bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative study of the effectiveness of slow‐release morphine and methadone for opioid maintenance therapy
Authors: Eder Harald , Jagsch Reinhold , Kraigher Dominik , Primorac Andjela , Ebner Nina , Fischer Gabriele
Published: July 2005

Aims  Slow‐release morphine may represent a much‐needed new pharmacological treatment for opioid dependence.

Design  In a 14‐week randomized, double‐blind, double‐dummy, cross‐over study oral slow‐release morphine was compared with methadone as a treatment for opioid dependency. During two study periods, each consisting of a 1‐week titration and a 6‐week fixed‐dose treatment phase, medication was administered daily under supervised conditions.

Setting  The study was carried out at the Addiction Clinic, Department of Psychiatry, Medical University Vienna.

Participants  Sixty‐four subjects (56 males, eight females) with opioid dependence participated in the trial.

Measurements  Efficacy was evaluated on the basis of retention, use of illicit substances based on urinalysis, extent of drug cravings, withdrawal symptoms and general wellbeing. Safety was assessed on the basis of adverse events and clinical and physical examination. Demographic and baseline characteristics were assessed using the European Addiction Severity Index.

Findings  Fifty‐five patients (86%) completed the study, with a mean methadone dose of 85 mg and a mean slow‐release morphine dose of 680 mg. No significant differences in retention or use of illicit substances (opioids, benzodiazepines, cocaine) were observed, irrespective of treatment group or medication. However, patients receiving slow‐release morphine had significantly lower depression (P < 0.001) and anxiety scores (P = 0.008) and fewer physical complaints (P < 0.001).

Conclusions  Oral slow‐release morphine is as effective as methadone in the treatment of opioid dependency, with comparable safety and tolerability and a greater benefit on patient wellbeing. Greater pharmaceutical diversity represents a modern development in mainstream medicine. Slow‐release morphine might represent a future treatment option that will improve long‐term outcomes for this target group.
Alcohol price elasticities in control and license states in the United States, 1982–99
Authors: Trolldal Björn , Ponicki William
Published: July 2005

Aim The demand for alcohol has been demonstrated repeatedly to be sensitive to price changes. However, estimated price elasticities vary by study region and over time. One explanation for these variations might be that different countries or parts of countries have had different alcohol control systems. The hypothesis addressed in this study was that a regulated market leads to higher transaction costs associated with purchasing alcohol, which in turn increases the full price of the beverages (the nominal cash price plus transaction costs). As a result, the cash price of alcohol represents a smaller part of the full price in a highly regulated market. Assuming that customers respond primarily to changes in full price, the demand for alcohol should be less sensitive to changes in cash price where regulation is stricter. This study examined whether variations in price elasticities were a function of the different regulatory systems in control and license states in the United States during the period 1982–99.

Data and methods Time‐series cross‐sectional analyses (in 50 states over 18 years) were conducted. Elasticities were estimated using a multiplicative model based upon first‐differences of time‐series within states. Disposable income and other socio‐demographic variables were used as control variables. All data were obtained from archival sources.

Findings The demand for spirits and beer were significantly more sensitive to price changes in license states than in control states. The estimated price elasticity for wine sales was also somewhat larger in license states, but not significantly so.

Conclusion The lower price elasticities for spirits and beer in the control states support the hypothesis that customers respond primarily to changes in the full price of alcohol.
Levo‐alpha‐acetylmethadol (LAAM) versus methadone: treatment retention and opiate use
Authors: Longshore Douglas , Annon Jeffrey , Anglin M. Douglas , Rawson Richard A.
Published: July 2005

Aims  To compare the effects of levo‐alpha‐acetylmethadol (LAAM) and methadone maintenance (MM) on treatment retention and abstinence from opiate use.

Design  A two‐group experimental design with patients randomly assigned (2 : 1 LAAM : MM) to receive LAAM (three doses per week) or methadone (daily dosing).

Setting  A community clinic in Los Angeles, California.

Participants  A total of 315 patients seeking LAAM or methadone maintenance.

Intervention  LAAM or methadone maintenance, plus ancillary services available to all patients. LAAM and methadone dose levels varied according to clinical judgement. Electrocardiograms were administered to LAAM patients monthly.

Measurements  Treatment status at 26‐week follow‐up and number of days retained in treatment, weekly clinical urine tests and 26‐week research urine test.

Findings  LAAM and methadone patients did not differ on treatment retention. LAAM patients were less likely to test positive for opiate use during treatment (40% versus 60%) and at 26‐week follow up (39.8% versus 60.2%). Benefits of LAAM were confined to patients (n = 204) still in treatment at 26 weeks (33% positive in patients receiving LAAM and 61% in patients receiving methadone). No adverse events, cardiological or otherwise, were observed with LAAM administration.

Conclusions  LAAM is an effective medication for the treatment of opiate dependence with clinical advantages due not only to the reduction of opiate use but also to the alternate‐day dosing schedule. LAAM may be more effective than methadone in promoting abstinence from opiate use among patients for whom LAAM is an acceptable alternative to methadone.
The impact of borderline personality disorder on 12‐month outcomes for the treatment of heroin dependence
Authors: Darke Shane , Ross Joanne , Williamson Anna , Teesson Maree
Published: July 2005

Aims  To  determine  the  effects  of  borderline  personality  disorder  (BPD)  on 12‐month treatment retention and outcomes for the treatment of heroin dependence.

