bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours
Authors: Kaltsas Gregory A. , Kola Blerina , Borboli Ninetta , Morris Damian G. , Gueorguiev Maria , Swords Frankie M. , Czirják Sándor , Kirschner Lawrence S. , Stratakis Constantine A. , Korbonits Márta , Grossman Ashley B.
Published: March 2003

objective Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous and neural tumours, as well as a variety of pigmented lesions of the skin and mucosa. Pituitary GH‐secreting tumours are found in approximately 10% of patients with CNC. One of the genes responsible for CNC, the PRKAR1A gene located on human chromosome 17q22‐24, has recently been cloned. This represents a putative tumour suppressor gene, coding for the type 1α regulatory subunit of protein kinase A (PKA), which is found to be mutated in approximately half of the patients with CNC. However, it is currently unclear as to whether similar mutations occur in sporadic pituitary tumours. We have therefore investigated a series of GH‐secreting and other pituitary tumours for sequence abnormalities in the PRKAR1A gene. The mRNA produced by the PRKAR1A undergoes decay if it codes for a truncated protein; we therefore also determined PRKAR1A mRNA levels in the tumours, and compared them with known mutant PRKAR1A‐carrying lymphocyte samples.

methods We extracted RNA from a series of pituitary tumours, reverse transcribed it to cDNA, and directly sequenced the PRKAR1A coding sequence in 17 GH‐secreting, three prolactin‐secreting, three ACTH‐secreting, one FSH‐secreting and 10 nonfunctioning pituitary tumours. Lymphocyte and tumour tissue RNA from two patients with CNC was used as positive controls. Using duplex polymerase chain reaction (PCR) with the PRKAR1A and the ‘housekeeping’ gene GAPDH, we determined the relative expression of the PRKAR1A gene in the unknown as well as in the positive control samples.

results and conclusion No mutations were found in any of the exons sequenced. Relative mRNA expression was not decreased in any of the sporadic pituitary tumour samples. The present data thus do not suggest a major role for the PRKAR1A tumour suppressor gene in sporadic GH‐secreting or other pituitary tumours.
The effect of exogenous melatonin on stimulated neurohypophysial hormone release in man
Authors: Forsling Mary L. , Williams A. J.
Published: March 2003

objective Melatonin is known to have a dose‐dependent effect on basal neurohypophysial hormone release in man, low physiological doses being stimulatory and high doses inhibitory. We have performed a study to determine if this is true also for stimulated release.

design This was a double‐blind randomized crossover study with subjects being given oral doses of melatonin (0·5 mg or 5·0 mg) or placebo, before infusion of hypertonic saline or exercise.

subjects Studies were performed on a total of 24 male subjects aged 19–23 years, who were entrained to a normal light–dark cycle and who refrained from taking heavy exercise, alcohol and smoking for 24 h prior to study.

measurements Plasma vasopressin, oxytocin, sodium and osmolality and packed cell volume were measured in control samples and at regular intervals after the administration of melatonin and the challenge tests. Blood pressure and urine flow, sodium potassium and osmolality were determined during hypertonic saline infusion and blood pressure and pulse rate during exercise.

results Plasma vasopressin increased during hypertonic saline infusion and exercise, the responses being attenuated by 5·0 mg melatonin and augmented with 0·5 mg melatonin. Although exercise had no effect on oxytocin release, there was a small but statistically significant (P < 0·05) increase in plasma oxytocin after hypertonic saline administration, which was inhibited by 5·0 mg and augmented by 0·5 mg melatonin.

conclusions Melatonin modulates the neurohypophysial response to different stimuli, low doses enhancing the response. This effect could contribute to the night‐time increase in circulating concentrations of the hormones.
Early growth, pubertal development, body mass index and final height of patients with congenital adrenal hyperplasia: factors influencing the outcome
Authors: Manoli I. , Kanaka‐Gantenbein Ch. , Voutetakis A. , Maniati‐Christidi M. , Dacou‐Voutetakis C.
Published: March 2003

objective The management of children with congenital adrenal hyperplasia (CAH) remains a challenge, especially with regard to growth potentials. The objective of our analysis was to uncover the factors that influence the growth and final height of patients with CAH.

design The linear growth pattern and body mass index (BMI) at different developmental stages (birth to 2 years, 2 years to puberty initiation and puberty initiation to final height) and the final height achieved were analysed retrospectively in 48 patients with 21‐hydroxylase deficiency; 17 with the salt‐wasting (SW) form, 25 with the simple virilizing (SV) and six with the nonclassical (NC) form.

results Mean final height (FH) and FH‐SDS were, respectively, 170·8 ± 5·6 m and −0·57 ± 0·8 in males and 156·7 ± 6 cm and −0·61 ± 1 in females with the SW form, 166·1 ± 6·1 cm and −1·05 ± 1 in males and 151·6 ± 5·4 cm and −1·4 ± 1 in females with the SV form and 159·7 ± 6·9 cm and 0·3 ± 1·4 in females with the NC form. In subjects with the SW form, height SDS at 2 years, at puberty initiation and at FH were −0·18 ± 0·9, 0·11 ± 1·28 and −0·6 ± 1·0, respectively. FH achieved was not different from target height (TH) in the SW group, but it was significantly lower than TH in the SV group (P = 0·003). FH in the SW group showed a positive correlation to the height achieved at 2 years of age (r = 0·68, P = 0·019), and height at 2 years was negatively related to the hydrocortisone dose in the birth to 2‐year period (r = −0·79, P = 0·011). FH showed no correlation to hydrocortisone dose at any of the three developmental periods studied. BMI‐SDS were not different in the various forms of CAH and showed no correlation to FH or hydrocortisone dose. Age at menarche was comparable to that in our general population.

