Update on Asthma Management Guidelines.

The Global Initiative for Asthma (GINA) was established in 1993 and publishes a yearly global strategy to improve asthma awareness, prevention and management of asthma worldwide, based on a review of the most updated evidence. The current 2024 GINA update advises that all adults and adolescents with asthma receive inhaled corticosteroid (ICS)- containing medication and should not be treated with short acting beta agonist (SABA) alone. The 2024 GINA strategy divides treatment into two 'Tracks": Track 1 (preferred Track), the reliever is as-needed combination low dose ICS-formoterol; Track 2 uses SABA as the reliever along with a separate ICS inhaler.

Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection.

The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation.

An Atypical Presentation of Serotonin Syndrome.

The purpose of this paper is to highlight an uncommon presentation of serotonin syndrome and discuss important points such as causes, the manifestation of symptoms, and available treatments. The report highlights the importance of recognizing typical signs and symptoms in order to uncover an atypical presentation of serotonin syndrome. Serotonin toxicity can become life-threatening if not identified early in its course and the offending agents discontinued.

Post-Bariatric Abdominoplasty: Analysis of 406 Cases With Focus on Risk Factors and Complications.

Background: Post-bariatric patients present a surgical challenge within abdominoplasty because of residual obesity and major comorbidities. In this study, we analyzed complications following abdominoplasty in post-bariatric patients and evaluated potential risk factors associated with these complications.

Objectives: The authors sought to determine the complications and risk factors following abdominoplasty in post-bariatric patients.

Indwelling Tunneled Pleural Catheters for the Management of Hepatic Hydrothorax. A Pilot Study.

Rationale: Hepatic hydrothorax is a complication of cirrhosis in which hydrostatic imbalances result in fluid accumulation within the pleural space. Although uncommon, this may cause significant morbidity, resulting in dyspnea requiring repeated pleural drainage procedures. Liver transplantation is curative, but it is rarely immediately available to qualified patients, presenting the clinical challenge of managing recurrent pleural effusions.

Targeting myofibroblasts in model systems of fibrosis by an artificial alpha-smooth muscle-actin promoter hybrid.

Myofibroblasts are the main cell types producing extracellular matrix proteins in a variety of fibrotic diseases. Therefore, they are useful targets for studies of intracellular communication and gene therapeutical approaches in scarring diseases. An artificial promoter containing the -702 bp regulatory sequence of the alpha-smooth muscle actin (SMA) gene linked to the first intron enhancer sequence of the beta-actin gene and the beta-globin intron-exon junction was constructed and tested for myofibroblast-dependent gene expression using the green fluorescent protein as a reporter.

Regulation of human liver delta-aminolevulinic acid synthase by bile acids.

Unlabelled: Aminolevulinic acid synthase 1 (ALAS1) is the rate-limiting enzyme of heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target of the bile acid-activated nuclear receptor farnesoid X receptor (FXR). Experiments in primary human hepatocytes and in human liver slices showed that ALAS1 messenger RNA (mRNA) and activity is increased upon exposure to chenodeoxycholic acid (CDCA), the most potent natural FXR ligand, or the synthetic FXR-specific agonist GW4064.

FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption.

Bile acid malabsorption, which in patients leads to excessive fecal bile acid excretion and diarrhea, is characterized by a vicious cycle in which the feedback regulation of bile acid synthesis is interrupted, resulting in additional bile acid production. Feedback regulation of bile acid synthesis is under the control of an endocrine pathway wherein activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), induces enteric expression of the hormone, fibroblast growth factor 15 (FGF15). In liver, FGF15 acts together with FXR-mediated expression of small heterodimer partner to repress bile acid synthesis.

Analysis of bile acid-induced regulation of FXR target genes in human liver slices.

Information about the role of nuclear receptors has rapidly increased over the last decade. However, details about their role in human are lacking. Owing to species differences, a powerful human in vitro system is needed.

Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).

Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g.

Pregnane X receptor is a target of farnesoid X receptor.

The pregnane X receptor (PXR) is an essential component of the body's detoxification system. PXR is activated by a broad spectrum of xenobiotics and endobiotics, including bile acids and their precursors. Bile acids in high concentrations are toxic; therefore, their synthesis is tightly regulated by the farnesoid X receptor, and their catabolism involves several enzymes regulated by PXR.

The human Na+-taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism.

Na+-taurocholate cotransporting polypeptide (NTCP) is the major bile acid uptake system in human hepatocytes. NTCP and the ileal transporter ASBT (apical sodium-dependent bile acid transporter) are two sodium-dependent transporters critical for the enterohepatic circulation of bile acids. The hASBT gene is known to be activated by the glucocorticoid receptor (GR).

Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder associated with increased risk of intrauterine fetal death and prematurity. There is increasing evidence that genetically determined dysfunction in the canalicular ABC transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) might be risk factors for ICP development. This study aimed to (i).

The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma.

Background/aims: The organic anion transporting polypeptides (OATPs) mediate the uptake of numerous amphipathic compounds into hepatocytes. Our aim was to study the expression and regulation of OATP8 (OATP1B3, SLC21A8/SLCO1B3) and OATP-C (OATP1B1, SLC21A6/SLCO1B1) in hepatocellular carcinomas (HCC).

Methods: RNA and protein levels in 13 paired HCC and adjacent non-tumor liver samples were quantified by real-time polymerase chain reaction or Western blot, respectively.

Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene.

Hepatic uptake of bile acids is mediated by the Na(+)-taurocholate cotransporting polypeptide (NTCP; SLC10A1) of the basolateral hepatocyte membrane. Several cis-acting elements in the rat Ntcp gene promoter have been characterized. However, little is known about the mechanisms that control the expression of the human or mouse NTCP/Ntcp.

Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression.

Bile acids regulate the expression of genes involved in cholesterol homeostasis. They are ligands of the farnesoid X receptor, which induces small heterodimer partner (SHP)-1, a transcriptional repressor of bile acid synthetic enzymes. In cholestatic liver disease, hepatic bile acid concentrations are elevated and expression of the major Na+-independent bile acid uptake system, organic anion transporting polypeptide (OATP)-C (solute carrier gene family SLC21A6), is markedly decreased.

Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor.

Background & Aims: OATP8 (gene symbol: SLC21A8) is a multispecific uptake system for organic anions, xenobiotics, and peptides expressed at the basolateral (sinusoidal) membrane of human hepatocytes. We investigated whether OATP8 gene expression is regulated by the nuclear receptors farnesoid X receptor/bile acid receptor (FXR/BAR; NR1H4), pregnane X receptor (PXR), or liver X receptor (LXR).

Methods: OATP8 promoter function was studied in reporter assays.

Human apical sodium-dependent bile salt transporter gene (SLC10A2) is regulated by the peroxisome proliferator-activated receptor alpha.

The apical sodium-dependent bile salt transporter (ASBT/SLC10A2), also called the ileal bile acid transporter, mediates the intestinal absorption of bile salts. The efficiency of this transport process is a determinant of hepatic bile salt synthesis from cholesterol and of serum triglyceride levels. Our aim was to characterize the human ASBT gene promoter with respect to regulatory mechanisms that coordinately affect ASBT expression and hepatic lipid and bile salt metabolism.