Background There are conflicting reports with regard to the allele‐specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of the KCNQ1 gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele‐specific effects of 3 previously published 3'UTR‐KCNQ1's SNPs in a LQT1 founder population segregating a dominant‐negative mutation. Methods and Results Bidirectional sequencing of the KCNQ1's 3'UTR was performed in the p.Y111C founder population (n=232, 147 genotype positive), with a minor allele frequency of 0.1 for SNP1 (rs2519184) and 0.6 for linked SNP2 (rs8234) and SNP3 (rs107980). Allelic phase was assessed in trios aided by haplotype data, revealing a high prevalence of derived SNP2/3 in cis with p.Y111C (89%). Allele‐specific association analyses, corrected using a relatedness matrix, were performed between 3'UTR‐KCNQ1 SNP genotypes and clinical phenotypes. SNP1 in trans was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele in trans (58% versus 32%, corrected P=0.027). SNP2/3 in cis was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele in cis (32% versus 69%, corrected P=0.010). Conclusions Allele‐specific modifying effects on symptomatic phenotype of 3'UTR‐KCNQ1 SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant‐negative mutation. The high prevalence of suppressive 3'UTR‐KCNQ1 SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C KCNQ1 mutation.

Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1AP sequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations.

Background— Early diagnosis and risk stratification is of clinical importance in the long QT syndrome (LQTS), however, little genotype-specific data are available regarding fetal LQTS. We investigate third trimester fetal heart rate, routinely recorded within public maternal health care, as a possible marker for LQT1 genotype and phenotype. Methods and Results— This retrospective study includes 184 fetuses from 2 LQT1 founder populations segregating p.Y111C and p.R518X (74 noncarriers and 110 KCNQ1 mutation carriers, whereof 13 double mutation carriers). Pedigree-based measured genotype analysis revealed significant associations between fetal heart rate, genotype, and phenotype; mean third trimester prelabor fetal heart rates obtained from obstetric records (gestational week 29–41) were lower per added mutation (no mutation, 143±5 beats per minute; single mutation, 134±8 beats per minute; double mutations, 111±6 beats per minute; P <0.0001), and lower in symptomatic versus asymptomatic mutation carriers (122±10 versus 137±9 beats per minute; P <0.0001). Strong correlations between fetal heart rate and neonatal heart rate ( r =0.700; P <0.001), and postnatal QTc ( r =−0.762; P <0.001) were found. In a multivariable model, fetal genotype explained the majority of variance in fetal heart rate (−10 beats per minute per added mutation; P <1.0×10 –23 ). Arrhythmia symptoms and intrauterine β-blocker exposure each predicted −7 beats per minute, P <0.0001. Conclusions— In this study including 184 fetuses from 2 LQT1 founder populations, third trimester fetal heart rate discriminated between fetal genotypes and correlated with severity of postnatal cardiac phenotype. This finding strengthens the role of fetal heart rate in the early detection and risk stratification of LQTS, particularly for fetuses with double mutations, at high risk of early life-threatening arrhythmias.

BACKGROUND:The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p.R518X mutation.METHODS:The study included 19 Swedish p.R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software).RESULTS:Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%).A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p.R518X heterozygotes was suggested (~1:2000-4000).CONCLUSIONS:R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.

