bluuebunny/crossref_metadata_2025 huggingface dataset:
Progressive escape from parathyroid suppression: a common phenomenon in primary hyperparathyroidism (A calcium clamp study)
Authors: Sørensen H. A. , Schwarz P. , Hyldstrup L. , Transbøl I.
Published: September 2010

OBJECTIVE Induced aggravation of hypercalcaemia In vivo and in vitro causes partial suppression of parathyroid hormone (PTH) secretion in primary hyperparathyroidism (PHP). Furthermore, one in‐vitro study also demonstrates progressive escape from such action. The aim of the present in‐vivo study was to examine whether escape from suppression is a common feature of PHP.

DESIGN A rapid increment in blood ionized calcium (B‐Ca2+) to 0.25–0.30 mmol/l above individual baselines was achieved by intravenous calcium infusions. This induced or aggravated hypercalcaemia was kept constant for 2 hours (controls) or 4 hours (patients).

PATIENTS AND CONTROLS The study of PHP comprised 19 patients (18 females and one male) aged 39–85 years (geometric mean 66). For comparison we included the results obtained in a control group of 24 healthy subjects (11 women and 13 men) aged 20–68 years (geometric mean 32).

MEASUREMENTS The individual levels of B‐Ca2+ were controlled by frequent bedside measurements of B‐Ca2+. The changes in serum intact parathyroid hormone (S‐PTH(1–84)) were registered.

RESULTS After 30 minutes of calcium infusion average concentrations of S‐PTH(1–84) had decreased from 7.9 (6.7–9.4) pmol/l in PHP and 2.5 (2.1–2.9) pmol/l in controls to their respective nadir values of 2.9 (2.1–4.1) pmol/l and 0.6 (0.5–0.8) pmol/l. While S‐PTH(1–84) remained suppressed at a stable level for 120 minutes in controls, in PHP it started to escape progressively after 30 minutes to a level of 4.2 (3.0–5.8) pmol/l (P < 0.001). Linear regression analysis of the individual S‐PTH(1–84) observations in PHP, from 30 to 240 minutes of study, revealed that five patients did not escape (group A) while the remainder 14 patients escaped progressively (group B). Within group B, seven patients escaped significantly after 120 minutes, 10 after 180 minutes and 14 after 240 minutes. Although comparable respecting B‐Ca2+ before and during calcium infusion, group A and B presented different S‐PTH(1–84) curves. Thus, at times zero, 30, 120 and 240 minutes their respective average concentrations of S‐PTH(1–84) measured 9 9 (9.1–10.9) vs 7.3 (5.9–9.0) (P < 0.02), 4.6 (3.7–5.7) vs 2.5 (1.6–3.9) (P < 0.01), 5.0 (3.9–6.5) vs 3.0 (1.9–4.8) (P < 0.05) and 5.2 (3.6–7.4) vs 3.9 (2.6–6.0) (NS) pmol/l.

CONCLUSIONS We hypothesize that two different mechanisms are involved in the parathyroid response to the calcium clamp, an initial and fast inhibition of PTH release, while the subsequent course depends on the balance between the intra‐glandular secretion rate of PTH and the intra‐glandular capacity for PTH degradation. The escape from parathyroid suppression during a sustained stable increment in B‐Ca2+ suggests that the basal secretion over‐rides degradation in a majority of the patients with PHP.
TSH suppression by octreotide in differentiated thyroid carcinoma
Authors: Maini Carlo L. , Sciuto Rosa , Tofani Anna
Published: September 2010

OBJECTIVE This study evaluates the addition of octreotide and L‐thyroxine to shorten the period of exposure to unduly elevated TSH levels in patients with differentiated thyroid carcinoma undergoing total body scan with 131I.

DESIGN Fourteen thyroidectomized patients were studied after total body scan and the restarting of different doses of thyroxine. After one year a second total body scan and a schedule of the same dose of thyroxine combined with octreotide were performed in each subject.

PATIENTS Patients were divided into four groups according to the treatment: seven patients received initially 100 μg of L‐thyroxine (Group 1) and after 1 year 100 μg of L‐thyroxine plus 300 μg of octreotide/day (Group 3); the other seven received initially 150 μg of L‐thyroxine (Group 2) and then 150 μg of L‐thyroxine plus 300 μg of octreotide/day (Group 4).

MEASUREMENTS Serum TSH, T3 and T4 were measured on the day of radioiodine administration (day 0) and after 14, 21, 30, 45, 60 and 90 days.

RESULTS Mean basal TSH levels were elevated in all four groups ranging from 104 to 91 mU/l without significant differences. The patterns of TSH inhibition were however different in the four groups studied. TSH remained very elevated for a long time in Group 1 patients: at day 90 the TSH value was still 2.1±1.2 mU/l (mean ± SEM). Patients in Groups 2 and 3 showed a similar pattern: TSH was suppressed in 45 days. The most rapid TSH inhibition was observed in Group 4 patients with a mean decrease of 88% in 14 days and complete suppression in 30 days.

CONCLUSIONS TSH suppression by L‐thyroxine is very slow and it can be significantly enhanced by combined octreotide administration. Combined therapy is safe and offers an alternative choice when high dosages of L‐thyroxine are inappropriate or in conditions of advanced illness.
Prostate volume in testosterone‐treated and untreated hypogonadal men in comparison to age‐matched normal controls
Authors: Behre Hermann M. , Bohmeyer Jörg , Nieschlag Eberhard
Published: September 2010

OBJECTIVE The potential use of testosterone preparations for substitution therapy for ageing men and for male contraception, In addition to the well established substitution therapy of male hypogonadism, make increased testosterone use likely. However, little clinical information is available on the effect of testosterone therapy on the prostate in hypogonadal men.