Design  Longitudinal cohort study.

Setting  Sydney, Australia.

Participants  A cohort of 495 heroin users enrolled in the Australian Treatment Outcome Study.

Findings  Criteria for BPD were met by 45% of the cohort. At baseline there were no differences in heroin use, but the BPD group had higher levels of polydrug use, crime, needle risk‐taking, more injection‐related health problems, higher levels of overdose, poorer psychological health and more extensive suicide histories. At 12 months there was no group difference in the cumulative number of treatment days received, but the BPD group had enrolled in more different treatment episodes. Within both groups reductions had occurred in drug use and drug‐related problems, with no differences in heroin use, polydrug use or global physical health at 12 months. After taking into account the effects of treatment on outcome, however, BPD was associated independently with a higher level of needle sharing [odds ratio (OR) 3.21], more injection‐related health problems (OR 1.90), a higher likelihood of heroin overdose (OR 1.92), poorer global psychological health (OR 2.43), higher levels of current major depression (OR 3.19) and a higher likelihood of attempted suicide (OR 3.89). While BPD participants showed similar reductions in heroin and other drug use to other patients at 12 months, they continued to exhibit higher levels of risk and harm across a range of outcomes.

Conclusions  Screening would appear to be warranted to identify a group who may overtly respond to treatment in terms of drug use per se, but remain at substantially greater risk.
When smokers are resistant to change: experimental analysis of the effect of patient resistance on practitioner behaviour
Authors: Francis Nick , Rollnick Stephen , McCambridge Jim , Butler Chris , Lane Claire , Hood Kerenza
Published: July 2005

Aims  In the field of motivational interviewing, practitioner confrontational behaviour has been associated with lower levels of patient behaviour change. We set out to explore whether resistance to change among smokers affects practitioner confrontational and other behaviours.

Design  Experimental manipulation of levels of patient resistance in a role play.

Setting  The study was conducted at the start of a 2‐day health behaviour change workshop.

Participants  Thirty‐two practitioners who had registered for the workshop.

Intervention  The practitioners were assigned randomly to interview a standardized patient (actor) who portrayed a smoker who had been briefed to display either high or low levels of resistance to change.

Measurements  Interviews were audiotaped and transcribed. Practitioners and standardized patients completed interview ratings at the end of each interview. After listening to each taped interview practitioners were assigned a global score for confrontation, empathy and expert instructional style. Interviews were then submitted to a qualitative analysis.

Findings  Higher levels of practitioner confrontational behaviour were observed in the high resistance group. This was evident both from the global scores (median 2 versus 0, P = 0.001) and the qualitative analysis. Global scores for empathy and expert instruction were not significantly different. Qualitative analysis also suggests a pervasive negative impact on other practitioner behaviours.

Conclusions  Higher patient resistance probably leads to an increase in confrontational and other negative behaviours in health professionals attempting to promote behaviour change. This challenges important assumptions about the influence of practitioner behaviour on patient behaviour and subsequent health‐related outcomes.
A multi‐center randomized trial of buprenorphine–naloxone versus clonidine for opioid, detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network
Authors: Ling Walter , Amass Leslie , Shoptaw Steve , Annon Jeffrey J. , Hillhouse Maureen , Babcock Dean , Brigham Greg , Harrer Judy , Reid Malcolm , Muir Joan , Buchan Betty , Orr Debbie , Woody George , Krejci Jonathan , Ziedonis Douglas ,   the Buprenorphine Study Protocol Group
Published: July 2005

Aims  The clinical effectiveness of buprenorphine–naloxone (bup‐nx) and clonidine for opioid detoxification in in‐patient and out‐patient community treatment programs was investigated in the first studies of the National Institute of Drug Abuse Clinical Trials Network.

Design  Diagnostic and Statistical Manual version IV (DSM IV)‐diagnosed opioid‐dependent individuals seeking short‐term treatment were randomly assigned, in a 2 : 1 ratio favoring bup‐nx, to a 13‐day detoxification using bup‐nx or clonidine.

Methods  A total of 113 in‐patients (77 bup‐nx, 36 clonidine) and 231 out‐patients (157 bup‐nx, 74 clonidine) participated. Supportive interventions included appropriate ancillary medications and standard counseling procedures guided by a self‐help handbook. The criterion for treatment success was defined as the proportion of participants in each condition who were both retained in the study for the entire duration and provided an opioid‐free urine sample on the last day of clinic attendance. Secondary outcome measures included use of ancillary medications, number of side effects reported and withdrawal and craving ratings.

Findings  A total of 59 of the 77 (77%) in‐patients assigned to the bup‐nx condition achieved the treatment success criterion compared to eight of the 36 (22%) assigned to clonidine, whereas 46 of the 157 (29%) out‐patients assigned to the bup‐nx condition achieved the treatment success criterion, compared to four of the 74 (5%) assigned to clonidine.

