Somatostatin receptors in fibrotic myocardium.

A patient with a neuroendocrine tumor and history of coronary artery disease underwent PET with 68Ga-DOTATATE PET tracer for tumor visualization. Analysis of the scan showed uptake of 68Ga-DOTATATE in the left ventricle corresponding to previous myocardial infarct. 68Ga-DOTATATE binds by somatostatin receptors (SSTR) and it has been proposed that it may be useful for the detection of cardiac inflammatory lesions. We aimed to test whether SSTR could be upregulated in cardiac fibrotic scar. We analyzed SSTR in cardiac samples from patients with end-stage ischemic cardiomyopathy (ICM, n = 8) and control hearts (n = 5). In mature ICM tissue, SSTR1 and SSTR2 expression was unchanged and SSTR5 expression was significantly decreased in ICM samples vs. control. Immunohistochemistry showed increased SSTR1 and SSTR2 in ICM. Areas with SSTR1 or SSTR2 staining were often adjacent to fibrotic areas. The majority of SSTR1 and SSTR2 staining localized in cardiomyocytes in fibrotic scar-rich areas where CD68 macrophage staining was not present. SSTR are occasionally upregulated in cardiac fibrotic areas. When using 68Ga-DOTATATE PET tracer to detect cardiac sarcoidosis or atherosclerotic plaque, the possibility of tracer uptake in fibrotic areas should be considered.

Gene editing in allergic diseases: Identification of novel pathways and impact of deleting allergen genes.

Gene editing technology has emerged as a powerful tool in all aspects of health research and continues to advance our understanding of critical and essential elements in disease pathophysiology. The clustered regularly interspaced short palindromic repeats (CRISPR) gene editing technology has been used with precision to generate gene knockouts, alter genes, and identify genes that cause disease. The full spectrum of allergic/atopic diseases, in part because of shared pathophysiology, is ripe for studies with this technology. In this way, novel culprit genes are being identified and allow for manipulation of triggering allergens to reduce allergenicity and disease. Notwithstanding current limitations on precision and potential off-target effects, newer approaches are rapidly being introduced to more fully understand specific gene functions as well as the consequences of genetic manipulation. In this review, we examine the impact of editing technologies of novel genes relevant to peanut allergy and asthma as well as how gene modification of common allergens may lead to the deletion of allergenic proteins.

Rheumatic Heart Disease in the Developing World.

Despite recent public policy initiatives, rheumatic heart disease (RHD) remains a major source of morbidity worldwide. Rheumatic heart disease occurs as a sequela of Streptococcus pyogenes (group A streptococcal [GAS]) infection in patients with genetic susceptibility. Strategies for prevention of RHD or progression of RHD include prevention of GAS infection with community initiatives, effective treatment of GAS infection, and secondary prophylaxis with intramuscular penicillin. The cardiac surgical community has attempted to improve the availability of surgery in RHD-endemic areas with some success, and operative techniques and outcomes of valve repair continue to improve, potentially offering patients a safer, more durable operation. Innovation offers hope for a more scalable solution with improved biomaterials and transcatheter delivery technology; however, cost remains a barrier.

Photocatalyzed Perfluoroalkylation of Endoglycals.

The visible light-induced perfluoroalkyl (RF) radical reactions on peracetylglycals derived from hexoses and pentoses (galactal, glucal, arabinal, and xylal derivatives) were investigated. Various photocatalysts and perfluoroalkyl iodides (RF-I) were employed as sources of RF radicals with LEDs as the irradiation source. Particularly noteworthy was the use of an Iridium photocatalyst, Ir[dF(CF3)ppy]2(dtbpy))PF6, which yielded two distinct product types when applied to glucal. On the one hand, the 2-RF-substituted glucal was formed, a trend observed even when utilizing organic dyes as photocatalysts. On the other hand, the unexpected addition product, namely the 1-RF-2-iodo-α-manno-configured C-glycosyl derivative, was also obtained, as a result of a highly regioselective addition reaction of the RF moiety into the anomeric carbon, followed by attachment of the iodine atom on C-2 in axial disposition. This result contrasted with other radical reactions carried out on 2-unsubstituted glycals, where the incipient radical adds to C-2, generating a stabilized 1-glycosyl radical. The photocatalyzed radical perfluoroalkylations of peracetyl glycals derived from galactose, arabinose, and xylose all afforded the 2-RF-substituted glycals in good yields as a result of the expected vinylic substitution reaction. Mechanistic studies revealed that the 1-RF-2-iodo-α-manno-configured C-glycosyl derivatives arise from a radical chain reaction, whereas the 2-RF-substituted glycals proceed from inefficient chain processes.

