The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index; 2 of the 19 sources its claims cite were checked for support.
Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency
Open accessAbstract
BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.
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TL;DR
In a woman with orthostatic intolerance and her identical twin, the authors found evidence of impaired norepinephrine reuptake, including a heterozygous Ala457Pro mutation in the norepinephrine transporter gene that nearly abolished transporter function. The mutation tracked with higher standing heart rates and plasma norepinephrine and lower DHPG:norepinephrine ratios in relatives, suggesting a hyperadrenergic mechanism for some orthostatic intolerance.
Key findings
- The proband had a standing plasma norepinephrine concentration of 923 pg/mL versus 439±129 pg/mL in normal subjects, reduced systemic norepinephrine clearance of 1.56 versus 2.42±0.71 L/min, and a blunted plasma norepinephrine rise after tyramine of 12 versus 56±21 pg/mL.
- Plasma DHPG:norepinephrine ratios were low in the proband and her twin compared with normal subjects: supine 3.06 and 2.41 versus 5.52, and upright 1.05 and 1.17 versus 3.44.
- The proband was heterozygous for a G237C mutation in exon 9 of the norepinephrine transporter gene, producing Ala457Pro; expressed mutant transporter showed 2 percent or less of wild-type uptake activity, corresponding to more than 98 percent loss of function.
- The mother and four siblings were heterozygous for the mutation; heterozygous relatives had significantly higher standing heart rates and upright plasma norepinephrine concentrations and significantly lower DHPG:norepinephrine ratios, but none had the full syndrome. The mutation was absent in 254 unrelated persons.
Methods
- Case-family study of a 33-year-old proband with orthostatic intolerance, her identical twin, nine siblings, and their mother; clinical measurements included supine and upright blood pressure, heart rate, plasma catecholamines, tyramine challenge, and tritiated norepinephrine infusion with nitroprusside to assess spillover and clearance.
- Genetic and functional work included sequencing of norepinephrine-transporter gene exons, expression of wild-type and Ala457Pro cDNA in Chinese-hamster-ovary cells for tritiated norepinephrine uptake, and allele-specific oligonucleotide hybridization for genotyping.
- Comparisons used 10 normal subjects for blood pressure, heart rate, and catecholamines, 9 for tyramine response, and 8 for norepinephrine spillover and clearance; paired and unpaired t-tests were used with two-sided P values.
Limitations
- The paper states that the Ala457Pro mutation was not found in 254 unrelated persons and does not explain all cases of orthostatic intolerance; heterozygous relatives showed some abnormalities but none had the full syndrome, so other genetic or environmental factors likely contributed.
- Evident from the text: the study is very small, centered on one proband and her twin with limited family and normal comparison groups, and lacks independent replication.
- The functional evidence comes from heterologous cell expression rather than patient tissue, and the case-family design limits generalizability.
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Claims the paper makes
45 Own result · 21 Own interpretation · 11 No full text of the sources · 2 No basis given · 1 Supported · 1 Couldn’t confirm · 1 Not checked yet · 1 Own method · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“A deficiency of the norepinephrine transporter may explain several of the clinical findings in patients with this disorder: the high heart rate in the supine position, the high plasma concentration of norepinephrine in association with the relatively low plasma concentration of dihydroxyphenylglycol, the impaired response of norepinephrine to tyramine, 13 the reduced systemic clearance of norepine”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [13] Jacob G, 1999, Circulation source
- Could not verifycites [27] Furlan R, 1998, Circulation sourceExperimental — accuracy not yet measured
The Autonomic Control section reports elevated supine norepinephrine and tachycardia, but proposes a possible central nervous system abnormality rather than a norepinephrine-transporter deficiency. Searches for transporter deficiency, tyramine, and dihydroxyphenylglycol found no passage in our copy addressing the claimed explanation. (LLM, conf=0.76)
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Norepinephrine clearance did not change appreciably after the nitroprusside infusion in either the proband (1.76 liters per minute) or the normal subjects (2.31±0.68liters per minute).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
plainSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the proband and her twin, the plasma concentrations of dihydroxyphenylglycol, an intraneuronal metabolite of norepinephrine, 9 were low in relation to the plasma norepinephrine concentrations (ratio of dihydroxyphenylglycol to norepinephrine in the supine position, 3.06 in the proband and 2.41 in her twin, vs. 5.52 in the normal subjects; ratio in the upright position, 1.05 in the proband and 1”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Autonomic Responses
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In the paper
“Direct sequence analysis of the norepinephrinetransporter gene in the proband revealed no divergence from previously published sequences 14,18 in exons 1 through 8 and exons 10 through 15.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Identification of a Functional Missense Mutation in the Norepinephrine-Transporter Gene
What the sources say
plainSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We evaluated a patient and her identical twin, both of whom had symptoms typical of orthostatic intolerance”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Conclusions
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“reduced systemic norepinephrine clearance (1.56 vs. 2.42±0.71liters per minute)”
- Also stated in: § Spillover and Clearance of Systemic Norepinephrine · plain
“norepinephrine clearance in the proband was less than half that in the normal subjects (1.56 vs. 2.42±0.71liters per minute).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Spillover and Clearance of Systemic Norepinephrine · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The patient had a high mean plasma nor- epinephrine concentration while standing, as compared with the mean (±SD) concentration in normal subjects (923 vs. 439±129 pg per milliliter [5.46 vs. 2.59±0.76nmol per liter])”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237)”
- Also stated in: § T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U · plain
“The proband was heterozygous for both the C154A and the G237C polymorphisms (Fig. 2A).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Also stated in: § T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The arterial plasma norepinephrine concentration at rest was slightly higher in the proband than in the normal subjects (280 pg per milliliter [1.66 nmol per liter] vs. 204±51 pg per milliliter [1.21±0.30nmol per liter]).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56±63 pg per milliliter [0.07 vs. 0.33± 0.37 pmol per liter])”
- Also stated in: § Response to Tyramine · plain
“In the proband, the same dose of tyramine increased systolic blood pressure by 18 mm Hg but increased the plasma norepinephrine concentration by only 12 pg per milliliter (0.07 nmol per milliliter).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § Response to Tyramine · plain
- It may state two separate claims as one. 11
- Probably not a substantial claim. 2
Every source the paper cites for this claim was checked and supports it.
