Congenital absence of norepinephrine due to CYB561 mutations

ObjectiveCytochrome b561 (CYB561) generates ascorbic acid, a cofactor in the enzymatic conversion of dopamine to norepinephrine by dopamine β-hydroxylase. We propose that the clinical relevance of this pathway can be revealed by characterizing the autonomic and biochemical characteristics of patients with CYB561 mutations.MethodsWe performed autonomic evaluations in 4 patients with lifelong orthostatic hypotension in whom CYB561 mutations were determined by genomic sequencing.ResultsPatients had disabling lifelong orthostatic hypotension (OH) and impaired blood pressure response to the Valsalva maneuver (VM), with exaggerated hypotension during phase 2 and lack of overshoot during phase 4. Heart rate ratios for sinus arrhythmia and the VM were normal. Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal. Droxidopa restored norepinephrine levels and improved OH. Patients 1 and 2 were sisters and homozygous for a nonsense mutation in exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available. Patient 4 was compound heterozygous; one allele had a missense mutation in exon 2, c157C>T, p.His.53Tyr, and the other had an exon 2 deletion.ConclusionCYB561 deficiency is characterized by selective sympathetic noradrenergic failure with lifelong, disabling OH but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions. We report a novel case of CYB561 deficiency due to an exon 2 deletion in one allele and a missense mutation in the other. These patients highlight the critical role CYB561 plays in sympathetic function and cardiovascular regulation.

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Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects

Blood Advances ◽

10.1182/bloodadvances.2020002225 ◽

2020 ◽

Vol 4 (23) ◽

pp. 5888-5901

Author(s):

Christopher McKinney ◽

Michael Ellison ◽

Natalie J. Briones ◽

Angelina Baroffio ◽

John Murphy ◽

...

Keyword(s):

Missense Mutation ◽

Bacterial Infections ◽

Neutrophil Function ◽

Functional Improvement ◽

Human Neutrophils ◽

Compound Heterozygous ◽

Cd11b Expression ◽

Exon 2 ◽

Metabolic Defects ◽

Functional Defects

Abstract Severe congenital neutropenia type 4 (SCN-4) is an autosomal recessive condition in which mutations in the G6PC3 gene encoding for the catalytic 3 subunit of glucose-6-phosphatase-β result in neutropenia, neutrophil dysfunction, and other syndromic features. We report a child with SCN-4 caused by compound heterozygous mutations in G6PC3, a previously identified missense mutation in exon 6 (c.758G>A[p.R235H]), and a novel missense mutation in exon 2 (c.325G>A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony–stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient’s neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios >1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was <25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope–labeled tracers (U-13C-glucose, 13C,15N-glutamine, and U-13C-fructose) demonstrated dramatic impairments in early glycolysis (hexose phosphate levels), hexosemonophosphate shunt (required for the generation of the NADPH), and the total adenylate pool, which could explain the dramatic cell dysfunction displayed by the patient’s neutrophils. Preliminary experiments with fructose supplementation to bypass the enzyme block demonstrated that the metabolic profile could be reversed, but was not sustained long enough for functional improvement. In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.

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Plasma volume restoration with salt tablets and water after bed rest prevents orthostatic hypotension and changes in supine hemodynamic and endocrine variables

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00220.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. H839-H847 ◽

Cited By ~ 40

Author(s):

Wendy W. Waters ◽

Steven H. Platts ◽

Brett M. Mitchell ◽

Peggy A. Whitson ◽

Janice V. Meck

Keyword(s):

Heart Rate ◽

Orthostatic Hypotension ◽

Plasma Volume ◽

Bed Rest ◽

Plasma Norepinephrine ◽

Fluid Loading ◽

Secondary Effects ◽

Volume Depletion ◽

Fluid Load ◽

Upright Tilt

Head-down bed rest changes the values of many cardiovascular and endocrine variables and also elicits significant hypovolemia. Because previous studies had not controlled for hypovolemia, it is unknown whether the reported changes were primary effects of bed rest or secondary effects of bed rest-induced hypovolemia. We hypothesized that restoring plasma volume with salt tablets and water after 12 days of head-down bed rest would result in an absence of hemodynamic and endocrine changes and a reduced incidence of orthostatic hypotension. In 10 men, we measured changes from pre-bed-rest to post-bed-rest in venous and arterial pressures; heart rate; stroke volume; cardiac output; vascular resistance; plasma norepinephrine, epinephrine, vasopressin, renin activity (PRA), and aldosterone responses to different tilt levels (0°, −10°, 20°, 30°, and 70°); and plasma volume and platelet α2- and lymphocyte β2-adrenoreceptor densities and affinities (0° tilt only). Fluid loading at the end of bed rest restored plasma volume and resulted in the absence of post-bed-rest orthostatic hypotension and changes in supine hemodynamic and endocrine variables. Fluid loading did not prevent post-bed-rest increases in β2-adrenoreceptor density or decreases in the aldosterone-to-PRA ratio ( P = 0.05 for each). Heart rate, epinephrine, and PRA responses to upright tilt after bed rest were increased ( P < 0.05), despite the fluid load. These results suggest that incidents of orthostatic hypotension and many of the changes in supine hemodynamic and endocrine variables in volume-depleted bed-rested subjects occur secondarily to the hypovolemia. Despite normovolemia after bed rest, β2-adrenoreceptors were upregulated, and heart rate, epinephrine, and PRA responses to tilt were augmented, indicating that these changes are independent of volume depletion.