conclusions Under our conditions of management, the final height of patients with the salt‐wasting form was comparable to the target height and to the most favourable literature data. The patients with the simple virilizing form fare less well, mainly due to delayed diagnosis and consequent advancement of bone age and early puberty. In salt‐wasting patients, height at 2 years is comparable to normals, it is influenced by the hydrocortisone dose and is related to the final height. Some height is lost during puberty. Hence, monitoring treatment over the first 2 years and during puberty is critical for the outcome in these patients.
Effects of slow‐release octreotide on urinary metanephrine excretion and plasma chromogranin A and catecholamine levels in patients with malignant or recurrent phaeochromocytoma
Authors: Lamarre‐Cliche Maxime , Gimenez‐Roqueplo Anne‐Paule , Billaud Eliane , Baudin Eric , Luton Jean‐Pierre , Plouin Pierre‐François
Published: March 2003

objective Somatostatin receptors are present on human phaeochromocytomas. Catecholamine concentrations may decrease following short‐term administration of somatostatin agonists to patients with phaeochromocytomas. We carried out a prospective study on 10 patients with malignant or recurrent phaeochromocytomas to examine the clinical and hormonal effects of three monthly intramuscular injections of 20 mg slow‐release octreotide.

design and measurements Patients underwent somatostatin receptor scintigraphy using 111In‐pentetreotide before slow‐release octreotide was administered. The patients’ symptoms, blood pressure, blood glucose concentrations, glycosylated haemoglobin concentra‐tions, plasma insulin and noradrenaline concentrations, and the levels of two putative markers of tumour burden, urinary metanephrine excretion and plasma chromogranin A concentration, were recorded before the first injection and 28 days after the third injection.

results Slow‐release octreotide did not significantly alter symptoms, blood pressure, blood glucose concentrations, plasma catecholamine and chromogranin A concentrations or metanephrine excretion. Median glycosylated haemoglobin concentrations increased from 5·3% to 6·0% (P = 0·03). Patients whose tumours took up 111In‐ pentetreotide did not differ from those whose tumours did not after slow‐release octreotide treatment in terms of symptoms, blood pressure, blood glucose, plasma catecholamine and chromogranin A concentrations or metanephrine excretion.

conclusion Our data suggest that slow‐release octreotide is of limited value for the long‐term treatment of patients with malignant or recurrent benign phaeochromocytomas.
High prevalence and increasing incidence of Addison's disease in western Norway
Authors: Løvås Kristian , Husebye Eystein S.
Published: March 2003

objective Estimates of the prevalence of Addison's disease in Caucasians have varied from 39 to 117 per million. We have carried out an epidemiological study to obtain a confident point prevalence estimate in the Norwegian population for the end of 1999, and to find out whether the incidence is changing.

patients and methods The patients were identified by a search through registers of 10 hospitals and consultant endocrinologists serving a population of 916 000. The completeness of the list was tested by a survey of general practitioners in one district, and by the member list of the local Addison Association in another district.

results We identified 128 patients with Addison's disease (59 men and 69 women), yielding a prevalence of 140 per million. Recorded mean incidence in the past decade was 0·62 per 100 000 per year. Fifty‐one patients (40%) had concomitant endocrine diseases. The aetiology was almost exclusively idiopathic or autoimmune.

conclusions We found a higher prevalence of Addison's disease in western Norway than has previously been reported anywhere. Our findings support the hypothesis of a rising incidence of autoimmune adrenal insufficiency.
Two Italian kindreds with familial hypocalciuric hypercalcaemia caused by loss‐of‐function mutations in the calcium‐sensing receptor (CaR) gene: functional characterization of a novel CaR missense mutation
Authors: Cetani Filomena , Pardi Elena , Borsari Simona , Tonacchera Massimo , Morabito Eugenia , Pinchera Aldo , Marcocci Claudio
Published: March 2003

objectives Description of two unrelated Italian kindreds with familial hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease mostly caused by heterozygous inactivating mutations of the Ca2+ sensing receptor (CaR).

patients and design We studied 11 members of the two families. Genomic DNA was isolated from peripheral blood leucocytes in all family members and in 50 unrelated Italian controls. Total serum and ionized calcium, PTH, creatinine, phosphate, magnesium, and urinary calcium clearance to creatinine clearance ratio were measured. Direct sequencing of the entire coding region of the CaR was performed in the probands. Functional studies were performed in COS‐7 cells transiently expressing the mutated CaR.

results In the proband of family A direct sequencing revealed a novel heterozygous Y218C missense mutation in exon 4. The same mutation was identified in the affected but not in the unaffected family members or in any of the 50 unrelated Italian controls. Transient expression of the Y218C CaR in COS‐7 cells revealed a blunted Ca2+‐evoked accumulation of inositol trisphosphates, indicating that the Y218C is a loss‐of‐function mutation. Cotransfection experiments showed that the mutant receptor had no impact on the function of the wild‐type receptor, suggesting that a reduced expression of the normal CaR, rather than a dominant‐negative effect, accounted for the functional impairment. In the proband of family B an already described heterozygous P55L missense mutation in exon 2 of the CaR gene was found. The same mutation was identified in the affected family members.

