-
Neural Development Sep 2018Proper patterning of dendritic and axonal arbors is a critical step in the formation of functional neuronal circuits. Developing circuits rely on an array of molecular...
BACKGROUND
Proper patterning of dendritic and axonal arbors is a critical step in the formation of functional neuronal circuits. Developing circuits rely on an array of molecular cues to shape arbor morphology, but the underlying mechanisms guiding the structural formation and interconnectivity of pre- and postsynaptic arbors in real time remain unclear. Here we explore how Down syndrome cell adhesion molecule (DSCAM) differentially shapes the dendritic morphology of central neurons and their presynaptic retinal ganglion cell (RGC) axons in the developing vertebrate visual system.
METHODS
The cell-autonomous role of DSCAM, in tectal neurons and in RGCs, was examined using targeted single-cell knockdown and overexpression approaches in developing Xenopus laevis tadpoles. Axonal arbors of RGCs and dendritic arbors of tectal neurons were visualized using real-time in vivo confocal microscopy imaging over the course of 3 days.
RESULTS
In the Xenopus visual system, DSCAM immunoreactivity is present in RGCs, cells in the optic tectum and the tectal neuropil at the time retinotectal synaptic connections are made. Downregulating DSCAM in tectal neurons significantly increased dendritic growth and branching rates while inducing dendrites to take on tortuous paths. Overexpression of DSCAM, in contrast, reduced dendritic branching and growth rate. Functional deficits mediated by tectal DSCAM knockdown were examined using visually guided behavioral assays in swimming tadpoles, revealing irregular behavioral responses to visual stimulus. Functional deficits in visual behavior also corresponded with changes in VGLUT/VGAT expression, markers of excitatory and inhibitory transmission, in the tectum. Conversely, single-cell DSCAM knockdown in the retina revealed that RGC axon arborization at the target is influenced by DSCAM, where axons grew at a slower rate and remained relatively simple. In the retina, dendritic arbors of RGCs were not affected by the reduction of DSCAM expression.
CONCLUSIONS
Together, our observations implicate DSCAM in the control of both pre- and postsynaptic structural and functional connectivity in the developing retinotectal circuit, where it primarily acts as a neuronal brake to limit and guide postsynaptic dendrite growth of tectal neurons while it also facilitates arborization of presynaptic RGC axons cell autonomously.
Topics: Animals; Avoidance Learning; Axons; Cell Adhesion Molecules; Dendrites; Down-Regulation; Gene Expression Regulation, Developmental; Image Processing, Computer-Assisted; Microscopy, Confocal; Morpholinos; Neurons; Photic Stimulation; Retina; Superior Colliculi; Synapses; Transfection; Vesicular Glutamate Transport Proteins; Vesicular Inhibitory Amino Acid Transport Proteins; Visual Pathways; Xenopus Proteins; Xenopus laevis
PubMed: 30219101
DOI: 10.1186/s13064-018-0118-5 -
Pediatric Critical Care Medicine : a... May 2019Many hospitals aim to extubate children early after cardiac surgery, yet it remains unclear how this practice associates with extubation failure. We evaluated adjusted...
OBJECTIVES
Many hospitals aim to extubate children early after cardiac surgery, yet it remains unclear how this practice associates with extubation failure. We evaluated adjusted extubation failure rates and duration of postoperative mechanical ventilation across hospitals and assessed cardiac ICU organizational factors associated with extubation failure.
DESIGN
Secondary analysis of the Pediatric Cardiac Critical Care Consortium clinical registry.
SETTING
Pediatric Cardiac Critical Care Consortium cardiac ICUs.
PATIENTS
Patients with qualifying index surgical procedures from August 2014 to June 2017.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
We modeled hospital-level adjusted extubation failure rates using multivariable logistic regression. A previously validated Pediatric Cardiac Critical Care Consortium model was used to calculate adjusted postoperative mechanical ventilation. Observed-to-expected ratios for both metrics were derived for each hospital to assess performance. Hierarchical logistic regression was used to assess the association between cardiac ICU factors and extubation failure. Overall, 16,052 surgical hospitalizations were analyzed. Predictors of extubation failure (p < 0.05 in final case-mix adjustment model) included younger age, underweight, greater surgical complexity, airway anomaly, chromosomal anomaly/syndrome, longer cardiopulmonary bypass time, and other preoperative comorbidities. Three hospitals were better-than-expected outliers for extubation failure (95% CI around observed-to-expected < 1), and three hospitals were worse-than-expected (95% CI around observed-to-expected > 1). Two hospitals were better-than-expected outliers for both extubation failure and postoperative mechanical ventilation, and three were worse-than-expected for both. No hospital was an outlier in opposite directions. Greater nursing hours per patient day and percent nursing staff with critical care certification were associated with lower odds of extubation failure. Cardiac ICU factors such as fewer inexperienced nurses, greater percent critical care trained attendings, cardiac ICU-dedicated respiratory therapists, and fewer patients per cardiac ICU attending were not associated with lower odds of extubation failure.
