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.”
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Common Syndromes of Orthostatic Intolerance
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Sung, U., Apparsundaram, S., Galli, A., Kahlig, K. M., Savchenko, V. L., Schroeter, S., Quick, M. W., & Blakely, R. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-05-01697.2003 · Cited by 157
“…or NET density has been associated with attention and mood disorders (Hadley et al., 1995; Delgado and Moreno, 2000; Arnsten, 2001), suicide (Klimek et al., 1997), and cardiovascular disease (Esler et al., 1981; Liang et al., 1989; Merlet et al., 1992; Bohm et al., 1995; Shannon et al., 2000).”
BackgroundSelf-citationEndurance Exercise Training in Orthostatic Intolerance
Winker, R., Barth, A., Bidmon, D., Ponocny, I., Weber, M., Mayr, O., Robertson, D., Diedrich, A., Maier, R., Pilger, A., et al. (2005) · Hypertension · doi:10.1161/01.hyp.0000156540.25707.af · Cited by 156
Self-citationKim, C.-H., Hahn, M. K., Joung, Y., Anderson, S., Steele, A., Mazei-Robinson, M. S., Gizer, I., Teicher, M. H., Cohen, B., Robertson, D., et al. (2006) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0510836103 · Cited by 152
Self-citationRegulation of monoamine transporters: Role of transporter phosphorylation
Ramamoorthy, S., Shippenberg, T. S., & Jayanthi, L. D. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.09.009 · Cited by 151
“The hNET gene polymorphismwith an Ala-457Promutation in the coding region has been identified in an individual with the autonomic disorder orthostatic intolerance (OI) (Shannon et al., 2000).”
BackgroundJayanthi, L. D., Samuvel, D. J., & Ramamoorthy, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311172200 · Cited by 147
Differential physiological effects of a low dose and high doses of venlafaxine in major depression
Debonnel, G., Saint-André, É., Hébert, C., de Montigny, C., Lavoie, N., & Blier, P. (2006) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145705006413 · Cited by 148
Hahn, M. K., & Blakely, R. (2002) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500106 · Cited by 141
Self-citationSympathetic Nerve Biology In Essential Hypertension
Esler, M., Rumantir, M. S., Kaye, D. M., Jennings, G., Hastings, J., Socratous, F., & Lambert, G. W. (2001) · Clinical and Experimental Pharmacology and Physiology · doi:10.1046/j.1440-1681.2001.03566.x · Cited by 139
“We were encouraged in this line of thinking by the recent description of a missense mutation of the noradrenaline transporter gene in a family kindred with the postural tachycardia syndrome in whom the exaggerated reflex increase in heart rate with standing, which is a cardinal feature of the disorder, was due to the…”
BackgroundAlvarenga, M. E., Richards, J. C., Lambert, G., & Esler, M. D. (2006) · Psychosomatic Medicine · doi:10.1097/01.psy.0000195872.00987.db · Cited by 136
“It is perhaps noteworthy that this phenotype of impaired neuronal noradrenaline reuptake is also well documented in essential hypertension (48) and the postural tachycardia syndrome (49), both being conditions which commonly coexist with PD (41,49,50).”
BackgroundAutonomic dysfunction in peripheral nerve disease
Low, P. A., Vernino, S. A., & Suárez, G. A. (2003) · Muscle & Nerve · doi:10.1002/mus.10333 · Cited by 134
Psychiatric profile and attention deficits in postural tachycardia syndrome
Raj, V, Haman, K. L., Raj, S. R., Byrne, D., Blakely, R. D., Biaggioni, I., Robertson, D., & Shelton, R. C. (2009) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2008.144360 · Cited by 131
“[10–13] Peripheral plasma norepinephrine (NE) is frequently raised in patients with POTS, particularly when upright, and many clinical features of POTS such as tachycardia, palpitations, shortness of breath, chest discomfort and tremor mimic the hyperadrenergic features of a panic attack.”
BackgroundSelf-citationSelective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance
Schroeder, C., Tank, J., Boschmann, M., Diedrich, A., Sharma, A. M., Biaggioni, I., Luft, F. C., & Jordan, J. (2002) · Circulation · doi:10.1161/hc0302.102597 · Cited by 127
Self-citationHahn, M. K., Robertson, D., & Blakely, R. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-11-04470.2003 · Cited by 126
“Expression of hNET-A457P in COS-7 cells yielded transport activity at 1–2% of hNET-wt levels, consistent with our previous observations in several other cell lines (Shannon et al., 2000).”
