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Science Advances Sep 2023Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used...
Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat obesity require complete characterization of the central mechanisms that mediate both the food intake-suppressive and illness-like effects of GLP-1R signaling. Our studies, in the rat, demonstrate that GLP-1Rs in the locus coeruleus (LC) are pharmacologically and physiologically relevant for food intake control. Furthermore, agonism of LC GLP-1Rs induces illness-like behaviors, and antagonism of LC GLP-1Rs can attenuate GLP-1R-mediated nausea. Electrophysiological and behavioral pharmacology data support a role for LC GLP-1Rs expressed on presynaptic glutamatergic terminals in the control of feeding and malaise. Collectively, our work establishes the LC as a site of action for GLP-1 signaling and extends our understanding of the GLP-1 signaling mechanism necessary for the development of improved obesity pharmacotherapies.
Topics: United States; Animals; Rats; Appetite Depressants; Locus Coeruleus; Obesity; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Nausea
PubMed: 37729419
DOI: 10.1126/sciadv.adh0980 -
Acta Neuropathologica Communications Dec 2023The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as...
The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as "long COVID". Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169 macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues. In addition, complement system related proteins were more abundant in the serum of patients with PCS, matching observations on the transcriptomic level in the muscle tissue. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.
Topics: Humans; Capillaries; COVID-19; SARS-CoV-2; Muscle, Skeletal; Fatigue
PubMed: 38066589
DOI: 10.1186/s40478-023-01662-2 -
Respiratory Medicine Sep 2023Lung abscess (LA) is a serious respiratory infection often followed by several weeks of antibiotic treatment. This study described the clinical presentation of LA,...
INTRODUCTION
Lung abscess (LA) is a serious respiratory infection often followed by several weeks of antibiotic treatment. This study described the clinical presentation of LA, treatment duration and mortality in a contemporary Danish population.
METHODS
In a retrospective multicenter cohort study at four Danish hospitals, patients diagnosed with LA were identified using the International Classification of Diseases and Related Health Problems 10th revision (ICD-10) between 2016 and 2021. A predefined data collection tool was used to extract data on demographics, symptoms, clinical findings and treatment.
RESULTS
Of 302 patients, 222 with LA were included after review of patient records (76%). Mean age was 65 years (54-74), 62.9% was male and 74.9% were ever-smokers. Chronic obstructive pulmonary disease (COPD) (35.1%), use of sedatives (29.3%) and alcohol abuse (21.8%) were common risk factors. Dental status was reported in 51.4%, whereof 41.6% had poor dental status. Patients presented with cough (78.8%), malaise (61.3%) and fever (56.8%) Patients were hospitalized for a median of 14 days (interquartile ranges, IQR 7-21) and median duration of antibiotic treatment was 38 days (IQR 30-51). All-cause mortality after 1, 3 and 12 months was 2.7%, 7.7% and 15.8%, respectively.
CONCLUSION
Risk factors for LA include COPD and use of sedatives, alcohol abuse, and poor dental status. Despite long-term antibiotic treatment, long-term mortality is markedly high.
Topics: Humans; Male; Aged; Lung Abscess; Cohort Studies; Disease Progression; Alcoholism; Pulmonary Disease, Chronic Obstructive; Anti-Bacterial Agents; Denmark
PubMed: 37302422
DOI: 10.1016/j.rmed.2023.107305 -
Cureus Jul 2023Toxic shock syndrome (TSS) is a rare, life-threatening, acute multisystem disorder caused by exotoxin-producing streptococcal or staphylococcal bacteria. It is often...
Toxic shock syndrome (TSS) is a rare, life-threatening, acute multisystem disorder caused by exotoxin-producing streptococcal or staphylococcal bacteria. It is often characterised by pyrexia, diffuse erythroderma, malaise, confusion, and hypotension which may progress to multiorgan dysfunction and coma. A high index of suspicion along with immediate diagnosis and multidisciplinary management is required to improve the outcome of the disease. A 62-year-old male presented to the hospital a week after an open reduction and internal fixation of a left wrist fracture. He was confused, febrile, and hypotensive with a generalised maculopapular rash on admission. Surgical wound sepsis was a top differential diagnosis; however, other possible sources were considered. Diagnostic imaging and echocardiography effectively ruled out other possible aetiologies. Despite fluids, vasopressor support, and appropriate antibiotics, he showed no significant clinical improvement. Admission blood cultures grew and after a multidisciplinary meeting, he was taken to the theatre for wound exploration, debridement, and removal of the metal plate. He was eventually weaned off vasopressor support and recovered well. A high index of suspicion is important in recognising TSS in postoperative orthopaedic patients as wounds may appear healthy-looking and the onset of symptoms may be delayed. Early recognition, timely intervention, and multidisciplinary management are vital to the care of these patients.
