bluuebunny/crossref_metadata_2025 huggingface dataset:
Health status of children with cerebral palsy living in Europe: a multi‐centre study
Authors: Beckung E. , White‐Koning M. , Marcelli M. , McManus V. , Michelsen S. , Parkes J. , Parkinson K. , Thyen U. , Arnaud C. , Fauconnier J. , Colver A.
Published: September 2010

Aim The aim of this report is to describe the health status of 8–12‐year‐old children with cerebral palsy (CP) of all severities in Europe using the Child Health Questionnaire (CHQ).

Method A total of 818 children with CP from nine centres in defined geographical areas participated. CP type, gross and fine motor function, additional impairments were classified and family data were obtained. The CHQ was used to measure the parent's perception of their child's physical (PHY) and psychosocial (PSY) health.

Results PHY scores were lower than the reference samples with a median of 46. The severity of gross motor function influenced the CHQ scores significantly in the PHY scale with the lowest scores for children with least gross motor function. There were significant differences between the CP types in PHY with the higher scores for children with unilateral spastic and the lowest scores for children with bilateral spastic and dyskinetic CP type. Fine motor function severity significantly affected both the PHY and PSY scales. The severity of intellectual impairment was significantly associated with CHQ scores in most dimensions with higher scores for higher IQ level in PHY and PSY. Children with seizures during the last year had a significantly lower health compared with children without seizures. The results of the multivariate regression analyses (forward stepwise regression) of CHQ scores on CP subtype, gross and fine motor function, cognitive function, additional impairments, seizures, parental education and employment revealed gross motor function, cognitive level and type of school attended were significant prognostic factors.

Conclusion This report is based on the largest sample to date of children with CP. Health status as measured using the CHQ was affected in all children and was highly variable. Gross motor function level correlates with health from the PHY well‐being perspective but the PSY and emotional aspects do not appear to follow the same pattern.
OVARIAN ELECTROCAUTERY VERSUS HUMAN MENOPAUSAL GONADOTROPHINS AND PURE FOLLICLE STIMULATING HORMONE THERAPY IN THE TREATMENT OF PATIENTS WITH POLYCYSTIC OVARIAN DISEASE
Authors: GADIR AHMED ABDEL , MOWAFI RAOUF S. , ALNASER HUDA M. I. , ALRASHID ABDULLA H. , ALONEZI ONEZI M. , SHAW ROBERT W.
Published: September 2010

Eighty‐eight clomiphene citrate‐resistant infertile patients with oligomeno‐rrhoea or amenorrhoea attributable to polycystic ovarian disease were divided at random into three groups. Twenty‐nine patients were treated with ovarian electrocautery, 30 with human menopausal gonadotropins (hMG) and 29 with pure follicle stimulating hormone (FSH). Successful ovulation was induced in 71‐4, 70‐6 and 66‐7% of the cycles in the groups respectively. Ten patients conceived after electrocautery and pure FSH therapy while 15 conceived after hMG medication (chi‐squared = 1 ‐6464, P = 0–439). The six‐cycle cumulative pregnancy rate in the three consecutive groups was 521, 55‐4 and 38‐3%. Four further pregnancies were achieved after treating 10 patients in the electrocautery group with clomiphene citrate (100 mg/day for 5 days) for 25 cycles. The rate of pregnancy wastage in the corresponding groups was 21‐4, 53‐3 and 40% (chi‐squared = 3–127, P = 0–2039). Ovarian electrocautery is equally effective as hMG and pure FSH in the treatment of PCO patients resistant to clomiphene citrate therapy.
TREATMENT OF MACROPROLACTINOMAS WITH A NEW NON‐ERGOT, LONG‐ACTING DOPAMINERGIC DRUG, CV 205–502
Authors: van't VERLAAT JOHANNA W. , CROUGHS RONALD J. M. , BROWNELL JUDITH
Published: September 2010

Eleven patients with prolactin‐producing pituitary adenomas were treated with the new non‐ergot, long‐acting dopamine agonist, CV 205–502, for a period of 2–18 months (mean 11 months). Tumour volumes ranged from 1–9 to 64 ml in seven patients who were newly diagnosed, and from 01 to 31 ml in four patients who had been treated for macroprolactinomas by oral bromocriptine or depot bromocriptine (Parlodel LAR). Plasma prolactin values ranged from 3–5 to 360 U/l before institution of CV 205–502 treatment in these 11 patients. The following observations were made: (1) plasma prolactin values fell dramatically in all patients, and values within the normal range were obtained in five patients at once‐daily doses of CV 205–502 between 0075 and 0–300 mg; (2) tumour size reduction was obtained in all patients with macroadenomas on pretreatment CT scans. Tumour reduction was associated with the development of a partial empty sella in five patients, and with visualization of the pituitary in six cases; (3) bitemporal hemianopia (five patients) disappeared in four patients and improved in one patient. Oculomotor palsy receded in one patient; (4) signs of anterior pituitary insufficiency improved or normalized in most cases affected; (5) mild nausea or dizziness during the first days of CV 205–502 treatment and/ or during several days after a dose increase were observed in three patients. We conclude that CV 205–502 in a once daily dose is an effective and safe alternative in the long‐term treatment of macroprolactinomas.
THE EFFECT OF RADIOACTIVE IODINE TREATMENT ON THYROID C CELLS
Authors: BAYRAKTAR MIYASE , GEDIK OLCAY , AKALIN SEMA , USMAN AYDAN , ADALAR NEZAKET , TELATAR FERZAN
Published: September 2010