DESIGN AND MEASUREMENTS In a controlled cross‐sectional study, prostate volume measured by transrectal ultrasonography, serum levels of prostate‐specific antigen (PSA) and sex hormones, and uroflow parameters were determined.

PATIENTS Three groups of age‐matched men were enrolled in the study: 47 newly diagnosed hypogonadal men before testosterone treatment, 78 hypogonadal men with at least 6 months of effective testosterone therapy and 75 normal men.

RESULTS Regression analysis revealed a significant positive correlation of prostate volume with age in normal men and testosterone‐treated hypogonadal men, whereas no significant correlation was detected in untreated hypogonadal men. Prostate volume was significantly lower in untreated hypogonadal men (12.2 (11.0–13.5) ml) (mean (95% confidence limits)) compared to both other groups. However, no significant difference in prostate volume was detected between testosterone‐treated hypogonadal men (21.3 (19.9–22.8) ml) and normal men (22.9 (21.4–24.4) ml). Similar results were obtained for PSA with comparable values in the testosterone‐treated hypogonadal men (0.98 (0.88–1.10) μg/l) and normal men (1.02 (0.91–1.14) μg/l), and significantly lower concentrations in the untreated hypogonadal men (0.64 (0.55–0.73) μg/l). No differences in uroflow parameters were detected between the three study groups.

CONCLUSIONS Effective testosterone treatment of hypogonadal men results in prostate volume and prostate‐specific antigen levels comparable to age‐matched normal men. Therefore, testosterone‐induced prostate growth should not preclude hypogonadal men from testosterone substitution therapy.
The level of endothelin‐like immunoreactivity in seminal fluid correlates positively with semen volume and negatively with plasma gonadotrophin levels
Authors: Hammami Muhammad M. , Haq Afrozui , AlSedairy Sultan
Published: September 2010

OBJECTIVE The newly discovered vasoactive peptides, endothelin 1, 2 and 3, and their receptors are widely distributed in various non‐vascular tissues. Recent studies have suggested the presence, as well as possible regulatory roles, of endothelins at several levels of the pituitary‐gonadal axis. We determined the level of endothelin‐like immunoreactivity in the seminal fluid and examined its possible correlation with routine semen parameters or plasma levels of FSH, LH or testosterone.

DESIGN Prospective study in a tertiary care centre.

PATIENTS Ninety‐one men attending infertility clinics for male factor, female factor or both.

MEASUREMENTS Endothelin‐like immunoreactivity was determined in seminal fluid using two radioimunoassays, ET1–21 that measures endothelin and ET‐1,2 that measures both endothelin and big endothelin. In addition, the levels of FSH, LH and testosterone as well as routine semen parameters were determined.

RESULTS Sperm density ranged from 0 to 315 times 108with a mean (±SD) of 28.5 times 108(±48 times 108) sperm/ml and the percentage of motile sperm ranged from 0 to 85% with a mean of 16% (±20.5%). Mean levels of FSH (n= 33), LH (n= 35) and testosterone (n= 35) were 6.4 ± 4.9 IU/I, 3.5 ± 2.8 IU/I and 21 ± 9.4 nmol/l, respectively. Mean ET1‐21 level (n= 91) was 81 ± 16.5 pmol/l, and mean ET‐1,2 level (n= 33) was 630.5 ± 143 pmol/l. There were significant correlations between the levels of ET1–21 and ET‐1,2 (r= 0.37,P= 0.04), ET1–21 and FSH (r= −0.5,P= 0.006), ET1–21 and LH (r= −0.46,P= 0.01), and ET1–21 level and semen volume (r= 0.23,P= 0.03). Mean level of ET1–21 or ET‐1,2 was significantly lower in patients treated empirically with clomiphene citrate or gonadotrophins (n= 34) compared to untreated (n= 52) patients (P= 0.04).

CONCLUSIONS We conclude that in human seminal fluid (1) endothelin‐like immunoreactivity that is specific for active endothelin (ET1–21) represents about 13% of the total immunoreactivity; (2) inactive big endothelin or its N‐terminal derivative(s) may account for most of the immunoreactivity; (3) the production/secretion of endothelin may be inhibited by LH and/or FSH; and (4) endothelin level correlates positively with seminal fluid volume.
Metastatic thyroid cancer presenting as thyrotoxicosis: report of three cases
Authors: Kasagi K. , Takeuchi R. , Miyamoto S. , Misaki T. , Inoue D. , Shimazu A. , Mori T. , Konishi J.
Published: September 2010

Three patients with metastatic thyroid follicular carcinoma developed thyrotoxicosis. Two had mild T3 toxicosis without detectable TSH binding inhibitor immunoglobulins (TBII) or thyroid stimulating antibodies (TSAb). Considerable concentration of 131***I by tumours occurred, although serum TSH was undetectable. The third patient developed thyrotoxicosis several months after treatment with 131I had commenced and this was associated with concurrent increase in both TBII (90%; normal, less than 11%) and TSAb (2100%). We conclude that thyrotoxicosis in patients with metastatic thyroid carcinoma may result from a large bulk of tumour functioning either autonomously or after stimulation by TSH receptor antibodies.
The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma
Authors: Fougner Stine L. , Borota Olivera Casar , Berg Jens Petter , Hald John K. , Ramm‐Pettersen Jon , Bollerslev Jens
Published: September 2010

Objective  Reduced expression of the somatostatin receptor subtype 2 (SSTR2) has been suggested as an explanation for the poor response to octreotide in acromegaly, but studies correlating levels of SSTR2 mRNA to octreotide efficacy have been contradictory. Some studies have found better responses to somatostatin analogues in G‐protein α subunit (Gsα) mutation (gsp oncogene)‐positive adenomas. The aim of this study was to determine adenoma SSTR2a protein expression and gsp status in a large group of patients with acromegaly, and relate this to the clinical effect of octreotide.

