Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine S-arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity in vitro, covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.

Lymph Vessels Associate with Cancer Stem Cells from Initiation to Malignant Stages of Squamous Cell Carcinoma.

Tumor-associated lymph vessels and lymph node involvement are critical staging criteria in several cancers. In skin squamous cell carcinoma, lymph vessels play a role in cancer development and metastatic spread. However, their relationship with the cancer stem cell niche at early tumor stages remains unclear. To address this gap, we studied the lymph vessel localization at the cancer stem cell niche and observed an association from benign skin lesions to malignant stages of skin squamous cell carcinoma. By co-culturing lymphatic endothelial cells with cancer cell lines representing the initiation and promotion stages, and conducting RNA profiling, we observed a reciprocal induction of cell adhesion, immunity regulation, and vessel remodeling genes, suggesting dynamic interactions between lymphatic and cancer cells. Additionally, imaging analyses of the cultured cells revealed the establishment of heterotypic contacts between cancer cells and lymph endothelial cells, potentially contributing to the observed distribution and maintenance at the cancer stem cell niche, inducing downstream cellular responses. Our data provide evidence for an association of lymph vessels from the early stages of skin squamous cell carcinoma development, opening new avenues for better comprehending their involvement in cancer progression.

Generation and Reactions of an Octacyclic Hindered Pyramidalized Alkene.

Octacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadeca-5,8,14-triene (27), a hindered pyramidalized alkene, has been generated from a diiodide precursor. Contrary to the usual behavior of known pyramidalized alkenes, no Diels-Alder adducts were obtained from the present alkene when it was generated by different standard procedures in the presence of different dienes. However, products derived from the reduction, t-BuLi addition, condensation with the solvent, or dimerization were isolated from these reactions, depending on the conditions used to generate it. No [2 + 2] cross product among this pyramidalized alkene and tricyclo[3.3.1.03,7]non-3(7)-ene was formed when a mixture of the corresponding precursor diiodides was reacted with sodium amalgam. The analysis of selected geometrical and orbital parameters determined from quantum mechanical calculations indicates that the degree of pyramidalization of this alkene and its higher steric hindrance compared with other polycyclic pyramidalized alkenes may explain its peculiar reactivity.

Acute kidney injury is associated with bronchopulmonary dysplasia/mortality in premature infants.

BACKGROUND: Acute kidney injury (AKI) impairs electrolyte balance, alters fluid homeostasis and decreases toxin excretion. More recent data suggest it also affects the physiology of distant organs. METHODS: We performed a prospective cohort study which invloved 122 premature infants [birth weight (BW) ≤1200 g and/or gestational age (GA) <31 weeks] to determine relationships between AKI and bronchopulmonary dysplasia (BPD)/mortality. Days until oxygen discontinuation was compared between those with and without AKI in survivors who received oxygen for ≥24 h. RESULTS: Acute kidney disease, defined by a rise in serum creatinine (SCr) of ≥0.3 mg/dl or an increase in SCr of ≥150%, occurred in 36/122 (30%) of the premature infants. Those with AKI had a 70% higher risk of oxygen requirement or of dying at 28 days of life [relative risk (RR) 1.71, 95% confidence interval (CI) 1.22-2.39; p < 0.002]. This association remained after controlling for GA, pre-eclampsia, 5 min Apgar score and percentage maximum weight change (max % weight Δ) in the first 4 days (RR 1.45, 95% CI 1.07-1.97); p < 0.02). Similar findings were noted for receipt of mechanical ventilation/death by day 28 (adjusted RR 1.53, 95% CI 1.05-2.22; p < 0.03). Those without AKI were 2.5-fold more likely to come off oxygen [hazard ratio (HR) 1.3-5; p < 0.02) than those with AKI, even when controlling for GA, pre-eclampsia, 5 min Apgar and max % weight Δ (multivariate HR 2.0, 95% CI 0.9-4.0; p < 0.06). CONCLUSIONS: In premature infants, AKI is associated with BPD/mortality. As AKI could lead to altered lung physiology, interventions to ameliorate AKI could improve long-term BPD.