OBJECTIVES:To compare the plasma volume (PV) expanding effect of a fast infusion rate with that of a slow infusion rate of a fixed volume of 5% albumin, of the synthetic colloids, 6% hydroxyethyl starch 130/0.4 and 4% gelatin, and of 0.9% NaCl in a rat sepsis model and to compare the plasma-expanding effect among these fluids.DESIGN:Prospective, randomized animal study.SETTING:University hospital laboratory.SUBJECTS:One hundred and twelve adult male rats.INTERVENTIONS:Sepsis was induced by cecal ligation and incision followed by closure of the abdomen. After 3 hrs, an infusion of the PV expander under study was started at a volume of 12mL/kg for the colloids and of 48mL/kg for 0.9% NaCl, either for 15 mins or for 3 hrs. A control group underwent the same experimental procedure but no fluid was given.MEASUREMENTS AND MAIN RESULTS:Three hours after start of the infusion (end of experiment), the plasma-expanding effect was better with a slow than a fast infusion rate for the colloids, especially albumin, but the NaCl groups did not differ significantly from the control group. The PV for the control group was 28.7±3mL/kg. In the slow and the fast infusion groups, it was 38.9±4.3 and 32.6±4.2mL/kg for albumin (p < 0.001), 32.9±4.3 and 29.5±4.4mL/kg for hydroxyethyl starch 130/0.4 (p < 0.05), 31.8±3.9 and 28.2±4.1mL/kg for gelatin (p < 0.05), and 31.8±5.3 and 30.7±6.6mL/kg for NaCl (n.s), respectively.CONCLUSIONS:The study showed that the PV expansion by a colloid was greater when given at a slow than at a fast infusion rate, an effect more pronounced for albumin. This difference was not seen for NaCl. The PV-expanding effect was poor for NaCl and better for albumin than for the other colloids.

AIMS:To explore the national prevalence, mutation spectrum, cardiac phenotype, and outcome of the uncommon Jervell and Lange-Nielsen syndrome (JLNS), associated with a high risk of sudden cardiac death.METHODS AND RESULTS:A national inventory of clinical JLNS cases was performed. Genotype and area of origin were ascertained in index families. Retrospective clinical data were collected from medical records and interviews. We identified 19 cases in 13 Swedish families. A JLNS prevalence >1:200 000 was revealed (five living cases <10 years of age). The mutation spectrum consisted of eight KCNQ1 mutations, whereof p.R518X in 12/24 alleles. Geographic clustering of four mutations (20/24 alleles) and similarities to Norway's mutation spectrum were seen. A high prevalence of heterozygotes was suggested. Three paediatric cases on β-blockers since birth were as yet asymptomatic. Seven symptomatic cases had suffered an aborted cardiac arrest and four had died suddenly. QTc prolongation was significantly longer in symptomatic cases (mean 605 ± 62 vs. 518 ± 50 ms, P = 0.016). β-Blockers reduced, but did not abolish, cardiac events in any previously symptomatic case. β-Blocker type, dosage, and compliance probably affect outcome significantly. Implantable cardioverter-defibrillator therapy (ICD, n = 6) was associated with certain complications; however, no case of sudden death.CONCLUSION:Founder effects could explain 83% of the Swedish JLNS mutation spectrum and probably contribute to the high JLNS prevalence found in preadolescent Swedish children. Due to the severe cardiac phenotype in JLNS, the importance of stringent β-blocker therapy and compliance, and consideration of ICD implantation in the case of therapy failure is stressed.

Background: Genetic modifiers have been proposed to explain phenotypic variability in the long QT syndrome (LQTS). We investigate the origin and phenotype of the worldwide common R518X/KCNQ1 mutati ...

BACKGROUND:The Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro but a benign clinical phenotype in a Swedish long QT syndrome population.OBJECTIVE:The purpose of this study was to investigate the origin (genealogic, geographic, genetic, and age) of the Y111C/KCNQ1 mutation in Sweden.METHODS:We identified 170 carriers of the Y111C/KCNQ1 mutation in 37 Swedish proband families. Genealogic investigation was performed for all families. Haplotype analysis was performed in 26 probands, 21 family members, and 84 healthy Swedish controls, using 15 satellite markers flanking the KCNQ1 gene. Mutation age was estimated using ESTIAGE and DMLE computer software and regional population demographic data.RESULTS:All probands were traced back to a northern river valley region. A founder couple born in 1605/1614 connected 26 of 37 families. Haplotyped probands shared 2-14 (median 10) uncommon alleles, with frequencies ranging between 0.01 and 0.41 (median 0.16) in the controls. The age of the mutation was estimated to 24 generations (95% confidence interval 18; 34), that is, 600 years (95% confidence interval 450; 850) assuming 25 years per generation. The number of now living Swedish Y111C mutation carriers was estimated to approximately 200-400 individuals for the mutation age span 22-24 generations and population growth rates 25%-27%.CONCLUSION:The Y111C/KCNQ1 mutation is a Swedish long QT syndrome founder mutation that was introduced in the northern population approximately 600 years ago. Enrichment of the mutation was enabled by a mild clinical phenotype and strong regional founder effects during population development of the northern inland. The Y111C/KCNQ1 founder population constitutes an important asset for future genetic and clinical studies.