Conclusion  The benefits of bup‐nx for opioid detoxification are supported and illustrate important ways in which clinical research can be conducted in community treatment programs.
Impact of Federal drug law enforcement on the supply of heroin in Australia
Authors: Smithson Michael , McFadden Michael , Mwesigye Sue‐Ellen
Published: July 2005

Aims  To conduct an empirical investigation of the efficacy of law enforcement in reducing heroin supply in Australia. Specifically, this paper addresses the question of whether heroin purity levels in the Australian Capital Territory (ACT) could be predicted by heroin seizures at the national level by the Australian Federal Police (AFP) in the preceding year.

Design  We considered two forms of evidence. First, a Bayesian Markov Chain Monte Carlo (MCMC) change‐point model was used to discover (a) if there was a substantial increase in heroin seizures by the AFP, (b) when the increase began and (c) whether it occurred after increased funding to the Australian Federal Police for the purpose of drug law enforcement. Second, standard time‐series methods were used to ascertain whether fluctuations in heroin seizure weights or the frequency of large‐scale seizures after the aforementioned changes in seizure levels predicted fluctuations in heroin purity levels in the ACT after autocorrelation had been removed from the purity series.

Findings  A Bayesian MCMC change‐point model supported the hypothesis that heroin seizures rapidly increased about a year before the estimated decline in heroin purity and after the increased funding of AFP. The autoregression models suggested that 10–20% of the variance in the residuals of the heroin purity series was predicted by appropriately lagged residuals of the seizure‐number and log‐weight series, after autocorrelation had been removed.

Conclusion  The overall results are consistent with the hypothesis that large‐scale heroin seizures by the AFP reduce street‐level heroin supply a year or so later, although the short‐term dynamics suggest an ‘opponent’ response to residual fluctuations in seizures. To our knowledge, this is first time a connection has been identified between large‐scale heroin seizures and street‐level supply.
The feasibility of smoking reduction: an update
Authors: Hughes John R. , Carpenter Matthew J.
Published: July 2005

Aim To update conclusions of a previous review of smoking reduction on the extent to which (1) smokers spontaneously reduce their smoking, (2) smokers who try to quit and fail return to smoking less, (3) smokers can substantially reduce and maintain reductions via pharmacological and behavioral treatments and (4) smokers compensate when they reduce.

Method Qualitative systematic review.

Data sources Systematic computer searches and other methods.

Study selection Published and unpublished studies of smokers not trying to stop smoking. We located 13–26 studies for each of the four aims.

Data extraction The first author entered data with confirmation by second author.

Data synthesis Due to the heterogeneity of methods and necessity of extensive recalculation, a meta‐analysis was not feasible.

Results Few daily smokers spontaneously reduce. Among those who try to stop smoking and relapse, some return to reduced smoking but whether they maintain this reduction is unclear. Nicotine replacement (and perhaps behavior therapies) can induce smokers not interested in quitting to make significant reductions in their smoking and maintain these over time. Some compensatory smoking occurs with reduction but significant declines in smoke exposure still occur.

Conclusions These results indicate that reduction is feasible when aided by treatment. Whether reduction should be promoted will depend on the effect of reduction on health outcomes and future cessation.
Growth hormone deficiency and combined pituitary hormone deficiency: does the genotype matter?
Authors: Dattani Mehul T.
Published: July 2005

The past 12 years have witnessed an explosion in our understanding of the development of the anterior pituitary gland, and of mechanisms that underlie the diagnosis of growth hormone deficiency (GHD) and combined pituitary hormone deficiency (CPHD). The anterior pituitary is the end‐product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors that leads to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of GHD/CPHD. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, GLI2 and SOX3. Depending upon the expression patterns of these molecules, the phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo‐optic dysplasia (SOD) and holoprosencephaly. The phenotype and the mode of inheritance can be highly variable. Novel mutations within the GH‐1 and GHRHR genes have also shed light on the phenotype and pathogenesis of isolated GHD (IGHD). To date, genetic mutations have been identified in a modest proportion of patients with IGHD/CPHD and associated syndromes such as SOD. It is, however, clear that many genes remain to be identified, and characterization of these will further elucidate the pathogenesis of these complex conditions.
The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle‐aged men
Authors: Oh Ki Won , Lee Won Young , Rhee Eun Jung , Baek Ki Hyun , Yoon Kun Ho , Kang Moo Il , Yun Eun Joo , Park Cheol Young , Ihm Sung Hee , Choi Moon Gi , Yoo Hyung Joon , Park Sung Woo
Published: July 2005

Objective Body weight is a significant predictor of bone mass. Hormonal factors such as sex hormones, insulin, leptin and adiponectin are thought to play a role in the mechanisms controlling the association of body weight and fat mass with bone mass. However, contradictory results have been reported for the association between serum adipocytokines and bone mineral density (BMD). We therefore examined whether the serum adipocytokine and ghrelin levels, markers of fat metabolism, are associated with BMD in male adults.

Patients and measurements For 80 male adults (average age 54·5 ± 6·4 years; average body mass index (BMI) 24·4 ± 2·5 kg/m2), the correlations between serum resistin, leptin, adiponectin and ghrelin levels with BMD were investigated.