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Autonomic Heart Rate Regulation during Mild Dynamic Exercise in Humans: Insights from Respiratory Sinus Arrhythmia

The Japanese Journal of Physiology ◽

10.2170/jjphysiol.54.273 ◽

2004 ◽

Vol 54 (3) ◽

pp. 273-284 ◽

Cited By ~ 1

Author(s):

R. Sone ◽

N. Tan ◽

T. Nishiyasu ◽

F. Yamazaki

Keyword(s):

Heart Rate ◽

Respiratory Sinus Arrhythmia ◽

Dynamic Exercise ◽

Sinus Arrhythmia ◽

Rate Regulation ◽

Heart Rate Regulation ◽

Exercise In Humans

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Type 5 adenylyl cyclase plays a major role in stabilizing heart rate in response to microgravity induced by parabolic flight

Journal of Applied Physiology ◽

10.1152/japplphysiol.01166.2007 ◽

2008 ◽

Vol 105 (1) ◽

pp. 173-179 ◽

Cited By ~ 9

Author(s):

Satoshi Okumura ◽

Takashi Tsunematsu ◽

Yunzhe Bai ◽

Qibin Jiao ◽

Shinji Ono ◽

...

Keyword(s):

Heart Rate ◽

Adenylyl Cyclase ◽

Parabolic Flight ◽

Nervous Activity ◽

Heat Rate ◽

The Other ◽

Transgenic Mouse Models ◽

Genotype Group ◽

Heart Rate Regulation ◽

Β Adrenergic Receptors

It is well known that autonomic nervous activity is altered under microgravity, leading to disturbed regulation of cardiac function, such as heart rate. Autonomic regulation of the heart is mostly determined by β-adrenergic receptors/cAMP signal, which is produced by adenylyl cyclase, in cardiac myocytes. To examine a hypothesis that a major cardiac isoform, type 5 adenylyl cyclase (AC5), plays an important role in regulating heart rate during parabolic flights, we used transgenic mouse models with either disrupted (AC5KO) or overexpressed AC5 in the heart (AC5TG) and analyzed heart rate variability. Heart rate had a tendency to decrease gradually in later phases within one parabola in each genotype group, but the magnitude of decrease was smaller in AC5KO than that in the other groups. The inverse of heart rate, i.e., the R-R interval, was much more variable in AC5KO and less variable in AC5TG than that in wild-type controls. The standard deviation of normal R-R intervals, a marker of total autonomic variability, was significantly greater in microgravity phase in each genotype group, but the magnitude of increase was much greater in AC5KO than that in the other groups, suggesting that heart rate regulation became unstable in the absence of AC5. In all, AC5 plays a major role in stabilizing heat rate under microgravity.

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Measures of RSA Suppression, Attentional Control, and Negative Affect Predict Self-Ratings of Executive Functions

Journal of Psychophysiology ◽

10.1027/0269-8803/a000053 ◽

2011 ◽

Vol 25 (4) ◽

pp. 164-173 ◽

Cited By ~ 7

Author(s):

Brian Healy ◽

Aaron Treadwell ◽

Mandy Reagan

Keyword(s):

College Students ◽

Heart Rate ◽

Regression Analysis ◽

Individual Differences ◽

Negative Affect ◽

Respiratory Sinus Arrhythmia ◽

Attentional Control ◽

Executive Processes ◽

Sinus Arrhythmia ◽

Low Levels

The current study was an attempt to determine the degree to which the suppression of respiratory sinus arrhythmia (RSA) and attentional control were influential in the ability to engage various executive processes under high and low levels of negative affect. Ninety-four college students completed the Stroop Test while heart rate was being recorded. Estimates of the suppression of RSA were calculated from each participant in response to this test. The participants then completed self-ratings of attentional control, negative affect, and executive functioning. Regression analysis indicated that individual differences in estimates of the suppression of RSA, and ratings of attentional control were associated with the ability to employ executive processes but only when self-ratings of negative affect were low. An increase in negative affect compromised the ability to employ these strategies in the majority of participants. The data also suggest that high attentional control in conjunction with attenuated estimates of RSA suppression may increase the ability to use executive processes as negative affect increases.