Patients  Seventy‐one patients were included. All underwent transsphenoidal surgery, 23 patients after preoperative octreotide treatment.

Measurements  The adenoma SSTR2a expression was examined by immunohistochemistry and Western blot analysis, and gsp status determined. An acute octreotide test was performed, and the change in IGF‐1 level after 6 months preoperative octreotide treatment was recorded.

Results  The acute octreotide response in non‐pretreated patients and the preoperative long‐term octreotide response were significantly better in patients with adenomas containing a large proportion of cells that stained positively for SSTR2a by immunohistochemistry. However, the SSTR2a protein level assessed by Western blot did not correlate with the octreotide response. The preoperatively treated group had lower SSTR2a protein levels and fewer adenomas with a large percentage of positively stained cells. The gsp oncogene was detected in 43% of the adenomas but did not correlate to the octreotide response.

Conclusion  The clinical effect of octreotide correlates with the proportion of cells positive for SSTR2a in immunohistochemical staining, rather than the adenoma SSTR2a protein level. There may be a down‐regulation of SSTR2a during octreotide treatment.
A 12‐month randomized crossover study on the effects of Lanreotide Autogel and Octreotide long‐acting repeatable on GH and IGF‐l in patients with acromegaly
Authors: Andries Magdalene , Glintborg Dorte , Kvistborg Annette , Hagen Claus , Andersen Marianne
Published: September 2010

Background  Somatostatin analogues have been used successfully for the treatment of acromegaly but no randomized studies have compared the effects of lanreotide Autogel (LAN) and octreotide acetate long‐acting repeatable (OCT).

Objective  To compare the effect of LAN and OCT for the treatment of acromegaly in a randomized study design.

Material and methods  Twelve acromegalic patients were included and 10 patients completed treatment with LAN or OCT for 6 months and were then switched to the opposite treatment modality for 6 months without a washout period in a randomized crossover design. GH and IGF‐I profiles, clinical and biochemical evaluations were performed at 0, 4, 6, 10 and 12 months.

Results  After 6 months of treatment, five patients had GH levels < 0·38 µg/l during both therapies. The remaining patients had GH levels > 0·38 µg/l during both LAN and OCT treatment. Four patients had normalized IGF‐I levels during both treatment regimes. Two patients on LAN and one on OCT had normalized IGF‐I levels during one treatment and not during the other. In three patients, IGF‐I levels were elevated during both therapies. Four patients developed palpable nodules, two patients on LAN and two patients on OCT. Gastrointestinal complaints were seen in three patients during both therapies, in three patients only during LAN, and in one patient only during OCT. Two patients were withdrawn from the study because of serious adverse effects during LAN. After the study period, four patients preferred LAN and six patients preferred OCT treatment.

Conclusion  The effects of LAN and OCT therapy on GH and IGF‐I levels were comparable, but 3/10 patients had different treatment efficacies and 6/10 had different side‐effect profiles during the LAN and OCT treatment. These results indicate that a change from LAN to OCT or vice versa may be beneficial in some patients with treatment failure or side‐effects.
Pioglitazone (7·5 mg/day) added to flutamide–metformin in women with androgen excess: additional increments of visfatin and high molecular weight adiponectin
Authors: Ibáñez Lourdes , López‐Bermejo Abel , Díaz Marta , Enríquez Goya , Valls Carme , De Zegher Francis
Published: September 2010

Background and aim  Low‐dose pioglitazone (Pio), flutamide (Flu), metformin (Met) plus an oestro‐progestagen is a novel polytherapy lowering total and visceral adiposity, and reducing carotid intima media thickness (IMT) in hyperinsulinaemic women with androgen excess, without changing their body mass index (BMI). In a search for mediators of PioFluMet's actions, we measured serum levels of visfatin and high molecular weight (HMW) adiponectin.

Design and patients  In a double‐blind study, we enrolled 38 young women with hyperinsulinaemic androgen excess [mean BMI: 23·7 kg/m2], all of whom started on Flu (62·5 mg/day), Met (850 mg/day) and a transdermal oestro‐progestagen, each for 21/28 days over 1 year. Patients were randomly assigned to receive, in addition, placebo (n = 19) or Pio (7·5 mg/day; n = 19) on the same 21/28 days.

Measurements  Serum concentrations of visfatin and HMW adiponectin, visceral fat by magnetic resonance imaging, carotid IMT by ultrasound, all carried out during study start and after 1 year.

Results  PioFluMet raised visfatin by a mean 84% and HMW adiponectin by 157% (P < 0·001), and reduced visceral fat and IMT by a mean 22% and 31% (both P < 0·001). Low‐dose Pio accounted for about half of the PioFluMet effects on IMT, visfatin and HMW adiponectin.

Conclusion  In hyperinsulinaemic women with androgen excess, low‐dose polytherapy with PioFluMet evoked striking rises in both circulating visfatin and HMW adiponectin, while lowering IMT and reducing visceral adiposity within 1 year.
Kinetic epidemiological model for elucidating sexual difference of hypertension (KCIS no.20)
Authors: Yen Amy M.‐F. , Chen Tony H.‐H.
Published: September 2010

Background  Woman have lower rate of hypertension than man but it is still elusive how such gender difference can be explained by kinetic epidemiological curves.

Objective  The aim of this paper was to develop a multi‐state model for delineating the kinetic epidemiology of hypertension according to the Seventh Report of the Joint National Committee (JNC 7) classification criteria by gender, and to derive gender‐specific kinetic curves.

Methods  We used data from a population‐based screening programme with 42 027 participants to fit a four‐state Markov model corresponding to the classification of hypertension from the JNC 7.

Results  The young man had higher progression rate but lower regression rate for the movement between normal and pre‐hypertension than the young woman. Such gender difference disappeared after 50 years old. The mean sojourn time of pre‐ and stage 1 hypertension for man and stage 1 for woman was approximately 5 years. However, the corresponding figure for pre‐hypertension for woman was 25 years at age 30, 10 years at age 40 and 5 years afterwards.