Background: We still lack comparing data of the plasma volume (PV)-expanding effect of the most commonly used colloids including dextran 70. This study compares the PV-expanding effects of 6% dextran 70, 5% albumin, and 6% hydroxyethylstarch (HES) 130/0.4 after a standardized hemorrhage.Methods: The prospective and randomized study on 33 anesthetized adult male guinea pigs involved three groups (n = 11 each); the dextran group, the albumin group, and the HES group. The left carotis artery was cannulated for blood pressure measurements and blood samples, and the right jugular vein was cannulated for infusions. After hemorrhage of 20 mL/kg for 8 minutes, the animals were transfused with 20 mL/kg of the colloid for 10 minutes. PV was determined with a I-125-albumin tracer dilution technique at baseline and 3 hours after the colloid infusion. The PV just after hemorrhage was calculated as the baseline value minus bled PV. Blood gases were measured at baseline, after hemorrhage, just after the colloid infusion and at the end of the experiment.Results: The increase in PV 3 hours after the colloid infusion, including the 20 mL infused, was 36.3 mL/kg +/- 2.3 mL/kg in the dextran group, 26.4 mL/kg +/- 4.7 mL/kg in the albumin group, and 17.6 mL/kg +/- 3.5 mL/kg in the HIES group. At the end of the experiment, hematocrit was lower in the dextran group than in the albumin and the HES groups. Urine production was higher in the HES group than in the dextran and the albumin groups.Conclusion: After hemorrhage, the PV-expanding capacity of 6%, dextran 70 was better than that of 5% albumin, which was in turn better than that of HES 130/0.4 given in equal volumes.

To evaluate the effects of change in blood pressure on plasma volume under increased permeability.

To compare the colloids 5% albumin, 4% gelatin, and 6% HES 130/0.4 with one another and with normal saline regarding their plasma expanding effects at increased permeability and to compare the results with those from a previous study at normal permeability.

The purpose of this study was to study and try to optimise high intensity focused ultrasound treatment of the intervertebral disc. We demonstrated that it was possible to heat intervertebral discs with HIFU delivered by 50 or 5 mm diameter ultrasound transducers. Finite element studies indicated that it would be possible to heat the disc to a temperature of 65oC or above through an extradiscal minimally invasive procedure with a 5 mm diameter ultrasound transducer. Computational studies were in general validated by experiments. In vivo studies showed no sign of discomfort or abnormality to the treated animals. Histological changes due to collagen shrinkage in the discs were found, and no damage to the nerve or muscle could be found. The attenuation coefficient in bovine annulus fibrosus was found to be in the range of 1.1 to 1.3 dB cm-1 MHz-1 and the absorption coefficient 0.4 to 0.7 dB cm-1 MHz-1, which is approximately half of the attenuation coefficient. This indicates that a significant proportion of the ultrasound is scattered, due to the anisotropic nature of the annulus fibrosus. Using magnetic resonance thermometry in a bovine in vitro model, the possibility to measure the temperature distribution in the disc during HIFU treatment was demonstrated. This method can be used to evaluate future ultrasound transducers and treatment protocols.

Fluid comprises approximately 60% of total body volume with some variations with age and sex (1). The intracellular volume is about twice as large as the extracellular volume. About three-fourths of the extracellular volume comprises the interstitial space and the rest is plasma volume. The red blood cells belong to the intracellular compartment. Blood (intravascular volume) contributes to about 7% of body weight or 4 to 6 L in the adult man. At a normal hematocrit of about 40%, plasma volume in a 70 kg adult is about 3 L, but at lower hematocrit values, the plasma volume must be correspondingly larger to maintain normovolemia. In most organs of the body, the interstitial volume comprises 25% to 30% of total extravascular fluid volume of the tissue and the rest is intracellular volume. The relative interstitial volume is somewhat smaller in the brain (2).

