Phosphoregulation of the yeast Pma1 H+-ATPase autoinhibitory domain involves the Ptk1/2 kinases and the Glc7 PP1 phosphatase and is under TORC1 control.

Plasma membrane (PM) H+-ATPases of the P-type family are highly conserved in yeast, other fungi, and plants. Their main role is to establish an H+ gradient driving active transport of small ions and metabolites across the PM and providing the main component of the PM potential. Furthermore, in both yeast and plant cells, conditions have been described under which active H+-ATPases promote activation of TORC1, the rapamycin-sensitive kinase complex controlling cell growth. Fungal and plant PM H+-ATPases are self-inhibited by their respective cytosolic carboxyterminal tails unless this domain is phosphorylated at specific residues. In the yeast H+-ATPase Pma1, neutralization of this autoinhibitory domain depends mostly on phosphorylation of the adjacent Ser911 and Thr912 residues, but the kinase(s) and phosphatase(s) controlling this tandem phosphorylation remain unknown. In this study, we show that S911-T912 phosphorylation in Pma1 is mediated by the largely redundant Ptk1 and Ptk2 kinase paralogs. Dephosphorylation of S911-T912, as occurs under glucose starvation, is dependent on the Glc7 PP1 phosphatase. Furthermore, proper S911-T912 phosphorylation in Pma1 is required for optimal TORC1 activation upon H+ influx coupled amino-acid uptake. We finally show that TORC1 controls S911-T912 phosphorylation in a manner suggesting that activated TORC1 promotes feedback inhibition of Pma1. Our results shed important new light on phosphoregulation of the yeast Pma1 H+-ATPase and on its interconnections with TORC1.

Noninfectious causes of alopecia in the pediatric population.

PURPOSE OF REVIEW: To highlight recent advances in the knowledge base surrounding noninfectious causes of alopecia in the pediatric population. RECENT FINDINGS: Recent developments in the literature included assessments of treatment efficacy, diagnostic utility of trichoscopy, and retrospective studies characterizing the clinical picture of pediatric cases. SUMMARY: These findings will equip practitioners with the recent advances in the field's understanding of noninfectious causes of alopecia in the pediatric population.

Cervical Chondrocutaneous Branchial Remnant: A Case Report and Review of the Literature.

ABSTRACT: Cervical chondrocutaneous branchial remnant is a rare congenital developmental anomaly typically located on the lateral neck. Histologically, it has the appearance of an accessory tragus demonstrating a central cartilaginous core with surrounding fibrosis located in the subcutaneous tissue. The condition has been associated with a variety of congenital anomalies, particularly involving the auditory, cardiovascular, and visual systems. Given that research-based evidence related to cervical chondrocutaneous branchial remnant in dermatology literature is sparse, we present this case to raise more awareness about this entity among dermatopathologists and review the different histopathologic presentations and possible associated anomalies.

Off-Label Use of Baricitinib in Dermatology.

The current US Food and Drug Administration (FDA) indications for baricitinib include alopecia areata, rheumatoid arthritis, and COVID-19. However, increasing evidence indicates that baricitinib is effective in treating a variety of dermatological conditions. This review article comprehensively presents the available literature on this topic and will be of interest to practitioners in the field. These disorders may be broadly classified as connective tissue diseases, eczematous dermatoses, alopecias, vascular disorders, granulomatous diseases, neutrophilic dermatoses, vitiligo, psoriasis, lichenoid disorders, and other miscellaneous disorders. Shah A, Yumeen S, Qureshi A, et al. Off-label use of baricitinib in dermatology. J Drugs Dermatol. 2023;22(8):795-801. doi:10.36849/JDD.7360.

Coffee, Citrus, and Alcohol: A Review of What We Drink and How it May Affect our Risk for Skin Cancer.

Climate change and environmental health are closely linked with agriculture and food supply. The environment influences accessibility, quality, and variety of foods and drinks that are available for consumption, which in turn influences population health. A growing area of research is the role of dietary intake of nutrients and how they may influence risk for skin cancer. In recent years, our group has studied dietary nutrients, particularly those found in commonly consumed beverages, such as those containing caffeine, citrus products, and alcohol, in large prospective cohorts to evaluate how their intake may influence risk for skin cancer. Our data suggest that intake of citrus juices, when consumed around once per day or more, or around 5 to 6 times per week, may be associated with increased risk for both keratinocyte carcinomas (KC) and malignant melanoma (MM). With regards to alcohol consumption, we have found that intake of white wine may be associated with increased risk for both KC and MM, while beer and red wine have not shown such associations. Lastly, our work suggests caffeinated beverages, including coffee, tea, and cola, may be associated with decreased risk for basal cell carcinoma (BCC) and MM. While the associations between food intake and skin cancer development are complex, and remain to be further analyzed in future studies, we hope that our summary may help guide individuals to small changes they may make towards potentially reducing their risk for certain skin cancers.