Conclusion  Elucidating the kinetic epidemiological curves of hypertension explains higher prevalence rate in young man than woman. These findings fit with the role of sex hormones regulating blood pressure demonstrated in the animal model.
Out‐of‐hours demand in primary care: frequency, mode of contact and reasons for encounter in Switzerland
Authors: Huber Carola A. , Rosemann Thomas , Zoller Marco , Eichler Klaus , Senn Oliver
Published: September 2010

Rationale, aims and objectives To investigate the demand for traditional out‐of‐hours general practitioner (GP) emergency care in Switzerland including GPs' satisfaction and reasons for encounter (RFE).

Method During a 2‐month period (2009), a questionnaire‐based, cross‐sectional study was performed in GPs participating in the mandatory out‐of‐hours service in the city of Zurich, Switzerland. The number and mode of patient contacts were assessed to investigate the demand for GP care in traditional out‐of‐hours services. GPs and patient characteristics, including RFE according to the International Classification of Primary Care, were noted. Descriptive statistics and non‐parametric tests were conducted.

Results Out of the 295 out‐of‐hours episodes during the study period, 148 (50%) duty periods were documented by a total of 93 GPs (75% men) with a mean (SD) age of 48.0 (6.2) years. The median (interquartile range) number of out‐of‐hours contacts was 5 (3–8) and the demand for home visits was significantly more common compared with practice and telephone consultations. A total of 112 different RFEs were responsible for the 382 documented patient contacts with fever accounting for the most common complaint (13.9%). Although 80% of GPs agreed to be satisfied overall with their profession as primary care provider, 57.6% among them were dissatisfied with the current out‐of‐hours service. Inappropriate payment and interference with their daily work in practice were most frequently reported.

Conclusions Our findings indicate that there is still strong patient demand for out‐of‐hours care with special need for home visits, suggesting that new organizational models such as integrating GPs into emergency care may not be an appropriate approach for all patients. Therefore, the ongoing reorganization of the out‐of‐hours‐service in many health care systems has to be evaluated carefully in order not to miss important patient needs.
Magnitude of effect of lithium in short‐term efficacy studies of moderate to severe manic episode
Authors: Storosum Jitschak G , Wohlfarth Tamar , Schene Aart , Elferink Andre , Van Zwieten Barbara J , Brink Wim van den
Published: September 2010

Objectives:  To provide an accurate estimation of the magnitude of effect of lithium in short‐term efficacy studies conducted in patients with moderate to severe manic episode.

Methods:  All placebo‐controlled randomized studies submitted to the Medicines Evaluation Board (MEB) in which lithium was used as the third study arm were selected for the meta‐analysis. The studies were part of registration files submitted to the MEB between the years 1997 and 2005. In addition, Medline and EMbase searches were conducted with the key words ‘manic’ (‘mania’ for the EMbase search) and ‘placebo’ in order to identify additional placebo‐controlled studies of lithium. This search was updated until March 1, 2006. Two effect size indicators were used based on the primary outcome measure of each study: Cohen's standardized effect size based on the difference in mean change from baseline, and numbers needed to treat (NNT) based on the difference in treatment response defined as ≥50% improvement from baseline on day 21.

Results:  Six studies were identified. They involved a combined total of 470 patients in the lithium groups and 562 in the placebo groups. The overall standardized effect size was 0.40 [95% confidence interval (CI): 0.28, 0.53] and the overall NNT for response was 6 (95% CI: 4, 13). In the placebo groups response rates varied from 21% to 47%.

Conclusions:  The results indicate that lithium is an effective drug in the treatment of moderate to severe manic episode. The variability in placebo response indicates that a placebo control arm in efficacy studies among patients with moderate to severe manic episode is necessary.
Cognitive impairment in later life in patients with early‐onset bipolar disorder
Authors: Tsai Shang‐Ying , Lee Hsin‐Chien , Chen Chiao‐Chicy , Huang Yi‐Lin
Published: September 2010

Objectives:  Cognitive impairment may interfere with psychosocial functioning in bipolar disorder (BD). There is limited information regarding the cognitive function of elderly bipolar patients with onset at a young age. The present study aimed to investigate the frequency and the determinants of cognitive impairment in elderly early‐onset bipolar patients.

Methods:  Using the Clock‐drawing Test (CDT), the Mini Mental State Examination (MMSE), and the Cognitive Abilities Screening Instrument (CASI), we examined euthymic patients with bipolar I disorder in Taiwan, aged 60 years and older. Clinical data were obtained by reviewing medical records and personal interviews with patients and their family members. The onset of BD prior to the age of 40 years is defined as ‘early‐onset’.

Results:  Of the 52 early‐onset patients, 42.3% were determined to have cognitive impairment by exhibiting either abnormal CDT or education‐adjusted MMSE scores. In a multiple regression model, years of education and the age at the last manic/hypomanic (but not depressive) episode accounted for the greatest variance in both MMSE and CASI scores. While educational level and the age at the last manic/hypomanic episode were not considered in the regression model, onset with depressive syndrome and current age explained 21.5% of the variance in MMSE scores. Age at the first depressive episode, the first manic episode before the age of 40 years, and comorbid diabetes accounted for 16.7% of the variance in CASI scores.

Conclusions:  There appeared to be a sizable proportion of elderly early‐onset bipolar patients having cognitive impairment. It is suggested that clinical manifestation of first‐onset affective episode and impact of medical comorbidity affect the cognition of early‐onset BD in later life.
Long‐term outcome of patients with bipolar disorder commenced on lithium prophylaxis during hospitalization: a complete 15‐year register‐based follow‐up
Authors: Licht Rasmus W , Vestergaard Per , Brodersen Arne
Published: September 2010

Objectives:  From placebo‐controlled studies of up to two years duration, it has been established that lithium has preventive efficacy in bipolar disorder (BD). However, the effectiveness of lithium under routine conditions seems less pronounced. In the present study, the overall 15.3‐year outcome in BD patients commenced on lithium is described.