Results Among the adipocytokines, serum resistin levels were negatively correlated with lumbar spine BMD (r = –0·237, P = 0·05). After adjustment was made for age and BMI, log‐transformed serum leptin showed a significant negative correlation with lumbar spine BMD, which was not seen on bivariate analysis (r = –0·237, P = 0·039). Femoral neck BMD was marginally associated only with serum adiponectin levels (r = –0·226, P = 0·062). In multiple regression analyses, among the adipokines, only resistin was a significant determinant of lumbar spine BMD, although the variance was small (R2 = 0·256). Serum ghrelin levels were not correlated with the BMD of either body site.

Conclusions Serum resistin level showed a significant negative correlation with lumbar spine BMD, although the variance was small. Further studies are needed to elucidate the role of adipocytokines in bone metabolism.
Circulating acylated and total ghrelin and galanin in children with insulin‐treated type 1 diabetes: relationship to insulin therapy, metabolic control and pubertal development
Authors: Celi F. , Bini V. , Papi F. , Santilli E. , Ferretti A. , Mencacci M. , Berioli M. G. , De Giorgi G. , Falorni A.
Published: July 2005

Objective  To study the circulating levels of two gut‐derived peptides in children with type 1 (insulin‐dependent) diabetes mellitus (IDDM).

Research Design and Methods  Plasma levels of ghrelin, both total ghrelin (TG) and the acylated form (AG), and galanin and their relationships with insulin dosage, metabolic control, IGFBP‐1, body mass and pubertal development were evaluated in 91 children, aged 11·1 ± 2·7 years, affected by IDDM and treated with insulin. Ninety‐one healthy children were selected as controls.

Results  Body mass index (BMI)‐adjusted levels of both forms of ghrelin were reduced in IDDM compared with healthy subjects, with greater values in prepubertal than pubertal IDDM subjects. A negative association was found between AG and fasting insulin serum levels and insulin resistance [measured by using the homeostasis model assessment of insulin resistance (HOMA IR)] among the healthy children. IDDM children showed a negative association of their plasma ghrelin (both acylated and total) with daily insulin dosage, and the three adiposity indices (BMI, skinfold thickness and percentage fat mass). IGFBP‐1 levels were higher among the IDDM children without any association with ghrelin serum values. BMI‐adjusted plasma levels of galanin were higher among IDDM compared to healthy subjects, irrespective of sex or pubertal development. Greater values for galanin were found among pubertal than prepubertal subjects in both groups without any significant differences between the genders. A positive association was found between galanin and BMI in both groups and between galanin and haemoglobin A1c (HbA1c) among the IDDM children. No relationship existed between either galanin and fasting serum insulin among the healthy subjects or galanin and both insulin dosage or duration of treatment among the IDDM subjects.

Conclusions  The associations found between both ghrelin and galanin with adiposity indices could be considered as an indirect signal of involvement of the two peptides in the development of the nutritional status of the IDDM adolescents. The reduction in both forms of ghrelin could be involved in the development of the body mass increase of IDDM subjects with opposite effects, either influencing insulin sensitivity or exerting a compensatory restraint of feeding.
Thyrotropin receptor gene mutations and TSH resistance: variable expressivity in the heterozygotes
Authors: Camilot Marta , Teofoli Francesca , Gandini Alberto , Franceschi Roberto , Rapa Anna , Corrias Andrea , Bona Gianni , Radetti Giorgio , Tatò Luciano
Published: July 2005

Objective  TSH resistance ranges from overt nonautoimmune hypothyroidism to subclinical hypothyroidism, defined as mild hyperthyrotrophinaemia but a euthyroid state clinically. To date, 23 inactivating mutations of the TSH receptor (TSHR) gene have been proven responsible for the clinical condition, but an absence of mutations in the TSHR gene has been reported for several cases of TSH resistance as well. In this paper, we aimed to investigate the actual role of the TSHR gene in the development of both subclinical and congenital hypothyroidism.

Patients  14 hypothyroid newborns, 116 subclinical hypothyroid subjects and 120 healthy controls.

Measurements  Through denaturing high performance liquid chromatography (DHPLC), we screened for mutations the TSHR gene (the proximal promoter, the exons and their flanking regions), and evaluated the association between serum TSH and functionally characterized alleles identified.

Results  In the hypothyroid patients, one patient was heterozygous for a new missense variation, E34K, whereas two others patients were either homozygous or heterozygous for the P162A substitution. In the subclinical hypothyroid subjects, we detected only heterozygous substitutions: they are mostly new (123–124insTGCA, P27T, R46P, 555–561delTATTCTT, D403N, W488R, M527T), while six correspond to already published mutations (P162A, R109Q, L252P and three C41S). We only focused on those mutations that had been functionally characterized in vitro, and in whom serum TSH was available from family members.

Conclusions  A single grossly mutated allele (such as C41S or 555–561del) invariably leads to a condition of subclinical hypothyroidism, whereas in case of heterozygous carriers of mutations partially affecting the receptor function (such as P162A or L252P), a remarkable variable expressivity was detected among individuals belonging to different generations.
The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women
Authors: Schaap Laura A. , Pluijm Saskia M. F. , Smit Jan H. , Van Schoor Natasja M. , Visser Marjolein , Gooren Louis J. G. , Lips Paul
Published: July 2005

Objective  The objective of this study was to examine whether low levels of oestradiol and testosterone are associated with impaired mobility, low muscle strength and the incidence of falls in a population‐based sample of older men and women.