Sleep quality, stress, caregiver burden, and quality of life in maternal caregivers of young children with bronchopulmonary dysplasia.

Little is known about the influence of sleep quality, stress, and caregiver burden on quality of life in maternal caregivers of young children with bronchopulmonary dysplasia (BPD). In 61 maternal caregivers (mean age 29.59 years) of young children with BPD (mean age 13.93 months), caregivers reported sleeping a mean of 5.8 hours, and significant correlations were found between sleep quality and depressive symptoms and stress, as well as an inverse correlation with quality of life. Sleep quality was found to be the most significant predictor of quality of life in maternal caregivers.

The relationships among family management behaviors and asthma morbidity in maternal caregivers of children with asthma.

Numerous studies have identified the relationship of the family caregiver's perception regarding asthma management and the child's asthma outcomes, although few have examined family caregiver asthma management behaviors. The primary aim of this study was to examine the relationship among family management behaviors and asthma morbidity as perceived by maternal caregivers. The Family Management Style Framework was used to guide the research. Maternal caregivers (N = 101) with school-aged children diagnosed with persistent asthma and living in the United States were recruited from a specialty asthma clinic. When caregivers perceived they were expending much effort on their child's asthma management and were not confident in their ability to perform management activities, the child's asthma outcomes were worse. This is the first study to examine family management behaviors with maternal caregivers of school-aged children with asthma. Findings from this study encourage health care providers to tailor each educational opportunity with families to improve child asthma outcomes. An ongoing effort must be made to include families in asthma management. Health care partnerships between provider and family can lead to improved asthma management.

Prefrontal cortical regulation of REM sleep.

Rapid eye movement (REM) sleep is accompanied by intense cortical activity, underlying its wake-like electroencephalogram. The neural activity inducing REM sleep is thought to originate from subcortical circuits in brainstem and hypothalamus. However, whether cortical neurons can also trigger REM sleep has remained unknown. Here we show in mice that the medial prefrontal cortex (mPFC) strongly promotes REM sleep. Bidirectional optogenetic manipulations demonstrate that excitatory mPFC neurons promote REM sleep through their projections to the lateral hypothalamus and regulate phasic events, reflected in accelerated electroencephalogram theta oscillations and increased eye movement density during REM sleep. Calcium imaging reveals that the majority of lateral hypothalamus-projecting mPFC neurons are maximally activated during REM sleep and a subpopulation is recruited during phasic theta accelerations. Our results delineate a cortico-hypothalamic circuit for the top-down control of REM sleep and identify a critical role of the mPFC in regulating phasic events during REM sleep.

Prefrontal Cortical Regulation of REM Sleep.

Rapid-eye-movement (REM) sleep is accompanied by intense cortical activity, underlying its wake-like electroencephalogram (EEG). The neural activity inducing REM sleep is thought to originate from subcortical circuits in brainstem and hypothalamus. However, whether cortical neurons can also trigger REM sleep has remained unknown. Here, we show in mice that the medial prefrontal cortex (mPFC) strongly promotes REM sleep. Bidirectional optogenetic manipulations demonstrate that excitatory mPFC neurons promote REM sleep through their projections to the lateral hypothalamus (LH) and regulate phasic events, reflected in accelerated EEG theta oscillations and increased eye-movement density during REM sleep. Calcium imaging reveals that the majority of LH-projecting mPFC neurons are maximally activated during REM sleep and a subpopulation is recruited during phasic theta accelerations. Our results delineate a cortico-hypothalamic circuit for the top-down control of REM sleep and identify a critical role of the mPFC in regulating phasic events during REM sleep.

A catenane that is topologically achiral despite being composed of oriented rings.