JT002, a small molecule inhibitor of the NLRP3 inflammasome for the treatment of autoinflammatory disorders.

The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1ß and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle-Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders.

Influence of El Niño on the variability of global shoreline position.

Coastal zones are fragile and complex dynamical systems that are increasingly under threat from the combined effects of anthropogenic pressure and climate change. Using global satellite derived shoreline positions from 1993 to 2019 and a variety of reanalysis products, here we show that shorelines are under the influence of three main drivers: sea-level, ocean waves and river discharge. While sea level directly affects coastal mobility, waves affect both erosion/accretion and total water levels, and rivers affect coastal sediment budgets and salinity-induced water levels. By deriving a conceptual global model that accounts for the influence of dominant modes of climate variability on these drivers, we show that interannual shoreline changes are largely driven by different ENSO regimes and their complex inter-basin teleconnections. Our results provide a new framework for understanding and predicting climate-induced coastal hazards.

Should you adjust that herniated disc? Thoughts from a chiropractor/molecular scientist.

Low back pain accounts for the most years lost to disability of any malady worldwide but most cases of disc herniation (DH) and degenerative disc disease (DDD) resolve with conservative methods. Numerous tissue sources of pain affecting the degenerative/herniated disc have been identified, with changes secondary to the influence of inflammation figuring prominently among them. Due to the proven linkage of inflammation to the pain and progression of disc degeneration, anti-inflammatory/anti-catabolic and pro-anabolic repair strategies are gaining prominence for novel therapeutic approaches. Current treatments include conservative therapies such as modified rest, exercise, anti-inflammatory treatments, and analgesics. There is no accepted proposed mechanism of action to support the direct role of spinal manipulation for the treatment of the degenerative and/or herniated disc. However, there are published accounts of very serious adverse events accompanying such treatments leading to the question; 'should a patient with suspected painful IVD be treated with manipulation?

Les douleurs lombaires sont responsables du plus grand nombre d'années perdues pour cause d'invalidité, toutes pathologies confondues, mais la plupart des cas de hernie discale (HD) et de discopathie dégénérative (DD) sont résolus par des méthodes conventionnelles. De nombreuses sources tissulaires de douleur affectant le disque dégénératif/herniaire ont été identifiées, les changements secondaires à l'influence de l'inflammation figurant en bonne place parmi elles. En raison du lien avéré entre l'inflammation et la douleur et la progression de la dégénérescence discale, les stratégies de réparation anti-inflammatoires/anticataboliques et pro-anaboliques sont de plus en plus utilisées comme nouvelles approches thérapeutiques. Les traitements actuels comprennent des thérapies conventionnelles telles que le « repos modifié ¼, l'exercice, les traitements anti-inflammatoires et les analgésiques. Il n'existe pas de mécanisme d'action proposé et accepté pour soutenir le rôle direct de la manipulation de la colonne vertébrale dans le traitement de la dégénérescence et/ou de la hernie discale. Toutefois, des comptes rendus publiés font état d'effets indésirables très graves liés à ces traitements, ce qui amène à se poser la question suivante : « Un patient soupçonné de souffrir d'une discopathie dégénérative douloureuse doit-il être traité par manipulation? ¼.

An update on animal models of intervertebral disc degeneration and low back pain: Exploring the potential of artificial intelligence to improve research analysis and development of prospective therapeutics.