conclusions We described two familial hypocalciuric hypercalcaemia kindreds with loss‐of‐function mutations of the Ca2+ receptor gene and identified a novel heterozygous mutation (Y218C) characterized by a blunted response to Ca2+ stimulation compared to the wild‐type receptor and no interference with the function of the wild‐type Ca2+ receptor.
Effectiveness of alendronate treatment in postmenopausal women with osteoporosis: relationship with BsmI vitamin D receptor genotypes
Authors: Palomba Stefano , Numis Fabio Giuliano , Mossetti Giuseppe , Rendina Domenico , Vuotto Pietro , Russo Tiziana , Zullo Fulvio , Nappi Carmine , Nunziata Vincenzo
Published: March 2003

objective To assess whether there is a relationship between the effectiveness of alendronate treatment in postmenopausal women with osteoporosis and BsmI vitamin D receptor (VDR) genotypes.

design Prospective baseline‐controlled clinical trial.

patients Sixty‐eight Italian osteoporotic women were enrolled and treated with alendronate at a dose of 10 mg/day for 12 months.

measurements At entry and after treatment, lumbar bone mineral density (BMD) and serum osteocalcin (OC) and urinary deoxypyridinoline/creatinine ratio (DPD‐Cr) levels were evaluated. DNA was extracted from blood and analysed for the BsmI polymorphism of the VDR gene.

results The mean percentage (% ± SD) change from baseline in lumbar BMD was significantly higher (P < 0·01) in bb than in BB BsmI VDR genotypes (7·92 ± 4·31 vs. 3·40 ± 1·81). No significant difference in lumbar BMD was observed in Bb VDR patients (6·01 ± 3·89) in comparison with other groups. The mean percentage of change in serum OC and urinary DPD‐Cr levels was significantly (P < 0·01) lower in individuals with bb than in those with BB BsmI VDR genotypes (−14·34 ± 2·87 vs.−10·39 ± 1·43 and −9·61 ± 5·56 vs.−4·61 ± 2·31). No significant difference in serum OC and urinary DPD‐Cr levels was observed in Bb VDR patients (−12·31 ± 2·11 and −6·52 ± 2·65) in comparison with other groups.

conclusion The different BsmI vitamin D receptor genotypes modify the pharmacological response to alendronate treatment in postmenopausal women with osteoporosis.
Effect of head‐upright tilt on the dynamic of cerebral autoregulation
Authors: Lefthériotis  , Preckel  , Fizanne  , Victor  , Dupuis  , Saumet
Published: March 2003

The effect of head‐upright tilting on the rate of cerebral autoregulation was studied in 12 healthy volunteers (nine men and three women; age range 20–36 years). The dynamics of cerebral autoregulation was determined from the rate of change in cerebral resistance (RoR) during a drop in arterial blood pressure induced by rapid deflation of a 3‐min ischaemic thigh cuff and from the ratio of changes in cerebral blood flow and arterial blood pressure (CAI) during the recovery period after the drop in arterial blood pressure. The test was performed supine and with 40° head‐up tilt (40° HUT). Middle cerebral artery mean blood flow velocity was measured by transcranial Doppler simultaneously with peripheral arterial blood pressure using Finapres. The thigh cuff deflation induced a larger drop in arterial pressure during 40° HUT [median −28% (25 percentile −36, 75 percentile −19)] than in the supine position [−16% (−23, −15)] (P<0·01) and in cerebral resistance [supine: −12% (−15, −6); 40° HUT: −15% (−20, −12); P<0·05]. There was no significant change in RoR [15% s−1 (12, 15)] and CAI [1·9 (1·5, 3·1)] measured supine and during 40° HUT [RoR: 13% s−1 (12, 15); CAI: 1·3 (0·99, 1·9)]. During the drop in arterial pressure, the relationship between arterial blood pressure and systolic peak‐to‐peak interval exhibited an hysteresis loop, indicating a cardiopulmonary and/or baroreflex activation that was not observed with cerebral resistance. The rate of autoregulation is an intrinsic property of the cerebral vascular bed and is not affected by the vasodilator state in the range of arterial blood pressure changes induced by the tight cuff method.
Poor reproducibility of exercise test in assessment of claudication
Authors: Peräkylä  , Tikkanen  , Knorring J. von , Lepäntalo
Published: March 2003

To assess reproducibility of the exercise test in intermittent claudication, a prospective, comparative, randomized study was undertaken. Ten patients with stable intermittent claudication of ischaemic origin were exercised on a flat surface (0‐Ex), with 12% steady inclination (12‐Ex) and with progressively increasing inclination (p‐Ex) in a random order during three different sessions. The ankle–brachial index (ABI) at rest and after exercise (rABI, exABI), initial and maximum walking distance (IWD, MWD) and metabolic equivalent (MET) were obtained as the main outcome measures. The results were analysed using intraindividual coefficients of variation (CVs) and standard deviations (SDs). The ABI values of the worst extremity were used in evaluation of results. Reproducibility of the exercise ABI appeared to be good, especially during progressively increasing exercise, the mean CV being 9 ± 5%. The best mean CV was observed during p‐Ex (16% ± 14%) for maximum walking distance. The mean CV for initial walking distances ranged from 30% to 54%. Treadmill exercise testing to measure walking distances is highly inaccurate and the value of exercise on the flat treadmill should be questioned. Graded exercise appeared to be the most reproducible in this respect. The ABI after exercise, however, was a reliable single parameter when assessing arterial insufficiency causing decreased walking capacity.
Effects of intense exercise training on endothelium‐dependent exercise‐induced vasodilatation
Authors: Franke  , Stephens  , III
Published: March 2003

