Wiesbaden : Bergmann, 1900.

Paris : J.-B. Baillière, 1894.

Bank of Italy Working Papers by Andrea Gazzani and Alejandro Vicondoa

Bronchiolitis is the most common cause for hospital admission in patients aged <1 year. Hypoxia is a common reason for admission. Despite a multitude of studies looking at various treatment strategies, no clear benefit has been found.

With oxygen therapy being the main therapeutic option, home oxygen offers a novel way to manage bronchiolitis. This study shows that home oxygen is a safe and effective way to decrease hospital admissions in a select group of patients. (Read the full article)

The rising burden of allergy is most evident in infancy, indicating the importance of early exposures. Reduced vitamin D status in pregnancy has been associated with atopy and respiratory outcomes, but there is less information on other early allergic outcomes.

Cord blood 25-hydroxyvitamin D₃ concentrations <50 nmol/L were highly prevalent in an Australian population. Lower vitamin D levels were associated with increased risk of eczema at 12 months of age, whereas there was no association with sensitization or food allergy. (Read the full article)

Excess tissue oxygenation should be avoided during neonatal resuscitation, especially in premature infants. Delivered oxygen concentrations when using a self-inflating bag (SIB) at oxygen flows <1 L/min remain to be established.

Low oxygen concentrations (30%– 40%) can be delivered with a SIB at an oxygen flow <1 L/min. A practical scheme has been developed correlating the oxygen flow rate and the corresponding delivered fraction of oxygen when using a neonatal SIB. (Read the full article)

Universal oxygen saturation screening by pulse oximetry is now recommended for early detection of critical congenital heart disease. The distribution of saturations in asymptomatic newborns in a large population has not been described.

Our study is the largest to date to establish simultaneous pre- and postductal oxygen saturation nomograms in asymptomatic newborns at ~24 hours after birth. The mean postductal saturation is higher than preductal during this time. (Read the full article)

Persons with sickle cell anemia are known to have increased medical expenses, but little is known about the effects of hydroxyurea treatment on costs. In adults with severe sickle cell anemia, hydroxyurea has been reported to reduce expenses from hospitalization.

In this randomized placebo-controlled prospective multicenter trial of hydroxyurea in very young children with sickle cell anemia, not selected for severity, hydroxyurea was associated with significant medical cost savings due to a reduction in hospitalization expenses. (Read the full article)

Preterm infants can be successfully resuscitated with <100% oxygen (O₂); however, initiation with room air remains controversial. Current Neonatal Resuscitation Program (NRP) guidelines suggest using air or blended O₂ to titrate O₂ to meet target preductal saturation goals.

This is the first trial to compare a limited O₂ strategy to target NRP–recommended transitional goal saturations versus a high O₂ strategy in preterm infants. The limited O₂ strategy decreased integrated excess oxygen and oxidative stress and improved respiratory outcomes. (Read the full article)

A serum 25-hydroxyvitamin D (25(OH)D) concentration of 20 ng/mL meets the requirements of at least 97.5% of the population older than 1 year. A recommended dietary intake to achieve this serum 25(OH)D concentration has not been established during infancy.

Daily maternal (during pregnancy) and then infant vitamin supplementation with 1000/400 IU or 2000/800 IU increases the proportion of infants with 25(OH)D ≥20 ng/mL during infancy with the higher dose sustaining this increase for longer. (Read the full article)

In preterm infants receiving supplemental oxygen, manual control of the inspired oxygen fraction is often difficult and time consuming, which may increase the risk of complications. We developed a system for automatic oxygen control and proved its efficacy in the past.

A multicenter study adds evidence for the proposed automatic oxygen control system to significantly improve oxygen administration to preterm infants receiving mechanical ventilation or nasal continuous positive airway pressure while reducing workload compared with routine manual oxygen control. (Read the full article)

Home oxygen has been safely incorporated into emergency department management of bronchiolitis in certain populations. After discharge, a small proportion of patients (2.7%–6%) require subsequent admission. For patients managed successfully as outpatients, pediatricians report variable practice styles and comfort levels.

