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The neutrophil NADPH oxidase produces both intracellular and extracellular reactive oxygen species (ROS). Although oxidase activity is essential for microbial killing, and ROS can act as signaling molecules in the inflammatory process, excessive extracellular ROS directly contributes to inflammatory tissue damage, as well as to cancer progression and immune dysregulation in the tumor microenvironment. How specific signaling pathways contribute to ROS localization is unclear. Here we used a systems pharmacology approach to identify the specific Class I PI3-K isoform p110β, and PLD1, but not PLD2, as critical regulators of extracellular, but not intracellular ROS production in primary neutrophils. Combined crystallographic and molecular dynamics analysis of the PX domain of the oxidase component p47phox, which binds the lipid products of PI 3-K and PLD, was used to clarify the membrane-binding mechanism and guide the design of mutant mice whose p47phox is unable to bind 3-phosphorylated inositol phospholipids. Neutrophils from these K43A mutant animals were specifically deficient in extracellular, but not intracellular, ROS production, and showed increased dependency on signaling through the remaining PLD1 arm. These findings identify the PX domain of p47phox as a critical integrator of PLD1 and p110β signaling for extracellular ROS production, and as a potential therapeutic target for modulating tissue damage and extracellular signaling during inflammation.

FLASH radiation has been reported to efficiently suppress tumor growth while sparing normal tissue, however, the mechanism of the differential tissue sparing effect is still not known. Oxygen has long been known to profoundly impact radiobiological responses, and radiolytic oxygen depletion has been considered to be a possible cause or contributor to the FLASH phenomenon. This work investigates the impact of tissue pO2 profiles, oxygen depletion per unit dose (g), and the oxygen concentration yielding half-maximal radiosensitization (k) in tumor and normal tissue. We developed a model that considers the dependent relationship between oxygen depletion and change of radiosensitivity during FLASH irradiation. Cell survival was calculated based on the LQ-L model and the radiosensitivity related parameters were adjusted while delivering fractional doses of FLASH irradiation The model reproduced published experimental data and was used to analyze the impact of parameter uncertainties on the radiobiological responses. This study expands the oxygen depletion analysis of FLASH to normal human tissue and tumor based on clinically determined aggregate and individual patient pO2 profiles. The results show that the pO2 profile is the most essential factor that affects biological response and analyses based on the median pO2 rather than the full pO2 profile can be unreliable and misleading. Additionally, the presence of a small fraction of cells on the threshold of radiobiologic hypoxia substantially alters biological response to FLASH irradiation. We found that an increment in the k value is generally more protective of tumor than normal tissue due to a higher frequency of lower pO2 values in tumors. Variation in the g value affects the dose at which oxygen depletion impacts response, but does not alter the dose dependent response trends, if the g value is identical in both tumor and normal tissue.

AIMS: i) To evaluate the evolution of pregnancies and offspring after inflammatory bowel disease (IBD) surgery during pregnancy; and ii) to describe the indications, the surgical techniques, and the frequency of caesarean section concomitant to surgery. METHODS: Patients operated on due to IBD during pregnancy after 1998 were included. Participating clinicians were asked to review their databases to identify cases. Data on patients' demographics, IBD characteristics, medical treatments, IBD activity, pregnancy outcomes, surgery, delivery, foetal and maternal outcomes, were recorded. RESULTS: Forty-four IBD patients were included, 75% had Crohn's disease. Eighteen percent of the surgeries were performed in the 1 st trimester, 55% in the 2 nd, and 27% in the 3 rd trimester. One patient had complications during surgery, and 27% had postsurgical complications. No patient died. Seventy percent of deliveries were carried out by caesarean section. There were 40 newborns alive and 4 miscarriages/stillbirths (1 in the 1 st, 2 in the 2 nd, and 1 in the 3 rd trimester): 2 occurred during surgery, and another 2 occurred 2 weeks after surgery. Fourteen percent of the surgeries during the 2 nd trimester and 64% of those in the 3 rd trimester ended up with a simultaneous cesarean section or vaginal delivery. Of the 40 newborns, 61% were premature, and 47% had low birth weight; 42% of newborns needed hospitalisation (25% in the intensive care unit). CONCLUSIONS: IBD surgery during pregnancy remains an extremely serious situation. Therefore, surgical management should be performed in a multidisciplinary team, involving gastroenterologists, colorectal surgeons, obstetricians and neonatal specialists.

Aims Homozygous familial hypercholesterolaemia (HoFH) is an orphan disease defined by extreme elevations in low-density lipoprotein cholesterol, cutaneous xanthomas, and pre-mature atherosclerotic cardiovascular disease. Survival has more than doubled over the past three decades. Aortic stenosis (AS) [supravalvular aortic stenosis (SVAS) or valvular aortic stenosis (VAS)] is commonly encountered. There are no medical treatments available and complex high-risk surgeries represent the only available option in severe cases. A systematic review was performed to summarize the current evidence on AS in HoFH and to determine whether pharmacological treatment (statins) have had an impact on clinical presentation, phenotype and clinical course over the past nine decades (PROSPERO CRD42021250565). Methods and results MEDLINE, Embase Classic + Embase, Cochrane Central Register of Controlled Trials, PubMed, AfricaWide, and Scopus were searched from inception to 10 November 2021. Searches identified 381 publications, of which 19 were retained; they were cross-sectional or retrospective studies. Separately, 108 individual case reports were described. Within the 424 HoFH cases, AS was identified in 57% of patients in the pre-statin era vs. 35% in patients reported more recently (>2000, long-term statin period). With an increase in longevity due to statins and lipoprotein apheresis, a change in the proportion of patients with SVAS and VAS with a SVAS:VAS ratio of 47:53 and 10:90 for HoFH patients not on statin and on long-term statin, respectively, was noted. Conclusion These data suggest that SVAS and VAS are frequent in HoFH and that the phenotype has shifted towards calcific VAS as statins and lipoprotein apheresis improve survival in these patients.