Methods:  Ninety‐one patients with BD consecutively commenced on prophylactic lithium treatment during hospitalization at the Aarhus University Psychiatric Hospital from 1981 to 1983 were followed until death or censoring occurred during up to 15.3 years of observation. Register‐based outcome measures, available for all patients, included accumulated duration of admission and number of admissions. In addition, serious attempts were made to collect detailed information on treatment during follow up. Simple descriptive statistics were applied; potential independent associations between baseline variables and outcome were examined using logistic regression models.

Results:  Of the 91 patients, 27 patients died (six from suicide) during the observation period, which was an excess mortality compared to the general population. Fifty percent of the patients were admitted for more than one month per 20 months of observation and admitted more than once for each four years of observation. Only 19 (21%) patients were not admitted to hospital during the observation period. No statistically significant predictors of poor outcome could be identified. In addition to lithium prophylaxis given for variable lengths of time, the majority of the 36 (40%) patients, from whom treatment data were available, received various other drug treatments during follow‐up.

Conclusions:  The overall outcome in patients beginning prophylactic treatment is unsatisfactory. However, due to the observational design and the lack of detailed treatment information during the long follow‐up period, inferences about the efficacy of lithium cannot be made from this study.
Retrospective parent report of psychiatric histories: do checklists reveal specific prodromal indicators for postpubertal‐onset pediatric bipolar disorder?
Authors: Rucklidge Julia J
Published: September 2010

Objectives:  This study retrospectively investigated the relationship between prodromal symptoms described in the literature for pediatric bipolar disorder (BD) and the diagnosis of BD by comparing adolescents with BD to those in control and attention‐deficit hyperactivity disorder (ADHD) groups.

Methods:  Semi‐structured interviews [Schedule for Affective Disorders and Schizophrenia for School‐Age Children – Present and Lifetime version (K‐SADS‐PL) and Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH‐U‐KSADS)] and checklists (Conners’ Rating Scales and Child Behavior Checklist) identified participants (13–17 years) as either normal controls (NC; n = 28), ADHD (n = 29) or BD (n = 25). Bipolar disorder included BD I, BD II and BD not otherwise specified (NOS). Parents completed a widely used but unvalidated symptom checklist published by Papolos and Papolos (The Bipolar Child: the Definitive and Reassuring Guide to Childhood's Most Misunderstood Disorder) assessing across three developmental periods (preschool, latency, adolescence) for the presence/absence of psychiatric symptoms, many of which have been described in the literature as prodromal to the emergence of manic symptoms.

Results:  While both clinical groups had more psychiatric symptoms than the NC group, more problems were reported in the ADHD group, most of which were symptoms seen as cardinal features of ADHD (e.g., being easily distracted, interrupting, having trouble concentrating). Differences were present by the latency period. Depressed mood was higher in the BD group during latency, and elated mood and fire‐setting were higher in the BD group during adolescence. Results were more similar when comparing adolescents with BD only versus those with both ADHD and BD. Frequency of symptoms was comparable regardless of whether or not there was a family history of BD. Frequency of symptoms was also similar across the BD subtypes.

Conclusions:  Using retrospective parent report, a cluster of prodromal psychiatric symptoms specific to BD was not identified, which both questions the utility of a widely used yet unvalidated clinical scale and encourages caution when interpreting information collected via retrospective checklists. Although these data suggest that the presence of prodromal non‐specific psychiatric symptoms flags a more global risk for psychopathology, significant limitations exist when using retrospective report and, as such, further prospective research is required to investigate the progression of psychiatric symptoms across childhood disorders.
Proceedings of the Symposium ‘Angiotensin AT1Receptors: From Molecular Physiology to Therapeutics’: ANGIOTENSIN II AND THE ADRENAL
Authors: Giacchetti G. , Opocher G. , Sarzani R. , Rappelli A. , Mantero F.
Published: September 2010

Angiotensin II (AngII) evokes a variety of physiological responses in the adrenal gland. It is the major regulator of aldosterone secretion, in the medulla it enhances catecholamine release and it exerts trophic effects in the adrenal and stimulates growth factor secretion.

Angiotensin II acts via binding to specific receptors, located on the plasma membrane. Two pharmacologically distinct AngII receptor subtypes, type 1 (AT1) and type 2 (AT2) receptors, have been identified using the non‐peptide antagonists Dup753 and PD 123177, respectively, and cDNA encoding each type have been identified.

In the adrenal, the AT1receptor modulates all the known biological effects of AngII. The expression of the AT1receptor is modulated at the mRNA and protein levels by many factors: conditions that increase levels of AngII (low sodium diet, renovascular hypertension, AngII infusion) up‐regulate AT1receptor mRNA levels and binding and increase aldosterone secretion.

A tissue renin‐angiotensin system has been found in the adrenal, suggesting an important paracrine role for AngII in aldosterone regulation.

The possible involvement of AT1receptors in human disease has been investigated by examining the role of AngII receptors in adrenal tumours. Binding and gene expression studies have shown that AngII receptors are abundantly expressed in aldosterone‐producing adenoma (APA).

Densitometric analysis of AT1expression in APA showed no significant differences compared with normal and nontumorous adrenal. In addition, no mutations in the coding sequence of the AT1receptor have been found to date in adrenal tumours.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: STRUCTURAL CHANGES IN THE RENAL VASCULATURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT: NO EFFECT OF ANGIOTENSIN II BLOCKADE
Authors: Kett Michelle M , Anderson Warwick P , Bertram John F , Alcorn Daine
Published: September 2010

There is strong evidence for a renal basis to the development of hypertension in the spontaneously hypertensive rat (SHR). Alterations of the SHR renal vasculature, including the glomerulus, may be involved in the initiation and maintenance of hypertension in this animal model.

