Beta-adrenergic receptors (β-ARs) critically modulate long-lasting synaptic plasticity and long-term memory storage in the mammalian brain. Synaptic plasticity is widely believed to mediate memory ...storage at the cellular level. Long-term potentiation (LTP) is one type of synaptic plasticity that has been linked to memory storage. Activation of β-ARs can enhance LTP and facilitate long-term memory storage. Interestingly, many of the molecular signaling pathways that are critical for β-adrenergic modulation of LTP mirror those required for the persistence of memory. In this article, we review the roles of signaling cascades and translation regulation in enabling β-ARs to control expression of long-lasting LTP in the rodent hippocampus. These include the cyclic-AMP/protein kinase-A (cAMP–PKA) and extracellular signal-regulated protein kinase cascades, two key pathways known to link transmitter receptors with translation regulation. Future research directions are discussed, with emphasis on defining the roles of signaling complexes (e.g. PSD-95) and glutamatergic receptors in controlling the efficacy of β-AR modulation of LTP.
Long-term potentiation (LTP) in the hippocampus is thought to contribute to memory formation. In the Ca1 region, LTP requires the NMDA (N-methyl-D-aspartate) receptor-dependent influx of Ca2+ and ...activation of serine and threonine protein kinases. Because of the high amount of protein tyrosine kinases in hippocampus and cerebellum, two regions implicated in learning and memory, we examined the possible additional requirement of tyrosine kinase activity in LTP. We first examined the specificity in brain of five inhibitors of tyrosine kinase and found that two of them, lavendustin A and genistein, showed substantially greater specificity for tyrosine kinase from hippocampus than for three serine-threonine kinases: protein kinase A, protein kinase C, and Ca2+/calmodulin kinase II. Lavendustin A and genistein selectively blocked the induction of LTP when applied in the bath or injected into the postsynaptic cell. By contrast, the inhibitors had no effect on the established LTP, on normal synaptic transmission, or on the neurotransmitter actions attributable to the actions of protein kinase A or protein kinase C. These data suggest that tyrosine kinase activity could be required postsynaptically for long-term synaptic plasticity in the hippocampus. As Ca2+ calmodulin kinase II or protein kinase C seem also to be required, the tyrosine kinases could participate postsynaptically in a kinase network together with serine and threonine kinases.
PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted ...gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.
Background
Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression.
Methods
Anthropometric measurements in children < ...18 years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression.
Results
A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (
N
= 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (− 0.13 ± 1.21 vs. − 0.23 ± 1.71,
p
= 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (
β
− 7.5 × 10
−6
, CI − 1.2 × 10
−5
, − 3 × 10
−6
,
p
= 0.001) and incident cases of NS (vs. prevalent) (
β
− 1.1, CI − 2.22, − 0.11,
p
= 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (
β
0.16, CI 0.04, 0.29,
p
= 0.01) over time.
Conclusion
Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Background
In single-center studies, both preterm birth and low birth weight (LBW) are associated with worse outcomes in childhood nephrotic syndrome. Using the Nephrotic Syndrome Study Network ...(NEPTUNE) observational cohort, we tested the hypothesis that in patients with nephrotic syndrome, hypertension, proteinuria status, and disease progression would be more prevalent and more severe in subjects with LBW and prematurity singly or in combination (LBW/prematurity).
Methods
Three hundred fifty-nine adults and children with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and available birth history were included. Estimated glomerular filtration rate (eGFR) decline and remission status were primary outcomes, and secondary outcomes were kidney histopathology, kidney gene expression, and urinary biomarkers. Logistic regression was used to identify associations with LBW/prematurity and these outcomes.
Results
We did not find an association between LBW/prematurity and remission of proteinuria. However, LBW/prematurity was associated with greater decline in eGFR. This decline in eGFR was partially explained by the association of LBW/prematurity with
APOL1
high-risk alleles, but the association remained after adjustment. There were no differences in kidney histopathology or gene expression in the LBW/prematurity group compared to normal birth weight/term birth.
Conclusion
LBW and premature babies who develop nephrotic syndrome have a more rapid decline in kidney function. We did not identify clinical or laboratory features that distinguished the groups. Additional studies in larger groups are needed to fully ascertain the effects of (LBW) and prematurity alone or in combination on kidney function in the setting of nephrotic syndrome.
A Questionnaire on Monuments Allais, Lucia; Anderson, Noel W.; Weiner, Andrew ...
October,
08/2018, Volume:
165, Issue:
165
Magazine Article
Open access
“A Questionnaire on Monuments” features 49 responses to questions formulated by Leah Dickerman, Hal Foster, David Joselit, and Carrie Lambert-Beatty: “From Charlottesville to Cape Town, there have ...been struggles over monuments and other markers involving histories of racial conflict. How do these charged situations shed light on the ethics of images in civil society today? Speaking generally or with specific examples in mind, please consider any of the following questions: What histories do these public symbols represent, what histories do they obscure, and what models of memory do they imply? How do they do this work, and how might they do it differently? What social and political forces are in play in their erection or dismantling? Should artists, writers, and art historians seek a new intersection of theory and praxis in the social struggles around such monuments and markers? How might these debates relate to the question of who is authorized to work with particular images and archives?”
This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and ...factors associated with complete proteinuria remission (CRever).
We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) <0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever.
We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m(2) (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis.
In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.
BackgroundPre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their ...impact on the rate of recovery following discharge is not known.ObjectivesTo determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.MethodsIn a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.ResultsFrom a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).ConclusionPatients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration numberISRCTN10980107.
Expanding American Anthropology, 1945&ndash;1980: A Generation Reflects takes an inside look at American anthropology&rsquo;s participation in the enormous expansion of the social sciences ...after World War II. During this time the discipline of anthropology itself came of age, expanding into diverse subfields, frequently on the initiative of individual practitioners. The Association of Senior Anthropologists of the American Anthropological Association (AAA) called upon a number of its leaders to give accounts of their particular innovations in the discipline. This volume is the result of the AAA venture&mdash;a set of primary documents on the history of American anthropology at a critical juncture. In preparing the volume, the editors endeavored to maintain the feeling of &ldquo;oral history&rdquo; within the chapters and to preserve the individual voices of the contributors. There are many books on the history of anthropology, but few that include personal essays from such a broad swath of different perspectives. The passing of time will make this volume increasingly valuable in understanding the development of American anthropology from a small discipline to the profession of over ten thousand practitioners.
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