In the paper
“The dihydroxyphenylglycol then enters the circulation and can serve as a marker of norepinephrine uptake and monoamine oxidase activity 9 (Fig. 4).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
What the sources say
- Supportedcites [9] source
The Introduction (p. 1) identifies DHPG as a norepinephrine metabolite present in human plasma. The Conclusions (p. 7) link plasma DHPG to neuronal norepinephrine uptake, and the DHPG/NE ratio discussion (p. 7) predicts a changed DHPG response when either uptake or monoamine oxidase is blocked. The paper presents this as information obtained from DHPG measured alongside norepinephrine, rather than as a standalone measure of enzyme activity. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the normal subjects, the mean (±SD) systolic blood pressure increased by 19±2 mm Hg and the mean plasma norepinephrine concentration increased by 56 ±21 pg per milliliter (0.33±0.12 nmol per liter) in response to 3 mg of tyramine.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The proband and her twin sister had normal autonomic reflexes, but their blood pressure and heart rate were variable (Fig. 1).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Autonomic Responses
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Their heart rates while supine were slightly but not significantly greater than those of their family members with the wild-type genotype, but their heart rates while standing were significantly higher (Fig. 3A and 3B).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Likewise, plasma norepinephrine concentrations in the supine position were somewhat higher and plasma norepinephrine concentrations in the upright position were significantly higher in the heterozygous family members than in those with the normal genotype (Fig. 3C and 3D).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In contrast, the Ala457Pro mutation renders the transporter nonfunctional and segregates with altered heart-rate regulation and altered norepinephrine metabolism.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Chinese-hamster-ovary cells that had been transiently transfected with cDNA encoding the human norepinephrine transporter, uptake of tritiated norepinephrine was 10 times that in vector-transfected cells, whereas in cells transfected with cDNA encoding the Ala457Pro mutation in the norepinephrine transporter, the uptake was 2 percent or less (Fig. 2D).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Approximately 80 to 90 percent of the norepinephrine released into many synapses is cleared by this mechanism, and the remaining 10 to 20 percent spills over into the circulation or extraneuronal tissue.8”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Conclusions
What the sources say
- Not checked — no full text of the sourcecites [8] Esler M, 1990, Physiol Rev source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The reduced DHPG concentration in the neuron results in lower concentrations of this metabolite in the plasma and, consequently, a ratio of plasma DHPG to plasma norepinephrine that is lower than normal.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: DHPG diffuses out of the neuron into the circulation.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All samples of genomic DNA were coded before genotype analysis in order to preserve the anonymity of the subjects.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Genotyping of Ala457Pro Alleles
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because acute pharmacologic blockade of the norepinephrine transporter causes a decrease in sympathetic outflow, 33 one would expect a decrease in sympathetic tone with a deficiency of the norepinephrine transporter.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In persons with norepinephrine-transporter deficiency, the release of norepinephrine into the synaptic space is normal, but because of the decreased activity of the norepinephrine transporter, less than 80 percent of norepinephrine is taken up into the neuron that released it, so that the spillover into the circulation is greater than 20 percent.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Approximately 80 percent of norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because the substitution of proline disrupts alpha-helical secondary structures that are supported by alanine residues, this mutation may disrupt the transport of norepinephrine.”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The in vitro loss of norepinephrine transport caused by the Ala457Pro mutation reflects impaired norepinephrine clearance in the patients.
“nephrine transport was greatly diminished by the Ala457Pro mutation.”
The paper relies on this without support.
Under normal conditions, norepinephrine is released from vesicles in the neuron into the synaptic space, where it can interact with presynaptic and postsynaptic alpha- and beta-adrenergic receptors.
“Under normal conditions, norepinephrine is released from vesicles in the neuron into the synaptic space, where it can interact with presynaptic and postsynaptic a-and b-adrenergic receptors.”
The paper relies on this without support.
Approximately 80 percent of norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.
“Approximately 80 percent of the norepinephrine in the synaptic space is taken up by the norepinephrine transporter into the neuron that released it, and approximately 20 percent spills over into the circulation.”
The paper relies on this without support.
Norepinephrine taken up by the neuron that released it is preferentially converted to DHPG by monoamine oxidase; some is repackaged into synaptic vesicles.
“Norepinephrine taken up by the neuron that released it is preferentially converted to dihydroxyphenylglycol (DHPG) by monoamine oxidase; some is repackaged into the synaptic vesicles.”
The paper relies on this without support.
DHPG diffuses out of the neuron into the circulation.
“DHPG diffuses out of the neuron into the circulation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Many patients with POTS have increased sympathetic nervous system tone measured with direct nerve recordings 5 or biochemically with an elevated plasma norepinephrine on standing 6–8.”
From Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less Is More (2009) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“With 1 notable exception of a particular mutation causing POTS in members of a single family, 37 no evidence supports a monogenic cause of POTS.”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [37]
Experimental — accuracy not yet measuredIn the citing paper
“A very rare form of hyperadrenergic POTS is caused by a loss-of-function mutation in the gene for the norepinephrine transporter (NET) [54].”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [54]
In the citing paper
“While many conditions, such as mast cell activation disorders (9), Ehlers-Danlos syndrome (10, 11), deconditioning (12), and genetic mutations of norepinephrine transporters (13), coexist with POTS, their downstream effects also funnel into these three principal pathophysiologic mechanisms.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Shannon et al. (13) discovered a single missense mutation (ALA457Pro) in the norepinephrine transporter gene ( SLC6A2 ) that resulted in a 98% loss of function in the transporter and was present in two identical twins with POTS.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Each twin had normal levels of supine plasma norepinephrine (269 pg/ml and 199 pg/ml), but standing plasma norepinephrine exceeded 900 pg/ml.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“Alteration of norepinephrine metabolism, congenital or iatrogenic, is another well-described cause of hyperadrenergic POTS.”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“One of the twins even became hypertensive with standing (13).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“In certain cases, it may be possible to recognize key endophenotypes (13, 73, 79).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [13]
In the citing paper
“A loss of function single point mutation in the NET gene SLC6A2 was identified in one family with orthostatic tachycardia”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Shannon et al., 2000
In the citing paper
“In a subgroup of these patients, a rare mutation of norepinephrine-transporter gene was found, resulting in reduced synaptic norepinephrine reuptake and excessive sympathetic activation [56].”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [56]
In the citing paper
“The cardinal diagnostic features of this condition are exaggerated reflex increases in heart rate and plasma NE concentration with standing, 9 attributable in the kindred reported although not in the majority of patients with the condition to the NE transporter fault.”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“Near-total absence of activity of the neuronal NE transporter was recently reported in a family kindred with the postural tachycardia syndrome, in which a missense mutation of the NE transporter gene has been identified.9”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“We were encouraged in this line of thinking by the recent description of a missense mutation of the NE transporter gene in a family kindred with the postural tachycardia syndrome 9 in whom the exaggerated reflex increase in heart rate with standing, which is a cardinal feature of the disorder, was due to the NE transporter fault.”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“The transporter gene mutation recently described in the postural tachycardia syndrome kindred differs from the 5 identified earlier and is associated with almost total absence of transporter activity.9”
From Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension (2000) · cites this paper as [9]
In the citing paper
“It should be kept in mind that sinus tachycardia paroxysms may be due to anxiety as in panic disorder44 (epinephrine-mediated), norepinephrine reuptake inhibition45 (a very rare condition; norepinephrine-mediated) or drug intake (e.g. beta-agonists in asthma).”
From Sinus Tachycardia: a Multidisciplinary Expert Focused Review (2022) · cites this paper as [45]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
“12 vs. 56±63 pg per milliliter”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“the mean plasma norepinephrine concentration increased by 56 ±21 pg per milliliter”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Segregation of the Ala457Pro Mutation with a Phenotype
“The mother and four siblings (including the twin sister) were heterozygous for the mutant allele (Fig. 2E).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
“the proband and nine family members (three family members with the Ala457Pro mutation and six with the normal genotype)”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Results
“0.33± 0.37 pmol per liter”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“0.33±0.12 nmol per liter”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“norepinephrine clearance in the proband was less than half that in the normal subjects (1.56 vs. 2.42±0.71liters per minute)”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Spillover and Clearance of Systemic Norepinephrine
Reported 0.5 · recomputed 0.644628
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > DISCUSSION
“This change from cytosine to guanine results in a change from alanine to proline at amino acid position 457 (Ala457Pro).”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > T ABLE 1. B LOOD P RESSURE , H EART R ATE , AND P LASMA C ATECHOLAMINE C ONCENTRATIONS IN THE P ROBAND , H ER T WIN S ISTER , AND 10 U
“a missense mutation in which guanine was replaced by cytosine at position 237 (G237C)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Response to Tyramine
“increased the plasma norepinephrine concentration by only 12 pg per milliliter (0.07 nmol per milliliter)”
§ OR THOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPOR TER DEFICIENCY ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCY > Identification of a Functional Missense Mutation in the Norepinephrine-Transporter Gene
“To convert values for plasma norepinephrine to nanomoles per liter, multiply by 0.005911.”
Citations
Cites
Expression cloning of a cocaine-and antidepressant-sensitive human noradrenaline transporter
Pacholczyk, T., Blakely, R. D., & Amara, S. G. (1991) · Nature · doi:10.1038/350350a0 · Cited by 933
Self-citationOverflow of catecholamine neurotransmitters to the circulation: source, fate, and functions
Esler, M., Jennings, G., Lambert, G., Meredith, I., Horne, M., & Eisenhofer, G. (1990) · Physiological Reviews · doi:10.1152/physrev.1990.70.4.963 · Cited by 794
Idiopathic postural orthostatic tachycardia syndrome: An attenuated form of acute pandysautonomia?
Schondorf, R., & Low, P. A. (1993) · Neurology · doi:10.1212/wnl.43.1_part_1.132 · Cited by 548
Molecular Physiology of Norepinephrine and Serotonin Transporters
Blakely, R. D., De Felice, L. J., & Hartzell, H. C. (1994) · Journal of Experimental Biology · doi:10.1242/jeb.196.1.263 · Cited by 404
Self-citationADLER‐GRASCHINSKY, E., & LANGER, S. Z. (1975) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1975.tb07328.x · Cited by 335
Postural tachycardia syndrome (POTS)
Lamotte, G., & Low, P. A. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-85492-4.00118-6 · Cited by 301
Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans.
Goldstein, D. S., Eisenhofer, G., Stull, R., Folio, C. J., Keiser, H. R., & Kopin, I. J. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113298 · Cited by 245
Chronic Orthostatic Intolerance: A Disorder With Discordant Cardiac and Vascular Sympathetic Control
Furlan, R., Jacob, G., Snell, M., Robertson, D., Porta, A., Harris, P., & Mosqueda-Garcia, R. (1998) · Circulation · doi:10.1161/01.cir.98.20.2154 · Cited by 229
Self-citationEffects of volume loading and pressor agents in idiopathic orthostatic tachycardia
Jacob, G., Shannon, J. R., Black, B., Biaggioni, I., Mosqueda-Garcia, R., Robertson, R. M., & Robertson, D. (1997) · Circulation · doi:10.1161/01.cir.96.2.575 · Cited by 206
Self-citationHypocapnia and Cerebral Hypoperfusion in Orthostatic Intolerance
Novak, V., Spies, J. M., Novak, P., McPhee, B. R., Rummans, T. A., & Low, P. A. (1998) · Stroke · doi:10.1161/01.str.29.9.1876 · Cited by 191
Research works printed but not linked: 6
- Low PA, 1995, Neurology, 45, S19
- Apparsundaram S, 1998, J Pharmacol Exp Ther, 287, 733
- Davis D, 1987, Circ Res, 61, I87
- Tung CS, 1983, J Pharmacol Exp Ther, 227, 484
- Esler MD, 1991, Am J Physiol, 260, R817
- Shannon JR, 1998, Circulation, 98, I
Cited by
Sorted by citations
Items 301–400 of 595
Zhang, Q., Xu, B., & Du, J. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00525 · Cited by 20
“Hyperadrenergic POTS can be caused by norepinephrine transporter deficiency (36), pheochromocytoma, mast-cellactivation disorders (37), and baroreflex failure resulting from trauma to or irradiation of the neck.”