Superficial temporal artery pseudoaneurysm: Report of two cases and review.

Superficial temporal artery pseudoaneurysm is a rare complication of arterial injury developing on the forehead following blunt trauma. There is little written on this entity in the dermatopathology literature. We describe two cases of superficial temporal artery pseudoaneurysm in two men aged 53 and 25 years, one of whom had a recent history of head trauma. This report reviews the classic histopathologic findings of STA pseudoaneurysm and highlights ways to distinguish it from other entities in the differential diagnosis.

Duration of mechanical ventilation is more critical for brain growth than postnatal hydrocortisone in extremely preterm infants.

Hydrocortisone is used in preterm infants. However, early disruption of growth velocities was observed in infants exposed to hydrocortisone. This retrospective study aimed to explore the postnatal brain growth of extremely preterm infants requiring hydrocortisone treatment as well as its association with perinatal factors. Extremely preterm infants exposed to hydrocortisone from 2011 to 2016 who survived up to 12 months were included. Each of them was matched with two infants not treated with hydrocortisone exhibiting similar gestational ages and nearly similar birth head circumferences. The outcome variables were brain tissue areas on MRIs performed at term-equivalent age and postnatal head circumference growth up to a corrected age of 12 months. Univariate and multiple regression analyses were performed. Infants treated with hydrocortisone (n=20) were matched with 40 infants not exposed to hydrocortisone. The infants exposed to hydrocortisone exhibited a lower birth weight (p=0.04) and a longer duration of mechanical ventilation (p<0.0001). Infants treated with hydrocortisone exhibited a smaller basal ganglia/thalamus area (p=0.04) at term-equivalent age and a smaller head circumference at a corrected age of 12 months (p=0.003). However, the basal ganglia/thalamus area and the postnatal brain growth were independently associated with the duration of mechanical ventilation and not with hydrocortisone. Interestingly, a significant interaction between hydrocortisone and sex was observed (p=0.04).Conclusion: This study supports previous data that indicated no obvious impact of hydrocortisone on brain growth and highlights the relationship between the severity of the neonatal course and postnatal brain growth in extremely preterm infants. What is Known: • Postnatal hydrocortisone disrupts transiently growth velocities including the head circumference growth. • Postnatal hydrocortisone has less impact on neurodevelopment than dexamethasone. What is New: • Hydrocortisone prescribed for infants in the most severe conditions did not show independent effect on brain growth up to the corrected age of 12 months. However, a different effect of hydrocortisone according to sex can't be excluded and needs further explorations. • Perinatal factors as birth weight and duration of mechanical ventilation were determinant for the subsequent brain growth.

Fluconazole-induced acute generalized exanthematous pustulosis.

Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse reaction usually caused by drugs. The annual incidence is one to five cases per million. It is characterized by an acute febrile episode, accompanied by numerous small primarily non-follicular, sterile pustules arising within large areas of edematous erythema. There have been several case reports to date of AGEP following exposure to antifungals. Terbinafine is most commonly implicated in AGEP. We report a case of 7-year-old boy who developed AGEP shortly after commencing oral fluconazole for Tinea capitis. To our knowledge, this is the fourth reported case of AGEP due to fluconazole.

Mycoplasma pneumonia and atypical acute hemorrhagic edema of infancy.

Acute hemorrhagic edema of infancy is a benign rare presentation of leukocytoclastic vasculitis that affects children between 4 and 24 months of age. It usually involves the distal extremities, face, and ears. We report an atypical presentation of AHEI in a 1 year 5 months old boy starting initially over the trunk and back, then spreading to the face and extremities. Mycoplasma pneumonia IgM was found to be positive. The rash resolved spontaneously within two weeks. Herein we present a case of Mycoplasma induced AHEI with an atypical clinical presentation followed by a review of the literature.

Comparative study of preterm infants fed new and existing human milk fortifiers showed favourable markers of gastrointestinal status.

