Reducing acetylated tau is neuroprotective in brain injury.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

A Multiplex Enzymatic Machinery for Cellular Protein S-nitrosylation.

S-nitrosylation, the oxidative modification of Cys residues by nitric oxide (NO) to form S-nitrosothiols (SNOs), modifies all main classes of proteins and provides a fundamental redox-based cellular signaling mechanism. However, in contrast to other post-translational protein modifications, S-nitrosylation is generally considered to be non-enzymatic, involving multiple chemical routes. We report here that endogenous protein S-nitrosylation in the model organism E. coli depends principally upon the enzymatic activity of the hybrid cluster protein Hcp, employing NO produced by nitrate reductase. Anaerobiosis on nitrate induces both Hcp and nitrate reductase, thereby resulting in the S-nitrosylation-dependent assembly of a large interactome including enzymes that generate NO (NO synthase), synthesize SNO-proteins (SNO synthase), and propagate SNO-based signaling (trans-nitrosylases) to regulate cell motility and metabolism. Thus, protein S-nitrosylation by NO in E. coli is essentially enzymatic, and the potential generality of the multiplex enzymatic mechanism that we describe may support a re-conceptualization of NO-based cellular signaling.

Increased mortality in infants with abnormal T-cell receptor excision circles.

BACKGROUND: T-Cell Receptor Excision Circles based newborn screening (TREC-NBS) allows for early detection of T-cell lymphopenia in infants with primary immunodeficiency disorders (PIDD). The utility of abnormal TREC-NBS in infants without PIDD is not well studied. We sought to evaluate the association of abnormal TREC-NBS with mortality. METHODS: 365,207 TREC-NBS from October 2011 to December 2014 were reviewed. 467 newborns had abnormal screens and did not meet the criteria for a PIDD diagnosis. Cases were matched to controls (1:3) based on gestational age, birth weight, neonatal intensive care unit status (NICU), and race. Data were obtained through NBS, birth and death certificates records from the Michigan Department of Health and Human Services (MDHHS) databases. RESULTS: Infants with abnormal TREC-NBS had higher mortality even when PIDD was ruled-out. Transient abnormal TREC-NBS was not associated with higher mortality, but unresolved or late abnormal TREC-NBS was associated with higher mortality. Infants with late abnormal TREC-NBS had severe prematurity, lower birth weight, lower Apgar scores, and higher percentage of congenital anomalies. CONCLUSION: Infants with abnormal TREC-NBS may be at a higher risk of morbidity and mortality and should be carefully followed, especially if discharged home before a repeat screen can be completed. IMPACT: This study explores the risk factors and mortality for newborns with secondary T-cell lymphopenia captured on T-Cell Receptor Excision Circles based newborn screening (TREC-NBS). Abnormal TREC-NBS allows for prompt life-saving interventions for primary immunological conditions such as Severe Combined Immunodeficiency (SCID), but can also be associated with non-immunologic conditions. Unresolved and late abnormal TREC-NBS is associated with higher mortality even without primary immunodeficiency, likely detected in infants with more severe prematurity, lower birth weight, and congenital anomalies. TREC-NBS positive infants with secondary T-cell lymphopenia require special attention and close monitoring.

Use of activity trackers to improve blood pressure in young people at risk for cardiovascular disease: a pilot randomized controlled trial.

BACKGROUND: Promoting physical activity among young individuals with cardiovascular disease (CVD) risk factors such as hypertension, diabetes, or chronic kidney disease can lower systolic blood pressure (BP). We sought to determine whether a 6-month intervention using a physical activity tracker was feasible and effective, compared with usual care. METHODS: Participants were recruited at a single academic medical center. Those aged 8-30 years were randomized in a 2:1 ratio to either the intervention (use of a Fitbit physical activity tracker coupled with feedback regarding the participant's step count) or usual care. The primary feasibility outcomes were screening-to-enrollment ratio and 6-month retention rates; the primary clinical outcome was a change in systolic BP from 0-6 months. RESULTS: Sixty-three participants were enrolled (57% male; mean age: 18 ± 4 years). The screening-to-enrollment ratio was 1.8:1. Six-month retention was 62% in the intervention group and 86% in the control group (p = 0.08). Mean change in systolic BP in the intervention group was not significantly different from the control group at 6 months (- 2.3 mmHg; 95% CI - 6.5, 1.8 vs. 3.0 mmHg; 95% CI - 2.5, 8.4, respectively, p = 0.12). CONCLUSIONS: Among children and young adults at elevated CVD risk, the use of a physical activity tracker coupled with tailored feedback regarding their step count progress was feasible but not sustained over time. Physical activity tracker use did not have a statistically significant effect on BP after 6 months. Augmented strategies to mitigate risk in young patients at high risk for early-onset CVD should be explored. This trial is registered at ClinicalTrials.gov (NCT03325426).