Design  Cross‐sectional population‐based study, based on data of the Longitudinal Ageing Study Amsterdam (LASA), including 623 men and 663 women, aged 65–88 years.

Measurements  Serum levels of oestradiol, testosterone, albumin and sex hormone‐binding globulin (SHBG) were measured. Physical performance, functional limitations and muscle strength were assessed, and a follow‐up on falls was performed prospectively within 3 years.

Results  After adjustment for age, level of education, alcohol use, physical activity, chronic disease and body mass index (BMI), men in the highest quartile of the oestradiol/SHBG ratio had significantly higher physical performance scores than men in the lowest quartile (β = 0·103). Serum levels of total testosterone were positively associated with muscle strength (β = 0·085). Calculated bioavailable testosterone levels were positively associated with physical performance and muscle strength (β = 0·128 and 0·109 respectively). No associations of oestradiol levels with mobility were seen in women. Levels of oestradiol and testosterone were not associated with falls.

Conclusions  It can be concluded that low levels of sex hormones were associated with impaired mobility and low muscle strength in men, but not in women. Levels of sex hormones were not associated with the incidence of falls neither in men, nor in women.
High prevalence of differentiated thyroid carcinoma in acromegaly
Authors: Tita Patrizia , Ambrosio Maria Rosaria , Scollo Claudia , Carta Anna , Gangemi Pietro , Bondanelli Marta , Vigneri Riccardo , Uberti Ettore C. degli , Pezzino Vincenzo
Published: July 2005

Objective Acromegaly is a chronic disease caused by increased GH secretion and associated with a greater risk of developing both benign and malignant tumours. In the present study we evaluated the prevalence of thyroid disorders and thyroid malignancies in a series of acromegalic subjects.

Design and patients We studied, retrospectively, a continuous series of 125 acromegalic patients referred to the Endocrinology Centres at the University Hospitals of Catania and Ferrara, Italy, over a 22‐year period.

Measurements Diagnosis and management of acromegaly were based on standardized criteria. In all patients thyroid function and morphology were evaluated by serum free T4, free T3, TSH measurements and ultrasound scanning, respectively. Fine‐needle aspiration biopsy (FNAB) was performed in all solid‐mixed thyroid nodules of diameter greater than 1 cm. IGF‐1 expression was assessed by semiquantitative immunohistochemical analysis in some patients with differentiated thyroid cancer.

Results Abnormal thyroid function was found in eight cases (6%). A diffuse or nodular goitre was present in 102 cases (82%). Thyroidectomy was performed in 17 patients. Histological examination revealed a differentiated thyroid cancer in seven of the patients. No significant association of thyroid cancer with GH or IGF‐1 levels was found. Semiquantitative assessment of IGF‐1 expression by immunohistochemistry revealed a more intense staining in thyroid cancer from acromegalic subjects than in papillary thyroid cancer from nonacromegalic subjects.

Conclusions The frequency of thyroid disorders in our series of acromegalic subjects was similar to that previously observed in these patients. However, the prevalence of thyroid cancer was not only strikingly elevated (5·6%) in comparison to the estimated prevalence in the general population (0·093%), but it was even higher than that reported for acromegalic subjects. Sustained exposure to high serum IGF‐1 levels is likely to play a role in the development of thyroid cancer in this disease. An additive role for the autocrine/paracrine action of locally produced IGF‐1 is also possible. Our results suggest that thyroid function and morphology should be carefully monitored in all acromegalic patients.
Treatment of acromegaly with octreotide‐LAR: extensive experience in a Brazilian institution
Authors: Jallad Raquel S. , Musolino Nina R. C. , Salgado Luiz R. , Bronstein Marcello D.
Published: July 2005

Objective  Somatostatin analogues have become the mainstay of the medical treatment of acromegaly. The aim of our study was to evaluate the efficacy and tolerability of octreotide‐LAR (OCT‐LAR) treatment in acromegalic patients.

Design  Prospective open trial.

Patients and methods  Eighty acromegalic patients (46 women; 18–80 years) were treated with OCT‐LAR. Mean ± SD duration of follow‐up was 16·6 ± 6·6 months (6–24 months). Twenty‐eight patients received OCT‐LAR as primary treatment. The target was to achieve normal IGF‐I levels. Clinical activity was evaluated by symptom score and fasting samples for GH and IGF‐I serum concentrations, obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging of the sella. A tumour volume reduction of at least 25% was considered significant.

Results  Clinical improvement was attained in most patients. Fifty‐nine (74%) of them attained mean GH < 2·5 ng/ml and 33 (41%) achieved normal IGF‐I by the 24th month of treatment. GH and IGF‐I control increased throughout treatment. Regarding the 46 patients treated for at least 12 months there was a significant decrease of GH and IGF‐I levels by the third month compared to basal levels, persisting with no subsequently variation.

In the patient group that achieved normal serum IGF‐1 during treatment (controlled group: n = 43) 20 patients maintained normal levels up to the latest follow‐up, whereas 23 of them once again showed altered serum IGF‐1‐values of some measurements during follow‐up, despite dose maintenance or elevation.