To determine the effect of radioiodine treatment on thyroid C cells, calcitonin (CT) levels were measured by RIA before and after intravenous calcium stimulation (2 mg/kg body‐weight elemental calcium) in 22 women treated with 131I for hyperthyroidism. The results were compared with sex, age and weight‐matched normal controls. There was a slight but statistically significant decrease in basal CT levels of the patients compared to the control group (mean±SE; 0–009±0–001 vs 0011 ±0001 pmol/1, P<005). The mean stimulated CT level of the patient group was significantly lower than that of the controls (0–010 ±0–001 vs. 0–018 ± 0–003 pmol/1, P< 0–001). The absence or presence of 131I‐induced hypothyroidism at the time of the study did not influence basal or stimulated CT levels. Basal and stimulated CT levels were significantly lower in the patients with Graves' disease than in the patients with toxic nodular goitre. We conclude that 131I used to correct hyperthyroidism may cause marked CT deficiency.
GLUCAGON IN WOMEN WITH POLYCYSTIC OVARY SYNDROME (PCO): RELATIONSHIP TO ABNORMALITIES OF INSULIN AND ANDROGENS
Authors: GOLLAND I. M. , WILLIAMS C. A. VAUGHAN , SHALET S. M. , LAING I. , ELSTEIN M.
Published: September 2010

To investigate the glucagon status of women with polycystic ovary syndrome (PCO) and to relate this to serum concentrations of insulin, androgens and SHBG, 44 women with PCO and 23 control subjects underwent a 75‐g oral glucose tolerance test. Although obese (body mass index > 30kg/m2) women with PCO had higher concentrations of glucose and insulin than overweight (BMI 25‐30kg/m2) and non‐obese (BMI <25kg/m2) women with PCO and control subjects, fasting and summed values of glucagon in response to oral glucose were similar in all groups. The fasting and summed concentrations of glucagon were inversely related to those of testosterone and androstenedione in obese women with PCO, but no other relationships were demonstrated between hormone values and those of glucagon in the other groups. We conclude that glucagon is not implicated in peripheral insulin resistance in women with PCO.
Molecular prenatal diagnosis of partial androgen insensitivity syndrome based on the Hind III polymorphism of the androgen receptor gene*
Authors: Lobaccaro Jean‐Marc , Belon Charles , Lumbroso Serge , Olewniczack Georges , Carré‐Pigeon Françoise , Job Jean‐Claude , Chaussain Jean‐Louis , Toublanc Jean‐Edmond , Sultan† Charles
Published: September 2010

OBJECTIVE Partial androgen Insensitivity syndromes are the cause of genital ambiguity that is at times quite severe; there is, therefore, a high demand for prenatal diagnosis in families already afflicted with this syndrome. When the mutation has not been identified, the diagnosis can be made by the study of the polymorphisms of the androgen receptor gene. To perform molecular prenatal diagnosis in a family with partial androgen insensitivity syndrome, we studied the Hind III polymorphism of the androgen receptor gene on the trophoblastic DNA. The use of this restriction fragment length polymorphism tracked maternal X chromosome segregation and established prenatal diagnosis although the mutation had not yet been identified in this family.

FAMILY The mother had been previously described as heterozygous for the Hind III polymorphism and chromosomal segregation analysis showed that the affected allele was associated with the 6.7‐kb Hind III fragment.

MEASUREMENTS Hind III RFLP with an androgen receptor gene cDNA probe was realized on the trophoblastic DNA, along with measurement of androgen binding activity on the trophoblastic cells.

RESULTS We detected the presence of the 6.7‐kb fragment In the DNA of the trophoblastic cells suggesting the fetus was affected. Partial androgen insensitivity syndrome was confirmed by a considerable decrease in androgen binding activity on the trophoblastic cells and by sonography of the fetus. After a therapeutic abortion requested by the parents, the diagnosis was confirmed by clinical examination of the fetus, biochemical analyses of the fetal androgen receptor, and molecular studies of the fetal DNA.

CONCLUSIONS When the mutation of the androgen receptor gene has not been identified, Hind III polymorphism of the trophoblastic DNA is useful in the prenatal diagnosis of androgen insensitivity syndrome in high‐risk families.
Decreased blood pressure response to infused noradrenaline in normotensive as compared to hypertensive patients with primary hypothyroidism
Authors: Bramnert Margareta , Hallengren Bengt , Lecerof Harry , Werner Richard , Manhem Per
Published: September 2010

OBJECTIVE AND PATIENTS To further explore the difference in plasma noradrenaline in normotensive and hypertensive hypothyroid patients we have investigated the pressor response to exogenous noradrenaline in 11 normotensive and five hypertensive patients with primary hypothyroidism before and after thyroxine replacement. Seven healthy subjects served as controls.

DESIGN The patients were studied under metabolic ward conditions and received a Na+ and K+ defined diet for 4 days. The controls received the same diet on an ambulatory basis for 3 days and were admitted to the ward in the evening on the third day. In the morning of day 4 a graded noradrenaline infusion was given. When the increase in systolic blood pressure in two consecutive registrations was at least 20 mmHg as compared to basal values the noradrenaline infusion was stopped. The dose required to increase systolic blood pressure by 20 mmHg (I20) was determined.

RESULTS During hypothyroidism the I20 was 120 ng/kg BW/min in normotensive patients and 39 in hypertensive patients as compared to 62 in controls. The I20 was higher in normotensives as compared to hypertensives (P = 0.041). The I20 was not different in hypertensives as compared to controls. When the patients had become euthyroid I20 decreased to 51 ng/kg BW/min (P=0.04) in the normotensives, but remained unchanged in the hypertensives. There was no difference in I20 between normotensive and hypertensive patients in the euthyroid state, or when compared to controls.

