Risk of Incident Asthma Among Young Asian American, Native Hawaiian, and Pacific Islander Children from Age 3 to 7 Years in a Northern California Healthcare System.

Incident childhood asthma risk has not been examined among diverse Asian American, Native Hawaiian, and Pacific Islander subgroups. In a large California healthcare system, incident asthma was higher among young Filipino/a, Native Hawaiian/Pacific Islander, and South Asian children compared with non-Hispanic White children, whereas Chinese and Japanese children were similar.

Hairless regulates heterochromatin maintenance and muscle stem cell function as a histone demethylase antagonist.

Skeletal muscle possesses remarkable regenerative ability because of the resident muscle stem cells (MuSCs). A prominent feature of quiescent MuSCs is a high content of heterochromatin. However, little is known about the mechanisms by which heterochromatin is maintained in MuSCs. By comparing gene-expression profiles from quiescent and activated MuSCs, we found that the mammalian Hairless (Hr) gene is expressed in quiescent MuSCs and rapidly down-regulated upon MuSC activation. Using a mouse model in which Hr can be specifically ablated in MuSCs, we demonstrate that Hr expression is critical for MuSC function and muscle regeneration. In MuSCs, loss of Hr results in reduced trimethylated Histone 3 Lysine 9 (H3K9me3) levels, reduced heterochromatin, increased susceptibility to genotoxic stress, and the accumulation of DNA damage. Deletion of Hr leads to an acceleration of the age-related decline in MuSC numbers. We have also demonstrated that despite the fact that Hr is homologous to a family of histone demethylases and binds to di- and trimethylated H3K9, the expression of Hr does not lead to H3K9 demethylation. In contrast, we show that the expression of Hr leads to the inhibition of the H3K9 demethylase Jmjd1a and an increase in H3K9 methylation. Taking these data together, our study has established that Hr is a H3K9 demethylase antagonist specifically expressed in quiescent MuSCs.

A case report and systematic literature review: insulin-induced type III hypersensitivity reaction.

Insulin-induced type III hypersensitivity reactions (HSRs) are exceedingly rare and pose complex diagnostic and management challenges. We describe a case of a 43-year-old woman with type 1 diabetes mellitus (DM), severe insulin resistance, and subcutaneous nodules at injection sites, accompanied by elevated anti-insulin IgG autoantibodies. Treatment involved therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) as bridge therapy, followed by long-term immunosuppression, which reduced autoantibody levels and improved insulin tolerance. Given the limited treatment guidelines, we conducted a comprehensive literature review, identifying 16 similar cases. Most patients were females with a median age of 36.5 years; 63% had type 1 DM, and 44% had concurrent insulin resistance (56% with elevated autoantibodies). Treatment approaches varied, with glucocorticoids used in 67% of cases. Patients with type 1 DM were less responsive to steroids than those with type 2 DM, and had a more severe course. Of those patients with severe disease necessitating immunosuppression, 66% had poor responses or experienced relapses. The underlying mechanism of insulin-induced type III HSRs remains poorly understood. Immunosuppressive therapy reduces anti-insulin IgG autoantibodies, leading to short-term clinical improvement and improved insulin resistance, emphasizing their crucial role in the condition. However, the long-term efficacy of immunosuppression remains uncertain and necessitates continuous evaluation and further research.

Beneficial effects of bempedoic acid treatment in polycystic kidney disease cells and mice.

ADPKD has few therapeutic options. Tolvaptan slows disease but has side effects limiting its tolerability. Bempedoic acid (BA), an ATP citrate-lyase (ACLY) inhibitor FDA-approved for hypercholesterolemia, catalyzes a key step in fatty acid/sterol synthesis important for cell proliferation. BA is activated by very long-chain acyl-CoA synthetase (FATP2) expressed primarily in kidney and liver. BA also activates AMPK. We hypothesized that BA could be a novel ADPKD therapy by inhibiting cyst growth, proliferation, injury, and metabolic dysregulation via ACLY inhibition and AMPK activation. Pkd1-null kidney cell lines derived from mouse proximal tubule (PT) and collecting duct (IMCD) were grown in 2D or 3D Matrigel cultures and treated ± BA, ± SB-204990 (another ACLY inhibitor) or with Acly shRNA before cyst analysis, immunoblotting or mitochondrial assays using MitoSox and MitoTracker staining. Pkd1 fl/fl ; Pax8-rtTA; Tet-O-Cre C57BL/6J mice were induced with doxycycline injection on postnatal days 10 and 11 (P10-P11) and then treated ± BA (30 mg/kg/d) ± tolvaptan (30-100 mg/kg/d) by gavage from P12-21. Disease severity was determined by % total-kidney-weight-to-bodyweight (%TKW/BW) and BUN levels at euthanasia (P22). Kidney and liver homogenates were immunoblotted for expression of key biomarkers. ACLY expression and activity were upregulated in Pkd1-null PT and IMCD-derived cells vs. controls. Relative to controls, both BA and SB-204990 inhibited cystic growth in Pkd1-null kidney cells, as did Acly knockdown. BA inhibited mitochondrial superoxide production and promoted mitochondrial elongation, suggesting improved mitochondrial function. In ADPKD mice, BA reduced %TKW/BW and BUN to a similar extent as tolvaptan vs. untreated controls. Addition of BA to tolvaptan caused a further reduction in %TKW/BW and BUN vs. tolvaptan alone. BA generally reduced ACLY and stimulated AMPK activity in kidneys and livers vs. controls. BA also inhibited mTOR and ERK signaling and reduced kidney injury markers. In liver, BA treatment, both alone and together with tolvaptan, increased mitochondrial biogenesis while inhibiting apoptosis. We conclude that BA and ACLY inhibition inhibited cyst growth in vitro, and BA decreased ADPKD severity in vivo. Combining BA with tolvaptan further improved various ADPKD disease parameters. Repurposing BA may be a promising new ADPKD therapy, having beneficial effects alone and along with tolvaptan.