Animal models have been invaluable in the identification of molecular events occurring in and contributing to intervertebral disc (IVD) degeneration and important therapeutic targets have been identified. Some outstanding animal models (murine, ovine, chondrodystrophoid canine) have been identified with their own strengths and weaknesses. The llama/alpaca, horse and kangaroo have emerged as new large species for IVD studies, and only time will tell if they will surpass the utility of existing models. The complexity of IVD degeneration poses difficulties in the selection of the most appropriate molecular target of many potential candidates, to focus on in the formulation of strategies to effect disc repair and regeneration. It may well be that many therapeutic objectives should be targeted simultaneously to effect a favorable outcome in human IVD degeneration. Use of animal models in isolation will not allow resolution of this complex issue and a paradigm shift and adoption of new methodologies is required to provide the next step forward in the determination of an effective repairative strategy for the IVD. AI has improved the accuracy and assessment of spinal imaging supporting clinical diagnostics and research efforts to better understand IVD degeneration and its treatment. Implementation of AI in the evaluation of histology data has improved the usefulness of a popular murine IVD model and could also be used in an ovine histopathological grading scheme that has been used to quantify degenerative IVD changes and stem cell mediated regeneration. These models are also attractive candidates for the evaluation of novel anti-oxidant compounds that counter inflammatory conditions in degenerate IVDs and promote IVD regeneration. Some of these compounds also have pain-relieving properties. AI has facilitated development of facial recognition pain assessment in animal IVD models offering the possibility of correlating the potential pain alleviating properties of some of these compounds with IVD regeneration.

Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor ß1 (TGFß1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

Autophagy-associated immune dysregulation and hyperplasia in a patient with compound heterozygous mutations in ATG9A.

ABBREVIATIONS: BCL2: BCL2 apoptosis regulator; BCL10: BCL10 immune signaling adaptor; CARD11: caspase recruitment domain family member 11; CBM: CARD11-BCL10-MALT1; CR2: complement C3d receptor 2; EBNA: Epstein Barr nuclear antigen; EBV: Epstein-Barr virus; FCGR3A; Fc gamma receptor IIIa; GLILD: granulomatous-lymphocytic interstitial lung disease; HV: healthy volunteer; IKBKB/IKB kinase: inhibitor of nuclear factor kappa B kinase subunit beta; IL2RA: interleukin 2 receptor subunit alpha; MALT1: MALT1 paracaspase; MS4A1: membrane spanning 4-domain A1; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH: transcription factor; NCAM1: neural cell adhesion molecule 1; NFKB: nuclear factor kappa B; NIAID: National Institute of Allergy and Infectious Diseases; NK: natural killer; PTPRC: protein tyrosine phosphatase receptor type C; SELL: selectin L; PBMCs: peripheral blood mononuclear cells; TR: T cell receptor; Tregs: regulatory T cells; WT: wild-type.

Molecular networks in atopic mothers impact the risk of infant atopy.

BACKGROUND: The prevalence of atopic diseases has increased with atopic dermatitis (AD) as the earliest manifestation. We assessed if molecular risk factors in atopic mothers influence their infants' susceptibility to an atopic disease. METHODS: Pregnant women and their infants with (n = 174, high-risk) or without (n = 126, low-risk) parental atopy were enrolled in a prospective birth cohort. Global differentially methylated regions (DMRs) were determined in atopic (n = 92) and non-atopic (n = 82) mothers. Principal component analysis was used to predict atopy risk in children dependent on maternal atopy. Genome-wide transcriptomic analyses were performed in paired atopic (n = 20) and non-atopic (n = 15) mothers and cord blood. Integrative genomic analyses were conducted to define methylation-gene expression relationships. RESULTS: Atopic dermatitis was more prevalent in high-risk compared to low-risk children by age 2. Differential methylation analyses identified 165 DMRs distinguishing atopic from non-atopic mothers. Inclusion of DMRs in addition to maternal atopy significantly increased the odds ratio to develop AD in children from 2.56 to 4.26. In atopic compared to non-atopic mothers, 139 differentially expressed genes (DEGs) were identified significantly enriched of genes within the interferon signaling pathway. Expression quantitative trait methylation analyses dependent on maternal atopy identified 29 DEGs controlled by 136 trans-acting methylation marks, some located near transcription factors. Differential expression for the same nine genes, including MX1 and IFI6 within the interferon pathway, was identified in atopic and non-atopic mothers and high-risk and low-risk children. CONCLUSION: These data suggest that in utero epigenetic and transcriptomic mechanisms predominantly involving the interferon pathway may impact and predict the development of infant atopy.

The Wales Endoscope: The First American Cystoscope.