The arterial walls of pre‐glomerular vessels of the SHR are hypertrophied compared with WKY vessels. Unlike other vascular beds in the SHR, this hypertrophy is independent of angiotensin II (AngII).

Glomerular number and volume are similar between SHR and the normotensive Wistar‐Kyoto (WKY) rats. These results provide no support for the theory that a reduced filtration surface area within the kidneys of the SHR contributes to the elevated blood pressure in these animals.

Intrarenal hypertrophy may have similar haemodynamic consequences to clipping of the main renal artery, as in Goldblatt hypertension. Further analysis of the role of pre‐glomerular arterial hypertrophy is warranted to determine its involvement in the initiation and maintenance of hypertension in the SHR.
Proceedings of the Symposium ‘Angiotensin AT1Receptors: From Molecular Physiology to Therapeutics’: PRESENCE OF ANGIOTENSIN II AT2RECEPTOR BINDING SITES IN THE ADVENTITIA OF HUMAN KIDNEY VASCULATURE
Authors: Zhuo Jialong , Dean Rachael , MacGregor Duncan , Alcorn Daine , Mendelsohn Frederick AO
Published: September 2010

Angiotensin II (AngII) receptor subtypes in adult human kidney were pharmacologically characterized byin vitroautoradiography using the AngII receptor subtype‐selective antagonists, losartan and PD 123319, and the sensitivity to the reducing agent, dithiothreitol.

High densities of AngII AT1receptor binding occur in the glomeruli and the inner stripe of the outer medulla, while a moderate AT1receptor binding is localized in the proximal convoluted tubules.

AT2receptor binding is observed predominantly in the intrarenal large blood vessels, including the arcuate, inter‐ and intra‐lobular arteries, and in the renal capsule.

In the major renal artery, AT1receptor binding is abundant in the media and adventitia, while AT2receptor binding is observed mainly in the adventitia.

At the light microscopic level using emulsion autoradiography, AT1receptors are localized in the glomeruli and juxtaglomerular apparatus, as expected. However, in larger renal blood vessels, including the arcuate arteries, inter‐ and intra‐lobular arteries, intense AT2receptor labelling occurs primarily in the adventitia, while the endothelium and vascular smooth muscle layers contain only low levels of AngII receptor binding.

These results indicate that the adult human kidney displays two pharmacologically distinct AngII receptor subtypes, with AT1predominating in the glomeruli, juxtaglomerular apparatus, proximal tubules and the inner stripe of the outer medulla, while AT2predominates in the adventitia of the arcuate and interlobular arteries and the renal capsule. The functional significance of AT2receptor binding sites in the adventitia of adult human kidney vessels remains to be elucidated.
COMPARISON OF LOW and HIGH DOSES OF CARVEDILOL ON RESTORATION OF CARDIAC FUNCTION and CALCIUM‐HANDLING PROTEINS IN RAT FAILING HEART
Authors: Sun Yi‐Lan , Hu Shen‐Jiang , Wang Li‐Hong , Hu Ying , Zhou Jian‐Ying
Published: September 2010

1. The β‐adrenoceptor antagonist carvedilol reverses cardiac dysfunction in the failing heart. A recent study showed that β‐adrenoceptor antagonists indirectly normalize Ca2+‐regulatory proteins. The relationship between these two phenomena and the suitable dosage of carvedilol remains unclear.

2. We investigated the change in left ventricular (LV) remodelling and function in a rat model of heart failure due to myocardial infarction (MI) with or without carvedilol (30 or 2 mg/kg per day) treatment for 6 weeks. The expression of mRNA and proteins of sarcoplasmic reticulum Ca2+‐ATPase (SERCA) and phospholamban (PLB) in cardiomyocytes was also measured.

3. There was significant LV remodelling and cardiac contractile dysfunction in MI rats. The expression of SERCA mRNA and protein were downregulated (P < 0.01), but the expression of PLB mRNA and protein were upregulated (P < 0.01) in MI rats compared with sham‐operated rats. After treatment with carvedilol, LV remodelling and cardiac contractile dysfunction were clearly improved. Low‐dose carvedilol was better at improving some parameters of LV remodelling and function than the high dose. Carvedilol partially restored the low expression of SERCA (P < 0.05), but had no effect on PLB expression (P > 0.05). Moreover, low‐dose carvedilol induced a more significant improvement in SERCA expression than did the high dose (P < 0.05).

4. The results of the present study suggest that carvedilol is effective in improving LV remodelling and cardiac contractile dysfunction after MI. This may be related to the normalization of SERCA expression.
EFFECT OF PERINATAL HYPOXIA ON CARDIAC TOLERANCE TO ACUTE ISCHAEMIA IN ADULT MALE AND FEMALE RATS
Authors: Netuka Ivan , Szarszoi Ondrej , Maly Jiri , Besik Josef , Neckar Jan , Kolar Frantisek , Ostadalova Ivana , Pirk Jan , Ostadal Bohuslav
Published: September 2010

The number of adult patients undergoing surgery for congenital cyanotic defects in childhood has increased significantly. Therefore, the aim of the present study was to examine the effect of perinatal hypoxia on the tolerance of the adult myocardium to acute ischaemia–reperfusion injury.

Pregnant Wistar rats were exposed to intermittent hypobaric hypoxia 7 days before delivery; pups were born under normoxic conditions and exposed to hypoxia again for 10 postnatal days. After the last hypoxic exposure, all animals were kept for an additional 3 months under normoxic conditions. All experiments were performed on 90‐day‐old rats.