PubMed: 37641753
DOI: 10.7759/cureus.42609 -
Revue Medicale de Liege Nov 2023Rheumatoid arthritis is a chronic inflammatory systemic disease. Pulmonary manifestations are the most common extra-articular involvements and can impact all components...
Rheumatoid arthritis is a chronic inflammatory systemic disease. Pulmonary manifestations are the most common extra-articular involvements and can impact all components of the respiratory system: parenchyma, pleura, vessels and airways, all complications that are briefly described in this article. Interstitial lung disease is the most common of these and is associated with significant morbidity and mortality. Its detection and monitoring are based on spirometry and thoracic imaging. Specific treatments are initiated in order to reduce the risk of disease flare up but may themselves in case of toxicity be associated with respiratory manifestations, either directly or by promoting infectious complications.
Topics: Humans; Lung Diseases; Arthritis, Rheumatoid; Lung Diseases, Interstitial
PubMed: 37955294
DOI: No ID Found -
Molecular Cancer Therapeutics Apr 2024We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve...
We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma (la/mUC). TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarkers of response were assessed. In 36 patients enrolled, the ORR was 33.3% (complete response: 7 patients; partial response: 5 patients). Median PFS was 5.0 months; 6- and 12-month progression-free rates were 46.4% and 36.5%, respectively. Median OS was not reached; 6-, 12-, and 24-month OS rates were 83.3%, 72.2%, and 55.1%, respectively. In post hoc analysis, patients with a tumor infiltrating CD8+ lymphocyte (CD8+ TIL) count ≥99 and/or programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥50 and lymphocyte count >1,380 cells/μL had higher ORRs and prolonged PFS versus patients with a CD8+ TIL count <99, PD-L1 CPS <50, and lymphocyte count ≤1,380 cells/μL. Thirty-four (94.4%) patients receiving combination therapy experienced treatment-related adverse events (AE), with pyrexia (n = 15, 41.7%), injection-site reactions (n = 15, 41.7%), injection-site induration (n = 6, 16.7%), and malaise (n = 6, 16.7%) the most common. No grade ≥3 treatment-related AEs occurred in ≥10% of patients. TAS0313 plus pembrolizumab combination therapy showed promising efficacy and manageable safety in la/mUC. Clinical Trial Registration: JapicCTI-183824.
Topics: Humans; Immune Checkpoint Inhibitors; Carcinoma, Transitional Cell; B7-H1 Antigen; Antineoplastic Agents, Immunological; Urinary Bladder Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal, Humanized
PubMed: 38060587
DOI: 10.1158/1535-7163.MCT-23-0187 -
Cureus Feb 2024Malaria by Plasmodium falciparum (P. falciparum) usually does not exceed one year, but chronic infection, although rare, is a possibility. We present the clinical case...
Malaria by Plasmodium falciparum (P. falciparum) usually does not exceed one year, but chronic infection, although rare, is a possibility. We present the clinical case of a 37-year-old male who came to the emergency department with intermittent fever, chills, and malaise. He had malaria more than 1 year ago while working in Huíla province, Angola. On admission, Plasmodium testing by light microscopy and antigens was negative. Doxycycline was started empirically, but on the third day of hospitalization, he had a new fever spike. Plasmodium DNA and antibodies were tested, confirming P. falciparum. The therapy with artemether-lumefantrine, already after discharge, allowed the consolidation of the treatment and eradicator of the parasite. Detection of parasite DNA by PCR should not be routine, but it is a more sensitive method, which confirmed this chronic infection by P. falciparum after one year.
PubMed: 38318275
DOI: 10.7759/cureus.53589 -
Pediatric Rheumatology Online Journal May 2024Vitamin C deficiency, or scurvy, is rare but poses risks for children with poor diets, limited resources, or malabsorption issues. It may also be common in children with...
BACKGROUND
Vitamin C deficiency, or scurvy, is rare but poses risks for children with poor diets, limited resources, or malabsorption issues. It may also be common in children with restrictive or selective dietary habits in children with global developmental delay, autism spectrum disorder, and physical disabilities. Symptoms include fatigue, irritability, joint and muscle pain, joint swellings, edema, swollen gums, easy bruising, and delayed wound healing. Early recognition and prompt intervention are essential to prevent the progression of symptomatic vitamin C deficiency in children.