BackgroundChronic depolarization stimulates norepinephrine transporter expression via catecholamines
Habecker, B. A., Willison, B. D., Shi, X., & Woodward, W. R. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03792.x · Cited by 18
Spraggs, C. F., Pillai, S. G., Dow, D. J., Douglas, C., McCarthy, L. C., Manasco, P. K., Stubbins, M. J., & Roses, A. D. (2005) · Pharmacogenetics and Genomics · doi:10.1097/01213011-200512000-00006 · Cited by 18
Elevated Peroxynitrite as the Cause of Chronic Fatigue Syndrome
Pall, M. L. (2000) · Journal of Chronic Fatigue Syndrome · doi:10.1300/j092v07n04_05 · Cited by 17
Ruzieh, M., & Grubb, B. P. (2018) · Herzschrittmachertherapie + Elektrophysiologie · doi:10.1007/s00399-018-0563-1 · Cited by 18
“increased release of norepinephrine in response to a change in position and, in some patients, genetic mutation of the norepinephrine transporter, leading to decreased norepinephrine inactivation/ reuptake in the intrasynaptic cleft [17].”
BackgroundUtility of Corrected QT Interval in Orthostatic Intolerance
Kim, J. B., Hong, S., Park, J., Cho, D., Park, K., & Kim, B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106417 · Cited by 18
“Various hypotheses, such as hypovolemia [37], venous pooling [38], hyperadrenergic states [39–41], and restricted adrenergic neuropathies [42] have been suggested to be possible mechanisms underlying POTS.”
BackgroundDiagnosis and Treatment of Neurally Mediated Syncope
Kaufmann, H., & Bhattacharya, K. (2002) · The Neurologist · doi:10.1097/00127893-200205000-00004 · Cited by 17
“This hypothesis is supported by the recent finding of a patient with postural tachycardia who was heterozygous for a mutation in the norepinephrine transporter gene That resulted in dramatic (more than 98%) loss of function (26).”
Postural orthostatic tachycardia syndrome: an underrecognized disorder
Pandian, J. D., Dalton, K., Henderson, R. D., & McCombe, P. (2007) · Internal Medicine Journal · doi:10.1111/j.1445-5994.2007.01356.x · Cited by 17
Functional adrenergic receptor polymorphisms and idiopathic orthostatic intolerance
Winker, R., Barth, A., Valic, E., Maier, R., Osterode, W., Pilger, A., & R�diger, H. W. (2005) · International Archives of Occupational and Environmental Health · doi:10.1007/s00420-005-0605-y · Cited by 17
“Indeed, in recent studies of the rare entity familial orthostatic intolerance, a mutation of the coding region of the norepinephrine transporter gene (which is not polymorphic) has been identified as causative ( Shannon et al. 2000 ).”
BackgroundClinical Catecholamine Neurochemistry: A Legacy of Julius Axelrod
Goldstein, D. S., Eisenhofer, G., & Kopin, I. J. (2006) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-006-9041-0 · Cited by 17
“The finding of relatively high plasma NE levels compared to DHPG levels was a key clue enabling the discovery that postural tachycardia syndrome, a mysterious, controversial disorder manifesting as chronic orthostatic intolerance, can result from hypofunctional mutation of the gene encoding the cell membrane NE transp…”
BackgroundJacob, G., Garland, E. M., da Costa, F. A. A., Stein, C. M., Xie, H., Robertson, R. M., Biaggioni, I., & Robertson, D. (2006) · Hypertension · doi:10.1161/01.hyp.0000205120.46149.34 · Cited by 18
Self-citationKim, C., Ardayfio, P. A., & Kim, K. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101279200 · Cited by 17
The genetics of human hypertension
Crook, E. D. (2002) · Seminars in Nephrology · doi:10.1053/snep.2002.28641 · Cited by 17
Neurological Aspects of Syncope and Orthostatic Intolerance
Weimer, L. H., & Zadeh, P. (2009) · Medical Clinics of North America · doi:10.1016/j.mcna.2008.10.002 · Cited by 16
“Interestingly, genetic defects in a norepinephrine transporter gene manifests a phenotype with many overlapping clinical features with OI and blocking this transporter with reboxetine reproduced many OI symptoms and signs in normal subjects.(124,125) Not surprisingly, many patients are inappropriately diagnosed, somet…”
BackgroundNickander, K. K., Carlson, P. J., Urrutia, R. A., Camilleri, M., & Low, P. A. (2005) · Autonomic Neuroscience · doi:10.1016/j.autneu.2005.05.001 · Cited by 16
“d Percent of control alleles: a2CAR from Small et al. (2000), NET from Stöber e Number of heterozygous subjects reported in the literature (Shannon et al.”
BackgroundPharmacogenetics of Monoamine Transporters
Glatt, C. E., & Reus, V. I. (2003) · Pharmacogenomics · doi:10.1517/phgs.4.5.583.23789 · Cited by 16
“TTTCCTTCTC [G/C]CCCTGTTCTG < 1 A/P x9 [47]”
BackgroundKiyono, Y., Kanegawa, N., Kawashima, H., Fujiwara, H., Iida, Y., Nishimura, H., & Saji, H. (2003) · Nuclear Medicine and Biology · doi:10.1016/s0969-8051(03)00085-4 · Cited by 16
Garland, E. M., Anderson, J. C., Black, B. K., KESSLER, R. M., Konrad, P. E., & Robertson, D. (2002) · Clinical Autonomic Research · doi:10.1007/s10286-002-0051-9 · Cited by 16
“A deficiency of norepinephrine uptake as a result of a functional mutation in the gene encoding the norepinephrine transporter has also been reported recently in a large family with OI [16].”