CONCLUSIONS
We saw no evidence that hospitals trade higher extubation failure rates for shorter duration of postoperative mechanical ventilation after pediatric cardiac surgery. Increasing specialized cardiac ICU nursing hours per patient day may achieve better extubation outcomes and mitigate the impact of inexperienced nurses.
Topics: Airway Extubation; Cardiac Surgical Procedures; Child; Female; Hospitals; Humans; Infant; Infant, Newborn; Male; Nursing Staff, Hospital; Outcome Assessment, Health Care; Postoperative Period; Registries; Respiration, Artificial; Time Factors
PubMed: 30807544
DOI: 10.1097/PCC.0000000000001877 -
Human Reproduction (Oxford, England) Jan 2010Inhibin B (Inh B) is produced by pre-antral and early antral follicles whereas estradiol (E(2)) is a product of follicles undergoing antrum formation. This temporal...
BACKGROUND
Inhibin B (Inh B) is produced by pre-antral and early antral follicles whereas estradiol (E(2)) is a product of follicles undergoing antrum formation. This temporal distinction is evident in the patterns of Inh B and E(2) release earlier and later during the follicular phase of the menstrual cycle, respectively. However, in previous studies of women with polycystic ovary syndrome (PCOS) and normal controls, release of these granulosa cell (GC) products appears to be simultaneous in response to FSH stimulation. In order to reconcile these disparate findings, we conducted dose-response studies in both PCOS women and normal controls to determine whether GC product responses were due to the amount of FSH administered. In addition, we compared FSH-stimulated responses in PCOS women at various stages of recovery following ovarian suppression with a long-acting GnRH agonist to examine whether Inh B and E(2) responses reflected the level of ovarian follicle activity (i.e. circulating E(2) levels).
METHODS
Women with PCOS, 18-35 years (n = 23), and normal ovulatory controls, 18-35 years (n = 10) were recruited for study. Dose-responses were assessed over 24 h following intravenous administration of 0 (saline), 37.5, 75 and 150 IU of recombinant human FSH (r-hFSH) in PCOS and normal women. In addition, E(2) and Inh B responses to 150 IU of r-hFSH were assessed at baseline and 4, 6 and 8 weeks following suppression of ovarian steroidogenesis by a long-acting GnRH agonist in PCOS women.
RESULTS
In PCOS women and normal controls, serum Inh B and E(2) exhibit similar and simultaneous dose-responsiveness to FSH stimulation. During recovery from ovarian suppression, basal and stimulated Inh B release appear to be restored earlier than that of E(2) in PCOS women.
CONCLUSIONS
These findings are consistent with the notion that, in PCOS women, the level of ovarian follicle activity largely determines the earlier release of Inh B compared with E(2).
Topics: Adolescent; Adult; Estradiol; Female; Follicle Stimulating Hormone; Hormones; Humans; Inhibins; Injections, Intravenous; Polycystic Ovary Syndrome
PubMed: 19850592
DOI: 10.1093/humrep/dep373 -
BioRxiv : the Preprint Server For... Jul 2023The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the...
UNLABELLED
The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in , , and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of via captopril or RNAi promoted dauer larvae formation, suggesting is a gene. Captopril-mediated lifespan extension xwas abrogated by and mutations. Our results indicate that captopril and control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.
SUMMARY STATEMENT
Captopril and control aging. By demonstrating they regulate dauer formation and interact with genes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.
PubMed: 37502959
DOI: 10.1101/2023.07.17.549402 -
Molecular Syndromology Jun 2020Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are rare diseases caused by biallelic variants within the insulin receptor gene (). Here, we report 2 cases:...
Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are rare diseases caused by biallelic variants within the insulin receptor gene (). Here, we report 2 cases: one with DS and the other with RMS. The case with DS presented with intrauterine growth retardation, nipple hypertrophy, clitoromegaly, distended abdomen, hypertrichosis, and dysmorphic features. The second case showed severe acanthosis nigricans, hyperkeratosis, and hypertrichosis. In both cases, abnormal glucose homeostasis due to severe insulin resistance was observed. The diagnosis of DS and RMS was established based on clinical characteristics, abnormal glucose homeostasis, high serum insulin levels, and determination of pathogenic variants in the gene. The first case with DS has 2 novel homozygous variants, NM_000208.3, c.3122delA (p.N1041Mfs*16) and c.3419C>G (p.A1140G), and the second case with RMS has a previously reported homozygous variant NM_000208.3, c.3529+5G>A (IVS19+5G>A) in the gene.