Baseline percentage of the upper limit of IGF‐I normal range, GH levels by the third month and length of treatment were predictive factors of IGF‐I normalization. Tumour shrinkage occurred in 76% of primary patients. Among 21 diabetic patients, four worsened and five improved glycaemic control, based on glycated haemoglobin. One previously intolerant patient progressed to overt diabetes. Nine patients developed gall bladder sludge, other nine patients acquired microlithiasis and one patient developed gallstone pancreatitis.

Conclusion  OCT‐LAR is an effective agent in alleviating symptoms, suppressing GH, normalizing IGF‐I and inducing tumour shrinkage in many acromegalic patients. Overall, OCT‐LAR is well tolerated and should be recommended for nonsurgically cured acromegalics, and also be considered as primary therapy for selected cases, mainly for those with a low probability of surgical cure.
The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients
Authors: Van Der Hoek Joost , Van Der Lelij Aart‐Jan , Feelders Richard A. , De Herder Wouter W. , Uitterlinden Piet , Poon Kwai W. , Boerlin Viktor , Lewis Ian , Krahnke Tillmann , Hofland Leo J. , Lamberts Steven W.
Published: July 2005

Objective  Recently, our first clinical study with the novel multiligand somatostatin (SRIF) analogue SOM230 in acromegalic patients showed that SOM230, due to its beneficial inhibitory effects on GH levels compared with octreotide (OCT), might increase the number of patients that can be biochemically controlled. Since SRIF analogues are also known to interact with other metabolic pathways, IGF‐I, IGFBP‐1, glucose and insulin concentrations on the control day (CD) and on treatment days following a single s.c. injection SOM230 100 and 250 µg, were compared to those following OCT 100 µg.

Design and patients  Randomized, cross‐over, double‐blinded proof‐of‐concept trial in 12 patients with active acromegaly.

Results  Free IGF‐I levels were suppressed after 24 h by OCT, SOM230 250 and 100 µg, whereas at 48 h only both SOM230 dosages still induced these inhibitory effects. Circulating IGFBP‐1 levels (AUC; 0830–1430 h) compared with CD, increased sharply after OCT (from 48 to 237 µg/l/h; P < 0·001 vs. CD), while SOM230 250 and 100 µg elicited a lower and dose‐dependent effect (163 and 90 µg/l/h, respectively, P < 0·05 vs. CD and OCT). Neither insulin nor GH levels showed statistically significant correlation with IGFBP‐1 levels either after SOM230 or OCT. An early rise in glucose levels 1 h postinjection with SOM230 250 µg compared with OCT and CD was observed 8·3 ± 0·8, 4·4 ± 0·5 and 4·9 ± 0·4 mmol/l, respectively: P < 0·05). SOM230 250 µg (19 ± 4 vs. 46 ± 3 mU/l on CD: P < 0·05), although clearly less potent than OCT (5·4 ± 0·4 mU/l: P < 0·01 vs. CD), inhibited insulin release. Since these corresponding absolute insulin levels cannot entirely explain this hyperglycaemic effect of SOM230, other mechanisms seem involved in this glucose rise. If SOM230 would influence glucose homeostasis in peripheral target tissues of insulin action, expression of SS‐receptors (sst) seems a logical necessity. In normal human liver tissues, analysed by quantitative polymerase chain reaction (PCR), the average sst1 mRNA expression level appeared significantly higher compared with sst2 (n = 6, relative copy number 161 ± 46 vs. 57 ± 6; P < 0·05). Fat tissue expressed both sst1 and sst2 mRNA, whereas in muscle only sst2 mRNA was found.

Conclusion  Both dosages of SOM230 inhibit free IGF‐I in a more sustained fashion compared to OCT, implying longer duration of action. The superior action of OCT compared with SOM230 in stimulating IGFBP‐1 levels, suggests direct regulation of IGFBP‐1 by SRIF analogues via sst2. Finally, expression of only sst1 and sst2 in target tissues of insulin action, might point towards additional modulatory effects by SOM230 on glucose homeostasis.
Final height after treatment of early puberty in short adopted girls with gonadotrophin releasing hormone agonist with or without growth hormone
Authors: Mul D. , Oostdijk W. , Waelkens J. J. J. , Drop S. L. S.
Published: July 2005

Objective  To compare final height data after treatment with gonadotrophin releasing hormone agonist (GnRHa) alone or in combination with growth hormone (GH) in short adopted girls with early puberty.

Design  A randomized controlled trial.

Patients and methods  Twenty‐six girls with onset of puberty before 10 years of age were treated for 3 years with either GnRHa alone (group A, n = 12) or with GnRHa and GH (group B, n = 14). Mean age at start of treatment was 9·6 years in both groups, bone age was 10·7 (SD 1·1) years in group A and 11·6 (0·8) years in group B.

Results  Initial height prediction with average Bayley & Pinneau tables was 149·8 (5·6) and 146·8 (4·8) cm, respectively. Bone age at discontinuation of treatment was 12·3 (0·9) and 13·0 (0·6) years in group A and B, respectively.

Height gain defined as the difference between initial height prediction and attained final height, was significantly different between group A and B (5·2 (3·7) and 8·2 (3·4) cm, P < 0·05) using average tables for height prediction. With accelerated tables for prediction the numbers were −1·0 (3·6) and 3·3 (3·5) cm, respectively.

