Autonomic dysfunction and impaired cerebral autoregulation in cirrhosis.

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Autonomic dysfunction and impaired cerebral autoregulation in cirrhosis.
Clin Auton Res. 2006 Jun;16(3):208-16
Authors: Frøkjaer VG, Strauss GI, Mehlsen J, Knudsen GM, Rasmussen V, Larsen FS
Abstract
Cerebral blood flow autoregulation is lost in patients with severe liver cirrhosis. The cause of this is unknown. We determined whether autonomic dysfunction was related to impaired cerebral autoregulation in patients with cirrhosis. Fourteen patients with liver cirrhosis and 11 healthy volunteers were recruited. Autonomic function was assessed in response to deep breathing, head-up tilt and during 24-h Holter monitoring. Cerebral autoregulation was assessed by determining the change in mean cerebral blood flow velocity (MCAVm, transcranial Doppler) during an increase in blood pressure induced by norepinephrine infusion (NE). The severity of liver disease was assessed using the Child-Pugh scale (class A, mild; class B, moderate; class C, severe liver dysfunction).NE increased blood pressure similarly in the controls (27 (24-32) mmHg) and patients with the most severe liver cirrhosis (Child-Pugh C, 31 (26-44) mmHg, p=0.405 Mann-Whitney). However, the increase in MCAVm was greater in cirrhosis patients compared to the controls (Child-Pugh C, 26 (24-39) %; controls, 3 (-1.3 to 3) %; respectively, p=0.016, Mann-Whitney). HRV during deep breathing was reduced in the cirrhosis patients (Child-Pugh C, 6.0+/-2.0 bpm) compared to the controls (21.7+/-2.2 bpm, p=0.001, Tukey’ test). Systolic blood pressure fell during head-up tilt only in patients with severe cirrhosis. Our results imply that cerebral autoregulation was impaired in the most severe cases of liver cirrhosis, and that those with impaired cerebral autoregulation also had severe parasympathetic and sympathetic autonomic dysfunction. Furthermore, the degree of liver dysfunction was associated with increasing severity of autonomic dysfunction. Although this association is not necessarily causal, we postulate that the loss of sympathetic innervation to the cerebral resistance vessels may contribute to the impairment of cerebral autoregulation in patients with end-stage liver disease.
PMID: 16572350 [PubMed – indexed for MEDLINE]
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Quantification of 123I-PE2I binding to dopamine transporter with SPECT after bolus and bolus/infusion.

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Quantification of 123I-PE2I binding to dopamine transporter with SPECT after bolus and bolus/infusion.
J Nucl Med. 2005 Jul;46(7):1119-27
Authors: Pinborg LH, Ziebell M, Frøkjaer VG, de Nijs R, Svarer C, Haugbøl S, Yndgaard S, Knudsen GM
Abstract
UNLABELLED: The aim of the present study was to describe a method combining easy implementation in a clinical setting with accuracy and precision in quantification of 123I-labeled N-(3-iodoprop-(2E)-enyl)-2beta-carboxymethoxy-3beta-(4′-methylphenyl)nortropane (PE2I) binding to brain dopamine transporter.
METHODS: Five healthy subjects (mean age, 50 y; range, 40-68 y) were studied twice. In the first experiment, dynamic SPECT data and arterial plasma input curves obtained after 123I-PE2I bolus injection were assessed using Logan, kinetic, transient equilibrium, and peak equilibrium analyses. Accurate and precise determination of BP1 (binding potential times the free fraction in the metabolite-corrected plasma compartment) and BP2 (binding potential times the free fraction in the intracerebral nonspecifically bound compartment) was achieved using Logan analysis and kinetic analysis, with a total study time of 90 min. In the second experiment, (123)I-PE2I was administrated as a combined bolus and constant infusion. The bolus was equivalent to 2.7 h of constant infusion.
RESULTS: The bolus-to-infusion ratio of 2.7 h was based on the average terminal clearance rate from plasma in the bolus experiments. Steady state was attained in brain and plasma within 2 h, and time-activity curves remained constant for another 2 h. Even when an average bolus-to-infusion ratio was used, the striatal BP1 and BP2 values calculated with kinetic analysis (BP1 = 21.1 +/- 1.1; BP2 = 4.1 +/- 0.4) did not significantly differ from those calculated with bolus/infusion analysis (BP1 = 21.0 +/- 1.2; BP2 = 4.3 +/- 0.3). Computer simulations confirmed that a 2-fold difference in terminal clearance rate from plasma translates into only a 10% difference in BP1 and BP2 calculated from 120 to 180 min after tracer administration.
CONCLUSION: The bolus/infusion approach allows accurate and precise quantification of 123I-PE2I binding to dopamine transporter and is easily implemented in a clinical setting.
PMID: 16000280 [PubMed – indexed for MEDLINE]
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MR-based automatic delineation of volumes of interest in human brain PET images using probability maps.