Adaptation and Validation of Overall Assessment of the Speaker's Experience of Stuttering for Adults in Kannada (OASES-A-K).

INTRODUCTION: Psychosocial aspects of stuttering may affect the quality of life of a person who stutters (PWS). Further, the social stigma and experiences of PWS may vary globally. The WHO-ICF guidelines recommend quality of life as an essential component in the assessment of individuals who stutter. However, the availability of linguistically and culturally appropriate tools is often a challenge. Thus, the current study adapted and validated the OASES-A for Kannada-speaking adults who stutter. METHOD: The original English version of OASES-A was adapted to Kannada using a standard reverse translation process. The adapted version was administered on 51 Kannada-speaking adults with very mild to very severe stuttering. The data were analyzed for item characteristics, reliability, and validity assessment. RESULTS: The results revealed floor and ceiling effects for six and two items, respectively. The mean overall impact score indicated a moderate impact of stuttering. Further, the impact score for section II was relatively higher when compared to the data from other countries. The reliability and validity analyses showed good internal consistency and test-retest reliability for OASES-A-K. CONCLUSION: The findings of the current research suggest that OASES-A-K is a sensitive and reliable tool to assess the impact of stuttering in Kannada-speaking PWS. The findings also highlight cross-cultural differences and the need for research in this direction.

Discordances between pediatric and adult thresholds in the diagnosis of hypertension in adolescents with CKD.

BACKGROUND: Adolescents with chronic kidney disease (CKD) are a unique population with a high prevalence of hypertension. Management of hypertension during the transition from adolescence to adulthood can be challenging given differences in normative blood pressure values in adolescents compared with adults. METHODS: In this retrospective analysis of the Chronic Kidney Disease in Children Cohort Study, we compared pediatric versus adult definitions of ambulatory- and clinic-diagnosed hypertension in their ability to discriminate risk for left ventricular hypertrophy (LVH) and kidney failure using logistic and Cox models, respectively. RESULTS: Overall, among 363 adolescents included for study, the prevalence of systolic hypertension was 27%, 44%, 12%, and 9% based on pediatric ambulatory, adult ambulatory, pediatric clinic, and adult clinic definitions, respectively. All definitions of hypertension were statistically significantly associated with LVH except for the adult ambulatory definition. Presence of ambulatory hypertension was associated with 2.6 times higher odds of LVH using pediatric definitions (95% CI 1.4-5.1) compared to 1.4 times higher odds using adult definitions (95% CI 0.8-3.0). The c-statistics for discrimination of LVH was statistically significantly higher for the pediatric definition of ambulatory hypertension (c=0.61) compared to the adult ambulatory definition (c=0.54), and the Akaike Information Criterion was lower for the pediatric definition. All definitions were associated with progression to kidney failure. CONCLUSION: Overall, there was not a substantial difference in pediatric versus adult definitions of hypertension in predicting kidney outcomes, but there was slightly better risk discrimination of the risk of LVH with the pediatric definition of ambulatory hypertension.

Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase.

BACKGROUND: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). METHODS: Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR-/-) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. RESULTS: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P=0.045). CONCLUSIONS: CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

Real-world use of chemotherapy for Kaposi's sarcoma in a large community-based HIV primary care system in Kenya.