Ventricular arrhythmias were assessed on isolated perfused hearts during 30 min occlusion of the left anterior descending coronary artery. Infarct size was measured on isolated hearts (40 min regional ischaemia and 120 min reperfusion) and on open‐chest animals (20 min regional ischaemia and 3 h reperfusion).

Perinatal exposure to hypoxia significantly increased cardiac tolerance to ischaemic injury in adult females, as evidenced by the lower incidence and severity of ischaemic ventricular arrhythmias, compared with the normoxic group. The effect of perinatal hypoxia on ischaemic arrhythmias in males was quite the opposite. Myocardial infarct size measured in open‐chest animals only was significantly smaller in normoxic females compared with normoxic males. Perinatal exposure to hypoxia had no effect on infarct size in either setting or sex.

The results of the present study support the hypothesis that perinatal hypoxia is a primary programming stimulus in the heart that may lead to sex‐dependent changes in cardiac tolerance to acute ischaemia in later adult life. This would have important implications for patients who have experienced prolonged hypoxaemia in early life.
BEHAVIOUR OF THE ANTI‐OXIDANT DEFENCE SYSTEM AND HEME OXYGENASE‐1 PROTEIN EXPRESSION IN FRUCTOSE‐HYPERTENSIVE RATS
Authors: Polizio Ariel H , Gonzales Soledad , Muñoz Marina C , Peña Clara , Tomaro María L
Published: September 2010

Addition of fructose to a rat diet for various periods of time leads to hypertension, hyperinsulinaemia and dyslipidaemia and provides a model for testing oxidative stress parameters in the animals.

In the present study, oxidative stress generation, the soluble and enzymatic defence system and heme oxygenase‐1 (HO‐1) protein expression were investigated in the heart, liver and kidney of rats fed fructose for a period of 1 or 8 months.

Compared with the control group, fructose‐hypertensive rats showed increased in lipid peroxidation only in the heart after both 1 and 8 months of fructose treatment. Changes in the behaviour of the soluble and enzymatic defence system and HO‐1 protein expression were different depending on the organ. Increased or unaltered activities of anti‐oxidant enzymes were found in the liver and kidney, respectively. Induction of HO‐1 prevented the generation of oxidative stress in the liver, where the activity of anti‐oxidant defence enzymes was not reduced. Increased expression of HO‐1 protein was not able to prevent the generation of oxidative stress in the heart, where fructose treatment diminished the activity of anti‐oxidant enzymes.

The results of the present study demonstrate that upregulation of HO‐1 may prevent the generation of oxidative stress only when the anti‐oxidant defence system is still operative.
CEREBROVASCULAR DYSFUNCTION IS AN ATTRACTIVE TARGET FOR THERAPY IN HEAT STROKE¶
Authors: Chen Sheng‐Hsien , Niu Ko‐Chi , Lin Mao‐Tsun
Published: September 2010

The aim of the present review is to summarize clinical observations and results of animal models that advance the knowledge of the attenuation of cerebrovascular dysfunction in the setting of heat stroke. It is a narrative review of selected published literature from Medline over the period 1959–2005.

All heat‐stressed rodents, even under general anaesthesia, have hyperthermia, systemic inflammation, hypercoagulable state, arterial hypotension and tissue ischaemia and injury in multiple organs. These findings demonstrate that rodent heat stroke models can nearly mirror the full spectrum of human heat stroke. Experimental heat stroke fulfills the empirical triad used for the dignosis of classical human heat stroke, namely hyperthermia, central nervous system alterations and a history of heat stress.

These physiological dysfunctions and survival during heat stroke can be improved by whole‐body or brain cooling therapy adopted immediately after the onset of heat stroke.

However, in the absence of body or brain cooling, these heat stroke reactions can still be reduced by the following measures: (i) fluid replacement with 3% NaCl solution, 10% human albumin or hydroxyethyl starch; (ii) intravenous delivery of anti‐inflammatory drugs, free radical scavengers or interleukin‐1 receptor antagonists; (iii) hyperbaric oxygen therapy; or (iv) transplantation of human umbilical cord blood cells.

In addition, before initiation of heat stress, prior manipulations with one of the following measures was found to be able to protect against heat stroke reactions: (i) systemic delivery of α‐tocopherol, mannitol, inducible nitric oxide synthase inhibitors, mu‐opioid receptor antagonists, endothelin ETAreceptor antagonists, serotoninergic nerve depletors or receptor antagonists, or glutamate receptor antagonists; or (ii) heat shock portein 72 preconditioning.

There is compelling evidence that cerebrovascular dysfunction is an attractive target for therapy in heat stroke.
CHRONIC FLUVASTATIN TREATMENT ALTERS VASCULAR CONTRACTION BY INHIBITING THE RHO/RHO‐KINASE PATHWAY
Authors: Kansui Yasuo , Fujii Koji , Goto Kenichi , Oniki Hideyuki , Iida Mitsuo
Published: September 2010

In the present study, we investigated the effects of chronic treatment of stroke‐prone spontaneously hypertensive rats (SHRSP) with the statin fluvastatin on vascular Rho/Rho‐kinase pathway mediated contraction, which has been shown to be upregulated in hypertension.

Contribution of the Rho/Rho‐kinase pathway to noradrenaline‐induced contraction of arteries from SHRSP was assessed by the inhibitory effect of Y‐27632, a Rho/Rho‐kinase inhibitor. Stroke‐prone spontaneously hypertensive rats were treated with fluvastatin (10 mg/kg per day) for 1 month.

Treatment with fluvastatin tended to attenuate the contraction to noradrenaline and significantly decreased the Y‐27632‐sensitive component of the contraction in controls compared with fluvastatin‐treated rats.

RhoA, as assessed by western blotting, was also reduced by fluvastatin treatment.