BackgroundSelf-citationInfluence of St John's wort on catecholamine turnover and cardiovascular regulation in humans
Schroeder, C., Tank, J., Goldstein, D. S., Stoeter, M., Haertter, S., Luft, F. C., & JORDAN, J. (2004) · Clinical Pharmacology & Therapeutics · doi:10.1016/j.clpt.2004.08.005 · Cited by 16
Self-citationKICHLOO, A., ALJADAH, M., GRUBB, B., & KANJWAL, K. (2021) · Journal of Innovations in Cardiac Rhythm Management · doi:10.19102/icrm.2021.120705 · Cited by 15
Postural orthostatic tachycardia syndrome: Diagnosis and treatment
Thanavaro, J. L., & Thanavaro, K. L. (2011) · Heart & Lung · doi:10.1016/j.hrtlng.2009.12.014 · Cited by 15
The chronic fatigue syndrome is a disease of the autonomic nervous system. Sometimes.
Freeman, R. L. (2002) · Clinical Autonomic Research · doi:10.1007/s10286-002-0058-2 · Cited by 16
“Investigators, studying the disorder from different standpoints,have documented hypovolemia [15,19], or a trend toward hypovolemia [20], reduced erythrocyte mass [21], baroreflex dysfunction [10, 20], excessive venous pooling [22],venous denervation [23], decreased venous compliance [24], α-adrenoreceptor [15, 23] and…”
BackgroundLi, H., Han, Z., Chen, S., Liao, Y., Wang, Y., Liu, P., Chen, Y., Tang, C., Lin, J., Du, J., et al. (2015) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2015.03.032 · Cited by 15
Novotný, M., Quaiserová‐Mocko, V., Wehrwein, E. A., Kreulen, D. L., & Swain, G. M. (2007) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2007.02.008 · Cited by 15
“For example, dysfunction of the SNS, specifically NE reuptake, has been implicated in several cardiovascular disorders including hypertension, heart failure, orthostatic intolerance and postural tachycardia (de Champlain et al., 1966; Eisenhofer et al., 1996; Julius and Valentini, 1998; Esler and Kaye, 2000; Patel et…”
BackgroundAutonome Dysfunktion und orthostatische Intoleranz
Klingenheben, T. (2002) · Der Internist · doi:10.1007/s00108-002-0689-3 · Cited by 15
Ivancsits, S., Heider, A., Rüdiger, H. W., & Winker, R. (2003) · The American Journal of the Medical Sciences · doi:10.1097/00000441-200302000-00002 · Cited by 15
Vuorenpää, A., Jørgensen, T. N., Newman, A. H., Madsen, K. L., Scheinin, M., & Gether, U. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.702050 · Cited by 15
Carson, R. P., Diedrich, A., & Robertson, D. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00033.2002 · Cited by 15
“Postural tachycardia in humans after tricyclic antidepressants or the selective NET blocker reboxetine (9), postural tachycardia in patients with NET deficiency (25), and an excessive tachycardia after a vasodilatory stimulus in DMI-treated rabbits (7) suggest that baroreflex sensitivity may be altered after NET block…”
BackgroundResultSelf-citationNeural autonomic control in orthostatic intolerance
Furlan, R., Barbic, F., Casella, F., Severgnini, G., Zenoni, L., Mercieri, A., Mangili, R., Costantino, G., & Porta, A. (2009) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2009.04.008 · Cited by 14
Consequences of the evolutionary cardiovascular challenge of human bipedalism
Esler, M., Julius, S., Coghlan, B., Sari, C. I., Guo, L. J., & Esler, D. (2019) · Journal of Hypertension · doi:10.1097/hjh.0000000000002198 · Cited by 14
“Faulty reuptake of noradrenaline by sympathetic nerves has been reported in POTS, first described as a gene point mutation in a family kindred [33] with subsequent reporting of epigenetic suppression of the NET gene [34], and low NET protein content in sympathetic nerves [35].”
BackgroundAtremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics
Cacabelos, R., Carrera, I., Martínez, O., Alejo, R., Fernández‐Novoa, L., Cacabelos, P., Corzo, L., Rodríguez, S., Alcaraz, M., Nebril, L., et al. (2021) · Medicinal Research Reviews · doi:10.1002/med.21838 · Cited by 14
Postural Orthostatic Tachycardia Syndrome (POTS)
Mizumaki, K. (2011) · Journal of Arrhythmia · doi:10.1016/s1880-4276(11)80031-1 · Cited by 19
Posturales orthostatisches Tachykardiesyndrom (POTS): Ätiologie, Diagnose und Therapie
Grubb, B. P., & Klingenheben, T. (2000) · Medizinische Klinik - Intensivmedizin und Notfallmedizin · doi:10.1007/s000630050004 · Cited by 14
“[29] erstmals eine Mutation des Noradrenalintransportgens bei einer Patientin mit POTS mit der Folge einer deutlich gestörten synaptischen Noradrenalinclearance als mögliche Ursache eines hyperadrenergen Status mit orthostatischer Intoleranz nach.”
Kawada, T., Miyamoto, T., Uemura, K., Kashihara, K., Kamiya, A., Sugimachi, M., & Sunagawa, K. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00527.2003 · Cited by 14
“Because deficiency of neuronal NE uptake is associated with a subgroup of patients with orthostatic intolerance (32, 33) or essential hypertension (30), elucidating the effects of neuronal NE uptake blockade on dynamic baroreflex function would contribute to better understanding the pathology underlying such cardiovas…”
BackgroundParker, L. K., Shanks, J. A., Kennard, J. A. G., et al. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00574.x · Cited by 13
“NET polymorphisms have been associated with orthostatic intolerance (Shannon et al., 2000) and hypertension in people with type 2 diabetes (Ksiazek et al., 2006), yet it is their promiscuous response to drugs that makes them most interesting.”
BackgroundLo, A., Kaufmann, H., Vickery, R. G., Bourdet, D. L., & Kanodia, J. (2021) · Clinical Autonomic Research · doi:10.1007/s10286-021-00800-x · Cited by 12
Postural Tachycardia Syndrome and Neurally Mediated Syncope
Cutsforth‐Gregory, J. K. (2020) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000000818 · Cited by 14
Functional Neuroimaging of Sympathetic Innervation of the Heart
Goldstein, D. S. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1296.028 · Cited by 13
Lesch, K., & Murphy, D. L. (2003) · Springer eBooks · doi:10.1007/978-1-4419-9023-5_23 · Cited by 13
Cho, S., Kim, C., Cubells, J. F., et al. (2003) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.20194 · Cited by 13
“Indeed, a recent report showed that a mutation in norepinephrine transporter (NET), which mediates NE reuptake into presynaptic nerve endings, underlies a hereditary form of OI, a tachycardia (but not hypotension) [Shannon et al., 2000].”