AIM: This study examined the influence of different human milk fortifiers on biomarkers of gastrointestinal immaturity and inflammation in preterm infants. METHODS: We report secondary outcomes from a controlled, double-blind, randomised, parallel group study conducted from 2011 to 2014 in neonatal intensive care units at 11 metropolitan hospitals in France, Belgium, Germany, Switzerland and Italy. Preterm infants born at up to 32 weeks or weighing up to 1500 g were randomised to a new powdered human milk fortifier (n = 77) or a control fortifier (n = 76) for a minimum of 21 days. We analysed faecal markers of gut inflammation, namely alpha-1 antitrypsin and calprotectin, and maturity, namely elastase-1. RESULTS: Faecal alpha-1 antitrypsin was slightly lower in the new than control fortifier group after 21 days of full enteral feeding, with a geometric mean and standard deviation of 1.52 ± 1.32 vs 1.82 ± 1.44 mg/g stools (P = .01). There was no significant difference in faecal calprotectin (median [Q1-Q3] of 296 [136-565] µg/g stools in both groups combined at study day 21). Faecal elastase-1 was lower in the new fortifier than control fortifier group (202.5 ± 1.6 vs 257.7 ± 1.5 µg/g stools, P = .016). CONCLUSION: Mean values for each parameter were within the ranges in healthy term infants, indicating favourable markers of gastrointestinal status in both groups. In addition, for faecal calprotectin, the relatively high concentration observed in preterm infants fed fortified human milk suggests that the threshold level for detecting necrotising enterocolitis should be revised.

TRActs constrained by UnderLying INfant anatomy (TRACULInA): An automated probabilistic tractography tool with anatomical priors for use in the newborn brain.

The ongoing myelination of white-matter fiber bundles plays a significant role in brain development. However, reliable and consistent identification of these bundles from infant brain MRIs is often challenging due to inherently low diffusion anisotropy, as well as motion and other artifacts. In this paper we introduce a new tool for automated probabilistic tractography specifically designed for newborn infants. Our tool incorporates prior information about the anatomical neighborhood of white-matter pathways from a training data set. In our experiments, we evaluate this tool on data from both full-term and prematurely born infants and demonstrate that it can reconstruct known white-matter tracts in both groups robustly, even in the presence of differences between the training set and study subjects. Additionally, we evaluate it on a publicly available large data set of healthy term infants (UNC Early Brain Development Program). This paves the way for performing a host of sophisticated analyses in newborns that we have previously implemented for the adult brain, such as pointwise analysis along tracts and longitudinal analysis, in both health and disease.

Prematurity alters skin conductance and behavioural scoring after acute stress in term-equivalent age infants.

AIM: The primary objective was to assess the effect of prematurity at term-equivalent age on skin conductance and behavioural responses to acute stress. The secondary objective was to explore the reliability of skin conductance in detecting neonatal discomfort in preterm and full-term populations. METHODS: Very preterm infants at term-equivalent age and healthy full-term neonates, 34 infants in each group, underwent the hip dysplasia screening test. The acute pain in newborn infants (APN) scale was scored before and 15, 45 and 90 seconds after stimulus. Skin conductance was measured in the 30-second time-lap before and after stimulus. RESULTS: The APN score was lower in preterm infants after intervention (term: 5.4 ± 2.8 vs. preterm: 3.9 ± 2.2; p = 0.03). Peaks-per-second, a skin conductance parameter, exhibited lower basal values in preterm infants than in term infants, with similar rise induced by stressful challenge. Peaks-per-second values were correlated to the 15-second APN score in both groups (term: r = 0.55, p < 0.001; preterm: r = 0.43, p = 0.01). CONCLUSION: Preterm birth changed skin conductance signal and behavioural response to stress at term-equivalent age. The skin conductance device may be an objective tool for a continuous monitoring of acute neonatal stress.

Effect of Atropine With Propofol vs Atropine With Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Nonemergency Intubation: A Randomized Clinical Trial.