CASE PRESENTATION
We present a case of a 13-year-old boy with developmental delay secondary to Lennox Gastaut syndrome referred for suspected recurrent, severe, and atypical IgA vasculitis. He presented with irritability, loss of appetite, petechial and ecchymotic lower limb lesions, unilateral gum swelling, severe arthritis, peripheral oedema, severe weight loss, anaemia, and raised inflammatory markers. Multiple investigations were performed before the diagnosis of scurvy was made. A surgical finding of friable gingival tissue with multiple loose teeth, a skin biopsy with follicular hyperkeratosis and extravasated perifollicular red blood cells, and a typical X-ray finding led to the diagnosis of scurvy.
CONCLUSION
Scurvy should be given careful consideration as a differential diagnosis in patients presenting with musculoskeletal issues, mucocutaneous complaints, and constitutional symptoms such as malaise, asthenia, irritability, and loss of appetite. A focused and detailed dietary history looking for a lack of good sources of vitamin C can be an easy indicator of this differential. Imaging studies revealing the typical features can also help make the diagnosis. Pathology of the skin revealing pathognomonic features can add to the certainty of the diagnosis. In the absence of all else, the rapid response to treatment with an appropriate dose of vitamin C has a diagnostic and therapeutic role.
Topics: Humans; Scurvy; Male; Adolescent; Diagnosis, Differential; Ascorbic Acid; IgA Vasculitis
PubMed: 38760753
DOI: 10.1186/s12969-024-00992-2 -
Journal of Medicinal Chemistry Aug 2023Growth differentiation factor 15 (GDF15) is a contributor to nausea, emesis, and anorexia following chemotherapy via binding to the GFRAL-RET receptor complex expressed...
Growth differentiation factor 15 (GDF15) is a contributor to nausea, emesis, and anorexia following chemotherapy via binding to the GFRAL-RET receptor complex expressed in hindbrain neurons. Therefore, GDF15-mediated GFRAL-RET signaling is a promising target for improving treatment outcomes for chemotherapy patients. We developed peptide-based antagonists of GFRAL that block GDF15-mediated RET recruitment. Our initial library screen led to five novel peptides. Surface plasmon resonance and flow cytometric analyses of the most efficacious of this group, termed GRASP, revealed its capacity to bind to GFRAL. studies in rats revealed that GRASP could attenuate GDF15-induced nausea and anorexia resulting from cisplatin. Combined with Ondansetron, GRASP led to an even greater attenuation of the anorectic effects of cisplatin compared to either agent alone. Our results highlight the beneficial effects of GRASP as an agent to combat chemotherapy-induced malaise. GRASP may also be effective in other conditions associated with elevated levels of GDF15.
Topics: Animals; Rats; Anorexia; Cell Membrane; Cisplatin; Growth Differentiation Factor 15
PubMed: 37506293
DOI: 10.1021/acs.jmedchem.3c00667 -
Frontiers in Pharmacology 2023Mepolizumab has been approved by the FDA for add-on maintenance treatment of severe asthma with an eosinophilic phenotype. Real-world studies on mepolizumab-associated...
Mepolizumab has been approved by the FDA for add-on maintenance treatment of severe asthma with an eosinophilic phenotype. Real-world studies on mepolizumab-associated adverse events are limited. The present study aimed to explore mepolizumab-related adverse events based on the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. A disproportionality analysis was performed to assess the safety profile of mepolizumab based on the reports from the FAERS database between October 2015 and December 2022. Demographic information, the time to onset, the safety of long-term mepolizumab exposure as well as safety in pediatric patients were also investigated. A total of 736 significant preferred terms (PTs) were identified among the 13,497 mepolizumab-associated adverse events (AEs) reports collected from the FAERS database. The frequently reported AEs including dyspnea, fatigue, and headache were in line with drug instruction and previous studies. Unexpected significant AEs such as cough, malaise, and chest discomfort were also identified. Most AEs occurred within the first month after mepolizumab initiation. Pneumonia and wheezing were frequently reported in patients with long-term mepolizumab exposure as well as in the pediatric population. Our results were consistent with the observations in previous clinical and real-world studies. New and unexpected AE signals of mepolizumab were also identified. Close attention should be paid to the long-term safety of mepolizumab as well as safety in the pediatric population. Prospective studies are required for optimal use of mepolizumab.
PubMed: 38143494
DOI: 10.3389/fphar.2023.1280490