To determine whether intense exercise training affects exercise‐induced vasodilatation, six subjects underwent 4 weeks of handgrip training at 70% of maximal voluntary contraction. Exercise forearm vascular conductance (FVC) responses to an endothelium‐dependent vasodilator (acetylcholine, ACH; 15, 30, 60 μg min−1) and an endothelium‐independent vasodilator (sodium nitroprusside, SNP; 1·6, 3·2, 6·4 μg min−1) and FVC after 10 min of forearm ischaemia were determined before and after training. Training elicited significant (P<0·001) increases in grip strength (43·4 ± 2·3 vs. 64·1 ± 3·5 kg, before vs. after, mean ± SEM), forearm circumference (26·7 ± 0·4 vs. 27·9 ± 0·4 cm) and maximal FVC (0·4630 ± 0·0387 vs. 0.6258 ± 0·0389 units, P<0·05). Resting FVC did not change significantly with training (0·0723 ± 0·0162 vs. 0.0985 ± 0·0171 units, P>0·4), but exercise FVC increased (0·1330 ± 0·0190 vs. 0.2534 ± 0·0387 units, P<0·05). Before and after the training, ACH increased exercise FVC above the control (no drug) exercise FVC, whereas SNP did not. Training increased (P<0·05) the exercise FVC responses to ACH (0·3344 ± 0·1208 vs. 0.4303 ± 0·0858 units, before vs. after training, 60 μg min−1) and SNP (0·2066 ± 0·0849 vs. 0.3172 ± 0·0628 units, 6·4 μg min−1). However, these increases were due to the increase in control (no drug) exercise FVC, as the drug‐associated increase in exercise FVC above control did not differ between trials (P>0·6). These results suggest that exercise FVC is increased by both exercise training and stimulating the release of endothelium‐dependent vasodilators. However, training does not affect the vascular response to these vasodilators.
The venoarteriolar response of the skin in healthy legs measured at different depths
Authors: Malanin K. , P. J. Kolari
Published: March 2003

The venoarteriolar response (VAR) of the skin in healthy legs of 20 subjects was investigated. The laser Doppler flux (LDF), at an experimental venous hypertension of 30 mmHg, 45 mmHg and 60 mmHg, produced by a pneumatic cuff around the thigh in a recumbent position, was compared with the LDF in a sitting position. The LDF of the skin was measured simultaneously at the same site of the superficial capillary layer (with 543 nm) and of the deeper capillary layer (with 780 nm). At 543 nm the LDF did not differ significantly at any cuff pressure from the LDF recorded in a sitting position, whereas at 780 nm the LDF was significantly higher at the cuff pressure of 30 mmHg than the LDF in a sitting position (P = 0·002). The VAR was much weaker at 543 nm than at 780 nm, and the scatter of the VAR values was high. In a sitting position the VAR at 543 nm was 9·3% and at 780 nm 34·6% (P<0·001). The VAR at 543 nm at the cuff pressure of 30 mmHg did not differ significantly from the VAR caused by the sitting position, whereas at 780 nm the VAR at the cuff pressure of 30 mmHg was significantly less than the VAR caused by the sitting position (P = 0·001). Despite the high scatter of the VAR values, these findings suggest that the VAR in the superficial capillary layer is smaller, and that it reached maximum at lower venous hypertension, than the VAR in the deeper capillary layer.
Pulsed tissue Doppler evaluation of mitral annulus motion: a new window to assessment of diastolic function
Authors: Lindström Lena , Wranne Bengt
Published: March 2003

Diastolic dysfunction is an important cause of cardiac heart failure. To date detailed assessment of diastolic left ventricular (LV) function has required invasive methods which are impractical in the clinical routine. The prevailing non‐invasive method has been Doppler echocardiography with use of mitral inflow and pulmonary vein inflow parameters, measurements providing no direct assessment of either ventricular relaxation or compliance, and influenced by multiple haemodynamic factors. We sought to determine the tissue Doppler pattern from the mitral annulus motion in normals and in patients with expected LV‐diastolic dysfunction. Using pulsed tissue Doppler we recorded peak velocities from the mitral annulus motion in 16 young normals, 10 older normals and in two groups of patients expected to have an LV‐diastolic relaxation abnormality, i.e. 15 patients with systemic hypertension and 10 patients with significant aortic stenosis. The peak early diastolic (E) annulus velocity was significantly (P < 0·001) lower in older normals compared with young, and the late diastolic velocity (A) was higher (P < 0·01). Compared with the older normals, patients showed significantly lower E‐velocities (P < 0·05 hypertensive patients), more pronounced in the patients with aortic stenosis (P < 0·001), but the A‐velocities were not higher. In systole a decrease in peak velocity was noted with increasing age and in patients with aortic stenosis. In conclusion, pulsed tissue Doppler measurement of annulus motion seems to provide valuable and easily obtainable information about LV‐diastolic function, and furthermore there is a striking change in velocity pattern with increasing age which necessitates age‐matched reference values.
The effect of breathing frequency on deposition of drug aerosol using an inhalation‐synchronized dosimeter in healthy adults
Authors: Häkkinen  , Uusi‐Heikkilä  , Järvinen  , Saali  , Karhumäki
Published: March 2003