BackgroundSelf-citationCatecholaminergic Pathways, Chromaffin Cells, and Human Disease
Parmer, R. J., & Zinder, O. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04514.x · Cited by 13
The Baroreceptor Reflex: Novel Methods and Mechanisms
Chapleau, M. W., & Abboud, F. M. (2004) · Springer eBooks · doi:10.1007/978-1-4419-9054-9_1 · Cited by 13
Lambert, G. W., Patel, M., & Lambert, É. (2025) · Metabolites · doi:10.3390/metabo15050286 · Cited by 15
“…level of haemoglobin 4 of 30 Additionally, the expression of the noradrenaline transporter may be reduced due to single-nucleotide polymorphisms [43] and epigenetic mechanisms involving histone modi fi cations on the gene promotor [44]. and extracellular compounds, including signalling…”
Genomics of Cardiovascular Measures of Autonomic Tone
Sigurdsson, M. I., Waldron, N. H., Bortsov, A. V., Smith, S. B., & Maixner, W. D. (2018) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000559 · Cited by 12
“This results in increased activity and spillage of norepinephrine into circulation, resulting in elevated baseline heart rate and a profound response to orthostatic challenge.(76) Pathogenic mutations affecting the expression or increased copy numbers of the Parkinson disease 1 or 4 gene (SNCA, PARK1, PARK4) result in…”
BackgroundTao, C., Chen, S. Y., Li, H., Wang, Y., Wang, Y., Liu, P., Liao, Y., Zhang, C., Tang, C., Jin, H., et al. (2018) · Frontiers in Pediatrics · doi:10.3389/fped.2018.00343 · Cited by 12
Targeting Treatment Refractory NET by EZH2 Inhibition in Postural Tachycardia Syndrome
Kaipananickal, H., Khan, A. W., Okabe, J., Corcoran, S. J., Esler, M., & El-Osta, A. (2020) · Circulation Research · doi:10.1161/circresaha.119.315654 · Cited by 12
Kesserwani, H. N. (2020) · Cureus · doi:10.7759/cureus.10881 · Cited by 12
“A rare genetic mutation of the norepinephrine transporter protein leads to reduced synaptic uptake of norepinephrine and excess sympathetic stimulation that mimics POTS [13].”
BackgroundWang, Y., Sun, Y. K., Zhang, Q., Zhang, C., Liu, P., Wang, Y., Tang, C., Jin, H., & Du, J. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.808512 · Cited by 13
Norepinephrine Transporter Gene (NET) Polymorphism in Patients with Type 2 Diabetes
Książek, P., Buraczyńska, K., & Buraczyńska, M. (2006) · Kidney & Blood Pressure Research · doi:10.1159/000097356 · Cited by 12
“NET regulates many central and sympathetic nervous system functions including learning, memory, stress and blood flow. Orthostatic intolerance is associated with NET dysfunction [”
BackgroundOgimoto, A., Okayama, H., Nagai, T., et al. (2012) · Circulation Journal · doi:10.1253/circj.cj-11-1014 · Cited by 12
Sheraton, T. E., Gildersleve, C. D., & Hall, J. E. (2006) · Anaesthesia · doi:10.1111/j.1365-2044.2006.04857.x · Cited by 13
Management of orthostatic intolerance in children: the state of the art
Tao, C., Jin, H., & Du, J. (2020) · World Journal of Pediatrics · doi:10.1007/s12519-019-00329-0 · Cited by 11
“Studies suggest that the impaired clearance of intra-synaptic norepinephrine or excessive synthesis of norepinephrine may be the cause [18, 19].”
BackgroundSchwartz, J., Piston, D. W., & DeFelice, L. J. (2006) · Springer eBooks · doi:10.1007/3-540-29784-7_2 · Cited by 12
“Membrane proteins are often fit to a two-dimensional diffusion model, because the protein movement is restricted to a single plane ( Schwille et al. 1999 ).”
BackgroundLucini, D., Furlan, R., Villa, P., Mosqueda‐Garcia, R., Diedrich, A., Robertson, D., Malliani, A., Porta, A., & Pagani, M. (2004) · Journal of Hypertension · doi:10.1097/01.hjh.0000125457.28861.ad · Cited by 13
Self-citationDopamine-β-hydroxylase in postural tachycardia syndrome
Garland, E. M., Black, B. K., Harris, P. A., & Robertson, D. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01389.2006 · Cited by 12
Self-citationZeitz, C., Méjécase, C., Stévenard, M., Michiels, C., Audo, I. S., & Marmor, M. F. (2018) · BioMed Research International · doi:10.1155/2018/7694801 · Cited by 12
“phenotype [49], a finding which was further validated in a mouse model carrying the same mutation [50].”
BackgroundCerebrovascular and cardiovascular responses associated with orthostatic intolerance and tachycardia
Harms, M. P. M., & LIESHOUT, J. J. V. (2001) · Clinical Autonomic Research · doi:10.1007/bf02317800 · Cited by 12
“orthostatic tachycardia syndrome [2] or orthostatic intolerance [3]) is characterized by symptoms, including fatigue, light-headedness, or dizziness, that occur when the patient-free of orthostatic hypotension [ 3-5 ] or evidence of cardiac or metabolic disease--assumes the standing position.”