PubMed: 32655340
DOI: 10.1159/000506722 -
Clinical Infectious Diseases : An... Oct 2022Households have emerged as important venues for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Little is known, however, regarding the...
BACKGROUND
Households have emerged as important venues for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Little is known, however, regarding the magnitude and determinants of household transmission in increasingly vaccinated populations.
METHODS
From September 2020 to January 2022, symptomatic nonhospitalized individuals with SARS-CoV-2 infection by RNA detection were identified within 5 days of symptom onset; all individuals resided with at least 1 other SARS-CoV-2-uninfected household member. These infected persons (cases) and their household members (contacts) were subsequently followed with questionnaire-based measurement and serial nasal specimen collection. The primary outcome was SARS-CoV-2 infection among contacts.
RESULTS
We evaluated 42 cases and their 74 household contacts. Among the contacts, 32 (43%) became infected, of whom 5 (16%) were asymptomatic; 81% of transmissions occurred by 5 days after the case's symptom onset. From 21 unvaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection among contacts was 18/40 (45% [95% confidence interval {CI}, 29%-62%]), most of whom were unvaccinated. From 21 vaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection was 14/34 (41% [95% CI, 25%-59%]) among all contacts and 12/29 (41% [95% CI, 24%-61%]) among vaccinated contacts. At least 1 comorbid condition among cases and 10 or more days of RNA detection in cases were associated with increased risk of infection among contacts.
CONCLUSIONS
Among households including individuals with symptomatic SARS-CoV-2 infection, both vaccinated-to-vaccinated and unvaccinated-to-unvaccinated transmission of SARS-CoV-2 to household contacts was common. Because vaccination alone did not notably reduce risk of infection, household contacts will need to employ additional interventions to avoid infection.
Topics: COVID-19; Cohort Studies; Humans; Longitudinal Studies; RNA; SARS-CoV-2
PubMed: 35788827
DOI: 10.1093/cid/ciac545 -
Medicine Dec 2022Severe insulin receptor gene (INSR)-related insulin resistance syndromes (SIR) include Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS), and type A insulin...
RATIONALE
Severe insulin receptor gene (INSR)-related insulin resistance syndromes (SIR) include Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS), and type A insulin resistance. The incidence of DS is about 1 in 4 million births. We identified novel INSR mutations (c.2246delG and c.2646 + 5G > A) in a patient with SIR, which expanded the variant spectrum and helped to improve the understanding of the diagnosis and treatment of this condition.
PATIENT CONCERNS
A 10-year-old Chinese boy was admitted to the hospital for deepening skin color. He presented with growth retardation, peculiar facial features, acanthosis nigricans, hypertrichosis, extremely high insulin levels, fasting hypoglycemia, and postprandial hyperglycemia, Whole-exome gene testing suggested compound heterozygous mutations in INSR (c.2246delG and c.2646 + 5G > A).
DIAGNOSIS
The diagnosis was SIR. What's more, based on the phenotypic and biographical results, this child did not present typical RMS and DS but rather an intermediate phenotype between the 2 conditions.
INTERVENTIONS
On the basis of a sensible diet and exercise, the patient was prescribed metformin (250 mg) at breakfast and lunch, which was increased to 500 mg after 1 month.
OUTCOMES
After 2 months of treatment, the patient's glycated hemoglobin (HbA1c) levels decreased to 6% but his insulin resistance did not improve significantly.
LESSONS
In children who are not obese but with severe insulin resistance, growth retardation, hirsutism, and hyperglycemia, genetic testing should be performed for early diagnosis, active treatment, and follow-up.
Topics: Humans; Male; Antigens, CD; Donohue Syndrome; East Asian People; Growth Disorders; Insulin Resistance; Metabolic Syndrome; Mutation; Receptor, Insulin; Child
PubMed: 36626508
DOI: 10.1097/MD.0000000000032266 -
The Journal of Infectious Diseases Jun 2023From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and...
From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and specimen collection for 14 days, 61% (43/70) of primary cases had culturable virus detected ≥6 days post-onset. Risk of secondary infection among household contacts tended to be greater when primary cases had culturable virus detected after onset. Regardless of duration of culturable virus, most secondary infections (70%, 28/40) had serial intervals <6 days, suggesting early transmission. These data examine viral culture as a proxy for infectiousness, reaffirm the need for rapid control measures after infection, and highlight the potential for prolonged infectiousness (≥6 days) in many individuals.