INTRODUCTION: Philipp Bozzini, a German army surgeon, in 1807 invented the Lichtleiter, the predecessor of the modern cystoscope. By the mid-1800s, several new instruments were created including one, a variation on Bozzini's instrument by Antoine Desormeaux in Paris. The William P. Didusch Museum of Urologic History acquired the Wales endoscope, a rare and unique cystoscope that was invented around the same time in the United States. METHODS: We researched the life of Philip Wales and the description of his cystoscope as well as Horatio Kern, the instrument maker that produced Wales' instrument. We examined the Wales cystoscope acquired by the William P. Didusch Museum. RESULTS: Philip Skinner Wales (1837-1906) was a surgeon who entered the United States Navy in 1856 and served throughout the Civil War. He organized and held charge of the Naval Hospital at New Orleans during the operations of Admiral Farragut's fleet in the Mississippi River. He was one of the first surgeons to attend President Garfield when he was shot. He was Surgeon General of the Navy (1879-1884) and founded the Museum of Naval Hygiene in Washington D.C. which later, combined with the naval laboratory and Department of Instruction, became the prototype of the Naval Medical School. In 1868 he published a series of papers in the Philadelphia Medical and Surgical Reporter on "Instrumental Diagnosis," with a paper entitled "Description of a New Endoscope." The instrument contained a metal shaft with an acute beak and used an ophthalmologic mirror to reflect light down the channel. The surgeon peered through the center hole to look into the bladder. Wales used his instrument multiple times in his private practice. Wales writes that the advantages of his cystoscope were that it was simple to produce and cheap compared to Desormeaux's endoscope. Furthermore it was light, weighing approximately 2 pounds. The main drawbacks of Wales' cystoscope were the inadequate illumination, as the light source was external and projected from the outside through a narrow channel into the bladder, and that without an optical system the image appeared relatively small. Horatio Kern, a well-known instrument maker in Philadelphia, that also supplied surgical sets and instruments for the U.S. Army during the Civil War, produced Wales' cystoscope. While he was Chief of the Bureau of Medicine, a subordinate embezzled Navy funds and Dr, Wales was court-martialed. Though he was eventually exonerated, he lived the rest of his life in disgrace in France. CONCLUSION: The Wales endoscope is unique in that it had an American inventor, was simple in design and cheap to produce. It is an important historical artifact and is one of the earliest and rarest cystoscopes developed.

CFTR-mediated monocyte/macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons.

Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the CF transmembrane conductance regulator (CFTR) gene. Converging evidence suggests that CF carriers with only 1 defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control (HC) PBMCs or THP-1 cells incubated with the plasma of these participants. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1ß, CXCL8, CREM), implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents. These data suggest that a homozygous as well as a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the finding of lower numbers of circulating monocytes in CF probands and their parents, compared with HCs, and the abundance of mononuclear phagocyte subsets, which correlated with Pseudomonas aeruginosa infection, lung disease severity, and CF progression in the probands. This study provides insight into demonstrated CFTR-related innate immune dysfunction in individuals with CF and carriers of a CFTR mutation that may serve as a target for personalized therapy.

Fluctuations in quality of life and immune responses during intravenous immunoglobulin infusion cycles.

Despite adequate infection prophylaxis, variation in self-reported quality of life (QOL) throughout the intravenous immunoglobulin (IVIG) infusion cycle is a widely reported but infrequently studied phenomenon. To better understand this phenomenon, subjects with humoral immunodeficiency receiving replacement doses of IVIG were studied over 3 infusion cycles. Questionnaire data from 6 time points spread over 3 IVIG infusions cycles (infusion day and 7 days after each infusion) were collected in conjunction with monitoring the blood for number of regulatory T-cells (Treg) and levels of 40 secreted analytes: primarily cytokines, chemokines, and growth factors. At day 7, self-reported well-being increased, and self-reported fatigue decreased, reflecting an overall improvement in QOL 7 days after infusion. Over the same period, percentage of Treg cells in the blood increased (p<0.01). Multiple inflammatory chemokine and cytokine levels increased in the blood by 1 hour after infusion (CCL4 (MIP-1b), CCL3 (MIP-1a), CCL2 (MCP-1), TNF-α, granzyme B, IL-10, IL-1RA, IL-8, IL-6, GM-CSF, and IFN- γ). The largest changes in analytes occurred in subjects initiated on IVIG during the study. A significant decrease in IL-25 (IL-17E) following infusion was seen in most intervals among subjects already receiving regular infusions prior to study entry. These findings reveal several short-term effects of IVIG given in replacement doses to patients with humoral immunodeficiency: QOL consistently improves in the first week of infusion, levels of a collection of monocyte-associated cytokines increase immediately after infusion whereas IL-25 levels decrease, and Treg levels increase. Moreover, patients that are new to IVIG experience more significant fluctuations in cytokine levels than those receiving it regularly.