The deposition of inhaled drug aerosol between the tongue, the upper and lower respiratory tract, the lungs and the gastrointestinal tract (GI tract) in 11 healthy adults was studied by using a nebulizer with an inhalation‐synchronized dosimeter. The effect of breathing frequency on deposition was studied using radioaerosol (mixture of salbutamol and technetium bound to diethylenetriamine pentacetate, [99mTc]DTPA) and a gamma‐camera. In healthy subjects who were breathing at their own frequency (16 ± 5 breaths min–1, mean ± SD), the proportion of inhaled aerosol deposited in the lungs was 48 ± 14 (mean percentage ± SD). The proportion deposited in the upper airway tract and the GI tract was 19 ± 13 and 25 ± 9 respectively, and the remainder was deposited on the tongue (6 ± 4) and in the lower airway tract (3 ± 2). Guided, slower breathing frequency (11 ± 5 breaths min–1) changed the deposition remarkably. The proportion of the pulmonary deposition of the inhaled dose increased significantly (P<0·004) to 60 ± 17, and the proportion of the upper airway tract deposition decreased significantly (P<0·005) by half of the initial deposition. We conclude that a slow controlled breathing frequency is an important factor if we want to increase the drug deposition in the lungs. It is also essential in decreasing the variation in the deposition of the lungs.
Atrophy of the quadriceps muscle in children with a painful hip
Authors: Robben Simon G. F. , Lequin Maarten H. , Meradji Morteza , Diepstraten Ad F. M. , Hop Wim C. J.
Published: March 2003

The objective of this study was to determine the degree of muscle wasting of various components of the quadriceps muscle in children with a painful hip. Between January 1994 and September 1997, 327 consecutive children with a unilateral painful hip and/or limping were evaluated prospectively with ultrasonography. Quadriceps thickness was measured on both sides. Moreover, muscle thickness was measured in 59 control subjects. The patients were divided into eight groups; transient synovitis (n=134), Perthes’ disease (n=35), slipped capital femoral epiphysis (n=5), osteomyelitis (n=4), aspecific synovitis (n=5), rheumatoid arthritis (n=3) and miscellaneous (n=16). In 125 patients, no sonographic and radiological abnormalities were found and during follow‐up the symptoms disappeared (‘no pathology’ group). Ipsilateral muscle wasting was present in all patient groups, whereas the control subjects showed no significant difference in muscle thickness between legs. The degree of muscle wasting was compared between transient synovitis, the ‘no pathology’ group, Perthes’ disease and control subjects. For both quadriceps and vastus intermedius muscles, there was a significant difference between these groups, except between control subjects and the ‘no pathology’ group. For the rectus femoris muscle, there was a significant difference between these groups, except between transient synovitis and ‘no pathology’. Muscle wasting showed a positive correlation with duration of symptoms and pre‐existing muscle mass. In conclusion, different diseases show different degrees of muscle wasting, and there are different patterns of muscle wasting of various components of the quadriceps femoris muscle.
Endothelium‐dependent vasodilation and structural and functional changes in the cardiovascular system are dependent on age in healthy subjects
Authors: Lind Lars , Sarabi Mahziar , Millgård Jonas , Kahan Thomas , Edner Magnus
Published: March 2003

The aim of this study was to evaluate possible associations between endothelium‐dependent vasodilatation (EDV) and cardiovascular structure and function. EDV could influence peripheral resistance and be affected by atherosclerosis and might thereby influence indices of cardiovascular structure and function. In a group of 31 apparently healthy men and 25 women (age range 20–69 years), EDV was evaluated by infusion of metacholine (4 μg min–1), and endothelium‐independent vasodilatation (EIDV) was assessed by nitroprusside infusion (SNP, 10 μg min–1) in the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Left ventricular (LV) geometry and function and the intima‐media thickness in the carotid artery were assessed by ultrasonography. The stroke index to pulse pressure ratio was used to evaluate arterial compliance. Several indices of cardiovascular structure and function were found to be related to an index of endothelial function, the EDV to EIDV ratio. Furthermore, left ventricular mass (LVM), the atrio‐ventricular plane displacement, E/A ratio, IVRT, the intima‐media thickness of the carotid artery and arterial compliance were all significantly related to both EDV and EIDV in women. However, most indices of cardiovascular structure and function, as well as endothelial function, change with age and only the relation between LV diastolic function and endothelial function in men remained significant (P<0·05) after including age in multiple regression analysis. Age was related to both cardiovascular structure and function, as well as to endothelial function. Multiple regression analysis showed that ageing generally affects cardiovascular characteristics and endothelial function in parallel in these healthy subjects.
A confident decision support system for interpreting electrocardiograms
Authors: Holst Holger , Ohlsson Mattias , Peterson Carsten , Edenbrandt Lars
Published: March 2003

Computer‐aided interpretation of electrocardiograms (ECGs) is widespread but many physicians hesitate to rely on the computer, because the advice is presented without information about the confidence of the advice. The purpose of this work was to develop a method to validate the advice of a computer by estimating the error of an artificial neural network output. A total of 1249 ECGs, recorded with computerized electrocardiographs, on patients who had undergone diagnostic cardiac catheterization were studied. The material consisted of two groups, 414 patients with and 835 without anterior myocardial infarction. The material was randomly divided into three data sets. The first set was used to train an artificial neural network for the diagnosis of anterior infarction. The second data set was used to calculate the error of the network outputs. The last data set was used to test the network performance and to estimate the error of the network outputs. The performance of the neural network, measured as the area under the receiver operating characteristic (ROC) curve, was 0·887 (0·845–0·922). The 25% test ECGs with the lowest error estimates had an area under the ROC curve as high as 0·995 (0·982–1·000), i.e. almost all of these ECGs were correctly classified. Neural networks can therefore be trained to diagnose myocardial infarction and to signal when the advice is given with great confidence or when it should be considered more carefully. This method increases the possibility that artificial neural networks will be accepted as reliable decision support systems in clinical practice.
Upright body position and weight loss improve respiratory mechanics and daytime oxygenation in obese patients with obstructive sleep apnoea
Authors: Hakala  , Maasilta  , Sovijärvi
Published: March 2003