Our results define the clinical course and outpatient burden associated with discharge on home oxygen. By using an integrated health care system, we captured slightly higher rates (9.4%) of subsequent admission and found fever to be associated with this outcome. (Read the full article)

After neonatal extracorporeal membrane oxygenation treatment, children are at risk for neurodevelopmental problems including delayed motor function. So far this has only been studied cross-sectionally until age 7 years.

We describe, in a nationwide evaluation, the longitudinal course of motor function development after neonatal extracorporeal membrane oxygenation with persisting problems up to 12 years. At risk are children with congenital diaphragmatic hernia and those with chronic lung disease. (Read the full article)

Prone sleeping is a major risk factor for sudden infant death syndrome (SIDS). Cerebral oxygenation and blood pressure are reduced in the prone sleeping position in healthy term infants. Preterm infants are at significantly increased risk of SIDS.

Preterm infants display reduced cerebral oxygenation compared with term infants, most prominently at 2 to 3 months corrected age in the prone position when blood pressure is concurrently reduced. This may contribute to the increased risk for SIDS among infants born preterm. (Read the full article)

Growth impairment in sickle disease has been a consistent finding in published reports. Hydroxyurea (HU) decreases vasoocclusive events and increases hemoglobin levels, which may improve growth. However, HU may adversely affect growth in young children by its effect on DNA synthesis.

Height, weight, and head circumference were normal in HU-treated children in the study as compared with the World Health Organization standards. Height, weight, and BMI z scores were similar in placebo and treatment groups. There were no harmful effects of HU on growth. (Read the full article)

Hydroxyurea is a treatment option for young patients with sickle cell disease (SCD). Establishing the safety of hydroxyurea is of paramount importance. The effect of hydroxyurea on immune function and immunizations in SCD has not been studied previously.

Children with SCD receiving hydroxyurea have lower lymphocyte, CD4, and memory T-cell counts compared with those receiving placebo, but still in the range for healthy children. Despite slower response to measles vaccine, measles, mumps, and rubella and pneumococcal vaccines are effective. (Read the full article)

Carbapenem pharmacokinetic profiles are significantly changed in critically ill patients because of the drastic variability of the patients' physiological parameters. Published population PK studies have mainly focused on specific diseases and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of Extracorporeal Membrane Oxygenation (ECMO) and Continuous Renal Replacement Therapy (CRRT). A two-compartment population PK model with Creatinine clearance (CrCL), body weight (WT), and ECMO as fixed effects was developed using the non-linear mixed effect model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (f%T>MIC) for the range of clinically relevant minimum inhibitory concentrations(MICs). The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750mg Q6h could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than that of non-ECMO patients, therefore dosage may need to be increased. The dosage may need adjustment for patients with CrCL ≤ 70ml/min, but dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients within the WT ranging from 50-80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, TDM should be carried out to optimize drug regimens.

Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at the concentrations of 0.5 μg/mL and 2 μg/mL, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3-log₁₀ within six hours. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficile in vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs.

The STOP-ROP Multicenter Study Group
Feb 1, 2000; 105:295-310
ARTICLES

Andrew T. Shennan
Oct 1, 1988; 82:527-532
ARTICLES

Lima, Peru, May 7, 2020 / 06:00 am (CNA).- Two priests in a rural area of Peru aimed to fight the coronavirus pandemic by finding a way to supply oxygen tanks, much needed for medical treatment, to their region.

The recent death of two doctors from coronavirus in Iquitos, Peru, underscored the hard-hit region’s shortage of medical equipment and medications. Both doctors died because of the lack of oxygen to treat them.

The Medical Corps of Hospital III of Iquitos and the Medical College of Peru said in a joint statement last month that there is a shortage of medications in the Loreto region, and its capital Iquitos is "one of the cities hardest hit by the infection."