Topics: Humans; SARS-CoV-2; COVID-19; Tennessee; Family Characteristics; California
PubMed: 36705269
DOI: 10.1093/infdis/jiad018 -
Frontiers in Neuroscience 2022Peripheral veno-arterial extracorporeal membrane oxygenation (ECMO) artificially oxygenates and circulates blood retrograde from the femoral artery, potentially exposing...
Peripheral veno-arterial extracorporeal membrane oxygenation (ECMO) artificially oxygenates and circulates blood retrograde from the femoral artery, potentially exposing the brain to asymmetric perfusion. Though ECMO patients frequently experience brain injury, neurologic exams and imaging are difficult to obtain. Diffuse correlation spectroscopy (DCS) non-invasively measures relative cerebral blood flow (rBF) at the bedside using an optical probe on each side of the forehead. In this study we observed interhemispheric rBF differences in response to mean arterial pressure (MAP) changes in adult ECMO recipients. We recruited 13 subjects aged 21-78 years (7 with cardiac arrest, 4 with acute heart failure, and 2 with acute respiratory distress syndrome). They were dichotomized Glasgow Coma Scale Motor score (GCS-M) into comatose (GCS-M ≤ 4; = 4) and non-comatose (GCS-M > 4; = 9) groups. Comatose patients had greater interhemispheric rBF asymmetry (ASYM) vs. non-comatose patients over a range of MAP values (29 vs. 11%, = 0.009). ASYM in comatose patients resolved near a MAP range of 70-80 mmHg, while rBF remained symmetric through a wider MAP range in non-comatose patients. Correlations between post-oxygenator pCO or pH vs. ASYM were significantly different between comatose and non-comatose groups. Our findings indicate that comatose patients are more likely to have asymmetric cerebral perfusion.
PubMed: 35478849
DOI: 10.3389/fnins.2022.858404 -
Arthritis and Rheumatism Oct 2002To determine the prevalence of anti-high-density lipoprotein (anti-HDL) antibodies and to establish a possible relationship between anti-HDL, anticardiolipin antibodies...
Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome.
OBJECTIVE
To determine the prevalence of anti-high-density lipoprotein (anti-HDL) antibodies and to establish a possible relationship between anti-HDL, anticardiolipin antibodies (aCL), anti-beta(2)-glycoprotein I (anti-beta(2)GPI), and paraoxonase (PON) activity in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS).
METHODS
Thirty-two patients with SLE and 36 with primary APS were enrolled in a cross-sectional study. Twenty age- and sex-matched healthy subjects were used as controls. Serum levels of IgG and IgM aCL, anti-beta(2)GPI, and antiprothrombin antibodies and IgG anti-HDL were measured by enzyme-linked immunosorbent assay. Total cholesterol, HDL cholesterol, HDL(2), and HDL(3) were determined by standard enzymatic techniques. PON activity was assessed by quantification of nitrophenol formation, and total antioxidant capacity (TAC) by chemiluminescence.
RESULTS
Levels of total HDL, HDL(2), and HDL(3) were reduced in patients with SLE compared with controls (mean +/- SD 0.51 +/- 0.3, 0.37 +/- 0.3, and 0.14 +/- 0.1 mmoles/liter, respectively, versus 1.42 +/- 0.9, 1.01 +/- 0.7, and 0.40 +/- 0.2). Patients with SLE and primary APS had higher titers of anti-HDL antibodies and lower PON activity than controls. In the SLE population, PON activity was inversely correlated with IgG anti-HDL titers (r = -0.48, P = 0.005) whereas in the primary APS population, IgG anti-beta(2)GPI was the only independent predictor of PON activity (r = -0.483, P = 0.003). In the SLE group, anti-HDL was inversely correlated with TAC (r = -0.40, P < 0.02), and PON activity was positively correlated with TAC (r = 0.43, P < 0.02).
CONCLUSION
IgG anti-HDL and IgG anti-beta(2)GPI antibodies are associated with reduced PON activity in patients with SLE and primary APS. Since the physiologic role of PON is to prevent low-density lipoprotein oxidation with its attendant atherogenic effects, the reported interactions may be relevant to the development of atherosclerosis in SLE and primary APS.
Topics: Adult; Antibodies, Anticardiolipin; Antioxidants; Antiphospholipid Syndrome; Arteriosclerosis; Aryldialkylphosphatase; Biomarkers; Cholesterol; Esterases; Female; Glycoproteins; Humans; Lipoproteins, HDL; Lupus Erythematosus, Systemic; Male; Middle Aged; Prothrombin; Regression Analysis; beta 2-Glycoprotein I
PubMed: 12384928
DOI: 10.1002/art.10542