Variations in Sugar Content of Flavored Milks and Yogurts: A Cross-Sectional Study across 3 Countries.

BACKGROUND: The consumption of dairy products is encouraged at all life stages as a nutrient-rich component of the diet. However, many milk and yogurt products, particularly flavored varieties, may contain large amounts of free sugar. OBJECTIVES: The aim of this paper was to evaluate the availability and sugar content of flavored milks and yogurts in supermarkets across 3 countries: Australia, England, and South. METHODS: Nutrition information for flavored milks and yogurts was collected by trained researchers and supplemented by crowd-sourced data from a smartphone application. Data were extracted in April 2018 and 3724 milk and yogurt products were available for analysis. Mean sugar concentrations were compared across countries with the use of ANOVA followed by Tukey's post-hoc pairwise comparisons. Sugar concentrations were compared with the UK's "green" traffic-light classifications. RESULTS: Approximately 74% (n = 2753) of all products were flavored. Flavored products contained nearly twice the average total sugar content of unflavored products, with substantial variability: mean total sugar was 9.1 g/100 mL (range: 4.3-15.0 g/100 mL) and 11.5 g/100 g (range: 0.1-22.6 g/100 g) for flavored milks and yogurts, respectively. Free sugars contributed an estimated 41% and 42% of total sugar in milks and yogurts, respectively. Flavored milks in England had ∼0.7 g/100 mL higher total sugar on average compared with Australia and South Africa (P ≤ 0.04), whereas flavored yogurts in South Africa had the lowest average total sugar (∼2 g/100 g lower than England and Australia; P < 0.001). Less than 4% of flavored products would receive a "green" rating under the UK traffic-light labeling scheme. CONCLUSIONS: In Australia, England, and South Africa, flavored milks and yogurts are highly prevalent in the food supply and contain significantly higher concentrations of total and added sugars than unflavored products.

Cochlear FLAIR Signal Changes in Hearing Preservation Vestibular Schwannoma Surgery.

OBJECTIVE: Cochlear fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) signal intensity has been shown to be elevated in patients with vestibular schwannomas (VS). This study evaluated the preoperative and postoperative cochlear signal on FLAIR sequences in patients undergoing hearing preservation surgery. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: All patients undergoing middle cranial fossa or retrosigmoid craniotomy for VS at a single institution from September 2013 to January 2017 were screened.Hearing was graded according to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) hearing classification. Inclusion criteria included preoperative AAO-HNS class A or B hearing and available preoperative and postoperative FLAIR sequences. MAIN OUTCOME MEASURE: Signal intensity of cochlear FLAIR signal was measured in the affected cochlea and normalized to the contralateral cochlea. Hearing preservation was defined as AAO-HNS class A or B postoperatively. RESULTS: Eighteen patients met all inclusion criteria, and 12/18 experienced hearing preservation. There was no difference in preoperative FLAIR ratio between hearing preserved and nonpreserved groups (2.02 vs 2.32, p = 0.52). Postoperatively, FLAIR ratio was lower in the hearing preserved group compared to the nonpreserved group (1.19 vs 1.87, p = 0.033). CONCLUSIONS: The current study is the first to examine postoperative cochlear FLAIR changes in VS patients undergoing hearing preservation surgery. In our study population, abnormal hyperintense FLAIR signal normalized in patients experiencing successful hearing preservation, while those who lost hearing maintained abnormal signal. Future studies may investigate the role of FLAIR in guiding optimal timing of operative intervention in VS patients.

A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1) Enhancer-Derived Noncoding RNA Regulates Gnrh1 Gene Expression in GnRH Neuronal Cell Models.