Catenanes-molecules comprising two interlocking rings held together like links in a chain-are topologically non-trivial: a catenane is a topological isomer of its separated rings, but the rings cannot be disconnected without bond scission. Catenanes can exist as topological enantiomers if both rings have directionality conferred by a defined atom sequence, but this has led to the assumption that the stereochemistry of chiral catenanes composed of oriented rings is inherently topological in nature. Here we show that this assumption is incorrect by synthesizing an example that contains the same fundamental stereogenic unit but whose stereochemistry is Euclidean. One ring in this chiral catenane is oriented by the geometry of an exocyclic double rather than determined by atom sequence within the ring. Isomerization of the exocyclic double bond results in racemization of the catenane, confirming that the stereochemistry is not topological in nature. Thus, we can unite the stereochemistry of catenanes with that of their topologically trivial cousins, the rotaxanes, enabling a more unified approach to their discussion.

Variations in maximum urethral closure pressure in stress urinary incontinence.

INTRODUCTION: Urethral Pressure Profilometry (UPP) assesses the urethral closing function. The literature is scarce regarding the change in the Maximum Urethral Closure Pressure (MUCP) values during Pelvic Floor Muscle Contraction (PFMC). The objective was to evaluate the change in the urethral closure pressure (UCP) at rest and during a PFMC in patients with Stress Urinary Incontinence. MATERIALS AND METHODS: This was a descriptive, comparative, and observational study. The study comprised female patients with either Pure Stress Urinary Incontinence (PSUI) or Complicated Stress Urinary Incontinence (CSUI). The urethral closure pressure was measured at rest and during PFMC using urethral profilometry. The effect of the pelvic musculature contraction was evaluated by comparing the changes in the indicated values. RESULTS: Patients with pure stress urinary incontinence had a mean age of 57.18 ± 10.74 years (p = 0.12), while those with complicated stress urinary incontinence had a mean age of 58.26 ± 14.39 years (p = 0.12). UCP in PSUI was 58.58 ± 26.96 cmH2O at rest compared to 61.26 ± 34.17 cmH2O in CSUI (p = 0.59), with MUCP increasing to 73.93 ± 31.51 and 79.71 ± 36.26 cmH2O during PFMC (p = 0.001). Between the two measurements, there was an average rise of 26.2% (range 26.2%-32.59%) (p = 0.001). MUCP during PFM contractions was found to be inversely associated to age (r = -0.28, p = 0.007). CONCLUSION: The urethral pressure profile is the same for all types of urinary stress incontinence, whether simple or complicated. When comparing UCP at rest to MUCP during PFMC, there is at least a functional 25% increase.

On the reaction of 1,3-diphenylisobenzofuran and (2-iodoethynyl)(phenyl)iodonium triflate. A unique case of oxygen transfer from the Diels-Alder adduct to the diene.

Reaction of 1,3-diphenylisobenzofuran (DPIBF) with 2-(iodoethynyl)(phenyl)-iodonium triflate at room temperature gave the expected Diels-Alder adduct, but using an excess of DFIBF (2 equiv.) and performing the reaction at 55 °C or heating at this temperature during the concentration stage, the initial orange solution or product mixture became dark brown and the products 1,2-phenylene-1,2-bis(phenylmethanone) and 2-(3-iodo-1,4-diphenylnaphthyl)(phenyl)iodonium triflate were obtained, which suggests an oxygen transfer between DPIBF and the initial adduct.

Mechanically axially chiral catenanes and noncanonical mechanically axially chiral rotaxanes.

Chirality typically arises in molecules because of a rigidly chiral arrangement of covalently bonded atoms. Less generally appreciated is that chirality can arise when molecules are threaded through one another to create a mechanical bond. For example, when two macrocycles with chemically distinct faces are joined to form a catenane, the structure is chiral, although the rings themselves are not. However, enantiopure mechanically axially chiral catenanes in which the mechanical bond provides the sole source of stereochemistry have not been reported. Here we re-examine the symmetry properties of these molecules and in doing so identify a straightforward route to access them from simple chiral building blocks. Our analysis also led us to identify an analogous but previously unremarked upon rotaxane stereogenic unit, which also yielded to our co-conformational auxiliary approach. With methods to access mechanically axially chiral molecules in hand, their properties and applications can now be explored.