BackgroundMethodResultInfluentialSelf-citationSeidel, S., Singer, E. A., Just, H., et al. (2005) · PubMed · doi:10.1124/mol.67.1 · Cited by 126
The Functional Impact of SLC6 Transporter Genetic Variation
Hahn, M. K., & Blakely, R. (2006) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105242 · Cited by 128
Self-citationKucharik, A. H., & Chang, C. (2020) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-019-08755-8 · Cited by 122
Postural orthostatic tachycardia syndrome: mechanisms and new therapies
Mar, P. L., & Raj, S. R. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-041818-011630 · Cited by 122
Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification
Janssen, B. J., & Smits, J. F. M. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00714.2001 · Cited by 123
Sawamura, S., Kingery, W. S., Davies, M. F., Agashe, G. S., Clark, J. D., Kobilka, B. K., Hashimoto, T., & Maze, M. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-24-09242.2000 · Cited by 136
Postural Orthostatic Tachycardia Syndrome: A Clinical Review
Johnson, J. N., Mack, K. J., Kuntz, N. L., Brands, C. K., Porter, C. J., & Fischer, P. R. (2010) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2009.07.002 · Cited by 119
“One specific gene mutation in patients with orthostatic intolerance is norepinephrine transporter protein deficiency, first reported in a family in 2000 [27].”
BackgroundInfluentialAdolescent Fatigue, POTS, and Recovery: A Guide for Clinicians
Kizilbash, S. J., Ahrens, S. P., Bruce, B. K., Chelimsky, G., Driscoll, S. W., Harbeck-Weber, C., Lloyd, R. M., Mack, K. J., Nelson, D. E., Ninis, N., et al. (2014) · Current Problems in Pediatric and Adolescent Health Care · doi:10.1016/j.cppeds.2013.12.014 · Cited by 120
Mechanisms of sympathetic regulation in orthostatic intolerance
Stewart, J. M. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00266.2012 · Cited by 126
“Alternatively, synaptic NE may be increased: as epitomized by the norepinephrine transporter deficiency heterozygote (77), an autosomal mutation, found so far in only one pedigree with variable penetrance.”
BackgroundChronic orthostatic intolerance and the postural tachycardia syndrome (POTS)
Stewart, J. M. (2004) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2004.06.084 · Cited by 116
Cardiac Sympathetic Dysautonomia in Chronic Orthostatic Intolerance Syndromes
Goldstein, D. S., Holmes, C. S., Frank, S. M., Dendi, R., Cannon, R. O., Sharabi, Y., Esler, M., & Eisenhofer, G. (2002) · Circulation · doi:10.1161/01.cir.0000036015.54619.b6 · Cited by 114
Mason, J. N., Farmer, H., Tomlinson, I. D., Schwartz, J., Savchenko, V. L., DeFelice, L. J., Rosenthal, S. J., & Blakely, R. (2004) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.09.028 · Cited by 114
Self-citationOrthostatic hypertension: when pressor reflexes overcompensate
Fessel, J. P., & Robertson, D. (2006) · Nature Reviews Nephrology · doi:10.1038/ncpneph0228 · Cited by 113
Self-citationWilson, K., Girdler, N. M., & Welbury, R. R. (2003) · British Journal of Anaesthesia · doi:10.1093/bja/aeg278 · Cited by 110
Cardiovascular Abnormalities in Patients with Major Depressive Disorder
Brown, A. D. H., Barton, D. A., & Lambert, G. W. (2009) · CNS Drugs · doi:10.2165/00023210-200923070-00004 · Cited by 111
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Goldstein, D. S. (2010) · Clinical Autonomic Research · doi:10.1007/s10286-010-0065-7 · Cited by 112
“identify dysautonomia from NET hypofunction [112]; however, there are several other potential determinants of”
BackgroundHow LeuT shapes our understanding of the mechanisms of sodium‐coupled neurotransmitter transporters
Penmatsa, A., & Gouaux, E. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.259051 · Cited by 107
“Dysfunction of transport activity in SLC6 members has been associated with Parkinson’s disease, depression, schizophrenia, Tourette’s syndrome, attention deficit hyperactivity disorder (ADHD) and orthostatic intolerance (Masson et al. 1999; Shannon et al. 2000; Kristensen et al. 2011).”
BackgroundStructures of LeuT in bicelles define conformation and substrate binding in a membrane-like context
Wang, H., Elferich, J., & Gouaux, E. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2215 · Cited by 107
Norepinephrine transporter function and human cardiovascular disease
Schroeder, C., & Jordan, J. (2012) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00492.2012 · Cited by 109
“Most of the functional polymorphisms code for NET variants with decreased norepinephrine affinity (14) [R121Q, N292T, A369P, Y548H (45), and A457P (106, 116)].”