BACKGROUND: Kaposi's sarcoma (KS) is one of the most common HIV-associated malignancies in sub-Saharan Africa. Worldwide, the availability of antiretroviral therapy (ART) has improved KS survival. In resource-rich settings, survival has also benefited from chemotherapy, which is widely available. Little is known, however, about the epidemiology of chemotherapy use for HIV-associated KS in resource-limited regions such as sub-Saharan Africa. METHODS: We identified all patients newly diagnosed with HIV-related KS from 2009 to 2012 in the 26-clinic AMPATH network, a large community-based care network in Kenya. We ascertained disease severity at diagnosis, frequency of initiation of chemotherapy, and distribution of chemotherapeutic regimens used. Indications for chemotherapy included AIDS Clinical Trial Group T1 stage and/or "severe" disease defined by WHO KS treatment guidelines. RESULTS: Of 674 patients diagnosed with KS, charts were available for 588; 61% were men, median age was 35 years, and median CD4 at KS diagnosis was 185 cells/µl. At time of diagnosis, 58% had at least one chemotherapy indication, and 22% had more than one indication. For patients with a chemotherapy indication, cumulative incidence of chemotherapy initiation (with death as a competing event) was 37% by 1 month and 56% by 1 year. Median time from diagnosis to chemotherapy initiation was 25 days (IQR 1-50 days). In multivariable regression, patients with > 3 chemotherapy indications at time of diagnosis had a 2.30 (95% CI 1.46-3.60) increased risk of rapid chemotherapy initiation (within 30 days of diagnosis) compared to those with only one chemotherapy indication (p < 0.001). Initial regimens were bleomycin-vincristine (78%), adriamycin-bleomycin-vincristine (11%), etoposide (7%), and gemcitabine (4%). CONCLUSIONS: A substantial fraction of patients with KS in East Africa are diagnosed at advanced disease stage. For patients with chemotherapy indications, nearly half did not receive chemotherapy by one year. Liposomal anthracyclines, often used in resource-rich settings, were not first line. These findings emphasize challenges in East Africa cancer care, and highlight the need for further advocacy for improved access to higher quality chemotherapy in this setting.

Summer Buzz: All You Need to Know about Insect Sting Allergies.

Insect stings can generate a range of immune and clinical reactions. Most reactions are local and self-limiting. Allergic reactions to insect stings can occur at all ages, with or without previous stings. Individuals with a history of anaphylaxis carry a significant risk of life-threatening anaphylaxis with future stings. Health-care providers are often unaware of the tremendous clinical benefits of venom immunotherapy for these select patients. Scientific knowledge about the natural history, risk factors, and optimal therapy for insect sting allergies has improved considerably in recent years.

Over-the-counter light therapy for acne: a cross-sectional retrospective analysis.

Acne vulgaris affects a large portion of the population and drives many patients to seek over-the-counter (OTC) treatments. Light-emitting diode (LED) therapy has recently emerged as a potential therapeutic option for inflammatory acne. We used the U.S. Food and Drug Administration (FDA) 510(k) premarket submission database to assess the growth in OTC LED therapy devices for treatment of acne. We also used Google Trends data in searches for "acne light therapy mask" to characterize growth in consumer interest in these devices. Overall, 35 LED devices received pre-market approval from 2000 to 2018, with a peak in approvals in 2016. Similarly, there was a dramatic increase in public interest in these devices in 2016. Only two devices were associated with company-approved trials. The current regulatory process requires little evidence to substantiate specified uses and a better understanding of practice guidelines and the efficacy of this treatment modality is required.

Association of Socioeconomic and Geographic Factors With Google Trends for Tanning and Sunscreen.

BACKGROUND: Internet search trends are used to track both infectious diseases and noncommunicable conditions. OBJECTIVE: The authors sought to characterize Google Trends search volume index (SVI) for the terms "sunscreen" and tanning ("tanning salon" and "tanning bed") in the United States from 2010 to 2015 and analyze association with educational attainment, average income, and percent white data by state. METHODS: SVI is search frequency data relative to total search volume. Analysis of variance, univariate, and multivariate analyses were performed to assess seasonal variations in SVI and the association of state-level SVI with state latitudes and census data. RESULTS: Hawaii had the highest SVI for sunscreen searches, whereas Alaska had the lowest. West Virginia had the highest SVI for tanning searches, whereas Hawaii had the lowest. There were significant differences between seasonal SVI for sunscreen and tanning searches (p < .001). Sunscreen SVI by state was correlated with an increase in educational attainment and average income, and a decrease in latitude (p < .05) in a multivariate model. Tanning SVI was correlated with a decrease in educational attainment and average income, and an increase in latitude (p < .05). CONCLUSION: Internet search trends for sunscreen and tanning are influenced by socioeconomic factors, and could be a tool for skin-related public health.

Transmembrane Substrate Determinants for γ-Secretase Processing of APP CTFß.