“We don’t have medications” to treat coronavirus patients and “not enough oxygen tanks, pressure gauges and refilled tanks,” they reported.

One doctor was in intensive care at Loreto Regional Hospital and the other at a hospital under the country’s universal health insurance program, both in Iquitos, the Medical College of Peru said on social media.

Fr. Raymond Portelli, a parish pastor in Iquitos, along with the diocesan administrator of the Apostolic Vicariate of Iquitos, Fr. Miguel Fuertes, decided to start a fundraising campaign to acquire an oxygen plant for the city.

Portelli himself is a doctor caring for COVID-19 patients.

To purchase the machinery, they needed to raise about $118,000.

The city does have an oxygen plant, but it only produces between 100 and 160 tanks a day. The dean of the Medical College of Peru, Miguel Palacios, told local media that quantity is not enough and that current production would need to be tripled.

The priests’ campaign was launched the morning of May 3 on social media, and in less than a day, they had raised about $300,000.

Both priests thanked contributors, and said that thanks to the amount collected, a “high capacity” plant could be purchased for Iquitos.

Portelli added that Fuentes is currently in Lima coordinating with a specialist for the acquisition of the plant.

“Pray a lot that this work can be accomplished quickly. May God bless all who have contributed. We hope to continue to cover all the expenses,” he added.

  This story was first published by CNA's Spanish-language news partner, ACI Prensa. It has been translated and adapted by CNA.



 

The assistant professor of anaesthesia at AIIMS said there are contradictory reports on HCQ usage for treating COVID-19.

“We didn’t see any association between getting this medicine and the chance of dying or being intubated,” lead researcher Dr. Neil Schluger told Reuters in a telephone interview.

Australian authorities have reported a spike in drug smuggling – but not the kind they usually deal with. Aussies are importing hydroxychloroquine, an anti-malarial medication used as a controversial antidote to Covid-19.
Read Full Article at RT.com

A total of 396 people have recovered from coronavirus infection through early oxygen therapy at Chirayu Hospital in Madhya Pradesh's capital city Bhopal.

Meanwhile, a senior official at Zydus Cadila confirmed that the company is in the process of manufacturing the drug in large quantity.

Whitepaper that shows how easy you can build a fuzzer for the MQTT protocol by using the Polymorph framework.

Microsoft Windows Vista/Server 2008 nsiproxy.sys local kernel denial of service exploit.

This Metasploit module exploits a type confusion bug in the Javascript Proxy object in WebKit. The DFG JIT does not take into account that, through the use of a Proxy, it is possible to run arbitrary JS code during the execution of a CreateThis operation. This makes it possible to change the structure of e.g. an argument without causing a bailout, leading to a type confusion (CVE-2018-4233). The type confusion leads to the ability to allocate fake Javascript objects, as well as the ability to find the address in memory of a Javascript object. This allows us to construct a fake JSCell object that can be used to read and write arbitrary memory from Javascript. The module then uses a ROP chain to write the first stage shellcode into executable memory within the Safari process and kick off its execution. The first stage maps the second stage macho (containing CVE-2017-13861) into executable memory, and jumps to its entrypoint. The CVE-2017-13861 async_wake exploit leads to a kernel task port (TFP0) that can read and write arbitrary kernel memory. The processes credential and sandbox structure in the kernel is overwritten and the meterpreter payloads code signature hash is added to the kernels trust cache, allowing Safari to load and execute the (self-signed) meterpreter payload.

A large-scale study in New York looking at the antimalarial drug hydroxychloroquine has cast further doubt on its effectiveness in the treatment of Covid-19 patients.Researchers at Columbia University observed nearly 1,400 patients at a large medical centre in New York City in March and April. They found hydroxychloroquine use led to neither a higher nor lower chance of patients ending up with intubation or death.“Our results cannot completely exclude the possibility of either modest benefit or…

WASHINGTON: A study performed in New York hospitals found no evidence of either harm or benefit from giving the malaria drug hydroxychloroquine to severely ill coronavirus patients. “The risk of intubation or death was not significantly higher or lower among patients who received...