CONCLUSION The pressor response to noradrenaline was decreased in normotensive hypothyroid as compared to hypertensive hypothyroid patients, indicating a decreased peripheral sensitivity to noradrenaline in normotensive hypothyroid patients. Following thyroxine replacement the decreased response became normal.
Persistent elevation of serum oestradiol levels by functional ovarian cysts despite effective pituitary desensitization with GnRH agonists
Authors: Jenkins J. M. , Anthony F. W. , Lee A. , Masson G. M. , Thomas E.
Published: September 2010

OBJECTIVE This study assessed whether functional ovarian cysts may prevent suppression of serum oestradiol levels even after pituitary desensitization had been achieved with buserelin.

PATIENTS OI 288 in‐vitro fertilization (IVF) cycles studied 10 patients were found to have cysts with serum oestradiol levels > 200 pmol/l despite 3 weeks of buserelin.

DESIGN AND MEASUREMENTS The 10 patients with cysts were given 01 mg GnRH and serum gonadotrophins were measured at time 0, 30 and 60 minutes subsequently. Immediately following the GnRH stimulation test the cysts were aspirated transvaginally under ultrasound guidance. Serum oestradiol levels were again measured 3 days after cyst aspiration.

RESULTS Basal LH and FSH levels were < 3 U/I and there was no significant rise in response to GnRH. On the day of cyst aspiration serum oestradiol levels varied between 244 and 1127 pmol/l, and in all cases serum oestradiol levels fell to < 200 pmol/l within 3 days of cyst aspiration.

CONCLUSION In the presence of a functional ovarian cyst, failure to suppress the serum oestradiol level does not necessarily imply a failure of pituitary desensitization with a GnRH agonist.
The spectrum of endocrine dysfunction in active pulmonary tuberculosis
Authors: Post F. A. , Soule S. G. , Willcox P. A. , Levitt N. S.
Published: September 2010

OBJECTIVE Substantial variation in the prevalence (0–55%) of hypoadrenalism in tuberculosis (TB) has been reported. The aim of this study was to prospectively evaluate adrenal, thyroid and gonadal function in patients presenting with active pulmonary TB.

DESIGN A prospective study of 50 patients admitted to a single hospital.

PATIENTS Fifty hospitalized adults with newly diagnosed sputum positive pulmonary TB (mean age 38 years, mean body mass index 18 kg/m2, mean albumin 28 g/l) were studied.

MEASUREMENTS Adrenal reserve was assessed by intravenous tetracosactrin administration with measurement of basal and stimulated cortisol concentrations. Basal ACTH, thyroid and gonadal hormones were also measured.

RESULTS The mean basal serum cortisol was 625 nmol/l (range 394–1185). Basal plasma ACTH was undetectable (<4·4 pmol/l) in 32, normal in 17 (mean 11·45, range 4·4–24.9 pmol/l) and elevated in one (54·2 pmol/l) subjects and did not correlate with cortisol. The mean increment in cortisol following tetracosactrin was 256 nmol/l (range 0–650) and was unrelated to basal cortisol or ACTH. All 50 patients had a stimulated plasma cortisol exceeding 550 nmol/l, indicating intact adrenal reserve. Ninety‐two per cent of patients had the sick euthyroid syndrome, 72% of males had hypogonadotrophic hypogonadism and 4% of patients tested positive for the human immunodeficiency virus.

CONCLUSIONS Hypoadrenalism is uncommon in active pulmonary TB despite frequent dysfunction of the thyroid and gonadal axes.
Cholelithiasis and acromegaly: therapeutic strategies
Authors: Montini M. , Gianola D. , Paganl M. D. , Pedroncelli A. , Caldara R. , Gherardi F. , Bonelli M. , Lancranjan I. , Pagani G.
Published: September 2010

OBJECTIVE The aims of this study were (i) to evaluate gall‐bladder form and contents, (ii) to assess the prevalence of gallstones in acromegalic patients before octreotide treatment and the incidence of gallstone formation in patients with acromegaly during long‐term (6–90 months, mean 44 months) octreotide treatment, and (iii) to test the efficacy of ursodeoxycholic acid in preventing and treating octreotide‐induced cholelithiasis.

DESIGN Forty‐nine patients (23 men and 26 women, aged 19–81 years) were studied by repeated gall‐bladder ultrasonography performed at baseline and then every 6 months during octreotide therapy. All ultrasound scans were evaluated by the same radiologist. Statistical analysis was performed using the Chi‐squared and regression analysis tests.

RESULTS Asymptomatic stones were recorded in 13/49 patients (26·5%) prior to octreotide treatment (the prevalence of cholelithiasis in the Italian population is 9·5% in men and 18·9% in women). During octreotide therapy gallstones developed in 10/36 patients (27·7%). No significant correlations with sex, age, body mass index, duration of the disease, daily dose and duration of octreotide therapy, altered gall‐bladder form, family history of gallbladder stones, basal plasma values of cholesterol and triglycerides were found between the patients (10/36) who developed stones during octreotide treatment and the ones who did not (26/36). Fourteen patients (10 with newly developed stones and four with cholelithiasis diagnosed prior to octreotide) were put on ursodeoxycholic acid at the daily dose of 10 mg/kg. Gallstones completely disappeared in 6/14 patients (42·8%; five patients with newly developed stones and one with stones prior to octreotide therapy) after a mean of 30·8 months of ursodeoxycholic acid treatment. In addition, seven patients were treated with ursodeoxycholic acid at the preventive dose of 450 mg, administered as a once‐a‐day oral preparation in the evening. However, stones developed in one of these seven patients who was thereafter cured (gallstones completely disappeared) by the therapeutic dose of ursodeoxycholic acid of 10 mg/kg/day after 23 months of treatment.

