Extremely large nuchal translucency measurement predicts adverse pregnancy outcome.

A prospective study was conducted to determine the outcome of pregnancies with 1st trimester nuchal translucency measurement of ≥ 6.5 mm. The risk of fetal abnormalities increases with enlarging nuchal translucency, being around 45% with a measurement of ≥ 6.5 mm. A total of 27,144 women with singleton pregnancies participated in the combined Down syndrome screening within the public healthcare system in Northern Finland. The study period was 1 May 2002 to 31 May 2009. The nuchal translucency measurement was ≥ 6.5 mm in 16 cases (0.06%). Pregnancy outcome was normal in one case (6.3%). The risk of abnormality was higher in our study than reported in the literature. According to our study, immediate diagnostic tests should be offered after an nuchal translucency measurement of ≥ 6.5 mm. We should also consider analysis of fetal micro-deletions associated with certain syndromes.

Association of ADAM12-S protein with radiographic features of knee osteoarthritis and bone and cartilage markers.

ADAM12 (A disintegrin and metalloprotease) is one of the candidate genes demonstrating susceptibility to osteoarthritis. The purpose of this study was to investigate the relationship between ADAM12-S protein and radiographic knee osteoarthritis (KOA) and its correlation to several bone and cartilage biomarkers. The ADAM12-S protein was measured in 276 subjects (60% women, aged 32-60 years), including 181 individuals with and 95 without radiographic KOA features. The radiographs were obtained from both tibiofemoral (TF) and patellofemoral (PF) joints. The serum levels of ADAM12-S protein were measured by DELFIA1/AutoDELFIA research kit. The ADAM12-S protein was found in detectable ranges in 43 subjects (16 men), without statistical difference between the two genders. In the whole group, the ADAM12-S was related to radiographic KOA grades in TF (P = 0.004) as well in PF joint (P = 0.003). We also found a correlation between ADAM12-S protein and osteophytes in TF and/or PF joints (P = 0.003). No correlations were found between serum levels of S-CTx-I (C-terminal cross-linked telopeptides of type I collagen) or S-PINP (type I procollagen N-terminal propeptide) and ADAM12-S. Similarly, in the whole group, the ADAM12-S protein was not correlated with U-CTx-II (urinary C-telopeptide fragments of type II collagen); however, in the female group, trend to positive correlation between the investigated biomarkers (P = 0.019) was observed. The ADAM12-S protein could be elevated in some KOA cases, and this elevation correlates with the grades of the disease, mostly owning to development of osteophytes. This finding suggests the possible involvement of the ADAM12-S protein in the pathogenesis of KOA.

Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.

BACKGROUND: Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). METHODS AND RESULTS: In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. CONCLUSIONS: Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.

Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects.

OBJECTIVES: This study was performed to evaluate the QT interval and heart rate responses to exercise and recovery in gene and mutation type-specific subgroups of long QT syndrome (LQTS) patients. BACKGROUND: Reduced heart rate and repolarization abnormalities are encountered among long QT syndrome (LQTS) patients. The most common types of LQTS are LQT1 and LQT2. METHODS: An exercise stress test was performed in 23 patients with a pore region mutation and in 22 patients with a C-terminal end mutation of the cardiac potassium channel gene causing LQT1 type of long QT syndrome (KVLQT1 gene), as well as in 20 patients with mutations of the cardiac potassium channel gene causing LQT2 type of long QT syndrome (HERG gene) and in 33 healthy relatives. The QT intervals were measured on electrocardiograms at rest and during and after exercise. QT intervals were compared at similar heart rates, and rate adaptation of QT was studied as QT/heart rate slopes. RESULTS: In contrast to the LQT2 patients, achieved maximum heart rate was decreased in both LQT1 patient groups, being only 76 +/- 5% of predicted in patients with pore region mutation of KvLQT1. The QT/heart rate slopes were significantly steeper in LQT2 patients than in controls during exercise. During recovery, the QT/heart rate slopes were steeper in all LQTS groups than in controls, signifying that QT intervals lengthened excessively when heart rate decreased. At heart rates of 110 or 100 beats/min during recovery, all LQT1 patients and 89% of LQT2 patients had QT intervals longer than any of the controls. CONCLUSIONS: LQT1 is associated with diminished chronotropic response and exaggerated prolongation of QT interval after exercise. LQT2 patients differ from LQT1 patients by having marked QT interval shortening and normal heart rate response to exercise. Observing QT duration during recovery enhances the clinical diagnosis of these LQTS types.

Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns.

OBJECTIVES: We studied the clinical characteristics and molecular background underlying a severe phenotype of long QT syndrome (LQTS). BACKGROUND: Mutations of cardiac ion channel genes cause LQTS, manifesting as increased risk of ventricular tachycardia and sudden death. METHODS: We studied two siblings showing prolonged QT intervals corrected for heart rate (QTc), their asymptomatic parents with only marginally prolonged QTc intervals and their family members. The potassium channel gene HERG was screened for mutations by deoxyribonucleic acid sequencing, and the electrophysiologic consequences of the mutation were studied in vitro using the whole-cell patch-clamp technique. RESULTS: A novel missense mutation (L552S) in the HERG channel, present in the homozygous state in the affected siblings and in the heterozygous state in their parents, as well as in 38 additional subjects from six LQTS families, was identified. One of the homozygous siblings had 2:1 atrioventricular block immediately after birth, and died at the age of four years after experiencing unexplained hypoglycemia. The other sibling had an episode of torsade de pointes at the age of two years. The mean QTc interval differed significantly (p < 0.001) between heterozygous symptomatic mutation carriers (500 +/- 59 ms), asymptomatic mutation carriers (452 +/- 34 ms) and noncarriers (412 +/- 23 ms). When expressed in vitro, the HERG-L552S formed functional channels with increased activation and deactivation rates. CONCLUSIONS: Our data demonstrate that homozygosity for a HERG mutation can cause a severe cardiac repolarization disorder without other phenotypic abnormalities. Absence of functional HERG channels appears to be one cause for intrauterine and neonatal bradycardia and 2:1 atrioventricular block.

Association between HERG K897T polymorphism and QT interval in middle-aged Finnish women.

OBJECTIVES: The aim of this study was to test whether a recently reported polymorphism in the HERG gene coding for the rapidly activating delayed rectifier K+ channel has influence on myocardial repolarization. BACKGROUND: The length of myocardial repolarization, measured as the QT interval, has a hereditary component, but no genes that would explain the variability of repolarization have been identified in healthy subjects. METHODS: QT intervals were measured from the 12-lead electrocardiogram in a random middle-aged population (226 men/187 women). The longest QT interval at any of the 12 leads (QTmax), QTV(2), and the Tpeak-Tend interval were used as measures of repolarization. Deoxyribonucleic acid samples were genotyped for the nucleotide 2690A>C variation of the HERG gene, corresponding to the HERG K(lysine)897T(threonine) amino acid polymorphism. RESULTS: The allele frequencies were 0.84 (A) and 0.16 (C). Females with the genotype AC or CC had longer QTcmax (477 +/- 99 ms) and Tpeak-Tend intervals (143 +/- 95 ms) than females with the genotype AA (441 +/- 69 ms and 116 +/- 65 ms, p = 0.005 and p = 0.025, respectively). In males, the QTcmax and the Tpeak-Tend intervals did not differ between the genotypes. After adjustment for echocardiographic and various laboratory variables, the HERG K897T polymorphism remained as an independent predictor of QTcmax (p = 0.009) and the Tpeak-Tend intervals (p = 0.026) in females. CONCLUSIONS; The common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females.

Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects.

Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N-terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20-30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals.

Evaluation of first trimester maternal serum and ultrasound screening for Down's syndrome in Eastern and Northern Finland.

The current trend in prenatal diagnosis is that trisomy screening is being moved to the first trimester and ultrasonographic nuchal translucency measurement is included in risk calculation. It is likely that biochemical screening in the second trimester will gradually be given up. In Eastern and Northern Finland, during the year 1999 we offered first-trimester ultrasonographic and serum screening for trisomy 21, with measurements of maternal serum PAPP-A and beta-hCG. A total of 2515 pregnant women participated in the screening, yielding the detection of eight foetuses with Down's syndrome. Six affected foetuses (75%) were detected by means of first-trimester serum screening. Since we were in the phase of collecting data for the Finnish medians for PAPP-A and beta-hCG, the women were not given the estimates of risk for trisomy 21. Only 1602 of the 2515 enrolled women had the combination of first-trimester ultrasonographic and serum screening performed, and in that group there were five foetuses with Down's syndrome. The combination ultrasonographic and serum approach yielded a Down's syndrome detection rate of 80% (four out of five) with a 5% false positive rate, whereas in nuchal translucency based-screening the detection rate was 60%, with a 5% false positive rate.