All animals rely on oxygen at least at some stage of their life, but a parasite that infects fish seems to have completely lost the ability to use it – where it gets its energy from is still a mystery

Adjust oxygen and fluid therapy thresholds for pregnant patients with severe disease, experts advise; early use of a high-flow nasal cannula and prone positioning may help avoid mechanical ventilation.

ABSTRACT

Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae. Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa. Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE.

IMPORTANCE Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae. However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.

ABSTRACT

The obligatory intracellular pathogen Ehrlichia chaffeensis lacks most factors that could respond to oxidative stress (a host cell defense mechanism). We previously found that the C terminus of Ehrlichia surface invasin, entry-triggering protein of Ehrlichia (EtpE; EtpE-C) directly binds mammalian DNase X, a glycosylphosphatidylinositol-anchored cell surface receptor and that binding is required to induce bacterial entry and simultaneously to block the generation of reactive oxygen species (ROS) by host monocytes and macrophages. However, how the EtpE-C–DNase X complex mediates the ROS blockade was unknown. A mammalian transmembrane glycoprotein CD147 (basigin) binds to the EtpE-DNase X complex and is required for Ehrlichia entry and infection of host cells. Here, we found that bone marrow-derived macrophages (BMDM) from myeloid cell lineage-selective CD147-null mice had significantly reduced Ehrlichia-induced or EtpE-C-induced blockade of ROS generation in response to phorbol myristate acetate. In BMDM from CD147-null mice, nucleofection with CD147 partially restored the Ehrlichia-mediated inhibition of ROS generation. Indeed, CD147-null mice as well as their BMDM were resistant to Ehrlichia infection. Moreover, in human monocytes, anti-CD147 partially abrogated EtpE-C-induced blockade of ROS generation. Both Ehrlichia and EtpE-C could block activation of the small GTPase Rac1 (which in turn activates phagocyte NADPH oxidase) and suppress activation of Vav1, a hematopoietic-specific Rho/Rac guanine nucleotide exchange factor by phorbol myristate acetate. Vav1 suppression by Ehrlichia was CD147 dependent. E. chaffeensis is the first example of pathogens that block Rac1 activation to colonize macrophages. Furthermore, Ehrlichia uses EtpE to hijack the unique host DNase X-CD147-Vav1 signaling to block Rac1 activation.

IMPORTANCE Ehrlichia chaffeensis is an obligatory intracellular bacterium with the capability of causing an emerging infectious disease called human monocytic ehrlichiosis. E. chaffeensis preferentially infects monocytes and macrophages, professional phagocytes, equipped with an arsenal of antimicrobial mechanisms, including rapid reactive oxygen species (ROS) generation upon encountering bacteria. As Ehrlichia isolated from host cells are readily killed upon exposure to ROS, Ehrlichia must have evolved a unique mechanism to safely enter phagocytes. We discovered that binding of the Ehrlichia surface invasin to the host cell surface receptor not only triggers Ehrlichia entry but also blocks ROS generation by the host cells by mobilizing a novel intracellular signaling pathway. Knowledge of the mechanisms by which ROS production is inhibited may lead to the development of therapeutics for ehrlichiosis as well as other ROS-related pathologies.