Objective. Irradiation at FLASH dose rates (>40 Gy s−1) has received great attention due to its reported normal tissue sparing effect. The FLASH effect was originally observed in electron irradiations but has since been shown to also occur with both photon and proton beams. Several mechanisms have been proposed to explain the tissue sparing at high dose rates, including effects involving oxygen, such as depletion of oxygen within the irradiated cells. In this study, we investigated the protective role of FLASH proton irradiation on the skin when varying the oxygen concentration. Approach. Our double scattering proton system provided a 1.2 × 1.6 cm2 elliptical field at a dose rate of ∼130 Gy s−1. The conventional dose rate was ∼0.4 Gy s−1. The legs of the FVB/N mice were marked with two tattooed dots and fixed in a holder for exposure. To alter the skin oxygen concentration, the mice were breathing pure oxygen or had their legs tied to restrict blood flow. The distance between the two dots was measured to analyze skin contraction over time. Main results. FLASH irradiation mitigated skin contraction by 15% compared to conventional dose rate irradiation. The epidermis thickness and collagen deposition at 75 d following 25 to 30 Gy exposure suggested a long-term protective function in the skin from FLASH irradiation. Providing the mice with oxygen or reducing the skin oxygen concentration removed the dose-rate-dependent difference in response. Significance. FLASH proton irradiation decreased skin contraction, epidermis thickness and collagen deposition compared to standard dose rate irradiations. The observed oxygen-dependence of the FLASH effect is consistent with, but not conclusive of, fast oxygen depletion during the exposure.

THE USE OF SIX 16-MILLIMETER FILMS IN CHEMISTRY CLASSES WAS SUPPLEMENTED BY PURCHASE OF THEIR 8-MILLIMETER CARTRIDGE VERSIONS AND PROJECTION EQUIPMENT TO ENABLE STUDENTS TO VIEW THE FILMS AS AN INDEPENDENT STUDY PROCEDURE. STUDY GUIDES, QUIZZES AND EVALUATION FORMS WERE PREPARED FOR USE BY INDIVIDUAL STUDENTS. TOTAL COST FOR THE PROJECT WAS $1,552. THE FILMS INCLUDED IN THE PROJECT WERE (1) CHEMICAL FAMILIES, (2) EQUILIBRIUM, (3) ACID-BASE INDICATORS, (4) ELECTROCHEMICAL CELLS, (5) CRYSTALS AND THEIR STRUCTURES, AND (6) IONIZATION. EXAMPLES OF THE INSTRUCTIONAL MATERIALS ARE INCLUDED IN THE DOCUMENT. (WO)

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder. The most common cause is a mutation in both alleles of the gene encoding for the low-density lipoprotein (LDL) receptor, although other causative mutations have been identified. Complications of atherosclerotic cardiovascular disease are common in these patients; therefore, reducing the elevated LDL-cholesterol burden is critical in their management. Conventionally, this is achieved by patients initiating lipid-lowering therapy, but this can present challenges in clinical practice. Fortunately, novel therapeutic strategies have enabled promising innovations in HoFH treatment. This review highlights recent and ongoing studies examining new therapeutic options for patients with HoFH.

Aims Homozygous familial hypercholesterolaemia (HoFH) is a genetic condition characterized by extremely elevated levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease and death. Due to its rarity, accurate assessment of cardiovascular outcomes associated with HoFH and how they have changed over time has been challenging. The goal of this study was to assess the prevalence and age-of-onset of major adverse cardiovascular events (MACE) among patients with HoFH. Methods and results We searched MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Scopus, Africa-Wide, Google Scholar, Open Grey, and various clinical trial registries from inception to February 2020 to identify studies reporting on MACE in HoFH patients. We determined the pooled prevalence and mean age-of-onset of MACE outcomes individually using a random effects inverse variance model. We identified 94 studies that met our eligibility criteria. Myocardial infarction and coronary revascularization were common with a prevalence of 15.1% [95% confidence interval (95% CI) 10.7–20.0] and 28.3% (95% CI 22.5–34.3), respectively. The mean age-of-onset was 24.5 (95% CI 19.2–29.8) years for myocardial infarction and 32.2 (95% CI 26.6–37.8) years for revascularization. Sub-group analyses based on the year of publication revealed significant delays in the onset of MACE outcomes post-1990 compared to pre-1990. Egger’s regression suggested possible bias, likely due to small study effects. Conclusions Atherosclerotic cardiovascular disease is common among HoFH patients and occurs at a young age. Age-of-onset of myocardial infarction was delayed by more than a decade from pre-1990 to post-1990, likely attributable to widespread use of statins and other therapies, reflecting substantial progress in the management of this rare but severe disorder.