Low serum inhibin B concentrations in male survivors of childhood malignancy.

The aim of this study was to assess the value of serum inhibin B in detecting male gonadal dysfunction in childhood cancer survivors. 27 male postpubertal (Tanner's pubertal stage G5 or P6) and 12 pubertal (> or = G2) patients were drawn from the endocrine follow-up protocol of childhood cancer patients at the Paediatric Clinic of Turku University Hospital, Turku, Finland. The average time (mean +/- S.D.) between the diagnosis and this study was 11.7 +/- 4.5 years in the postpubertal and 7.0 +/- 3.9 years in the pubertal group. Serum samples for the determination of follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, testosterone, and inhibin A and B dimers were collected. The demographic factors, pubertal stage and testicular size of the patient were measured at the same routine outpatient visit. Serum inhibin concentrations were correlated to testicular volume and gonadotrophin concentrations. Strong correlations were observed between testicular size (r = 0.80, P < 0.001) or FSH (r = -0.58, P = 0.002) and inhibin B concentration in the postpubertal group. Inhibin A was not detectable (< 2 pg/ml). Testicular volume measurement was accurately documented in 21 postpubertal subjects. Patients with small testicles (< 10 ml) had inhibin B concentrations under 42 pg/ml and those whose testicular size was over 13 ml had inhibin B concentrations exceeding 100 pg/ml. In all 12 pubertal survivors, serum inhibin B levels were > or = 94 pg/ml, except in one case of testicular cancer where inhibin B was 8.1 pg/ml and the FSH concentration was elevated. Inhibin B seems to be an indicator of male gonadal function in postpubertal childhood cancer survivors and could be used in the estimation of gonadal function of male survivors earlier than testicular volume or semen analyses would be routinely possible. However, the correct cut-off level of serum inhibin B, as well as the details of inhibin B physiology during puberty, remain to be determined before semen analysis can be replaced by the measurement of inhibin B.

The inverse changes of mouse brain ornithine and S-adenosylmethionine decarboxylase activities by chlorpromazine and imipramine. Dependence of ornithine decarboxylase induction on beta-adrenoceptors.

Intraperitoneal injection of chlorpromazine and imipramine increases mouse brain ornithine decarboxylase but decreases S-adenosyl-L-methionine decarboxylase activity. Maximal effect was obtained 6-8 hr after treatment at which time single dose of chlorpromazine (50 mg/kg) stimulated ornithine decarboxylase activity 7-fold and decreased S-adenosylmethionine decarboxylase activity to 50% from the control level. Correspondingly, ornithine decarboxylase activity was 5.5 times higher than the control value and S-adenosylmethionine decarboxylase activity about 40% from that after imipramine injection (80 mg/kg). The possible dependence of the enzyme responses on adrenergic receptors was studied using alpha-adrenoceptor antagonist, phentolamine, and beta-adrenoceptor antagonist, propranolol, concurrently with chlorpromazine and imipramine. The stimulation of ornithine decarboxylase but not the inhibition of S-adenosylmethionine decarboxylase could be abolished by propranolol (10 mg/kg), whereas phentolamine (10 mg/kg) slightly increased ornithine decarboxylase activity even when given alone. This suggests that beta- but not alpha-adrenergic mediation is involved in the stimulation of mouse brain ornithine decarboxylase activity and that brain ornithine and S-adenosylmethionine decarboxylase activities are independently regulated. When chlorpromazine and imipramine were tested in vitro, both of them turned out to have an inhibitory effect on S-adenosylmethionine decarboxylase. The former caused 50% inhibition at a concentration of 1 mM and the latter at 2 mM. Preliminary tests suggest that the type of inhibition is noncompetitive for both of them.

Measured versus predicted oxygen consumption in children with congenital heart disease.