Photorespiration is an essential process in oxygenic photosynthetic organisms triggered by the oxygenase activity of Rubisco. In peroxisomes, photorespiratory HYDROXYPYRUVATE REDUCTASE1 (HPR1) catalyzes the conversion of hydroxypyruvate to glycerate together with the oxidation of a pyridine nucleotide cofactor. HPR1 regulation remains poorly understood; however, HPR1 phosphorylation at T335 has been reported. By comparing the kinetic properties of phosphomimetic (T335D), nonphosphorylatable (T335A), and wild-type recombinant Arabidopsis (Arabidopsis thaliana) HPR1, it was found that HPR1-T335D exhibits reduced NADH-dependent hydroxypyruvate reductase activity while showing improved NADPH-dependent activity. Complementation of the Arabidopsis hpr1-1 mutant by either wild-type HPR1 or HPR1-T335A fully complemented the photorespiratory growth phenotype of hpr1-1 in ambient air, whereas HPR1-T335D-containing hpr1-1 plants remained smaller and had lower photosynthetic CO₂ assimilation rates. Metabolite analyses indicated that these phenotypes were associated with subtle perturbations in the photorespiratory cycle of HPR1-T335D-complemented hpr1-1 rosettes compared to all other HPR1-containing lines. Therefore, T335 phosphorylation may play a role in the regulation of HPR1 activity in planta, although it was not required for growth under ambient air controlled conditions. Furthermore, improved NADP-dependent HPR1 activities in peroxisomes could not compensate for the reduced NADH-dependent HPR1 activity.

Emily J. Lombardi, Candice L. Bywater, and Craig R. White

The Oxygen and Capacity-Limited Thermal Tolerance (OCLTT) hypothesis proposes that the thermal tolerance of an animal is shaped by its capacity to deliver oxygen in relation to oxygen demand. Studies testing this hypothesis have largely focused on measuring short-term performance responses in animals under acute exposure to critical thermal maximums. The OCLTT hypothesis, however, emphasises the importance of sustained animal performance over acute tolerance. The present study tested the effect of chronic hypoxia and hyperoxia during development on medium to long-term performance indicators at temperatures spanning the optimal temperature for growth in the speckled cockroach, Nauphoeta cinerea. In contrast to the predictions of the OCLTT hypothesis, development under hypoxia did not significantly reduce growth rate or running performance, and development under hyperoxia did not significantly increase growth rate or running performance. The effect of developmental temperature and oxygen on tracheal morphology and metabolic rate were also not consistent with OCLTT predictions, suggesting that oxygen delivery capacity is not the primary driver shaping thermal tolerance in this species. Collectively, these findings suggest that the OCLTT hypothesis does not explain moderate-to-long-term thermal performance in Nauphoeta cinerea, which raises further questions about the generality of the hypothesis.

Brad A. Seibel and Curtis Deutsch

The capacity to extract oxygen from the environment and transport it to respiring tissues in support of metabolic demand reportedly has implications for species’ thermal tolerance, body-size, diversity and biogeography. Here we derive a quantifiable linkage between maximum and basal metabolic rate and their oxygen, temperature and size dependencies. We show that, regardless of size or temperature, the physiological capacity for oxygen supply precisely matches the maximum evolved demand at the highest persistently available oxygen pressure and this is the critical PO₂ for the maximum metabolic rate. For most terrestrial and shallow-living marine species, this "P_crit-max" is the current atmospheric pressure, 21 kPa. Any reduction in oxygen partial pressure from current values will result in a calculable decrement in maximum metabolic performance. However, oxygen supply capacity has evolved to match demand across temperatures and body sizes and so does not constrain thermal tolerance or cause the well-known reduction in mass-specific metabolic rate with increasing body mass. The critical oxygen pressure for resting metabolic rate, typically viewed as an indicator of hypoxia tolerance, is, instead, simply a rate-specific reflection of the oxygen supply capacity. A compensatory reduction in maintenance metabolic costs in warm-adapted species constrains factorial aerobic scope and the critical PO₂ to a similar range, between ~2 and 6, across each species’ natural temperature range. The simple new relationship described here redefines many important physiological concepts and alters their ecological interpretation.

Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation—sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1α and HIF-2α)—can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter–2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Taurine is one of the most abundant amino acids in mammalian tissues. It is obtained from the diet and by de novo synthesis from cysteic acid or hypotaurine. Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive. In large part, this is due to the incorrect assignment, in 1962, of the enzyme as an NAD-dependent hypotaurine dehydrogenase. For more than 55 years, the literature has continued to refer to this enzyme as such. Here we show, both in vivo and in vitro, that the enzyme that oxygenates hypotaurine to produce taurine is flavin-containing monooxygenase (FMO) 1. Metabolite analysis of the urine of Fmo1-null mice by ¹H NMR spectroscopy revealed a buildup of hypotaurine and a deficit of taurine in comparison with the concentrations of these compounds in the urine of wild-type mice. In vitro assays confirmed that human FMO1 catalyzes the conversion of hypotaurine to taurine, utilizing either NADPH or NADH as cofactor. FMO1 has a wide substrate range and is best known as a xenobiotic- or drug-metabolizing enzyme. The identification that the endogenous molecule hypotaurine is a substrate for the FMO1-catalyzed production of taurine resolves a long-standing mystery. This finding should help establish the role FMO1 plays in a range of biologic processes in which taurine or its deficiency is implicated, including conjugation of bile acids, neurotransmitter, antioxidant and anti-inflammatory functions, and the pathogenesis of obesity and skeletal muscle disorders.

SIGNIFICANCE STATEMENT

The identity of the enzyme that catalyzes the biosynthesis of taurine from hypotaurine has remained elusive. Here we show, both in vivo and in vitro, that flavin-containing monooxygenase 1 catalyzes the oxygenation of hypotaurine to produce taurine.

Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.

We recently reported that restoring the CYP27A1–27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti–prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6–JAK–STAT3 axis as a model given its prominent role in prostate cancer. As revealed by single molecule imaging of DU145 prostate cancer cells, 27HC treatment significantly reduced detected cholesterol density on the plasma membranes. Further, 27HC treatment of constitutively active STAT3 DU145 prostate cancer cells reduced STAT3 activation and slowed tumor growth in vitro and in vivo. 27HC also blocked IL6-mediated STAT3 phosphorylation in nonconstitutively active STAT3 cells. Mechanistically, 27HC reduced STAT3 homodimerization, nuclear translocation, and decreased STAT3 DNA occupancy at target gene promoters. Combined treatment with 27HC and STAT3 targeting molecules had additive and synergistic effects on proliferation and migration, respectively. Hallmark IL6–JAK–STAT gene signatures positively correlated with CYP27A1 gene expression in a large set of human metastatic castrate-resistant prostate cancers and in an aggressive prostate cancer subtype. This suggests STAT3 activation may be a resistance mechanism for aggressive prostate cancers that retain CYP27A1 expression. In summary, our study establishes a key mechanism by which 27HC inhibits prostate cancer by disrupting lipid rafts and blocking STAT3 activation.

Implications:

Collectively, these data show that modulation of intracellular cholesterol by 27HC can inhibit IL6–JAK–STAT signaling and may synergize with STAT3-targeted compounds.

The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1–4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a wide variety of tissues. MCTs 1 and 4 are overexpressed in a number of cancers, and current investigations have focused on transporter inhibition as a novel therapeutic strategy in cancers. MCT1 has also been used in strategies aimed at enhancing drug absorption due to its high expression in the intestine. Other MCT isoforms are less well characterized, but ongoing studies indicate that MCT6 transports xenobiotics such as bumetanide, nateglinide, and probenecid, whereas MCT7 has been characterized as a transporter of ketone bodies. MCT8 and MCT10 transport thyroid hormones, and recently, MCT9 has been characterized as a carnitine efflux transporter and MCT12 as a creatine transporter. Expressed at the blood brain barrier, MCT8 mutations have been associated with an X-linked intellectual disability, known as Allan-Herndon-Dudley syndrome. Many MCT isoforms are associated with hormone, lipid, and glucose homeostasis, and recent research has focused on their potential roles in disease, with MCTs representing promising novel therapeutic targets. This review will provide a summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease.