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MR-based automatic delineation of volumes of interest in human brain PET images using probability maps.
Neuroimage. 2005 Feb 15;24(4):969-79
Authors: Svarer C, Madsen K, Hasselbalch SG, Pinborg LH, Haugbøl S, Frøkjaer VG, Holm S, Paulson OB, Knudsen GM
Abstract
The purpose of this study was to develop and validate an observer-independent approach for automatic generation of volume-of-interest (VOI) brain templates to be used in emission tomography studies of the brain. The method utilizes a VOI probability map created on the basis of a database of several subjects’ MR-images, where VOI sets have been defined manually. High-resolution structural MR-images and 5-HT(2A) receptor binding PET-images (in terms of (18)F-altanserin binding) from 10 healthy volunteers and 10 patients with mild cognitive impairment were included for the analysis. A template including 35 VOIs was manually delineated on the subjects’ MR images. Through a warping algorithm template VOI sets defined from each individual were transferred to the other subjects MR-images and the voxel overlap was compared to the VOI set specifically drawn for that particular individual. Comparisons were also made for the VOI templates 5-HT(2A) receptor binding values. It was shown that when the generated VOI set is based on more than one template VOI set, delineation of VOIs is better reproduced and shows less variation as compared both to transfer of a single set of template VOIs as well as manual delineation of the VOI set. The approach was also shown to work equally well in individuals with pronounced cerebral atrophy. Probability-map-based automatic delineation of VOIs is a fast, objective, reproducible, and safe way to assess regional brain values from PET or SPECT scans. In addition, the method applies well in elderly subjects, even in the presence of pronounced cerebral atrophy.
PMID: 15670674 [PubMed – indexed for MEDLINE]
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[Renal stone and primary hyperparathyroidism. Risk of renal stone before and after parathyroidectomy].

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[Renal stone and primary hyperparathyroidism. Risk of renal stone before and after parathyroidectomy].
Ugeskr Laeger. 2004 Oct 11;166(42):3726-8
Authors: Mollerup CL, Vestergaard P, Frøkjaer VG, Mosekilde L, Christiansen PM, Blichert-Toft M
PMID: 15508296 [PubMed – indexed for MEDLINE]
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A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables.