The amyloid ß-peptide (Aß) of Alzheimer's disease (AD) is generated by proteolysis within the transmembrane domain (TMD) of a C-terminal fragment of the amyloid ß protein-precursor (APP CTFß) by the γ-secretase complex. This processing produces Aß ranging from 38 to 49 residues in length. Evidence suggests that this spectrum of Aß peptides is the result of successive γ-secretase cleavages, with endoproteolysis first occurring at the ε sites to generate Aß48 or Aß49, followed by C-terminal trimming mostly every three residues along two product lines to generate shorter, secreted forms of Aß: the primary Aß49-46-43-40 line and a minor Aß48-45-42-38 line. The major secreted Aß species are Aß40 and Aß42, and an increased proportion of the longer, aggregation-prone Aß42 compared to Aß40 is widely thought to be important in AD pathogenesis. We examined TMD substrate determinants of the specificity and efficiency of ε site endoproteolysis and carboxypeptidase trimming of CTFß by γ-secretase. We determined that the C-terminal negative charge of the intermediate Aß49 does not play a role in its trimming by γ-secretase. Peptidomimetic probes suggest that γ-secretase has S1', S2', and S3' pockets, through which trimming by tripeptides may be determined. However, deletion of residues around the ε sites demonstrates that a depth of three residues within the TMD is not a determinant of the location of endoproteolytic ε cleavage of CTFß. We also show that instability of the CTFß TMD helix near the ε site significantly increases endoproteolysis, and that helical instability near the carboxypeptidase cleavage sites facilitates C-terminal trimming by γ-secretase. In addition, we found that CTFß dimers are not endoproteolyzed by γ-secretase. These results support a model in which initial interaction of the array of residues along the undimerized single helical TMD of substrates dictates the site of initial ε cleavage and that helix unwinding is essential for both endoproteolysis and carboxypeptidase trimming.

All That Wheezes Is Not Asthma.

Wheezing is a high pitched, whistling sound generated when air flows through narrowed airways and is often equated with asthma. However, wheezing may be a presenting symptom of various other conditions including structural lesions of the airways, foreign body aspiration, pulmonary infections as well as cardiac causes. Underlying etiology of wheezing may also vary with age. Detailed history, physical examination, and laboratory investigations are often required to identify the underlying etiology of wheezing. Additional studies may sometimes be needed to accurately identify the underlying etiology such as pulmonary function test or spirometry, chest radiography (chest X-ray), and bronchoscopy. This review article discusses the common causes of wheezing encountered in clinical practice. [Pediatr Ann. 2024;53(5):e189-e194.].

Audiological and Speech and Language Characteristics of a Case with Hunter's Syndrome.

Hearing loss is a common manifestation of Hunter's syndrome, with reported rates ranging from 67.3 to 94%. The aim is to highlight the audiological profile and pathophysiology of mixed hearing loss in individuals with hunter's syndrome. A 7.6-year-old male child was brought to the department of audiology with a complaint of not responding to name call and regression in the speech and language skills. Detailed audiological showed severe to profound mixed hearing loss. REELS and 3DLAT results showed RLA to be 9 to 10 months and ELA to be 6 to 7 months. Owing to the progressive nature and high prevalence of hearing loss in hunter's syndrome, this case report highlights the importance of middle ear evaluation in the pediatric hearing assessment apart from OAE and ABR. Speech- language therapy must be considered with a focus on functional communication.

Positive Newborn Screening for Severe Combined Immunodeficiency: What Should the Pediatrician Do?

Severe combined immunodeficiency (SCID) is a group of diseases characterized by low T-cell count and impaired T-cell function, resulting in severe cellular and humoral immune defects. If not diagnosed and treated promptly, infants affected by this condition can develop severe infections which will result in death. Delayed treatment can markedly reduce the survival outcome of infants with SCID. T-cell receptor excision circle (TREC) levels are measured on newborn screening to promptly identify infants with SCID. It is important for primary care providers and pediatricians to understand the approach to managing infants with positive TREC-based newborn screening as they may be the first contact for infants with SCID. Primary care providers should be familiar with providing anticipatory guidance to the family in regard to protective isolation, measures to minimize the risk of infection, and the coordination of care with the SCID coordinating center team of specialists. In this article, we use case-based scenarios to review the principles of TREC-based newborn screening, the genetics and subtypes of SCID, and management for an infant with a positive TREC-based newborn screen.