Objective: To compare 5% albumin, 6% dextran 70, 3.5% gelatin, 6% hydroxyethyl starch 130/0.4, and saline regarding their plasma volume expanding effect after a surgical skeletal muscle trauma and their simultaneous effects on transvascular fluid exchange in skeletal muscle.Design: Controlled, prospective, randomized laboratory study.Setting: University research laboratory.Subjects: Thirty-six adult cats.Interventions: Systemic arterial pressure and tissue volume variations of and blood flow to a surgically isolated and autoperfused calf muscle placed in a plethysmograph were recorded. Arterial and venous pressures to the muscle were kept constant. After preparation, plasma volumes were determined by a 125 1 albumin tracer technique just before and 3 hrs after a bolus infusion of the plasma expander (25 mL/kg).Measurements and Main Results: Plasma volume was 20.9 +/- 2.9 mL/kg (n = 36) just before infusion of the plasma expander (normal plasma volume for the cat is 34-37 mL/kg). The remaining volume expansion of the infusion after 3 hrs was 6.8 mL/kg for albumin, 11.2 mL/kg for dextran, 1.8 mL/kg for gelatin, 2.2 mL/kg for hydroxyethyl starch, and 0.9 mL/kg for saline. Plasma volume decreased by 1.1 mL/kg when no solution was given (n = 6 per group). Colloid osmotic pressure was better preserved with dextran and albumin than with the other solutions. Albumin and dextran reduced muscle volume by absorption after 3 hrs, whereas the initial absorption turned to net filtration in the gelatin and hydroxyethyl starch groups. Saline infusion increased muscle volume by filtration for about 20 mins, followed by an approximately constant volume.Conclusion: The relatively poor plasma expansion for all solutions analyzed can most likely be explained by increased transcapillary leakage due to increased microvascular permeability following trauma. Under such circumstances, for equal volumes, plasma expansion was better preserved with 6% dextran 70 than with 5% albumin, which was better than 3.5% gelatin, 6% hydroxyethyl starch 130/0.4, and saline.

To compare the colloids 5% albumin, 4% gelatin and 6% hydroxyethyl starch (HES) 130/0.4 with each other and with saline, regarding their plasma-expanding effects after haemorrhage; these were also compared with the intravascular volume-expanding effect of re-transfusion with erythrocytes.

Background Vasopeptidase inhibition is a new antihypertensive approach combining inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), but severe oedema, mainly angio-oedema, has been reported. As ACE and NEP catalyse degradation of the permeability-increasing peptide bradykinin, and NEP also catalyses degradation of permeability-increasing peptides such as atrial natriuretic peptide, substance P, endothelin-1 and angiotensin II, vasopeptidase inhibition may increase microvascular permeability. Objective To analyse the effects of vasopeptidase inhibition on permeability. Design The study was performed on the autoperfused cat calf skeletal muscle, evaluating the effects on fluid and protein permeability of a clinically relevant dose of the vasopeptidase inhibitor, omapatrilat. The effects were compared with those of the vehicle, of selective ACE and NEP inhibition, and of omapatrilat during bradykinin receptor blockade. Methods Effects on fluid permeability were determined with a capillary filtration coefficient (CFC) technique, and effects on protein permeability were assessed from changes in the osmotic reflection coefficient for albumin. Results After 1.5 h of intravenous infusion of omapatrilat (0.35 mg/kg per hour), mean arterial pressure was reduced from 114 mmHg to 86 mmHg (P< 0.01) and skeletal muscle vascular resistance was reduced from 14.5 peripheral resistance units (PRU) to 11.5 PRU (P< 0.05). CFC was increased by 22% (P< 0.01) and the reflection coefficient was decreased by 17% (P< 0.01). Infusion of vehicle had no effects. Inhibition of NEP increased permeability without affecting blood pressure, whereas ACE inhibition decreased blood pressure without affecting permeability. The increase in permeability associated with omapatrilat was reduced by bradykinin blockade. Conclusions A clinically relevant antihypertensive dose of omapatrilat reduces vascular resistance and increases fluid and protein permeability, the permeability effect more by inhibition of NEP than by inhibition of ACE, by a mechanism involving bradykinin.

gene-related peptide 105 Calcium 1, 28 Capillary filtration coefficient