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A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables.
Neuroimage. 2004 Mar;21(3):1105-13
Authors: Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbøl S, Madsen K, Frøkjaer V, Martiny L, Paulson OB, Knudsen GM
Abstract
This study presents the results of an analysis of 5-hydroxytryptamine (5-HT)(2A) receptors in 52 healthy subjects. Thirty men and twenty-two women aged between 21 and 79 years were investigated with magnetic resonance imaging (MRI) and [(18)F]-altanserin positron emission tomography (PET). The distribution volumes of specific tracer binding (DV(3)’) was calculated for 15 brain regions using either cerebellum or pons as reference regions and correlations between DV(3)’ and physiological and demographic variables were made. The regional distribution of [(18)F]-altanserin binding in the healthy human brain was in agreement with existing in vitro post-mortem human 5-HT(2A) data. Apart from nonspecific cerebellar binding (DV(2)), there was no gender difference in 5-HT(2A) binding. A positive correlation between cerebellar binding and age was observed and negative correlations between age and DV(3)’ were found in all cortical regions, except occipital cortex, corresponding to a decrease in DV(3)’ of 6% or 4% per decade with cerebellum or pons as reference regions, respectively. In several temporal and frontal cortical regions, positive correlations were found between body mass index (BMI) and DV(3)’. Our findings provide a resource to aid design of clinical studies of the 5-HT(2A) receptors. [(18)F]-altanserin binding appears to be unaffected by gender, but the effects of ageing must be considered for clinical studies. The correlations between different cortical regions’ 5-HT(2A) binding and BMI should be explored in future studies.
PMID: 15006678 [PubMed – indexed for MEDLINE]
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Cardiovascular events before and after surgery for primary hyperparathyroidism.

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Cardiovascular events before and after surgery for primary hyperparathyroidism.
World J Surg. 2003 Feb;27(2):216-22
Authors: Vestergaard P, Mollerup CL, Frøkjaer VG, Christiansen P, Blichert-Toft M, Mosekilde L
Abstract
Cardiovascular disease [atherosclerosis and subsequent myocardial infarction (MI)] has been associated with primary hyperparathyroidism. We aimed at studying cardiovascular events before and after surgery and mortality after surgery for primary hyperparathyroidism using a historical follow-up design. A total of 674 patients who underwent surgery at three Danish centers between January 1, 1979 and December 31, 1997 were compared with 2021 age- and gender-matched controls. There was an increased incidence of acute MI up to 10 years prior to surgery [relative risk (RR) 2.5, 95% confidence interval (95% CI) 1.5-4.2] and within the first year following surgery (RR 3.6, 95% CI 1.7-7.6). The risk of MI subsequently declined to a normal level more than 1 year after surgery. Patients with MI prior to diagnosis also had a higher postoperative risk of new infarction than did patients without [odds ratio (OR) 6.0, 95% CI 1.2-30.0]. The risk of hypertension, stroke, congestive heart failure, and diabetes was increased before surgery. More than 1 year after surgery only hypertension and congestive heart failure were more frequent in patients than controls. Preoperative cardiovascular disease was associated with an increased risk of death (RR 1.8, 95% CI 1.1-2.8). Mortality following surgery was higher than in the general population between 1979 and 1990 but not between 1991 and 1997. We concluded that there was an increase in acute MI up to 10 years prior to surgery. The risk of MI decreased to a normal level after surgery, which may be important for preventing cardiovascular disease in patients with primary hyperparathyroidism.
PMID: 12616440 [PubMed – indexed for MEDLINE]
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Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study.

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Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study.
BMJ. 2002 Oct 12;325(7368):807
Authors: Mollerup CL, Vestergaard P, Frøkjaer VG, Mosekilde L, Christiansen P, Blichert-Toft M
Abstract
AIM: To study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery.
DESIGN: Register based, controlled retrospective follow up study.
SETTING: Tertiary hospitals in Denmark.
PARTICIPANTS: 674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed.
MAIN OUTCOME MEASURES: Number of renal stone episodes; comparison of hospital admissions for renal stones in patients and controls; assessment of risk factors for renal stones.
RESULTS: Relative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones.
CONCLUSIONS: The risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.
PMID: 12376441 [PubMed – indexed for MEDLINE]
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Primary hyperparathyroidism: renal calcium excretion in patients with and without renal stone sisease before and after parathyroidectomy.