Importance: Propofol or a combination of a synthetic opioid and muscle relaxant are both recommended for premedication before neonatal intubation but have yet to be compared. Objective: To compare prolonged desaturation during neonatal nasotracheal intubation after premedication with atropine-propofol vs atropine-atracurium-sufentanil treatment. Design, Setting, and Participants: Multicenter, double-blind, randomized clinical trial (2012-2016) in 6 NICUs in France that included 173 neonates requiring nonemergency intubation. The study was interrupted due to expired study kits and lack of funding. Interventions: Eighty-nine participants were randomly assigned to the atropine-propofol group and 82 to the atropine-atracurium-sufentanil group before nasotracheal intubation. Main Outcomes and Measures: The primary outcome was prolonged desaturation (Spo2 <80% lasting > 60 seconds), using intention-to-treat analysis using mixed models. Secondary outcomes assessed the characteristics of the procedure and its tolerance. Results: Of 173 neonates randomized (mean gestational age, 30.6 weeks; mean birth weight, 1502 g; 71 girls), 171 (99%) completed the trial. Of 89 infants, 53 (59.6%) in the atropine-propofol group vs 54 of 82 (65.9%) in the atropine-atracurium-sufentanil group achieved the primary outcome (adjusted RD, -6.4; 95% CI, -21.0 to 8.1; P = .38). The atropine-propofol group had a longer mean procedure duration than did the atropine-atracurium-sufentanil group (adjusted RD, 1.7 minutes; 95% CI, 0.1-3.3 minutes; P = .04); a less frequent excellent quality of sedation rate, 51.7% (45 of 87) vs 92.6% (75 of 81; P < .001); a shorter median time to respiratory recovery, 14 minutes (IQR, 8-34 minutes) vs 33 minutes (IQR, 15-56 minutes; P = .002), and shorter median time to limb movement recovery, 18 minutes (IQR, 10-43 minutes) vs 36 minutes (IQR, 19-65 minutes; P = .003). In the 60 minutes after inclusion, Spo2 was preserved significantly better in the atropine-propofol group (time × treatment interaction P = .02). Of the atropine-propofol group 20.6% had head ultrasound scans that showed worsening intracranial hemorrhaging (any or increased intraventricular hemorrhage) in the 7 days after randomization vs 17.6% in the atropine-atracurium-sufentanil group (adjusted RD, 1.2; 95% CI, -13.1 to 15.5, P = .87). Severe adverse events occurred in 11% of the atropine-propofol group and in 20% of the atropine-atracurium-sufentanil group. Conclusions and Relevance: Among neonates undergoing nonemergency nasotracheal intubation, the frequency of prolonged desaturation did not differ significantly between atropine used with propofol or atropine used with atracurium and sufentanil. However, the study may have been underpowered to detect a clinically important difference, and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01490580, EudraCT number: 2009-014885-25.

Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial.

OBJECTIVES: The aim of this study was to assess growth and nutritional biomarkers of preterm infants fed human milk (HM) supplemented with a new powdered HM fortifier (nHMF) or a control HM fortifier (cHMF). The nHMF provides similar energy content, 16% more protein (partially hydrolyzed whey), and higher micronutrient levels than the cHMF, along with medium-chain triglycerides and docosahexaenoic acid. METHODS: In this controlled, multicenter, double-blind study, a sample of preterm infants ≤32 weeks or ≤1500 g were randomized to receive nHMF (n = 77) or cHMF (n = 76) for a minimum of 21 days. Weight gain was evaluated for noninferiority (margin = -1 g/day) and superiority (margin = 0 g/day). Nutritional status and gut inflammation were assessed by blood, urine, and fecal biochemistries. Adverse events were monitored. RESULTS: Adjusted mean weight gain (analysis of covariance) was 2.3 g/day greater in nHMF versus cHMF; the lower limit of the 95% CI (0.4 g/day) exceeded both noninferiority (P < 0.001) and superiority margins (P = 0.01). Weight gain rate (unadjusted) was 18.3 (nHMF) and 16.8 g ·â€Škg ·â€Šday (cHMF) between study days 1 and 21 (D1-D21). Length and head circumference (HC) gains between D1 and D21 were not different. Adjusted weight-for-age z score at D21 and HC-for-age z score at week 40 corrected age were greater in nHMF versus cHMF (P = 0.013, P = 0.003 respectively). nHMF had higher serum blood urea nitrogen, pre-albumin, alkaline phosphatase, and calcium (all within normal ranges; all P ≤ 0.019) at D21 versus cHMF. Both HMFs were well tolerated with similar incidence of gastrointestinal adverse events. CONCLUSIONS: nHMF providing more protein and fat compared to a control fortifier is safe, well-tolerated, and improves the weight gain of preterm infants.

Melatonin modulates neonatal brain inflammation through endoplasmic reticulum stress, autophagy, and miR-34a/silent information regulator 1 pathway.

