maxillary sinus with bony destruction, suggesting the malignant nature of the lesion. The mass was surgically excised and histopathological examination further confirmed the diagnosis. DISCUSSION: Adenoid cystic carcinoma is a rare malignancy of the nose and paranasal sinus, although it is quite common in salivary glands. It should be considered in the differentials in a patient presenting with sinonasal mass, pain, nasal obstruction, epistaxis, and auditory symptoms. CONCLUSION: As the tumor can be missed clinically owing to its rarity in paranasal sinuses and can present at an advanced stage, early diagnosis and management of adenoid cystic carcinoma are important.

Acute acalculous cholecystitis in a patient with dengue fever: A case report.

Introduction: and importance: Although dengue fever classically presents with fever, headache, retro-orbital pain, myalgia, arthralgia, and vomiting, it can have unusual manifestations like acalculous cholecystitis. The study highlights the importance of atypical presentations of dengue fever in suspecting dengue earlier, especially during outbreaks. Case presentation: Herein, we report a case of a 29 years old female who presented with fever for 5 days which was associated with headache, body ache, vomiting, and abdominal pain in the right hypochondriac region. Lab results came positive for dengue NS1 antigen, and ultrasonography showed features suggestive of acalculous cholecystitis. She was managed conservatively after which her symptoms resolved gradually. Clinical discussion: Acute acalculous cholecystitis in dengue could be due to increased vascular permeability leading to edematous thickening of the gall bladder wall. It should be suspected if a patient presents with fever, right upper quadrant pain, abnormal liver function tests, and thickened gall bladder wall without stones on abdominal ultrasonography. Conclusion: Acute acalculous cholecystitis is an atypical presentation of dengue fever. Awareness of atypical presentations of dengue helps in identifying dengue earlier and preventing complications.

An Outbreak Investigation of Varicella Zoster among Male Military Personnel in a Military Training Centre.

Introduction: Chickenpox is an acute, highly infectious disease. Outbreaks can occur in adults in closed institutional settings like hostels and barracks. This study aims to report varicella zoster outbreak among male military personnel in a military training centre. Methods: An outbreak investigation of chickenpox in a military training school and tertiary hospital was conducted. Ethical approval was taken from the Institutional Review Committee (Reference number: 267). Data was collected from February 5, 2020 to April 10, 2020 by questionnaire and clinical examination. Case definitions were prepared as per the Centre for Disease Control and Prevention criteria. Data was entered and analysed in Microsoft Excel 2010. Results: Out of the 167 male personnel in the training centre, 90 (53.89%) were susceptible to varicella and 84 (50.29%) were close contacts. The secondary attack rate of varicella zoster was 21.43% (18 cases). The mean age of the patients was 22.33±1.72 years. The mean days of admission were 5±2.28 days. The most common clinical features were generalised rash in 18 (100%), fever in 15 (83.33%), and body ache in 12 (66.67%) cases. Conclusions: Natural history, clinical, and epidemiological features of varicella zoster in a closed institutional setting was studied with the secondary attack rate being less as compared to other studies. Keywords: chickenpox; military; outbreak.

Regional anesthesia as a safe anesthesia technique for clavicle surgery in a COVID-19 positive patient at rural setup: A case report.

INTRODUCTION: Clavicle fractures are less commonly managed under regional anesthesia compared to general anesthesia. The study highlights the advantage of regional anesthesia in reducing the risk of aerosol generation and viral transmission during the times of COVID-19 and avoiding the complications associated with general anesthesia. PRESENTATION OF CASE: We report a case of 42 years old COVID-19 positive male with a left clavicle fracture due to a fall from a tree, who was managed under regional anesthesia with open reduction and internal fixation. A combination of interscalene brachial plexus and superficial cervical plexus block was performed. DISCUSSION: The dual innervation of the clavicle makes combined interscalene brachial plexus and superficial cervical plexus block an effective method of anesthesia for clavicle surgery. It provides better analgesia, has fewer postoperative complications, less infection transmission via aerosol, and earlier hospital discharge as compared to general anesthesia. CONCLUSION: Ultrasound-guided combined interscalene brachial plexus and superficial cervical plexus block can be used as a safe anesthetic technique in clavicle surgery.