CONCLUSIONS This study indicates that (i) acromegaly by itself is correlated with a high prevalence of gallbladder stones, (ii) the long‐term treatment with octreotide increases the incidence of cholelithiasis, and (iii) ursodeoxycholic acid is useful in the treatment of gallstones in acromegalic patients but its prophylactic effect in patients on octreotide treatment requires further assessment.
Expression of pituitary tumour‐derived, N‐terminally truncated isoform of fibroblast growth factor receptor 4 (ptd‐FGFR4) correlates with tumour invasiveness but not with G‐protein alpha subunit (gsp) mutation in human GH‐secreting pituitary adenomas
Authors: Morita Koji , Takano Koji , Yasufuku‐Takano Junko , Yamada Shozo , Teramoto Akira , Takei Mao , Osamura Robert Yoshiyuki , Sano Toshiaki , Fujita Toshiro
Published: September 2010

Objective  Apart from the constitutively activating mutation of the G‐protein alpha subunit (Gsα) (gsp mutation), factors involved in tumorigenesis or those in tumour behaviour remain elusive in sporadic GH‐secreting pituitary adenomas. Recently, the N‐terminally truncated form of fibroblast growth factor receptor‐4 (ptd‐FGFR4) was identified in pituitary adenomas. This aberrant receptor has transforming activity, and causes pituitary adenomas in transgenic mice. The clinical relevance of this receptor warrants investigation. Our objective was twofold: first, to examine how the expression of ptd‐FGFR4 relates to gsp mutations; and second, to see whether patients with this receptor have unique clinical characteristics.

Materials and methods  mRNA was extracted from excised adenomas of 45 Japanese acromegalic patients. ptd‐FGFR4 expression and gsp mutations were determined by reverse transcription polymerase chain reaction (RT‐PCR) and direct sequencing. Preoperative clinical data were collected by reviewing medical charts and pituitary magnetic resonance imaging (MRI) scans.

Results  ptd‐FGFR4 mRNA expression was detected in 19 out of 45 tumours (42·2%) while gsp mutations were detected in 25 out of 45 tumours (55·6%). The prevalence of ptd‐FGFR4 expression did not differ between gsp‐positive (44·0%) and gsp‐negative (40·0%) tumours (P = 1·00). ptd‐FGFR4‐positive tumours invaded the cavernous sinus more frequently (P = 0·0098) than did the ptd‐FGFR4‐negative tumours. Tumour size was not statistically different between ptd‐FGFR4‐positive and ‐negative tumours (P = 0·198). The presence of ptd‐FGFR4 did not correlate with age at operation, sex, preoperative serum GH or IGF‐1 levels.

Conclusions  We found that ptd‐FGFR4 expression and gsp mutations occur independently of each other, and that ptd‐FGFR4 expression is associated with more invasive tumours in patients with GH‐secreting pituitary adenomas.
Fatty fish and supplements are the greatest modifiable contributors to the serum 25‐hydroxyvitamin D concentration in a multiethnic population
Authors: Van Der Meer Irene M. , Boeke A. Joan P. , Lips Paul , Grootjans‐Geerts Ilse , Wuister Jan D. , Devillé Walter L. J. M. , Wielders Jos P. M. , Bouter Lex M. , Middelkoop Barend J. C.
Published: September 2010

Objective  Because vitamin D synthesis is lower in a heavily pigmented skin than in a lighter skin, the relative contribution of determinants to the vitamin D concentration might differ between ethnic groups. The aim of this study was to assess the prevalence of vitamin D deficiency and the relative contribution of vitamin D consumption and exposure to sunlight to the vitamin D concentration in a multiethnic population.

Design  Cross‐sectional study.

Patients  A total of 613 adults aged 18–65 years from a random sample from general practices in the Netherlands (52°N, 2003–05), stratified according to gender and ethnic group.

Measurements  Serum 25‐hydroxyvitamin D [25(OH)D], PTH, ethnic group, sunlight exposure, consumption of foods and supplements rich in vitamin D.

Results  The prevalence (95% confidence interval) of vitamin D deficiency [serum 25(OH)D < 25 nmol/l] was higher in Turkish (41·3%; 32·5–50·1), Moroccan (36·5%; 26·9–46·1), Surinam South Asian (51·4%; 41·9–60·9), Surinam Creole (45·3%; 34·0–56·6), sub‐Saharan African (19·3%; 9·1–29·5) and other adults (29·1%; 17·1–41·1) compared to the indigenous Dutch (5·9%; 1·3–10·5). Modifiable, significant determinants (standardized regression coefficients) for serum 25(OH)D concentration were: consumption of fatty fish (0·160), use of vitamin D supplements (0·142), area of uncovered skin (highest category 0·136; middle category 0·028), use of tanning bed (0·103), consumption of margarine (0·093) and preference for sun (0·089). We found no significant modification of ethnic group on the effect of sunlight determinants.

Conclusion  Of the modifiable determinants, fatty fish and supplements are the greatest contributors to the serum 25(OH)D concentration in a multiethnic population.
Elevated liver enzymes in Turner syndrome during a 5‐year follow‐up study
Authors: El‐Mansoury Mostafa , Berntorp Kerstin , Bryman Inger , Hanson Charles , Innala Eva , Karlsson Anders , Landin‐Wilhelmsen Kerstin
Published: September 2010

Objectives  To study the prevalence and incidence of elevated liver enzymes and their relationship with body weight, metabolic factors and other diseases in Turner syndrome (TS).

Design  Five‐year follow‐up.

Patients  Women with TS (n = 218, mean age 33 ± 13, range 16–71 years) from outpatient clinics at university hospitals in Sweden.

Measurements  Fasting blood samples for aspartate (AST) and alanine aminotransferase (ALT), bilirubin, alkaline phosphatase (ALP), γ‐glutamyl transferase (GT), viral hepatitis serology and hepatic auto‐antibodies, vitamin B12, blood glucose, lipids and hormones.