Significance Statement

The 14-member solute carrier family 16 of monocarboxylate transporters (MCTs) plays a fundamental role in maintaining intracellular concentrations of a broad range of important endogenous molecules in health and disease. MCTs 1, 2, and 4 (L-lactate transporters) are overexpressed in cancers and represent a novel therapeutic target in cancer. Recent studies have highlighted the importance of MCTs in glucose, lipid, and hormone homeostasis, including MCT8 in thyroid hormone brain uptake, MCT12 in carnitine transport, and MCT11 in type 2 diabetes.

Whether low plasma 25-hydroxyvitamin D concentrations cause osteoporotic fractures is unclear. We tested the hypothesis that low plasma 25-hydroxyvitamin D concentrations are associated with increased risk of osteoporotic fractures using a Mendelian randomization analysis.We genotyped 116 335 randomly chosen white Danish persons aged 20–100 years in 2 population-based cohort studies for plasma 25-hydroxyvitamin D decreasing genotypes in CYP2R1 (rs117913124 and rs12794714), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458), and HAL (rs3819817); 35 833 had information on plasma 25-hydroxyvitamin D. We assessed risk of total, osteoporotic, and anatomically localized fractures from 1981 through 2017. Information on fractures and vital status was obtained from nationwide registries.During up to 36 years of follow-up, we observed 17 820 total fractures, 10 861 osteoporotic fractures, and 3472 fractures of hip or femur. Compared with individuals with 25-hydroxyvitamin D ≥ 50nmol/L, multivariable adjusted hazard ratios (95% CIs) for total fractures were 1.03 (0.97–1.09) for individuals with 25–49.9 nmol/L, 1.19 (1.10–1.28) for individuals with 12.5–24.9 nmol/L, and 1.39 (1.21–1.60) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L. Corresponding hazard ratios were 1.07 (1.00–1.15), 1.25 (1.13–1.37), and 1.49 (1.25–1.77) for osteoporotic fractures and 1.09 (0.98–1.22), 1.37 (1.18–1.57), and 1.41 (1.09–1.81) for fractures of hip or femur, respectively. Hazard ratios per 1 increase in vitamin D allele score, corresponding to 3.0% (approximately 1.6 nmol/L) lower 25-hydroxyvitamin D concentrations, were 0.99 (0.98–1.00) for total fractures, 0.99 (0.97–1.00) for osteoporotic fractures, and 0.98 (0.95–1.00) for fractures of hip or femur.Low plasma 25-hydroxyvitamin D concentrations were associated with osteoporotic fractures; however, Mendelian randomization analysis provided no evidence supporting a causal role for vitamin D in the risk for osteoporotic fractures.

Doxycycline, an FDA-approved tetracycline, is used in tuberculosis in vivo models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant Mycobacterium tuberculosis carrying genes of interest under transcriptional control of the doxycycline-responsive TetR-tetO unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in tuberculosis (TB)-infected organs and lesions have not been conducted. Here, we first determined the tetracycline concentrations required to achieve silencing of M. tuberculosis target genes in vitro. Next, we measured doxycycline concentrations in plasma, major organs, and lung lesions in TB-infected mice and rabbits and compared these values to silencing concentrations measured in vitro. We found that 2,000 ppm doxycycline supplemented in mouse and rabbit feed is sufficient to reach target concentrations in TB lesions. In rabbit chow, the calcium content had to be reduced 5-fold to minimize chelation of doxycycline and deliver adequate oral bioavailability. Clearance kinetics from major organs and lung lesions revealed that doxycycline levels fall below concentrations that repress tet promoters within 7 to 14 days after doxycycline is removed from the diet. In summary, we have shown that 2,000 ppm doxycycline supplemented in standard mouse diet and in low-calcium rabbit diet delivers concentrations adequate to achieve full repression of tet promoters in infected tissues of mice and rabbits.