These findings suggest that chronic treatment with fluvastatin reduces the contractile response associated with Rho/Rho‐kinase in arteries of hypertensive rats.
EFFECTS OF PERINDOPRIL AND HYDROCHLOROTHIAZIDE ON SELECTED INDICES OF OXIDATIVE STRESS IN THE BLOOD OF ELDERLY PATIENTS WITH ESSENTIAL HYPERTENSION
Authors: Kȩdziora‐Kornatowska Kornelia , Czuczejko Jolanta , Szewczyk‐Golec Karolina , Motyl Jadwiga , Szadujkis‐Szadurski Leszek , Kornatowski Tomasz , Pawluk Hanna , Kȩdziora Józef
Published: September 2010

The aim of the present study was to determine the effect of hypotensive therapy with a diuretic (hydrochlorothiazide) and an angiotensin‐converting enzyme inhibitor (perindopril) on selected oxidative stress parameters in the blood of elderly patients with essential hypertension.

Studies were performed in 45 elderly patients with essential hypertension at baseline and after the 45th day of perindopril (n = 25) or hydrochlorothiazide (n = 20) therapy, as well as in 25 young and 25 elderly normotensive subjects. The following parameters were measured: systolic and diastolic blood pressure, nitric oxide (NO), carbonyl groups and malondialdehyde (MDA) concentrations, as well as the activity of ceruloplasmin (Cp) oxidase, Cu‐Zn superoxide dismutase (SOD‐1) and catalase (CAT).

The activity of SOD‐1 and NO levels were reduced with age.

Compared with elderly controls, hypertensive subjects showed increases in baseline MDA, carbonyl group concentrations and Cp oxidase activity and decreases in NO levels and SOD‐1 and CAT activities.

Treatment with perindopril, but not hydrochlorothiazide, resulted in significant increases in SOD‐1 and CAT activities and decreases in MDA concentration and Cp oxidase activity. Both therapies decreased the level of carbonyl groups and increased NO levels.

Angiotensin‐converting enzyme inhibitor therapy has significant anti‐oxidant effects that may be important in the treatment of elderly patients with essential hypertension.
REDUCED SINOATRIAL cAMP CONTENT PLAYS A ROLE IN POSTNATAL HEART RATE SLOWING IN THE RABBIT
Authors: Yang Zhi‐Fang , Sun Yun , Li Ci‐Zhen , Wang Hong‐Wei , Wang Xi‐Jun , Zheng Yan‐Qian , Liu Kai , Liu Yuan‐Mou
Published: September 2010

Decreasing heart rate during development is known to be the result of parasympathetic nervous system maturation that depresses the pacemaker current (If) by acetylcholine (ACh). However, a direct effect of ACh on If has been ruled out and the involvement of other secondary messengers, such as cAMP, was verified in previous studies. Therefore, we hypothesized that reduced basal cAMP production in sinoatrial (SA) nodal cells may contribute to the slowing of heart rate after birth.

The electrocardiogram and heart rate variability (HRV) were documented and measured in vivo and in vitro (in isolated perfused Langendorff preparations) for rabbits aged 2, 4, 6, 8 and 12 weeks. Sinoatrial node action potential (AP) recording and perforated patch‐clamp analyses were used to investigate the spontaneous depolarization rate and pacemaker If currents. Concentrations of cAMP in SA nodal tissues were determined by radioimmunoassay. Relative expression of adenylate cyclases (ADCY1, 5) and phosphodiesterases (PDE1A, 4A and 8A) were quantified by real‐time reverse transcription–polymerase chain reaction.

Significantly reduced heart rate, but unchanged HRV, was observed in perfused hearts in the older age groups, accompanied with a slowed phase 4 spontaneous depolarization rate (90.5 ± 4.7 vs 49.6 ± 2.6 mV/s for 2 week vs 4 week hearts, respectively; n = 5; P < 0.05), a negative shift of the If threshold potential (−45.5 ± 3.0 vs−51.1 ± 6.0 mV for 2 week vs 4 week hearts, respectively; n = 9; P < 0.05) and decreasing basal levels of SA nodal cAMP (0.31 ± 0.05 vs 0.025 ± 0.002 µmol/L for 2 week vs 4 week hearts, respectively; n = 6; P < 0.05). Gene expression levels of PDE1A, 4A and 8A were increased in the 12 week group compared with the 2 week group 1.5‐, 2‐ and 1.8‐fold, respectively (P < 0.05), with little change in ADCY1 and 5.

These data suggest that, in addition to autonomic innervation, slowing of heart rate during postnatal maturation can be attributed to a negative shift of the If activation caused by diminished baseline cAMP content in SA nodal cells.
REGULATION OF EPITHELIAL Na+CHANNELS BY ALDOSTERONE: ROLE OF Sgk1
Authors: Lee Il‐Ha , Campbell Craig R , Cook David I , Dinudom Anuwat
Published: September 2010

The epithelial sodium channel (ENaC) is tightly regulated by hormonal and humoral factors, including cytosolic ion concentration and glucocorticoid and mineralocorticoid hormones. Many of these regulators of ENaC control its activity by regulating its surface expression via neural precursor cell‐expressed developmentally downregulated (gene 4) protein (Nedd4‐2).

During the early phase of aldosterone action, Nedd4‐2‐dependent downregulation of ENaC is inhibited by the serum‐ and glucocorticoid‐induced kinase 1 (Sgk1).

Sgk1 phosphorylates Nedd4‐2. Subsequently, phosphorylated Nedd4‐2 binds to the 14‐3‐3 protein and, hence, reduces binding of Nedd4‐2 to ENaC.

Nedd4‐2 is also phosphorylated by protein kinase B (Akt1). Both Sgk1 and Akt1 are part of the insulin signalling pathway that increases transepithelial Na+absorption by inhibiting Nedd4‐2 and activating ENaC.