Gonadotropin-releasing hormone (GnRH), a neuropeptide released from a small population of neurons in the hypothalamus, is the central mediator of the hypothalamic-pituitary-gonadal axis, and is required for normal reproductive development and function. Evolutionarily conserved regulatory elements in the mouse, rat, and human Gnrh1 gene include three enhancers and the proximal promoter, which confer Gnrh1 gene expression specifically in GnRH neurons. In immortalized mouse hypothalamic GnRH (GT1-7) neurons, which show pulsatile GnRH release in culture, RNA sequencing and RT-qPCR revealed that expression of a novel long noncoding RNA at Gnrh1 enhancer 1 correlates with high levels of GnRH mRNA expression. In GT1-7 neurons, which contain a transgene carrying 3 kb of the rat Gnrh1 regulatory region, both the mouse and rat Gnrh1 enhancer-derived noncoding RNAs (GnRH-E1 RNAs) are expressed. We investigated the characteristics and function of the endogenous mouse GnRH-E1 RNA. Strand-specific RT-PCR analysis of GnRH-E1 RNA in GT1-7 cells revealed GnRH-E1 RNAs that are transcribed in the sense and antisense directions from distinct 5' start sites, are 3' polyadenylated, and are over 2 kb in length. These RNAs are localized in the nucleus and have a half-life of over 8 hours. In GT1-7 neurons, siRNA knockdown of mouse GnRH-E1 RNA resulted in a significant decrease in the expression of the Gnrh1 primary transcript and Gnrh1 mRNA. Over-expression of either the sense or antisense mouse GnRH-E1 RNA in immature, migratory GnRH (GN11) neurons, which do not express either GnRH-E1 RNA or GnRH mRNA, induced the transcriptional activity of co-transfected rat Gnrh1 gene regulatory elements, where the induction requires the presence of the rat Gnrh1 promoter. Together, these data indicate that GnRH-E1 RNA is an inducer of Gnrh1 gene expression. GnRH-E1 RNA may play an important role in the development and maturation of GnRH neurons.

Development and validation of an automated system for detection and assessment of scratching in the rodent.

Pruritus, the sensation of itch, which evokes reflex scratching behavior, has a diverse etiology. Because of its clinical significance, mechanisms of pruriception are an important topic. In the present work we describe and validate a paw motion detector (PMD) system. The system employs a small removable metal band placed on one hind paw that provides a signal indicative of paw movement through perturbation of an electromagnetic (EM) field. C57Bl/6 mice were fitted with a unilateral hind paw band and adapted to testing cylinders equipped with EM signal emission and detection. The following observations were made: (1) in mice, unilateral SQ injection of 48/80 into the dorsolateral aspect of the neck evoked periodic high frequency bursts of scratching at the injected site with the ipsilateral (banded) but not the contralateral (not banded) hind paw. (2) Cross correlation between PMD and human observer counts after SQ 48/80 using the specified computational algorithm revealed a highly significant correlation. (3) SQ histamine and 48/80 over a 1hour interval produced dose dependent scratching, which diphenhydramine dose dependently reversed. Chloroquine scratching displayed an inverse u-shaped dose response curve, which was insensitive to diphenhydramine. (4) SQ 48/80 at intervals over 28 days showed no change in the scratching response within the same cohort of mice. (5) Power analysis showed 40% changes in scratching activity could be detected at the p<0.05 level with groups of 4 mice. These observations indicate that the system described can efficiently define the actions and pharmacology of pruritogenic agents.

Spinal botulinum neurotoxin B: effects on afferent transmitter release and nociceptive processing.

Botulinum neurotoxin B (BoNT-B) mediates proteolytic cleavage of VAMP I/II (synaptobrevins I/II), which prevents vesicle-membrane fusion and blocks neurotransmitter release. In the present study, we investigated the effects of BoNT-B on neurotransmitter release in vivo from spinal primary afferent sensory fibers and the effects of this blockade on nociception. With intrathecally (IT) delivered BoNT-B in C57B/l6 mice, we characterized the effects of such block on the release of substance P (SP) from spinal afferent nociceptors (as measured by neurokinin-1 receptor, NK1-R, internalization), spinal neuronal activation (as indicated by spinal C-Fos expression) and nociceptive behavior after intraplantar (IPLT) formalin. In addition, we investigated the effect of IT BoNT-B on spinal nerve ligation-induced tactile allodynia. A single percutaneous IT injection of BoNT-B 0.5 U at 2 or 5 days prior to IPLT formalin reduced NK1-R internalization and C-Fos expression. These effects correlated with BoNT-B cleavage of VAMPI/II protein in tissue lysate. IT BoNT-B also produced a corresponding reduction in phase 2 of formalin-evoked flinching behavior for over 30 days after IT injection. In mice with spinal nerve ligation (SNL), tactile allodynia was observed, which was attenuated by IT BoNT-B 0.5 U over the next 15 days, as compared to vehicle animals. These effects were observed without effects upon motor function. The specificity of the IT BoNT-B effect is indicated by: i) IT co-injection of BoNT-B and anti-BoNTB antibody prevented effects on SP release, and ii) IT BoNT-B 50 U in the Sprague Dawley rats showed no effect on formalin-evoked flinching or SNL-induced tactile allodynia, which is consistent with rat resistance to BoNT-B. IT BoNT-B blocks transmitter release from spinal primary afferents, and attenuates inflammatory nociceptive response and spinal nerve injury-induced neuropathic pain, in the absence of motor impairment. These observations provide an initial assessment of the ability of IT BoNT-B to regulate spinal nociceptive processing.