At final height, there was no significant difference in height: group A: 155·0 (5·6) cm and group B: 155·0 (5·5) cm.

Conclusions  After 3 years of GnRHa treatment in adopted girls with early puberty, FH is significantly higher than initial height prediction. The addition of GH resulted in a limited further increase in height gain. In the interpretation of the results methodological issues concerning height prediction have to be taken into account.
Relation of anti‐TPO autoantibody titre and T‐lymphocyte cytokine production patterns in Hashimoto's thyroiditis
Authors: Karanikas Georgios , Schuetz Matthias , Wahl Katharina , Paul Matthias , Kontur Sylvester , Pietschmann Peter , Kletter Kurt , Dudczak Robert , Willheim Martin
Published: July 2005

Objective  Cytokines produced by cytotoxic T cells or autoantibodies lead to thyroid cell damage and/or cell death in Hashimoto's thyroiditis (HT). Anti‐TPO autoantibodies (TPOAb) are the most frequently represented autoantibodies in the sera of patients with HT. Data describing the quantitative correlation between TPOAb titre and cytokine pattern are missing so far. To our knowledge this is the first study systematically evaluating the correlation of possible parameters of disease activity such as changes in CD4 and CD8 T‐cell cytokine production and of TPOAb titre.

Methods  Twenty‐four consecutive patients (aged 29–58) with verified HT under levothyroxine therapy were included in the present study. The patients were divided into two groups. Group I: 12 HT patients with a high TPOAb titre (> 1000 U/ml), group II: 12 HT patients with a low TPOAb titre (< 100 U/ml). All patients underwent intracellular cytokine detection in CD4 and CD8 T cells of peripheral blood mononuclear cells (PBMC) by flow cytometry. Twelve healthy volunteers matched in sex and age consisted the control group (group III).

Results  T cells from patients with a high TPOAb titre (group I) had significantly higher percentages of cells producing IFN‐γ compared to healthy donors (group III). A detailed analysis of cytokine production patterns revealed that this was accompanied by an increased frequency of single IFN‐γ positive cells, i.e. cells not expressing other cytokines tested, such as IL‐2, IL‐4, IL‐5, IL‐6, IL‐10, IL‐13 or TNF‐β. Similarly, patients in group I also showed higher percentages of TNF‐α positive cells than healthy donors (group III). In this case, cells expressing TNF‐α alone as well as cells coexpressing TNF‐α and IFN‐γ were found at significantly higher frequencies. On the other hand, cytokine production patterns of patients with a low TPOAb titre (group II) showed significant difference neither to patients of group I nor to healthy donors (group III).

Conclusion  Taken together, we were able for the first time to demonstrate that high TPOAb titre correlates with increased frequencies of T cells producing Th/Tc1 cytokines, probably responsible for thyroid cell damage and/or death in Hashimoto's thyroiditis.
Hypocortisolism in survivors of severe acute respiratory syndrome (SARS)
Authors: Leow Melvin Khee‐Shing , Kwek Daniel Seow‐Khee , Ng Alan Wei‐Keong , Ong Kian‐Chung , Kaw Gregory Jon‐Leng , Lee Lawrence Soon‐U
Published: July 2005

Objective  Following the severe acute respiratory syndrome (SARS) outbreak, many survivors were observed to suffer from psychosomatic symptoms reminiscent of various endocrine disorders. Hence, we sought to determine the existence of any chronic endocrine sequelae in SARS survivors.

Design, patients, measurements  Sixty‐one survivors of SARS prospectively recruited were analysed for hormonal derangements 3 months following recovery. Patients with pre‐existing endocrine disorders were excluded. Any endocrine abnormalities diagnosed were investigated and treated where indicated up to a year. Serial evaluation facilitated characterization of trends and prognostication of any endocrinological aberrations.

Results  Twenty‐four (39·3%) patients had evidence of hypocortisolism. The hypothalamic–pituitary–adrenal (HPA) axis dysfunction of the majority resolved within a year. Two (3·3%) of the hypocortisolic cohort had transient subclinical thyrotoxicosis. Four (6·7%) were biochemically hypothyroid, being comprised of three with central hypothyroidism and one with primary hypothyroidism. Two of the three with central hypothyroidism had concomitant central hypocortisolism. Eight had subnormal DHEAS levels.

Conclusions  These preliminary findings highlight a possible aetiologic role of SARS‐associated coronavirus in causing a reversible hypophysitis or direct hypothalamic effect, with the HPA axis affected more frequently than the HPT axis.
The effects of thyroxine replacement on the levels of serum asymmetric dimethylarginine (ADMA) and other biochemical cardiovascular risk markers in patients with subclinical hypothyroidism
Authors: Ozcan Omer , Cakir Erdinc , Yaman Halil , Akgul Emin Ozgur , Erturk Kivilcim , Beyhan Zeynel , Bilgi Cumhur , Erbil Mehmet Kemal
Published: July 2005

Background  The relationship between subclinical hypothyroidism (SH) and cardiovascular disease (CVD) is still under debate. The purpose of the present study was to evaluate plasma total homocysteine (tHcy), high sensitive C‐reactive protein (hsCRP), small dense low‐density lipoprotein (sdLDL), l‐arginine and asymmetric dimethylarginine (ADMA) concentrations and their relationship to nitric oxide (NO) production, measured as plasma nitrite‐plus‐nitrate (NOx) concentration, in patients with SH before and after thyroxine replacement therapy and compared with control group values.