Results  Seventy‐nine subjects (36%) had one or more liver enzyme levels higher than the reference level, the most prevalent being GT. Karyotype 45,X was present in 51% of all TS women and in 48% of those with elevated liver enzymes. Body weight, body mass index (BMI), total cholesterol, triglycerides, and apolipoproteins A and B at start were higher in TS women with elevated liver enzymes than in TS women with normal levels. At 5 years, AST, ALT and GT were increased and another 23% of patients had developed elevated liver enzymes, that is, 59% in total (36% + 23%), while in 6%, the elevated liver enzymes had been normalized and all 6% also had lowered cholesterol levels. Multivariate analysis showed that GT was correlated with total cholesterol; P = 0·0032 at start and P = 0·0005 at 5 years, independently of other factors. Liver biopsy in six TS women showed one cholangitis, one hepatitis C, two steatosis and two normal biopsies. Withdrawal of oestrogen substitution did not influence the liver enzymes.

Conclusions  Pathological liver enzymes were common in TS women, with a prevalence of 36% at 33 years of age, an annual incidence over 5 years of 3·4%. There was no relation to karyotype, alcohol, viral hepatitis, E2 or autoimmunity, but a connection with total serum cholesterol.
Decision modelling of economic evaluation of intervention programme of breast cancer
Authors: Chang Jung‐Chen , Chen Tony H‐H. , Duffy Stephen W. , Yen Amy M‐F. , Chen Sam L‐S.
Published: September 2010

Objectives Economic appraisal of an intervention is a complex and multivariable problem, with probabilistic issues related not only to clinical outcomes but also to costs and willingness to pay.

Methods We provide a comprehensive framework for economic appraisal of a health intervention to prevent beast cancer mortality, involving probabilistic model of costs as well as of aspects of the disease process. The economic appraisal can give a range of probabilities of cost‐effectiveness depending on willingness or ability to pay.

Results We apply the method to the example of polychemotherapy for early breast cancer. Results indicate a 30% probability of cost‐effectiveness for a willingness to pay of $60 000 per quality‐adjusted life‐year and around 50% for a threshold of $100 000.

Conclusion The comprehensive economic appraisal model is a powerful tool for decision making over a range of economic environments.
Mokken scaling of the Myocardial Infarction Dimensional Assessment Scale (MIDAS)
Authors: Thompson David R. , Watson Roger
Published: September 2010

Aims  The purpose of this study was to examine the hierarchical and cumulative nature of the 35 items of the Myocardial Infarction Dimensional Assessment Scale (MIDAS), a disease‐specific health‐related quality of life measure.

Method  Data from 668 participants who completed the MIDAS were analysed using the Mokken Scaling Procedure, which is a computer program that searches polychotomous data for hierarchical and cumulative scales on the basis of a range of diagnostic criteria.

Results  Fourteen MIDAS items were retained in a Mokken scale and these items included physical activity, insecurity, emotional reaction and dependency items but excluded items related to diet, medication or side‐effects. Item difficulty, in item response theory terms, ran from physical activity items (low difficulty) to insecurity, suggesting that the most severe quality of life effect of myocardial infarction is loneliness and isolation.

Conclusions  Items from the MIDAS form a strong and reliable Mokken scale, which provides new insight into the relationship between items in the MIDAS and the measurement of quality of life after myocardial infarction.
Causal diagrams and change variables
Authors: Shahar Eyal , Shahar Doron J.
Published: September 2010

Background  The true change in the value of a variable between two time points is often assumed to be a cause or an effect of interest. To our knowledge, this assumption is based on intuition, rather than on any formal theoretical justification.

Methods  We used causal directed acyclic graphs to explore the causal properties of a change variable, and critically examined competing structures.

Results  Based on the proposed causal structure, a change variable (true change) is no more than a derived variable. It does not cause anything and is not of causal interest.

Conclusions  A true change is not a variable in the physical world. Therefore, modelling the change between two time points is justified only in a few situations.
The importance of communication in collaborative decision making: facilitating shared mind and the management of uncertainty
Authors: Politi Mary C. , Street Richard L.
Published: September 2010

Rationale  Quality medical decision making requires that clinicians and patients incorporate the best available clinical evidence with the patients' values and preferences to develop a mutually agreed upon treatment plan. The interactive process involved in medical decision making is complex and requires patients and clinicians to use both cognitive and communicative skills to reach a shared understanding of the decision.

Aims and objectives  The purpose of this paper is to present a communication model to help better understand quality medical decision making, and how patient‐centered, collaborative communication enhances the decision‐making process.

Methods  We present research on shared mind and cognitive and communicative skills to highlight how they can facilitate the management of uncertainty during the interactive process involved in medical decision making. We provide simple examples about how to frame messages to achieve shared mind and foster uncertainty tolerance.

Conclusions  Strategies such as providing clear explanations, checking for understanding, eliciting the patient's values, concerns, needs, finding common ground, reaching consensus on a treatment plan, and establishing a mutually acceptable follow‐up plan can facilitate collaborative decision making. Future research should explore ways to implement collaborative decision‐making processes in existing health care systems.
Rapid tryptophan depletion as a treatment for acute mania: a double‐blind, pilot‐controlled study
Authors: Applebaum Julia , Bersudsky Yuly , Klein Ehud
Published: September 2010

Objectives:  Rapid reduction of up to 80% in plasma tryptophan level can be accomplished by administering an oral tryptophan‐free amino acid solution, which induces hepatic protein synthesis and thereby depletes available plasma tryptophan. Rapid tryptophan depletion (RTD) has been shown to induce transient depressive symptoms in patients with remitted major depression. The effect of RTD in acutely manic patients has not been studied.