To determine whether upright body position and weight loss would improve daytime gas exchange in moderately obese patients with obstructive sleep apnoea (OSAS), 13 patients with mild or moderate OSAS were studied before and after weight loss. Pulmonary function tests, arterial blood gases and respiratory gas analysis were measured prior to and after a very low calorie diet (VLCD) period of six weeks. Arterial blood gases were measured in supine and standing positions and closing volume in supine and sitting positions before and after weight loss. In the upright position, there was a significant increase in PaO2 (P<0·005) accompanied by a significant decrease in alveolar–arterial PO2 difference (P<0·005) and closing volume (P<0·05). The median weight loss was 11 kg (range 5–18). The number of desaturation episodes (four percentage units or more per hour during sleep) (ODI4) decreased (P<0·01) after weight loss. The change in PaO2 with weight loss correlated with the decrease in ODI4 (r=0·73, P<0·01). The increase in expiratory reserve volume (ERV) was closely related to the amount of weight lost (r=0·895, P<0·01). The results indicate that weight loss and upright body position improved daytime respiratory mechanics and gas exchange in obese patients with OSAS. The findings suggest that obesity plays an important role in the pathogenesis of daytime gas exchange disturbances in obese OSAS patients. The adoption of a more upright sleep posture might improve nocturnal oxygenation in obese patients with OSAS.
Evaluation of the interrupter technique in measuring post‐exercise bronchodilator responses in children
Authors: Kannisto Senja , Vanninen Esko , Korppi Matti
Published: March 2003

A significant response in a bronchodilation test is one of the main diagnostic criteria of asthma. However, it is not known what the significant bronchodilator response (BDR) is by the interrupter technique (IR), measuring respiratory resistance (Rint) during tidal breathing. Fifty children with symptoms suggestive for asthma underwent an 8 min free running test outdoors. Flow‐volume spirometry (FVS) and IR measurements were performed before and 10 min after running. Thereafter, all children received a salbutamol inhalation, and pulmonary function measurements were repeated 15 min later. The study population was classified into three groups according to the post‐exercise pulmonary function: FEV1 > 100% of predicted (group I, n=15), FEV1 86–99% of predicted (group II, n=20) and FEV1 < 85% of predicted (group III, n=15). There were no differences in BDRs between groups I and II; the mean increases in FEV1 were 4–6% and in MMEF 20–23%, and the mean decreases in Rint were 23–26%. The mean changes in group III were significantly higher: 15% (P=0·004) in FEV1, 55% (P=0·021) in MMEF and 38% (P=0·014) in Rint. BDR was positive (FEV1 rise >10%) in 15 children; five were in group II and 10 in group III. For MMEF and Rint, the best combination of sensitivity and specificity was achieved by a limit of 35%. By this limit, MMEF identified 14 and Rint 17 positive cases. The IR technique agreed with both FEV1 and MMEF in 73% of the cases. The IR technique provides an alternative to conventional ventilatory function measurements in bronchodilation tests in children. We suggest a decrease of 35% or more in Rint as diagnostic in post‐exercise bronchodilation tests.
Adaptation related to cytokines in man: effects of regular swimming in ice‐cold water
Authors: Dugué  , Leppänen
Published: March 2003

The cytokine response after thermal stress (sauna + swimming in ice‐cold water) was investigated in subjectively healthy persons. Two groups were studied at the end of the winter season: habitual and inexperi‐ enced winter swimmers. Blood was collected at rest, after a sauna bath and after a short swim in ice‐cold water. Conventional methods and ELISA kits were used to determined the blood picture, serum cortisol and dehydroepiandrosterone sulphate, plasma anti‐diuretic hormone (ADH) levels, and the levels of several cytokines in plasma and in the supernatants of blood cell cultures which were stimulated with lipopolysaccharide (LPS). In regular winter swimmers, the concentrations of plasma interleukin 6 (IL‐6), leukocytes, and monocytes at rest were significantly higher than in inexperienced subjects. In experienced female winter swimmers, the plasma concentration of the soluble receptor for IL‐6 was significantly lower than in inexperienced female swimmers. In both groups, granulocytosis, haemoconcentration and significant increases in the concentrations of ADH, cortisol and IL‐6 were observed after the stimuli. However, the changes in the cortisol concentration were dramatically larger in habitual winter swimmers. A significant correlation was found between the delta values of cortisol and the basal concentrations of IL‐6. In cell cultures, the LPS‐induced release of IL‐1β and IL‐6 was higher at rest in the inexperienced winter swimmers. This release was dramatically suppressed after exposure to the stimuli in the inexperienced winter swimmers but tended to increase in the regular winter swimmers. These stresses appear to challenge both the neuro‐endocrine and the immune systems and the results indicate that adaptive mechanisms occur in habitual winter swimmers.
The effect of high‐ and low‐frequency transcutaneous electrical nerve stimulation upon cutaneous blood flow and skin temperature in healthy subjects
Authors: Cramp  , Gilsenan  , Lowe  , Walsh
Published: March 2003

The reported non‐analgesic effects of transcutaneous electrical nerve stimulation (TENS) include alterations to the local circulation; however, research in this area has produced equivocal findings. In the present study, the effect of low‐ (4 Hz) and high‐frequency (110 Hz) TENS on forearm skin blood perfusion was assessed using laser Doppler flowmetry. The effect on skin temperature was also assessed using a skin thermistor. Thirty healthy human volunteers were recruited and randomly assigned to a control or one of the two treatment groups. TENS was applied to the skin overlying the median nerve under double‐blind conditions for 15 min. Blood flow and skin temperature readings were recorded pre‐TENS, during TENS application and continued for 15 min post‐TENS application. Analysis of results showed significant increases in blood perfusion during the treatment period in the low‐frequency group when compared to the other two groups (P = 0·0106; ANOVA). No significant changes in skin temperature were observed. The results of this study demonstrate that low‐frequency TENS produces a local increase in cutaneous blood flow.
Technical achievement: transthoracic Doppler echocardiography can be used to detect LAD restenosis after coronary angioplasty
Authors: Saraste M. , Koskenvuo J. W. , Mikkola J. , Pelttari L. , Toikka J. O. , Hartiala J. J.
Published: March 2003