Self-citationThe Postural Orthostatic Tachycardia Syndrome:
Kanjwal, Y., KOSINSKI, D. J., & Grubb, B. P. (2003) · Pacing and Clinical Electrophysiology · doi:10.1046/j.1460-9592.2003.t01-1-00262.x · Cited by 103
Japanese clinical guidelines for juvenile orthostatic dysregulation version 1
Tanaka, H., Fujita, Y., 竹中, 義., Kajiwara, S., Masutani, S., Ishizaki, Y., Matsushima, R., 塩川宏郷, Shiota, M., Ishitani, N., et al. (2009) · Pediatrics International · doi:10.1111/j.1442-200x.2008.02783.x · Cited by 107
Apparsundaram, S., Sung, U., Price, R. D., & Blakely, R. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29276-4 · Cited by 105
“Recently, we identified a loss of function mutation in NET associated with symptoms of orthostatic intolerance (Shannon et al., 2000).”
Self-citationThe Postural Tachycardia Syndrome
Medow, M. S., & Stewart, J. M. (2007) · Cardiology in Review · doi:10.1097/01.crd.0000233768.68421.40 · Cited by 105
Seidel, S., Singer, E. A., Just, H., et al. (2005) · Molecular Pharmacology · doi:10.1124/mol.67.1.140 · Cited by 103
“4) A mutation in the norepinephrine transporter causes intracellular retention of the transporter (Hahn et al., 2003) and is associated with postural hypotension in people (Shannon et al., 2000).”
BackgroundVincent, S., Bieck, P. R., Garland, E. M., Loghin, C., Bymaster, F. P., Black, B. K., Gonzales, C., Potter, W. Z., & Robertson, D. (2004) · Circulation · doi:10.1161/01.cir.0000130847.18666.39 · Cited by 102
Self-citationEnhanced Serotonin Transporter Function during Depression in Seasonal Affective Disorder
Willeit, M., Sitte, H. H., Thierry, N., Michalek, K., Praschak-Rieder, N., Zill, P., Winkler, D., Brannath, W., Fischer, M. B., Bondy, B., et al. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301560 · Cited by 100
“Function and surface expression of the closely related norepinephrine and dopamine transporters are influenced by partly pathogenic mutations (Hahn et al, 2005, 2003; Nass et al, 2005; Shannon et al, 2000).”
Phenotypes associated with genes encoding drug targets are predictive of clinical trial side effects
Nguyen, P. A., Born, D. A., Deaton, A. M., Nioi, P., & Ward, L. D. (2019) · Nature Communications · doi:10.1038/s41467-019-09407-3 · Cited by 100
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Anderson, J. W., Lambert, E. A., Sari, C. I., Dawood, T., Esler, M. D., Vaddadi, G., & Lambert, G. W. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00230 · Cited by 96
“Noradrenaline transporter (NET) dysfunction is evident in patients with POTS (Shannon et al., 2000; Lambert et al., 2008) and in untreated patients with major depressive disorder (Barton et al., 2007).”
BackgroundKinase-dependent Regulation of Monoamine Neurotransmitter Transporters
Bermingham, D. P., & Blakely, R. D. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.012260 · Cited by 97
“Now that phenotypes have been defined in humans (Kim et al., 2006; Shannon et al., 2000) and rodents (Shirey-Rice et al.”
BackgroundSelf-citationPhenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension
Rumantir, M. S., Kaye, D. M., Jennings, G. L., Vaz, M., Hastings, J. A., & Esler, M. D. (2000) · Hypertension · doi:10.1161/01.hyp.36.5.824 · Cited by 95
Lambert, E., Eikelis, N., Esler, M., Dawood, T., Schlaich, M., Bayles, R., Socratous, F., Agrotis, A., Jennings, G., Lambert, G., et al. (2008) · Circulation: Arrhythmia and Electrophysiology · doi:10.1161/circep.107.750471 · Cited by 94
Diagnosis and management of postural orthostatic tachycardia syndrome
Raj, S. R., Fedorowski, A., & Sheldon, R. S. (2022) · Canadian Medical Association Journal · doi:10.1503/cmaj.211373 · Cited by 95
Neuronal Source of Plasma Dopamine
Goldstein, D. S., & Holmes, C. S. (2008) · Clinical Chemistry · doi:10.1373/clinchem.2008.107193 · Cited by 93
“Disorders involving decreased activity of the vesicular monoamine transporter or DBH would be expected to entail lower plasma NE than DA, as has been reported in DBH deficiency (36) andinMenkesdisease(37).InPOTS,increasedplasma concentrations of both DA and NE are consistent with increased overall sympathetic nerve tr…”
Background
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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