Methods:  We carried out a double‐blind, placebo‐controlled pilot study of RTD in acutely manic patients. Patients were randomized to the treatment groups. Sodium valproate treatment was started at a dose of 1000 mg/day and continued throughout the 7‐day study. On days 1‐7, patients received a daily tryptophan‐free amino acid drink or a placebo drink. The tryptophan‐free amino acid drink contained a mix of amino acids without tryptophan. The placebo drink contained the additives and constituents of the real mixture to provide identical flavor and texture without the amino acids. Ratings were administered at baseline and then repeated on days 3, 5, and 7. All ratings were carried out by an experienced rater who was blind to the group assignment of patients.

Results:  A total of 23 patients entered the study and 17 completed the 7‐day treatment protocol. The patients who received the amino acid drink showed greater improvement in mania ratings. The differences in Young Mania Rating Scale (YMRS) and Clinical Global Impression (GCI) scores were significant. However, the intolerance rate was high (23%) and the findings in this pilot study are based only on results from those patients who were able to tolerate the drink.

Conclusions:  Rapid tryptophan depletion may have an antimanic effect.
Mood‐stabilizing pharmacological treatment in bipolar disorders and risk of suicide
Authors: Søndergård Lars , Lopez Ana Garcia , Andersen Per Kragh , Kessing Lars Vedel
Published: September 2010

Objectives:  This study investigated the association between continued mood‐stabilizing treatment (lithium and anticonvulsants) in bipolar disorder (BD) and the risk of suicide.

Methods:  Using linkage of national registers, the association between continued mood‐stabilizing treatment and suicide was investigated among all patients discharged nationwide from hospital psychiatry as an in‐ or outpatient in a period from 1995 to 2000 in Denmark with a diagnosis of BD.

Results:  A total of 5,926 patients were included in the study and among these 51 patients committed suicide eventually during the study period. Although the rate of suicide was higher during periods when patients purchased anticonvulsants (293 suicides per 100,000 person‐years) than during periods with lithium (136 suicides per 100,000 person‐years), the suicide rate decreased with the number of prescriptions in a rather similar way for patients first treated with lithium and patients first treated with anticonvulsants: patients who continued treatment with mood‐stabilizing drugs had a decreased rate of suicide compared to patients who purchased mood stabilizers once only [rate ratio for anticonvulsants = 0.28, 95% confidence interval (CI) = 0.19–0.41; rate ratio for lithium = 0.20, 95% CI = 0.10–0.38]. Further, the rate of suicide decreased consistently with the number of additional prescriptions. Switch to or augmentation with lithium to patients initiated on anticonvulsants was associated with a significantly reduced rate of suicide (rate ratio = 0.28, 95% CI = 0.20–0.40), whereas a switch to or augmentation with anticonvulsants to patients first started on lithium showed no additional effect on the suicide rate.

Conclusions:  Although continued treatment with anticonvulsants and continued treatment with lithium was associated with a rather similar reduction in the rate of suicide, the results suggest that treatment with lithium may have some superiority in relation to prevention of suicide.
Further support for association of the mitochondrial complex I subunit gene NDUFV2 with bipolar disorder
Authors: Xu Chun , Li Peter P , Kennedy James L , Green Marty , Hughes Bronwen , Cooke Robert G , Parikh Sagar V , Warsh Jerry J
Published: September 2010

Background:  The nuclear‐encoded mitochondrial complex I subunit gene, NDUFV2, has been implicated in the pathogenesis of bipolar disorder (BD) in Japanese by virtue of association of variants in its promoter with BD and decreased NDUFV2 messenger ribonucleic acid (mRNA) levels in B lymphoblasts (BLCL) in BD patients compared to controls. We sought to determine if these same changes occur in non‐Japanese populations and, if so, their relationship to altered basal intracellular Ca2+ ([Ca2+]B) in BLCL from BD patients.

Methods:  Bipolar disorder patients and healthy subjects included 298 subjects of European Caucasian descent. The 5′‐nuclease allelic discrimination TaqMan assay was used to detect selected single nucleotide polymorphisms (SNPs) in promoter, introns and 3′UTR regions, spanning the NDUFV2 gene. NDUFV2 mRNA levels and [Ca2+]B in BLCLs were determined.

Results:  The A allele of the NDUFV2 SNP rs1156044 was significantly associated (Bonferroni‐corrected) with BD (p = 0.013) but differed in allele (rs1156044 G allele) from that previously reported as associated with BD. There was a trend for elevated BLCL [Ca2+]B associated with SNP rs977581 in BD patients, but NDUFV2 mRNA levels in BLCLs did not differ between patients and controls, nor represented genotypes.

Conclusions:  While genetic variants of NDUFV2 may increase risk for BD, the role of its altered expression and the link to intracellular Ca2+ abnormalities in BD remains equivocal.
Proceedings of the Symposium ‘Angiotensin AT1Receptors: From Molecular Physiology to Therapeutics’: ENDOGENOUS ANGIOTENSIN II LEVELS AND THE MECHANISM OF ACTION OF ANGIOTENSIN‐CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR TYPE 1 ANTAGONISTS
Authors: Campbell Duncan J
Published: September 2010

Modification of endogenous angiotensin II (AngII)‐mediated processes by inhibitors of the angiotensin‐converting enzyme (ACE) and antagonists of the angiotensin type 1 (AT1) receptor is dependent upon both the levels of each agent in the plasma and tissues and on the concomitant changes in plasma and tissue AngII levels.

Both ACE inhibitors and AT1receptor antagonists increase renin secretion and angiotensin peptide formation in plasma and extrarenal tissues. Clinical doses of ACE inhibitors produce incomplete inhibition of ACE and the increased AngI levels act to restore AngII towards basal levels. Clinical doses of AT1receptor antagonists produce incomplete blockade of AT1receptors and the increased AngII levels in plasma and extrarenal tissues counteract (to an unknown degree) the effects of the antagonist.