A chiral interlocking auxiliary strategy for the synthesis of mechanically planar chiral rotaxanes.

Rotaxanes can display molecular chirality solely due to the mechanical bond between the axle and encircling macrocycle without the presence of covalent stereogenic units. However, the synthesis of such molecules remains challenging. We have discovered a combination of reaction partners that function as a chiral interlocking auxiliary to both orientate a macrocycle and, effectively, load it onto a new axle. Here we use these substrates to demonstrate the potential of a chiral interlocking auxiliary strategy for the synthesis of mechanically planar chiral rotaxanes by producing a range of examples with high enantiopurity (93-99% e.e.), including so-called 'impossible' rotaxanes whose axles lack any functional groups that would allow their direct synthesis by other means. Intriguingly, by varying the order of bond-forming steps, we can effectively choose which end of an axle the macrocycle is loaded onto, enabling the synthesis of both hands of a single target using the same reactions and building blocks.

Functional and Prognostic Assessment in Comatose Patients: A Study Using Somatosensory Evoked Potentials.

Aim: The functional prognosis of patients after coma following either cardiac arrest (CA) or acute structural brain injury (ABI) is often uncertain. These patients are associated with high mortality and disability. N20 and N70 somatosensory evoked potentials (SSEP) are used to predict prognosis. We evaluated the utility of SSEP (N20-N70) as an early indicator of long-term prognosis in these patients. Methods: This was a retrospective cohort study of patients (n = 120) admitted to the intensive care unit (ICU) with a diagnosis of coma after CA (n = 60) or ABI (n = 60). An SSEP study was performed, including N20 and N70 at 24-72 h, after coma onset. Functional recovery was assessed 6-12 months later using the modified Glasgow scale (mGS). The study was approved by our local research ethics committee. Results: In the CA and ABI groups, the absence of N20 (36% of CA patients and 41% of ABI patients; specificity = 100%) or N70 (68% of CA patients and 78% of ABI patients) was a strong indicator of poor outcome. Conversely, the presence of N70 was an indicator of a good outcome (AC: specificity = 84.2%, sensitivity = 92.7%; ABI: specificity = 64.2% sensitivity = 91.3%). Conclusion: Somatosensory evoked potentials are useful early prognostic markers with high specificity (N20) and sensitivity (N70). Moreover, N70 has additional potential value for improving the prediction of good long-term functional outcomes. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [2018/01/001].

The Added Value of Somatosensory Potential N70 in Neurological Prognosis After Coma by Acute Brain Structural Injury: A Retrospective Study.

Background: Coma after acute brain structural injury (ABI) are associated with high mortality and disability. Somatosensory evoked potentials (SSEP) N20 and N70 are used to predict prognosis. Purpose: We assessed the utility of SSEP (N20-N70) as an early indicator of long-term functional prognosis in these patients. Methods: We conducted a retrospective cohort study of patients admitted to the intensive care unit (ICU) with a diagnosis of coma after ABI (n=60). An SSEP study including N20 and N70 was performed 24-72 hours after coma onset. Functional recovery was evaluated 6 to 12 months later using the Modified Glasgow Scale (mGS). The study was approved by our local research ethics committee. Results: The absence of N20 (41% specificity=100%) or N70 (78%) was a strong indicator of a poor outcome. In contrast, the presence of N70 was an indicator of a good outcome (specificity=64.2% sensitivity=91.3%). Conclusion: SSEP N20 and N70 are useful early prognostic markers with high specificity (N20) and sensitivity (N70). N70 has potential additional value for improving the prediction of good functional outcomes in the long term.

Interregional variability in the use of cardiovascular technologies (2011-2019). Correlation with economic indicators, admissions, and in-hospital mortality.