Maternal infection/inflammation represents one of the most important factors involved in the etiology of brain injury in newborns. We investigated the modulating effect of prenatal melatonin on the neonatal brain inflammation process resulting from maternal intraperitoneal (i.p.) lipopolysaccharide (LPS) injections. LPS (300 µg/kg) was administered to pregnant rats at gestational days 19 and 20. Melatonin (5 mg/kg) was administered i.p. at the same time as LPS. Melatonin counteracted the LPS sensitization to a second ibotenate-induced excitotoxic insult performed on postnatal day (PND) 4. As melatonin succeeded in reducing microglial activation in neonatal brain at PND1, pathways previously implicated in brain inflammation regulation, such as endoplasmic reticulum (ER) stress, autophagy and silent information regulator 1 (SIRT1), a melatonin target, were assessed at the same time-point in our experimental groups. Results showed that maternal LPS administrations resulted in an increase in CHOP and Hsp70 protein expression and eIF2α phosphorylation, indicative of activation of the unfolded protein response consequent to ER stress, and a slighter decrease in the autophagy process, determined by reduced lipidated LC3 and increased p62 expression. LPS-induced inflammation also reduced brain SIRT1 expression and affected the expression of miR-34a, miR146a, and miR-126. All these effects were blocked by melatonin. Cleaved-caspase-3 apoptosis pathway did not seem to be implicated in the noxious effect of LPS on the PND1 brain. We conclude that melatonin is effective in reducing maternal LPS-induced neonatal inflammation and related brain injury. Its role as a prophylactic/therapeutic drug deserves to be investigated by clinical studies.

EFFECTS OF PREOPERATIVE ENOXAPARIN ON BLEEDING AFTER CORONARY ARTERY BYPASS SURGERY.

BACKGROUND: Low molecular weight heparins are replacing unfractionated heparin in practice prior to cardiac surgery. This study examines postoperative (post-op) bleeding indicators in patients who received enoxaparin and underwent elective isolated first time coronary artery bypass graft. METHODS: A total of 125 consecutive patients who underwent this procedure between 2009 and 2011 at one tertiary center were reviewed and divided into three groups: Group A (n = 50) received the last dose of enoxaparin between 12 and 24 hours before surgery, Group B (n = 25) received the last dose before 24 hours and Group C (n = 50) did not receive enoxaparin. Perioperative bleeding indicators and transfusion rates were compared. RESULTS: Preoperative patients' characteristics were comparable between the three groups. There were no perioperative deaths, return to the operating room for any reason, nor major bleeding. Post-op bleeding indicators were similar in the three groups. The average chest tube drainage at 24 hours post-op was 880 mL, 695 mL and 830 mL in Group A, B and C respectively (p = 0.71). Transfusion rates of red blood cells were not statistically different (Group A 56%, B 64% & C 62%; p = 0.747). In multivariate analysis, female gender, older age, and preoperative clopidogrel intake (stopped 5 days prior to surgery) were associated with higher transfusion rates. CONCLUSION: In elective first time coronary artery bypass graft patients who had no aspirin or clopidogrel intake 5 days prior to surgery, the use of enoxaparin up to 12 hours prior to skin incision does not increase the risk of post-op bleeding.

G protein-coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration.

OBJECTIVE: The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. METHODS: We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1ß-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1ß sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation. RESULTS: We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. INTERPRETATION: Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.

The use of biologics and JAK inhibitors in the management of moderate to severe Hidradenitis Suppurativa treatment: a scoping review.

This scoping review aims to characterize the use of biologics and Janus Kinase inhibitors (JAKi) in the treatment of Hidradenitis Suppurativa (HS), which is a chronic inflammatory condition. A comprehensive literature search was conducted in PubMed/NCBI, Embase, Web of Science databases, and the Clinicaltrials.gov register. The search included interventional trials assessing the use of biologics or JAKi in HS, with no geographic or time restrictions. Secukinumab and adalimumab were identified as the only two drugs approved by the FDA for treating moderate to severe HS in adults. Several other drug classes showed promising results based on clinical studies reviewed. IL-12/23 inhibitor ustekinumab demonstrated improvements in disease severity scores and HiSCR rates in small trials. IL-17 inhibitors such as brodalumab, bimekizumab, and CJM112 showed preliminary positive responses in early-phase clinical studies and case reports. While evidence was mixed, some TNF-α inhibitors such as infliximab provided benefits according to a randomized controlled trial, though etanercept trials yielded non-significant or inconsistent findings. Larger, well-designed studies are required to further establish their efficacy and safety, but biologics and JAKis show potential as alternative treatment options for moderate to severe HS. The findings of this review contribute to the growing interest among patients and to enhancing the understanding of physician's regarding potential alternative therapeutic options for HS and provide a basis for further research in this field.