The effects of ACE inhibitors and AT1receptor antagonists on AngII levels show tissue specificity. Angiotensin II‐mediated processes in the kidney are most sensitive to inhibition by these agents. ACE inhibitors reduce renal AngII levels at doses much less than those required to reduce AngII levels in plasma and other tissues. Moreover, in contrast to increased AngII levels in plasma and extrarenal tissues, renal AngII levels do not increase in response to AT1receptor antagonists. The inhibition of AngII‐mediated processes in the kidney may, therefore, play a primary role in mediating the effects of ACE inhibitors and AT1receptor antagonists on blood pressure and other aspects of cardiovascular function and structure.

Combination of an ACE inhibitor with an AT1receptor antagonist prevents the rise in plasma AngII levels that occurs with AT1receptor antagonism alone. This combination would, therefore, be predicted to produce more effective inhibition of endogenous AngII‐mediated processes than either agent alone. We must await further studies to determine whether the combination of ACE inhibition and AT1receptor antagonism results in superior clinical outcomes.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: CYTOKINES AND CARDIAC HYPERTROPHY: ROLES OF ANGIOTENSIN II AND BASIC FIBROBLAST GROWTH FACTOR
Authors: Kaye David M , Kelly Ralph A , Smith Thomas W
Published: September 2010

While the haemodynamic influences that cause cardiac hypertrophy are well known, the cellular and molecular mechanisms by which a mechanical stimulus is translated into a growth response by cardiac muscle have remained uncertain.

Current evidence suggests that a number of trophic factors may be released by cellular constituents of the heart, acting in an autocrine or paracrine manner to influence the growth response and phenotype of neighbouring cells.

Angiotensin II, acting via the AT1 receptor subtype, and both basic fibroblast growth factor and heparin‐binding epidermal growth factor have been shown to exert hypertrophic actions in vivo and in vitro. Studies also indicate that cardiac myocytes themselves are capable of releasing all of these cytokines in response to increased mechanical load.
LACK OF INOTROPIC EFFECT OF NITRIC OXIDE ON THE RAT MYOCARDIUM
Authors: Worthley Matthew I , Horowitz John D , Zeitz Christopher J
Published: September 2010

1. Nitric oxide (NO) is an important mediator of contractile function in the heart. However, isolated papillary muscle preparations appear to lack NO responsiveness in certain animal species. Although cat, guinea‐pig and ferret models have been NO responsive, there have been mixed results in the rat papillary muscle. In null form, we tested three separate hypotheses in rat papillary muscle, specifically that the NO donor sodium nitroprusside (SNP) would not affect the contractility of: (i) the isolated papillary muscle; (ii) papillary muscle prestimulated with the β‐adrenoceptor agonist isoprenaline; and (iii) papillary muscle subjected to 15 min anoxia followed by 45 min reoxygenation.

2. Male Sprague‐Dawley rats were used. The left ventricular papillary muscle was mounted and maintained at 30°C and was stimulated at 10 b.p.m. Each experiment was performed in parallel with a control papillary muscle from the same animal. Papillary muscles were exposed to increasing concentrations of SNP (10−9to 10−5 mol/L) either alone or following pretreatment with 10−7 mol/L isoprenaline. Anoxia/reoxygenation was simulated by 15 min anoxia followed by 60 min reoxygenation in the presence or absence of 10−7 mol/L SNP.

3. Both isometric and isotonic parameters were assessed. As expected, isoprenaline had a significant positive inotropic response. Similarly, contractility was impaired during anoxia and partially recovered during reoxygenation. Nitric oxide did not alter either isotonic or isometric parameters in the three experimental protocols.

4. The rat isolated papillary muscle has no measurable response to exogenous NO. The inotropic effects of β‐adrenoceptor stimulation and anoxia/reoxygenation are NO independent.
BLOOD PRESSURE VARIABILITY, CARDIAC BAROREFLEX SENSITIVITY and ORGAN DAMAGE IN EXPERIMENTALLY HYPERTENSIVE RATS
Authors: Wang Di‐Song , Xie He‐Hui , Shen Fu‐Ming , Cai Guo‐Jun , Su Ding‐Feng
Published: September 2010

1. The present study was designed to investigate the haemodynamic features and morphological changes in experimentally hypertensive rat models.

2. Sprague‐Dawley rats were used to prepare the experimentally hypertensive models, including two‐kidney, one‐clip renovascular hypertensive (2K1C) rats, deoxycorticosterone acetate salt hypertensive (DOCA) rats and NG‐nitro‐l‐arginine methyl ester‐induced hypertensive (l‐NAME) rats. Six weeks after the induction of hypertension, 24 h blood pressure was recorded and blood pressure variability (BPV) expressed by 24 h (or 12 h in the daytime and night‐time study) standard deviation of the variables was calculated. Then, cardiac baroreflex sensitivity (BRS) was determined and four endogenous factors (tumour necrosis factor‐α, interleukin‐1β, angiotensin II and endothelin‐1) were measured. Finally, morphological changes were examined.

3. It was found that an increase in BPV and a decrease in BRS were accompanied by an elevation of blood pressure in all three hypertensive models. The DOCA rats had the highest BPV, whereas the l‐NAME rats had the lowest BRS.

4. Morphological changes were similar in DOCA and l‐NAME rats and the cardiac changes were relatively slight in 2K1C rats. Tumour necrosis factor‐α was increased in all the three models, especially in DOCA rats. Endothelin‐1 was higher in DOCA rats and angiotensin II was increased in 2K1C rats and decreased in DOCA rats.