Design  Eighty‐four women with SH and 33 healthy women as controls matched to the patient group for sex, age and body mass index (BMI), were enrolled in this study. Lipoprotein profile, tHcy, hsCRP, sdLDL, ADMA, l‐arginine and NOx were measured in pre‐ and post‐treatment blood samples.

Results  The pretreatment total cholesterol (TC), LDL‐C, hsCRP, ADMA and l‐arginine levels were significantly higher and NOx levels were lower than in the control group. After treatment, hsCRP, ADMA and l‐arginine levels were significantly reduced and sdLDL and NOx levels were significantly increased.

Conclusion  The present study demonstrated an elevation of hsCRP and ADMA plasma levels of patients with SH associated with a reduction in NO production, which may contribute to some cardiovascular alterations. The elevated ADMA and hsCRP levels were reduced after thyroxine replacement. Also the sdLDL levels of SH patients were found to be lower than the control group values whereas TC and LDL were elevated. Even though we found an elevation in sdLDL levels after treatment, those values were still not higher than in the control group.
Expression of three different mutations in the arginine vasopressin gene suggests genotype–phenotype correlation in familial neurohypophyseal diabetes insipidus kindreds
Authors: Siggaard Charlotte , Christensen Jane H. , Corydon Thomas J. , Rittig Søren , Robertson Gary L. , Gregersen Niels , Bolund Lars , Pedersen Erling B.
Published: July 2005

Objective and study design  The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease characterized by a severe and progressive deficiency of AVP secondary to mutations in the gene encoding the AVP precursor. Whereas a number of studies have investigated the pathogenetic mechanisms behind the disease only few studies have included detailed clinical characterization of the affected patients, thereby making genotype–phenotype correlations difficult. The aims of the present study were to investigate the cellular effects of three different adFNDI mutations (A19T, L81P and C110X) by heterologous expression in a neurogenic cell line and to correlate these findings to the corresponding clinical phenotype as determined by extensive clinical tests.

Results  The clinical studies showed a later age of onset in the family carrying the A19T mutation (3·4 years, range 2–9 years) compared with families with the L81P and C110X mutations [0·75 year, range 0·5–1 year and 1·0 year (n = 1), respectively]. No other differences could be demonstrated in the clinical phenotype between families. Expression studies showed that each of the three mutant genes caused significant reduction of the amount of immunoreactive AVP in the cell culture medium and severe impairment of the intracellular trafficking and processing of the AVP prohormone, supporting the disease causing nature of all three mutations. However, the A19T mutation was associated with some capacity for processing and trafficking consistent with the clinical observations. Immunoflourescence studies provided evidence of reticular accumulation of protein within the ER in the A19T and C110X mutants but a unique accumulation of much larger aggregates in the L81P, which were localized both within and immediately outside the ER.

Conclusion  The study suggests a genotype–phenotype correlation with regard to age of onset of diabetes insipidus symptoms and provides support by expression studies.
Ghrelin in preterm and term newborns: relation to anthropometry, leptin and insulin
Authors: Ng Pak C. , Lee Cheuk H. , Lam Christopher W. K. , Chan Iris H. S. , Wong Eric , Fok Tai F.
Published: July 2005

Aims  This study aimed to investigate (i) the plasma ghrelin concentration at birth, (ii) the relationship of ghrelin with metabolic hormones, including leptin and insulin, and (iii) its association with anthropometric parameters, in appropriately grown preterm (23–36 weeks gestation) and term (37–42 weeks gestation) newborns.

Patients and methods  Blood samples for hormonal assay were obtained from preterm (n = 81) and term newborns (n = 40) within the first 2 h of life and before milk feeding or energy intake. The relationship between plasma ghrelin and other metabolic hormones or anthropometric parameters was evaluated.

Results  Plasma ghrelin was detectable in all studied infants and the concentrations did not differ significantly between term and preterm infants [median (interquartile range): 1·21 (0·86–1·48) nmol/l vs. 1·04 (0·71–1·51) nmol/l, P = 0·52, respectively]. There was no overall significant correlation between plasma ghrelin and gestational age, anthropometric parameters and leptin or insulin. However, when term and preterm infants were analysed independently, plasma ghrelin was inversely correlated with birth weight (r = −0·31, P = 0·05) and body length (r = −0·33, P = 0·04) in the term infant group.

Conclusions  Our findings suggested that plasma ghrelin concentrations were relatively constant at birth, between 23 and 42 weeks gestation, and ghrelin secretion did not appear to undergo gestational age‐related variations. An inverse relationship between plasma ghrelin and anthropometric indices in term infants raised the possibility that ghrelin might adopt its physiological role in regulating growth and metabolism at a late stage of gestation (≥ 37 weeks gestation). This phenomenon could be beneficial to term newborns by stimulating their appetite and maintaining an adequate blood sugar level at the most critical period when nutrients from mothers are abruptly terminated after birth.