INTRODUCTION AND OBJECTIVES: Equal opportunities to access technical advances with recognized clinical value should be a priority of the publicly-funded health system. We analyzed variability among all the Spanish autonomous communities in the use of cardiovascular techniques with an established indication and its relationship with economic indicators, burden of disease, and hospital mortality. METHODS: The activity registries of various Associations of the Spanish Society of Cardiology from 2011 to 2019 were analyzed for coronary angiography, overall percutaneous coronary intervention (PCI), primary PCI, implantable cardioverter-defibrillators (ICD), cardiac resynchronization therapy, and transcatheter aortic valve replacement (TAVR). Economic indices (gross domestic product and per capita health care expenditure) were obtained from public sources and data on attendance rates and mortality from the Resources and Quality in Cardiology (RECALCAR) reports of the Spanish Society of Cardiology. We analyzed the coefficient of variation for activity and the correlation of activity with regional economic indices, attendance rates, and risk-adjusted rates of in-hospital mortality. RESULTS: We identified wide variability in the use of technologies, especially for primary PCI (18%), ICD (22%), cardiac resynchronization therapy (36%), and TAVR (42%). A certain correlation with attendance rates was seen only for overall PCI and ICD. In general, no significant correlation was found between the use of the techniques and the economic indices of wealth and expenditure. The correlation with in-hospital mortality showed no significant results, although this was the analysis with the greatest limitations because the impact of these techniques on survival is exerted more in the mid- and long-term. CONCLUSIONS: The results of this study, despite its inherent limitations, show marked variability between autonomous communities in the use of cardiovascular technologies, which is not explained by economic differences or by hospital attendance rates due to the corresponding diseases.

Recurring Severe Injection-Related Infections in People Who Inject Drugs and the Need for Safe Injection Sites in Madrid, Spain.

BACKGROUND: An estimated 58 749 people with opioid use disorder engaged in opioid agonist therapy (OAT) in 1132 centers in Spain during 2017. We aimed to calculate the incidence of severe injection-related infections in people who inject drugs (PWID) engaged in OAT in harm reduction settings without a safe consumption space. METHODS: A retrospective cohort study was performed in PWID engaged in OAT and in a mobile harm reduction unit to quantify admissions to a referral hospital for any severe injection-related infections between 1 January 2016 and 31 December 2019. A Cox proportional hazard regression analysis was used to assess factors associated with any severe injection-related infection. RESULTS: Two hundred thirty-seven PWID who engaged in OAT were included in the study. After a median follow-up of 5.5 months (interquartile range [IQR], 1.3-22.7 months), a total of 104 episodes of severe injection-related infections occurred among 56 individuals, and admission due to a second event occurred in 35.7% of this same group. The incidence density of any type of severe injection-related infection was 26.8 (95% confidence interval [CI], 20.2-34.8) episodes per 100 person-years, and the incidence density of complicated skin and soft tissue infections that required hospital admission was 20.4 (95% CI, 15.0-27.3) episodes per 100 person-years. Fifty-six (53.8%) of all the episodes were patient-directed discharge (PDD), and people who had 2 or more hospital admissions had a higher PDD frequency. CONCLUSIONS: Severe injection-related infections remain highly prevalent among PWID cared for in a harm reduction setting without a safe consumption space. PDD was more frequent among higher-risk individuals who presented 2 or more hospital readmissions.

Which Physical Exercise Interventions Increase HDL-Cholesterol Levels? A Systematic Review of Meta-analyses of Randomized Controlled Trials.