We investigated the capability of transthoracic Doppler echocardiography (TTE) to detect and quantify the severity of restenosis in the left anterior descending coronary artery (LAD) after percutaneous transluminal coronary angioplasty (PTCA). We studied 10 consecutive patients assigned for quantitative coronary angiography (qCA) due to a recurrent angina pectoris after PTCA of the LAD. The LAD was visualized by TTE, and the presence of local turbulence and an increase in the blood flow velocity was regarded to indicate coronary stenosis. To assess the severity of the stenosis, the increase of blood flow velocity was measured. Angiography showed stenoses of various degrees (27–100%) in all patients. All stenoses were detectable using TTE. Moreover, the ratio of maximal blood flow velocity at the site of stenosis to the pre‐stenotic blood flow velocity (M/P‐ratio) correlated significantly with the reduction of the luminal diameter of LAD (r=0·85, P<0·003). A M/P‐ratio higher than 3·0 predicted a diameter reduction of 50% or higher with sensitivity and specificity of 100% in patients with a subtotal stenosis (n=9). Our results indicate that stenoses in the LAD could be found and the severity of the stenoses could be quantified reliably with TTE. This approach is totally non‐invasive and less expensive than coronary angiography and can be used clinically in clarifying restenosis after coronary angioplasty.
Stress hormones initiate prolonged changes in the muscle amino acid pattern
Authors: Hammarqvist F. , Ejesson B. , Wernerman J.
Published: March 2003

Eight healthy volunteers were given an infusion containing cortisol, glucagon and adrenaline during 6 h. Muscle biopsies were taken before and at 6, 12 and 24 h. During the infusion serum cortisol, glucagon, glucose and insulin were increased. The stress hormone infusion induced characteristic changes in the muscle and plasma amino acid patterns similar to those seen early in protein catabolism. Muscle glutamine decreased at 12 and 24 h by −18·2 ± 3·8 and −28·8 ± 4·8%, respectively. The branched chain amino acids decreased at 6 h by −54·6 ± 4·2% while increased levels (by 54·7 ± 13·1%) were seen at 24 h. Plasma amino acids decreased during the infusion period and returned to basal during the postinfusion period. Despite a short‐term infusion during 6 h the muscle amino acid pattern was still affected at 12 and 24 h and some of the changes were more accentuated at those timepoints as compared with the changes seen at 6 h.
Influence of respiratory motor neurone activity on human autonomic and haemodynamic rhythms
Authors: Gonschorek A. S. , Lu L.‐L. , Halliwill J. R. , Beightol L. A. , Taylor J. A. , Painter J. A. , Warzel H. , Eckberg D. L.
Published: March 2003

Although humans hold great advantages over other species as subjects for biomedical research, they also bring major disadvantages. One is that among the many rhythmic physiological signals that can be recorded, there is no sure way to know which individual change precedes another, or which change represents cause and which represents effect. In an attempt to deal with the inherent complexity of research conducted in intact human subjects, we developed and used a structural equation model to analyse responses of healthy young men to pharmacological changes of arterial pressure and graded inspiratory resistance, before and after vagomimetic atropine. Our model yielded a good fit of the experimental data, with a system weighted R2 of 0·77, and suggested that our treatments exerted both direct and indirect influences on the variables we measured. Thus, infusions of nitroprusside and phenylephrine exerted all of their direct effects by lowering and raising arterial pressure; the changes of R‐R intervals, respiratory sinus arrhythmia and arterial pressure fluctuations that these drugs provoked, were indirect consequences of arterial pressure changes. The only direct effect of increased inspiratory resistance was augmentation of arterial pressure fluctuations. These results may provide a new way to disentangle and understand responses of intact human subjects to experimental forcings. The principal new insight we derived from our modelling is that respiratory gating of vagal‐cardiac motor neurone firing is nearly maximal at usual levels of arterial pressure and inspiratory motor neurone activity.
Chronotropic incompetence response to exercise in congestive heart failure, relationship with the cardiac autonomic status
Authors: Roche Frédéric , Pichot Vincent , Da Costa Antoine , Isaaz Karl , Costes Frédéric , Dall'Acqua Tiziana , Duverney David , Lacour Jean‐René , Barthélémy Jean‐Claude
Published: March 2003