BackgroundInfluentialHahn, M. K., & Blakely, R. (2003) · Humana Press eBooks · doi:10.1385/1-59259-158-2:111 · Cited by 12
Self-citationCarew, S., Cooke, J., O’Connor, M., Donnelly, T. M., Costelloe, Á., Sheehy, C. M., & Lyons, D. J. (2009) · EP Europace · doi:10.1093/europace/eup044 · Cited by 11
Perceptions of dentists, dentistry undergraduate students, and the lay public about dental sedation
Costa, L. R., Dias, A. D., Pinheiro, L. S., Chaves, M. E. P. D. S., Ferreira, R. D. A. R., de Almeida, R. B., & Lima, A. R. D. A. (2004) · Journal of Applied Oral Science · doi:10.1590/s1678-77572004000300004 · Cited by 11
Orthostatic Hypertension in Children and Adolescents with Postural Tachycardia Syndrome
Zhang, Q., Li, J., Xie, Y., Zhao, J., & Du, J. (2014) · Journal of Tropical Pediatrics · doi:10.1093/tropej/fmu055 · Cited by 12
Mu, L., Krämer, S. D., Warnock, G., et al. (2020) · EJNMMI Research · doi:10.1186/s13550-020-00700-7 · Cited by 11
Influence of an Insertion Variant in the 5ʹUTR of the Endothelin-1 Gene on Orthostatic Intolerance
Winker, R., Rüdiger, H. W., Garland, E. M., Diedrich, A., Biaggioni, I., Robertson, D., Ponocny, I., & Cascorbi, I. (2005) · The American Journal of the Medical Sciences · doi:10.1097/00000441-200510000-00003 · Cited by 11
Self-citationPharmacogenetics and Psychiatry
Basu, A., Tsapakis, E.-M., & Aitchison, K. (2004) · Current Psychiatry Reports · doi:10.1007/s11920-004-0053-5 · Cited by 11
“The Ala457Pro variant, although rare, has been associated with orthostatic intolerance and the transporter encoded by this variant has been shown to have a reduced affinity for noradrenaline [ 37 ].”
BackgroundKhan, A. W., Corcoran, S. J., Esler, M., & El-Osta, A. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.015 · Cited by 11
Familial orthostatic tachycardia
Keller, N. R., & Robertson, D. (2006) · Current Opinion in Cardiology · doi:10.1097/01.hco.0000221577.41125.c8 · Cited by 11
Self-citationHorvath, G., Torbati, A., Conner, G., Salathe, M., & Wanner, A. (2002) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2002-0030oc · Cited by 12
Signaling Pathways Take Aim at Neurotransmitter Transporters
Robinson, M. B. (2003) · Science s STKE · doi:10.1126/stke.2003.207.pe50 · Cited by 11
Orthostatic Intolerance in Behcet's Disease
Tellioğlu, T., & Robertson, D. (2001) · Autonomic Neuroscience · doi:10.1016/s1566-0702(01)00243-0 · Cited by 11
Self-citationRegulation of Monoamine Transporters: Regulated Phosphorylation, Dephosphorylation, and Trafficking
Ramamoorthy, S. (2003) · Humana Press eBooks · doi:10.1385/1-59259-158-2:001 · Cited by 12
Autonomic Dysfunction and Hypotension
Mathias, C. J. (2007) · Springer eBooks · doi:10.1007/978-1-84628-715-2_91 · Cited by 10
“In a family with identical twins, a genetic basis with a defect in the noradrenaline transporter system has been described, which accounted for the raised basal noradrenaline levels; mutation of the gene encoding the noradrenaline transporter was thought to be responsible.(119) The possibility of immunologically media…”
BackgroundAnimal Model of Neuropathic Tachycardia Syndrome
Carson, R. P., Appalsamy, M., Diedrich, A., Davis, T. L., & Robertson, D. (2001) · Hypertension · doi:10.1161/01.hyp.37.6.1357 · Cited by 10
Self-citationYoo, K. Y., Jeong, S. T., Ha, I. H., & Lee, A. J. (2003) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000058842.05373.e3 · Cited by 82
Chobanyan-Jürgens, K., Heusser, K., Duncker, D., Veltmann, C., May, M., Mehling, H., Luft, F. C., Schröder, C., Jordan, J., & Tank, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-26099-9 · Cited by 8
Self-citationLambert, É., Eikelis, N., Esler, M., Dawood, T., Schlaich, M. P., Bayles, R., Socratous, F., Agrotis, A., Jennings, G., Lambert, G. W., et al. (2008) · Autonomic Neuroscience · doi:10.1016/j.autneu.2008.10.003 · Cited by 9
Norepinephrine uptake mechanisms in cardiovascular disease deserve our attention.
Schroeder, C., & Jordan, J. (2011) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e31822eae22 · Cited by 8
“The patient was heterozygous for a previously unknown NET gene mutation (g237c).(3) The g237c mutation is associated with an alanine to proline (A457P) amino acid exchange.”
BackgroundSelf-citationVuorenpää, A., Ammendrup‐Johnsen, I., Jørgensen, T. N., et al. (2016) · Neurochemistry International · doi:10.1016/j.neuint.2016.03.013 · Cited by 9
Torres, G. E., & Caron, M. G. (2003) · Molecular Pharmacology · doi:10.1124/mol.64.2.196 · Cited by 9
“When considering other diseases, however, Shannon et al. (1999) have identified a loss-of-function mutation in the coding region of the norepinephrine transporter in a patient suffering from orthostatic intolerance and tachycardia.”
BackgroundIn vivo monitoring of norepinephrine and its metabolites in skeletal muscle
Tokunaga, N., Yamazaki, T., Akiyama, T., Sano, S., & Mori, H. (2003) · Neurochemistry International · doi:10.1016/s0197-0186(03)00064-0 · Cited by 10
Zhao, Y. (2004) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2004.01.011 · Cited by 9
Sučić, S., & Bönisch, H. (2016) · Neuromethods · doi:10.1007/978-1-4939-3765-3_1 · Cited by 8
Postural Tachycardia Syndrome: Diagnosis and Management in Adolescents and Young Adults
Heyer, G. L. (2017) · Pediatric Annals · doi:10.3928/19382359-20170322-01 · Cited by 10
Postural tachycardia syndrome and pregnancy
Bhatia, M., Kavi, L., & Nelson‐Piercy, C. (2018) · The Obstetrician & Gynaecologist · doi:10.1111/tog.12478 · Cited by 8
Dihydroxyphenylglycol as a Biomarker of Norepinephrine Transporter Inhibition by Atomoxetine
Bieck, P. R., Leibowitz, M. T., Lachno, D. R., Ledent, E., Padich, R. A., & Jhee, S. S. (2016) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000611 · Cited by 8
“Functional mutations of the human NET gene were first discovered in patients with orthostatic intolerance.(3) Drug-induced NET deficiency, using the selective NE reuptake inhibitor (NERI) reboxetine, created a phenotype mimicking idiopathic orthostatic intolerance.”