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) have shown the beneficial effect of exercise on HDL-cholesterol (HDL-C) levels. However, systematic reviews are not free of bias, and this could call into question their results. OBJECTIVES: The aim of this work was to conduct a critical assessment of meta-analyses of RCTs that analyze the association between exercise and HDL-C levels, evaluating their results and the risk of bias (RoB). METHODS: This systematic review of MEDLINE and EMBASE included meta-analyses of RCTs that studied the effects of exercise on HDL-C levels in healthy adults or patients at cardiovascular risk. The RoB was determined using AMSTAR-2, and information was obtained on exercise and the variation in HDL-C levels. RESULTS: Twenty-three meta-analyses were included. Great variability was found in exercise (different types, frequencies or intensities in the studied interventions). All the analyses found an improvement in HDL-C levels, ranging from 0.27 to 5.41 mg/dl, in comparison with the control group (no exercise). The RoB was very high, with 18 reviews obtaining a critically low confidence level and the remaining works obtaining the highest confidence level. CONCLUSIONS: Only one meta-analysis showed good quality, in which HDL-C levels increased by 3.09 mg/dl in healthy adults and patients at high cardiovascular risk who practiced yoga. The rest had high RoB. Therefore, new systematic reviews with low RoB are needed to apply the results to clinical practice. Register: CRD42020158471 (PROSPERO).

A case report of cobalt cardiomyopathy leading to electric storm and cardiogenic shock: the importance of the orthopaedic background in patients with heart failure of unknown aetiology.

BACKGROUND: The first series of cobalt cardiomyopathy was described in the 60s in relation to the abuse of a cobalt containing beer. Since then, millions of metal hip arthroplasties have been performed and a small number of cobalt cardiomyopathies related to metal prosthesis have been reported. CASE SUMMARY: We report a case of a 48-year-old man who developed a severe non-dilated restrictive cardiomyopathy in the setting of a systemic metallosis following several hip arthroplasties. The diagnosis was suspected by exclusion of other more common causes for restrictive cardiomyopathies and confirmed by the levels of cobalt and chromium in the serum and the endomyocardial biopsy performance that showed metal deposits in myocardial tissue. Despite the removal of the metal prosthesis and a significant decrease in serum metal levels, he suffered cardiogenic shock (CS) and electric storm that required emergency mechanical circulatory support as a bridge to heart transplant. DISCUSSION: Cobalt cardiomyopathy is a rare condition that has been observed in patients who develop cobalt toxicity after metal hip arthroplasty. The condition may improve after diagnosis and removal of the prosthesis or get worse and progress to end-stage heart failure or CS. The concern about the metal toxicity associated with metal hip prosthesis has increased in the last few years. Orthopaedic surgeons and cardiologists should be aware of this severe complication that is probably under diagnosed.

Gene expression analysis on growth, development and toxicity pathways of male Nile tilapia (Oreochromis niloticus), after acute and sub-chronic benzo (α) pyrene exposures.

Benzo[α]pyrene (BaP), a lipophilic polycyclic aromatic hydrocarbon (PAH), is a contaminant widely distributed in aquatic systems. Its presence in freshwater organisms is of great concern; particularly in Nile tilapia (Oreochromis niloticus), due to its economic relevance. The aim of this study is to evaluate the effects of acute and sub-chronic BaP exposures on molecular growth/development responses, toxicity to DNA pathways and xenobiotic metabolism. Negative morphometric changes (the growth condition factor, hepatosomatic and gonadosomatic indices), the fluorescent aromatic compounds (FACs) in bile were also studied in order to understand the mechanisms of action of BaP. Genes involved in the growth hormone GH/insulin-like growth factor 1 (IGF-1) were measured, such as IGF1-2 with the growth hormone receptor gene expression GHR1-2, and the endocrine disruption biomarker vitellogenin (VTG). Acute exposure elicited changes in the GH/IGF axis, mainly in the GHR1 and in IGF1 mRNA levels without affecting the GHR2 expression. While sub-chronic exposure had less effect on both GHR and IGF genes. The most notable tissue-specific effects and morphometric endpoints were observed upon sub-chronic exposure, such as changes in key genes involved in detoxification, DNA damage, and altered reproductive morphological endpoints; showing that sub-chronic BaP doses have longer-lasting toxic effects. This study shows that sub-chronic BaP exposure may compromise the health of Nile tilapia and sheds light on the changes of the GH/IGF axis and the biotransformation of the xenobiotics due to the presence of this contaminant.