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Influence of production factors on heart rate regulation

OCCUPATION AND HEALTH: Proceedings of the second international youth Forum ◽

10.31089/978-5-907032-51-4-2018-1-166-171 ◽

2018 ◽

Author(s):

Мелентьев А.В. Мелентьев А.В. ◽

Keyword(s):

Heart Rate ◽

Rate Regulation ◽

Production Factors ◽

Heart Rate Regulation

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Cardiopulmonary coupling indices to assess weaning readiness from mechanical ventilation

Scientific Reports ◽

10.1038/s41598-021-95282-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Pablo Armañac-Julián ◽

David Hernando ◽

Jesús Lázaro ◽

Candelaria de Haro ◽

Rudys Magrans ◽

...

Keyword(s):

Heart Rate ◽

Mechanical Ventilation ◽

Spontaneous Breathing Trial ◽

Sinus Arrhythmia ◽

Time Frequency ◽

Cardiopulmonary Coupling ◽

Cardiac Pumping ◽

Successful Weaning ◽

Frequency Coherence ◽

Subspace Projections

AbstractThe ideal moment to withdraw respiratory supply of patients under Mechanical Ventilation at Intensive Care Units (ICU), is not easy to be determined for clinicians. Although the Spontaneous Breathing Trial (SBT) provides a measure of the patients’ readiness, there is still around 15–20% of predictive failure rate. This work is a proof of concept focused on adding new value to the prediction of the weaning outcome. Heart Rate Variability (HRV) and Cardiopulmonary Coupling (CPC) methods are evaluated as new complementary estimates to assess weaning readiness. The CPC is related to how the mechanisms regulating respiration and cardiac pumping are working simultaneously, and it is defined from HRV in combination with respiratory information. Three different techniques are used to estimate the CPC, including Time-Frequency Coherence, Dynamic Mutual Information and Orthogonal Subspace Projections. The cohort study includes 22 patients in pressure support ventilation, ready to undergo the SBT, analysed in the 24 h previous to the SBT. Of these, 13 had a successful weaning and 9 failed the SBT or needed reintubation –being both considered as failed weaning. Results illustrate that traditional variables such as heart rate, respiratory frequency, and the parameters derived from HRV do not differ in patients with successful or failed weaning. Results revealed that HRV parameters can vary considerably depending on the time at which they are measured. This fact could be attributed to circadian rhythms, having a strong influence on HRV values. On the contrary, significant statistical differences are found in the proposed CPC parameters when comparing the values of the two groups, and throughout the whole recordings. In addition, differences are greater at night, probably because patients with failed weaning might be experiencing more respiratory episodes, e.g. apneas during the night, which is directly related to a reduced respiratory sinus arrhythmia. Therefore, results suggest that the traditional measures could be used in combination with the proposed CPC biomarkers to improve weaning readiness.

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Beyond the Reward Pathway: Coding Reward Magnitude and Error in the Rat Subthalamic Nucleus

Journal of Neurophysiology ◽

10.1152/jn.91009.2008 ◽

2009 ◽

Vol 102 (4) ◽

pp. 2526-2537 ◽

Cited By ~ 63

Author(s):

Sylvie Lardeux ◽

Remy Pernaud ◽

Dany Paleressompoulle ◽

Christelle Baunez

Keyword(s):

Subthalamic Nucleus ◽

Firing Pattern ◽

Sucrose Solution ◽

Critical Role ◽

The Other ◽

Reward Circuitry ◽

Reward Delivery ◽

Reward Pathway ◽

Subthalamic Neurons ◽

The Brain

It was recently shown that subthalamic nucleus (STN) lesions affect motivation for food, cocaine, and alcohol, differentially, according to either the nature of the reward or the preference for it. The STN may thus code a reward according to its value. Here, we investigated how the firing of subthalamic neurons is modulated during expectation of a predicted reward between two possibilities (4 or 32% sucrose solution). The firing pattern of neurons responding to predictive cues and to reward delivery indicates that STN neurons can be divided into subpopulations responding specifically to one reward and less or giving no response to the other. In addition, some neurons (“oops” neurons) specifically encode errors as they respond only during error trials. These results reveal that the STN plays a critical role in ascertaining the value of the reward and seems to encode that value differently depending on the magnitude of the reward. These data highlight the importance of the STN in the reward circuitry of the brain.

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