In chronic congestive heart failure (CHF), attenuated heart rate response to exercise, a manifestation of chronotropic incompetence (CI), contributes to limiting exercise capacity. The present study was thus conducted to evaluate the respective role of chronic attenuation of cardiac vagal tone associated with depressed baroreflex sensitivity or affected cardiac sympathetic responsiveness in CHF patients with CI. Spontaneous cardiac baroreflex sensitivity (BRS) assessed by sequence method and spectral‐ and time‐domain analysis of heart rate variability (HRV) were analysed in 21 chronic CHF patients. All patients performed a symptom‐limited exercise test with measurement of gas exchange. Chronic incompetence which was defined as failure to achieve ≥80% of the heart rate reserve (%HRR) given by (HRpeak – HRrest)/(predictive maximal heart rate – HRrest) was observed in 14 (66%) patients. There was no significant difference in age, heart rate, peak oxygen uptake or left ventricular ejection fraction between the patients with and without CI. Although there was no significant difference in BRS, low frequency power of HRV in normalized units (LFnu) and SDNN were significantly lower in CI patients. Percentage of HRR correlated significantly with LFnu on 15 min (r=0·64, P<0·005) and, with LFnu on 24 h (r=0·52, P<0·01), SDNN (r=0·48, P=0·03) and SDANN (r=0·48, P=0·03), but not BRS (r=0·04, P=NS). Autonomic nervous system derangement is a complex process in CHF. The role of basal depressed cardiac sympathetic tone seems to contribute more closely than depressed baroreflex sensitivity to the impaired heart rate response to exercise frequently observed in CHF patients.
Whole‐body vibration exercise leads to alterations in muscle blood volume
Authors: Kerschan‐Schindl K. , Grampp S. , Henk C. , Resch H. , Preisinger E. , Fialka‐Moser V. , Imhof H.
Published: March 2003

Occupationally used high‐frequency vibration is supposed to have negative effects on blood flow and muscle strength. Conversely, low‐frequency vibration used as a training tool appears to increase muscle strength, but nothing is known about its effects on peripheral circulation. The aim of this investigation was to quantify alterations in muscle blood volume after whole muscle vibration – after exercising on the training device Galileo 2000 (Novotec GmbH, Pforzheim, Germany). Twenty healthy adults performed a 9‐min standing test. They stood with both feet on a platform, producing oscillating mechanical vibrations of 26 Hz. Alterations in muscle blood volume of the quadriceps and gastrocnemius muscles were assessed with power Doppler sonography and arterial blood flow of the popliteal artery with a Doppler ultrasound machine. Measurements were performed before and immediately after exercising. Power Doppler indices indicative of muscular blood circulation in the calf and thigh significantly increased after exercise. The mean blood flow velocity in the popliteal artery increased from 6·5 to 13·0 cm s–1 and its resistive index was significantly reduced. The results indicate that low‐frequency vibration does not have the negative effects on peripheral circulation known from occupational high‐frequency vibration.
Polymorphisms in the renin–angiotensin system and endothelium‐dependent vasodilation in normotensive subjects
Authors: Kurland Lisa , Melhus Håkan , Sarabi Mahziar , Millgård Jonas , Ljunghall Sverker , Lind Lars
Published: March 2003

Background Our aim was to test the hypothesis that genes encoding components in the renin–angiotensin system influence endothelial vasodilatory function.

Methods In 59 apparently healthy, normotensive individuals, endothelium‐dependent vasodilation (EDV) and endothelial‐independent vasodilation (EIDV) was evaluated by infusing metacholine and sodium nitroprusside into the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography. The ACE insertion (I)/deletion (D) polymorphism, the T174M and M235T angiotensinogen restriction fragments length polymorphisms, the angiotensin II receptor type 1 (AT1R) A1166C, and the aldosterone synthase gene (CYP11B2) C‐344T polymorphisms were analysed.

Results When analysing the ACE, the two angiotensinogen and the aldosterone synthase CYP11B2 genotypes independently, no significant association with endothelial vasodilatory function was found. However, a significant reduction in endothelium‐dependent vasodilation was observed in the subjects (n=9) with the ACE D allele and the angiotensinogen T174M genotype (P<0·05). Subjects with the AT1R genotype AC showed a reduction in both EDV (P=0·05) and EIDV (P=0·04) when compared with those with the AA genotype.

Conclusions The subjects with the ACE D allele in combination with the angiotensinogen T174M genotype are associated with a reduced EDV. This together with the observation that the AC AT1R genotype is associated with a reduction in both EDV and EIDV, supports the hypothesis that endothelial vasodilatory function is influenced by genes in the renin–angiotensinogen system.
Ageing, soft‐palate tone and sleep‐related breathing disorders
Authors: Veldi M. , Vasar V. , Hion T. , Kull M. , Vain A.
Published: March 2003

We compared the tissue tone of the soft palate in 10 young (18–29 years) and 15 middle‐aged (30–70 years) apnoeics with 10 young and 10 middle‐aged non‐snorers and healthy volunteers of the same ages. The obstructive sleep apnoea syndrome (OSAS) was diagnosed by means of the self‐reported questionnaire about the medical history of the subjects and polysomnography (PSG) with overnight pulse oximetry. Computerized endopharyngeal myotonometry (CEM) was used to measure the tissue tone of the soft palate. The CEM study is performed while the subjects are awake. CEM records and analyses the biomechanical properties of tissue in response to a brief mechanical impact. Tissue stiffness is expressed as a frequency and elasticity as a logarithmic decrement of damped oscillation. Results: The values of the tissue stiffness (13·5, SD 2·5 Hz) and elasticity (1·2, SD 0·4) of the soft palate in young adults with OSAS reveal no important differences in comparison with the tissue stiffness (12·7, SD 2·4 Hz) and elasticity (0·9, SD 0·2) in non‐snoring young adults. The difference in the value of the tissue stiffness of the soft palate is significant among middle‐aged patients with OSAS (20·3, SD 4·7 Hz) and non‐snoring middle‐aged persons (13·9, SD 2·3 Hz). A non‐significant difference was observed in the value of the tissue elasticity among middle‐aged patients with OSAS (1·7, SD 0·8) and non‐snoring middle‐aged persons (1·6, SD 0·3). The tissue tone of the soft palate in young and middle‐aged healthy subjects differs by elasticity but not by stiffness. Conclusions: We found that some biomechanical properties of the tissues of the soft palate may be changed by OSAS and some by age.