OBJECTIVE: To compare measured and predicted oxygen consumption (VO2) in children with congenital heart disease. DESIGN: Retrospective study. SETTING: The cardiac catheterisation laboratory in a university hospital. PATIENTS: 125 children undergoing preoperative cardiac catheterisation. INTERVENTIONS: VO2 was measured using indirect calorimetry; the predicted values were calculated from regression equations published by Lindahl, Wessel et al, and Lundell et al. Stepwise linear regression and analysis of variance were used to evaluate the influence of age, sex, weight, height, cardiac malformation, and heart failure on the bias and precision of predicted VO2. An artificial neural network was trained and used to produce an estimate of VO2 employing the same variables. The various estimates for VO2 were evaluated by calculating their bias and precision values. RESULTS: Lindahl's equation produced the highest precision (+/- 42%) of the regression based estimates. The corresponding average bias of the predicted VO2 was 3% (range -66% to 43%). When VO2 was predicted according to regression equations by Wessel and Lundell, the bias and precision were 0% and +/- 44%, and -16% and +/- 51%, respectively. The neural network predicted VO2 from variables included in the regression equations with a bias of 6% and precision +/- 29%; addition of further variables failed to improve this estimate. CONCLUSIONS: Both regression based and artificial intelligence based techniques were inaccurate for predicting preoperative VO2 in patients with congenital heart disease. Measurement of VO2 is necessary in the preoperative evaluation of these patients.

Nitric oxide, oxygen, and prostacyclin in children with pulmonary hypertension.

OBJECTIVE: To test the vasodilatory response of the pulmonary vascular bed in children with pulmonary hypertension. DESIGN: Prospective dose response study in which the effects of inhaled nitric oxide (NO) are compared with those of oxygen and intravenous prostacyclin. PATIENTS AND INTERVENTIONS: The vasodilator test was performed in 20 patients in whom mean pulmonary artery pressure (PAPm) was > or = 40 mm Hg and /or pulmonary vascular resistance index was > or = 4 Um2. Haemodynamic effects of inhaled NO (20, 40, and 80 ppm) at a fractional inspired oxygen (FiO2) value of 0.3, pure oxygen, oxygen at FiO2 0.9-1.0 combined with NO as above or with intravenous prostacyclin at 10 and 20 ng/kg/min were measured. RESULT: NO decreased PAPm with a dose response from 20 to 40 ppm (mean change at 40 ppm-5.50, 95% confidence interval (CI) -7.98 to -3.02 mm Hg. Maximal decrease in the ratio of pulmonary to systemic vascular resistance was achieved with a combination of NO 80 ppm and oxygen (-0.18, 95% CI -0.26 to -0.10). Increase in the pulmonary flow index was greatest with pure oxygen in those with an intracardiac shunt (8.52, 95% CI -0.15 to 17.20 l/min/m2). Neither NO nor oxygen altered systemic arterial pressure but intravenous prostacyclin lowered systemic arterial pressure and resistance. CONCLUSIONS: NO selectively reduces pulmonary vascular resistance and pressure maximally at 40 ppm. Oxygen reduces pulmonary vascular resistance and NO potentiates this reduction without affecting the systemic circulation. Prostacyclin vasodilates the pulmonary and the systemic circulations.

The secretion of PAPP-A, ADAM12, and PP13 correlates with the size of the placenta for the first month of pregnancy.

OBJECTIVES: Pregnancy Associated Protein A (PAPP-A), A Disintegrin and Metalloproteinase 12 (ADAM12) and Placental Protein 13 (PP13) are secreted from the placental trophoblastic tissue and are involved in normal implantation and placental development. The aim of the study was to assess the connection between the secretion of these proteins and the growth of the gestational sac and the placenta. STUDY DESIGN: In an observational longitudinal study at Oulu University Hospital, women with naturally conceived pregnancies were followed-up weekly to pregnancy week 11. MAIN OUTCOME MEASURES: PAPP-A, ADAM12 and PP13 serum concentrations and their correlation with the volumes of the gestational sac and the placenta were assessed using three-dimensional ultrasonography. RESULTS: The study group consisted of 41 women. The PAPP-A, ADAM12 and PP13 serum concentrations increased continuously from pregnancy week 4 to week 11 and correlated closely with each other. The serum concentrations of PAPP-A, ADAM12 and PP13 also correlated with the volumes of the gestational sac and the placenta up to pregnancy week 8. CONCLUSIONS: The secretion of PAPP-A, ADAM12 and PP13 is closely related to the size of the placenta in the beginning of pregnancy. After 8 weeks of pregnancy, which is the time for luteoplacental shift, the correlation disappears, possibly reflecting the morphologic transformation in the placenta.

Participation of informal caregivers in the hospital care of elderly patients and their evaluations of the care given: pilot study in three different hospitals.