BackgroundRobertson, D., Diedrich, A., & Biaggioni, I. (2007) · Humana Press eBooks · doi:10.1007/978-1-59259-987-5_8 · Cited by 8
“Recently, norepinephrine transporter dysfunction has been identified as a disorder presenting with tachycardia and mildly increased blood pressure in certain circumstances ( 51 ).”
BackgroundSelf-citationFreeman, R., & Carson, P. (2003) · International Journal of Paediatric Dentistry · doi:10.1046/j.1365-263x.2003.00480.x · Cited by 8
Human Phenotypes and Animal Knockout Models of Genetic Autonomic Disorders
Usera, P. C., Vincent, S., & Robertson, D. (2004) · Journal of Biomedical Science · doi:10.1007/bf02256543 · Cited by 8
Self-citationKiyono, Y., Sugita, T., Ueda, M., et al. (2008) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2007.11.006 · Cited by 8
“Changes in NET have been reported in several cardiac failures [2–7].”
BackgroundNavigating Complexity in Postural Orthostatic Tachycardia Syndrome
Qu, H., & Hakonarson, H. H. (2024) · Biomedicines · doi:10.3390/biomedicines12081911 · Cited by 7
“Norepinephrine Transporter (NET) Deficiency: Mutation of the solute carrier family 6 member 2 gene ( SLC6A2 ) causes NET deficiency, which presents with symptoms similar to POTS [50].”
BackgroundDiehl, R. R. (2005) · Pacing and Clinical Electrophysiology · doi:10.1111/j.1540-8159.2005.00215.x · Cited by 7
Axelrod, F. B. (2013) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2012.12.002 · Cited by 7
Wehrwein, E. A., Novotný, M., Swain, G. M., Parker, L. M., Esfahanian, M., Spitsbergen, J. M., Habecker, B. A., & Kreulen, D. L. (2013) · Autonomic Neuroscience · doi:10.1016/j.autneu.2013.08.070 · Cited by 7
“…(Iversen, 1963, de Champlain et al., 1966, de Champlain et al., 1967, Kazda et al., 1969, Gudeska et al., 1976, LeLorier et al., 1976, Rascher et al., 1981, Krakoff et al., 1985) and in human subjects (Grassi et al., 1999, Shannon et al., 2000, Esler et al., 2001, Goldstein et al., 2002).”
BackgroundDominant Transmission Observed in Adolescents and Families With Orthostatic Intolerance
Posey, J. E., Martinez, R., Lankford, J. E., Lupski, J. R., Numan, M. T., & Butler, I. J. (2016) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2016.09.013 · Cited by 7
Mortensen, O. V., Larsen, M. B., & Amara, S. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00253 · Cited by 7
“Altered NET activity has been associated with mood disorders and cardiovascular diseases and a functional polymorphism causing the loss of NET function has been found in patients with orthostatic intolerance (Shannon et al., 2000).”
BackgroundBrown, C. R., Shetty, M., & Foster, J. D. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16241 · Cited by 6
Schroeder, C., Heusser, K., Zoerner, A. A., Großhennig, A., Wenzel, D., May, M., Sweep, F. C. G. J., Mehling, H., Luft, F. C., Tank, J., et al. (2014) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2014.25 · Cited by 6
Self-citationYuan, P., Lian, Z., Wang, Y., Wang, Y., Zhang, C., Du, J., Huang, Y., & Liao, Y. (2022) · Frontiers in Pediatrics · doi:10.3389/fped.2022.758100 · Cited by 7
“Most results supported that patients with VVS had relatively high vagal activity (16, 31– 33), while overactivation of sympathetic activity was one aspect of the pathogenesis of POTS (17, 34, 35).”
ResultPostural Orthostatic Tachycardia Syndrome as a Manifestation of Post-COVID-19 Syndrome
Trisvetova, E. L. (2022) · Rational Pharmacotherapy in Cardiology · doi:10.20996/1819-6446-2022-04-11 · Cited by 8
Orthostatic intolerance: potential pathophysiology and therapy.
Lu, C., Tseng, C., Tang, H., & Tung, C. (2004) · PubMed · Cited by 6
Clinical relevance of discoveries in psychopharmacogenetics1
Tsapakis, E.-M., Basu, A., & Aitchison, K. J. (2004) · Advances in Psychiatric Treatment · doi:10.1192/apt.10.6.455 · Cited by 6
Metadata
- Authors
- Shannon, J. R., Flattem, N. L., Jordan, J., Jacob, G., Black, B. K., Biaggioni, I., Blakely, R. D., & Robertson, D.
- Affiliations
- Vanderbilt University (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2000-02-24
- Volume
- 342
- Issue
- 8
- Pages
- 541-549
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2133465432
- Cited by
- 594
- References
- 34
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 14 · 2023: 9 · 2022: 17 · 2021: 13 · 2020: 22 · 2019: 17 · 2018: 18 · 2017: 15 · 2016: 22 · 2015: 11 · 2014: 15 · 2013: 23 · 2012: 16
- FWCI
- 49.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL056693)
- National Institute of Mental Health (MH 58921, R01MH058921)
- National Center for Research Resources (RR00095)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- orthostatic intolerance, postural orthostatic tachycardia syndrome, norepinephrine transporter, plasma norepinephrine, norepinephrine clearance, hyperadrenergic state, sympathetic hyperactivity, plasma catecholamines, dihydroxyphenylglycol, loss-of-function mutations
- MeSH terms
- Adult, Amino Acid Sequence, Base Sequence, Blood Pressure, Carrier Proteins, Female, Heart Rate, Humans, Male, Methoxyhydroxyphenylglycol, Molecular Sequence Data, Norepinephrine, Pedigree, Posture, Syncope, Tachycardia, Sequence Homology, Amino Acid, Mutation, Missense, Symporters, Norepinephrine Plasma Membrane Transport Proteins
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