5. In conclusion, increased BPV and decreased BRS accompanied the elevation of blood pressure in all three hypertensive models. The DOCA rats had the highest BPV and the l‐NAME rats had the lowest BRS. Obvious organ damage was seen in all three hypertensive models 6 weeks after the induction of hypertension.
WAGNER‐NELSON METHOD FOR ANALYSING THE ATYPICAL DOUBLE‐PEAKED [13CO2] EXCRETION CURVE IN THE [13C]‐OCTANOATE GASTRIC EMPTYING BREATH TEST IN HUMANS
Authors: Sanaka Masaki , Yamamoto Takatsugu , Tsutsumi Hiroko , Abe Koichiro , Kuyama Yasushi
Published: September 2010

1. In the [13C]‐octanoic acid breath test, the time versus pulmonary [13CO2] excretion rate curve is analysed using mathematical curve‐fitting techniques to calculate gastric emptying parameters. Thus, the goodness‐of‐fit highly influences the accuracy of the breath test. However, a double‐peaked [13CO2] excretion curve, which occasionally develops owing to the presence of an interval of quiescent gastric emptying (the plateau phase), is likely to be fitted poorly.

2. In pharmacokinetics, the Wagner‐Nelson method has been used to describe precisely the absorption kinetics of orally administered drugs and its reliability is independent of the nature of gastric emptying. A recent study has shown the potential of the Wagner‐Nelson method to generate a realistic gastric emptying flow curve from [13CO2] excretion data. In the present report, we have demonstrated that the Wagner‐Nelson method can visualize the plateau emptying phase responsible for the cases of double peaks.

3. Wagner‐Nelson analysis applied to the breath test described precisely the characteristic emptying pattern of the two emptying phases being interrupted by the plateau phase. Conventional analysis for the breath test failed to detect the plateau phase.

4. The Wagner‐Nelson method is a useful tool for analysing atypical double‐peaking [13CO2] excretion curves.
CHARACTERIZATION OF CATIONIC AMINO ACID TRANSPORT SYSTEMS IN RAT ERYTHROCYTES: LACK OF EFFECT OF URAEMIA ON l‐ARGININE INFLUX
Authors: Brunini TMC , Yaqoob MM , Roberts NB , Ellory JC , Moss MB , Siqueira MAS , Mann GE , Mendes Ribeiro AC
Published: September 2010

Chronic renal failure (CRF) is associated with the abnormal regulation of nitric oxide (NO) synthesis at the systemic level. The transport of l‐arginine, upregulated in blood cells from uraemic patients, modulates NO synthesis in this pathological condition. The model of partial nephrectomy in rats is widely accepted as a valid model of uraemia. Because there are no reports of l‐arginine transport in blood cells from uraemic rats, the aim of the present study was to investigate l‐arginine transport in red blood cells (RBCs) from these rats.

The kinetics of l‐arginine transport in RBC and plasma and the amino acid profiles of RBC were investigated in control, sham‐operated and subtotally nephrectomized rats.

l‐Arginine transport was mediated via the cationic amino acid transport system y+ and a transport system with kinetics resembling the human system y+L. In control RBC, the apparent Ki for l‐leucine inhibition of l‐arginine transport via system y+L was 0.16 ± 0.02 and 4.8 ± 2 mmol/L in the presence of Li+ and Na+, respectively.

The Vmax values for l‐arginine transport via system y+L and system y+ were similar in RBC from control sham‐operated and uraemic rats. Moreover, l‐arginine concentrations in plasma and RBC were not affected by uraemia.

The findings of the present study provide the first evidence that l‐arginine transport in rat erythrocytes is mediated by two distinct cationic transport systems with characteristics of systems y+ and y+L, which accept neutral amino acids only in the presence of Li+. In contrast with previous studies in uraemic patients, plasma levels and maximal transport rates of l‐arginine were not altered in this rat model of CRF.
RESETTING OF AORTIC BARORECEPTORS IN RESPONSE TO HYPOTENSION DOES NOT ALTER GAIN SENSITIVITY
Authors: Koike Marcia K , Moreira Edson D , Da Silva Gustavo JJ , Consolim‐Colombo Fernanda M , Ida Fumio , Irigoyen Maria CC , Krieger Eduardo M
Published: September 2010

In chronic hypertension, the baroreceptors reset to hypertensive levels with a decrease in gain sensitivity, but only a few studies have evaluated baroreceptor resetting during chronic hypotension and, under these conditions, no consistent information is available concerning changes in baroreceptor gain sensitivity. Therefore, in the present study, the aortic baroreceptor function curve and the baroreflex control of heart rate (HR) were evaluated in chronic hypotension produced by myocardial infarction (MI) with no heart failure.

Aortic baroreceptor function curves were studied in anaesthetized three groups of rats: (i) MI‐7, six rats 7 days after MI; (ii) MI‐30, nine rats 30 days after MI; and (iii) five control animals (SHAM). The pressure–nerve activity relationship was measured during rapid changes in blood pressure by integrating the whole‐nerve activity of the baroreceptors in a computerized beat‐to‐beat analysis.

Both long‐term periods (7 or 30 days) of hypotension were accompanied by complete resetting of the baroreceptor in rats (the leftward displacement of the baroreceptor curve matched the decrease in blood pressure). Moreover, the resetting of the baroreceptor function curve was not accompanied by changes in gain sensitivity (1.47, 1.64 and 1.67%/mmHg for SHAM, MI‐7 and MI‐30 groups, respectively) and the baroreflex control of HR was normal comparing SHAM and MI‐30 groups (bradycardic 1.62 ± 0.18 vs 1.99 ± 0.52 b.p.m./mmHg, respectively; tachycardic 3.6 ± 0.5 vs 4.1 ± 0.4 b.p.m./mmHg for, respectively).

The data indicate that the resetting of baroreceptors in chronic hypotension is stable and is not accompanied by changes in gain sensitivity, as observed in hypertension. This may account for the normal baroreflex control of HR observed in non‐anaesthetized rats.