This action research is an ongoing study which will last from 1991 to 1993. The main purpose of the study is to increase the participation of informal caregivers in the hospital care of elderly patients without decreasing the quality of care. The data reported here are from a pilot study. This study had three aims: (a) to test reliability and validity of the measure used, (b) to investigate the current participation of informal caregivers in the hospital care of elderly patients (aged over 75), and (c) to evaluate and compare the quality of care from both the patients' and the informal caregivers' point of view in three different hospitals. The measure of quality of care was developed on the basis of need theories, mainly those of Maslow and Alderfer. Patients and caregivers were also asked to rate the participation of the caregivers in the hospital care of elderly patients. Participation consisted of 18 activities of daily living. The pilot test with 18 elderly hospital patients and seven family members or significant others showed differences between the two groups in perception of care received. Statistically significant differences (P < 0.001) were found in the following categories: mainly social needs, psychic and spiritual needs and totals. The results supported earlier findings that elderly patients are satisfied with and do not criticize their care. The younger generation (i.e. their children) is more demanding and has precise perceptions about the care given. Relatives could be used more in planning, evaluation and even implementation of care; however, their current participation in patient hospital care is minimal.

Elderly patients' and their informal caregivers' perceptions of care given: the study-control ward design.

This preliminary study is part of an ongoing action research project. Elderly patients (n = 45) and their informal caregivers (n = 147) completed a questionnaire. The purpose of this study was to evaluate the quality of care from both the patients' and their informal caregivers' points of view and to compare differences in perceived quality of care between study and control wards in different hospitals. Results indicated that the great majority of elderly patients were satisfied with the fulfillment of their needs. Informal caregivers evaluated the quality of care more critically than did the patients. Statistically significant differences were found between the control and the study wards in acute-care settings; however, differences between the wards in long-term care settings were non-significant. Nurses and researchers must better understand the needs of an increasing population of elderly patients. Informal caregivers are in a key position to help nursing professionals to cope with the future challenges of elderly people's care. Their perceptions must also be taken into account.

Participation of caregivers in elderly-patient hospital care: informal caregiver approach.

This preliminary study is part of an ongoing action research project in three different kinds of hospitals. Two wards in each hospital volunteered for the study. The purpose was to discover in which activities of daily living informal caregivers currently participate and to what extent. Participation of informal caregivers consisted of 17 activities. Elderly patients (n = 45) eligible for the study and informal caregivers (n = 147) completed a questionnaire. They were asked in which daily activities informal caregivers participate and how often, options ranging from daily to never. Responses of informal caregivers are reported in this paper. Results indicated that relatives and other significant others visited elderly hospital patients often; however, their participation in activities of daily living in hospitals was limited. Mostly they gave emotional support and helped the patient to drink, stand up/get into bed and sit. Implications for nursing are discussed.

Involvement of an "antizyme" in the inactivation of ornithine decarboxylase.

DL-Allylglycine causes a marked increase in mouse brain ornithine decarboxylase (ODC) activity. The amount of immunoreactive enzyme protein increases concomitantly with the activity, but the enzyme protein decreases more slowly than that of the activity. The amount of immunoreactive ODC in brain is many hundred times that of the catalytically active enzyme. The fact that mouse brain cytosol contains high amounts of dissociable antizyme (an inactivating protein) indicates the existence of an inactive, immunoreactive ODC-antizyme pool. The total antizyme content does not change markedly, but instead there are significant changes in different antizyme pools. Putrescine concentrations start to increase 8 h after treatment with allylglycine and concomitantly with this increase, antizyme is released to inhibit enzyme activity. These results indicate the involvement of antizyme in the inactivation process of ODC.

Reasons for uses of physical restraint and alternatives to them in geriatric nursing: a questionnaire study among nursing staff.

This study is part of a major research project that is concerned with disruptive behaviour among elderly patients and the use of physical restraint in geriatric nursing. The purpose of this study was to describe the use of physical restraint and alternatives as reported by professional nurses. The data were collected by a structured questionnaire. Nursing staff (n = 287) from a geriatric unit of a health centre, a nursing home, and the medical and psychiatric clinics of a university hospital in one city in central Finland, volunteered for the study. The clear majority (85%) of the nurses stated that physical restraint had been used on the ward during the week preceding the questionnaire. Reasons cited most often for restraint use were reduced physical and cognitive capacity of demented patients. The most common alternative was to try to understand the reasons for the elderly patient's disruptive behaviour. A major challenge for future research and for field experiments is to provide new alternatives to the use of physical restraint in geriatric nursing.