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Primary hyperparathyroidism: renal calcium excretion in patients with and without renal stone sisease before and after parathyroidectomy.
World J Surg. 2002 May;26(5):532-5
Authors: Frøkjaer VG, Mollerup CL
Abstract
The effect of parathyroidectomy on renal calcium excretion per 24 hours in patients with primary hyperparathyroidism with and without a history of renal stone disease was evaluated. Altogether, 91 patients operated on for primary hyperparathyroidism formed the study group for preoperative analysis. Of these patients, 42 were evaluated 1 to 3 years postoperatively. The median preoperative serum calcium level was 2.92 mmol/L, and it was the same for patients with or without renal stones. Preoperatively we found no differences in renal calcium excretion between patients with and without renal stone disease. The median renal calcium excretion was 6.80 mmol/24 hr. At 1 to 3 years after successful parathyroidectomy the group with renal stone disease had higher renal calcium excretion than the group without renal stones (p = 0.03). The reduced effect of parathyroidectomy on renal calcium excretion in the patients with renal stone disease indicates that factors not related to the hyperparathyroid state could contribute to disturbances in renal calcium excretion and hence stone formation. In conclusion, the pathologic basis for renal stone formation in patients with primary hyperparathyroidism might not be the hyperparathyroid state alone; stone formation could be related to other predisposing factors as well. Therefore, although parathyroidectomy can cure hyperparathyroidism, the curative effect on renal stone disease should be reconsidered.
PMID: 12098039 [PubMed – indexed for MEDLINE]
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[Cohort study of fracture risk before and after surgery of primary hyperparathyroidism].

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[Cohort study of fracture risk before and after surgery of primary hyperparathyroidism].

Ugeskr Laeger. 2001 Sep 3;163(36):4875-8

Authors: Vestergaard P, Mollerup CL, Frøkjaer VG, Christiansen PM, Blichert-Toft M, Mosekilde L

Abstract
We studied the risk of fracture in 674 patients operated on for primary hyperparathyroidism compared to 2,021 age- and gender-matched controls, matched for age and gender, randomly drawn from the background population. Before surgery, there was an increased risk of fracture (relative risk 1.8, 9% confidence interval 1.3-2.3), but after surgery the relative risk was normalised (RR = 1.0, 0.8-1.3). The increased risk began ten years before surgery and peaked five to six years before surgery. After surgery, there was a temporary increase in the first year, but in the following years the fracture risk was normalised, with a small rise in distal forearm fractures more than ten years after surgery. Primary hyperparathyroidism may have started up to ten years before surgery, and the fracture risk is normalised after surgery.

PMID: 11571864 [PubMed – indexed for MEDLINE]

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Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism.

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Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism.
BMJ. 2000 Sep 9;321(7261):598-602
Authors: Vestergaard P, Mollerup CL, Frøkjaer VG, Christiansen P, Blichert-Toft M, Mosekilde L
Abstract
OBJECTIVES: To study whether fracture risk before and after surgery was increased in patients with primary hyperparathyroidism.
DESIGN: Cohort study.
SETTING: Three Danish university hospitals.
PARTICIPANTS: 674 consecutive patients with primary hyperparathyroidism (median age 61, range 13-89 years) operated on during the period 1 January 1979 to 31 December 1997; 2021 age and sex matched controls from national patient register.
MAIN OUTCOME MEASURE: Fractures.
RESULTS: The cases had an increased relative rate of fractures compared with the controls before surgery (1.8, 95% confidence interval 1.3 to 2.3) but not after surgery (1.0, 0.8 to 1.3). The risk of fracture was increased for the vertebrae (3.5, 1.3 to 9.7), the distal part of the lower leg and ankles (2.3, 1.2 to 4.3), and the non-distal part of the forearm (4.0, 1.5 to 10.6) before surgery but not after. The increase in risk of fracture began about 10 years before surgery. Risk peaked 5-6 years before surgery and remained raised, although at a lower level, in the five years immediately before surgery. A small increase in risk of fracture of the distal forearm emerged more than 10 years after surgery (2.9, 1. 3 to 6.7).
CONCLUSIONS: Risk of fracture is increased up to 10 years before surgery in patients with primary hyperparathyroidism. The risk returns to normal after surgery.
PMID: 10977834 [PubMed – indexed for MEDLINE]
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