bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the Pediatric Exclusivity Provision on children's access to medicines
Authors: Grieve Joanne , Tordoff June , Reith David , Norris Pauline
Published: June 2005

Aims

To determine the paediatric licensing status in the USA, UK, Australia and New Zealand of the 79 medicines granted paediatric exclusivity in the USA, and to assess the importance of those medicines to paediatric practice.

Methods

The medicines granted a patent extension in the USA as of 10 November 2003 were identified from the FDA website. Data on paediatric licensing were obtained from the Physicians Desk Reference (USA), the Electronic Medicines Compendium (UK), the Australian Prescription Products Guide (Australia) and the MedSafe website (New Zealand). A questionnaire was administered to seven paediatric consultants to assess the importance of the 79 PEMs for use in children. The questionnaire sought opinions on each drug, by age grouping, regarding: usefulness in patients with the condition, number of patients likely to be treated with each drug in a year, and acceptable therapeutic alternatives.

Results

Fifty‐eight (73%) of the medicines had attained paediatric licensing in the USA. Sixty were licensed for adults in all four countries and of these 45 (75%) were licensed for children under 12 years in the USA compared with 31 (52%) to 33 (55%) for the other three countries. The proportion of these medicines licensed for children under 1 month, under 2 years and under 6 years of age ranged from 10% to 58% and there were no significant differences between the countries. For all four countries perceived usefulness and predicted numbers of patients both had some influence on the odds of a medicine having paediatric licensing.

Conclusions

Improvements in licensing of some medicines for children have occurred in the USA, relative to the UK, Australia and New Zealand, subsequent to the Paediatric Exclusivity Provision. Improvements occurred for children over the age of six, but not for younger children.
Utility of routinely acquired primary care data for paediatric disease epidemiology and pharmacoepidemiology
Authors: Helms Peter J. , Ekins Daukes Suzie , Taylor Michael W. , Simpson Colin R. , McLay James S
Published: June 2005

Background

The majority of medicines prescribed for children are prescribed in primary care for common acute and chronic conditions. This is in contrast to prescribing in secondary care where the population of children admitted is small but where a large number of different medicines are prescribed to treat more serious and less common conditions.

Methods

Data on prescribing was extracted from the General Practice Administration System for Scotland (GPASS) for the year November 1999 to October 2000 and prescribing patterns for children aged 0–16 years expressed as percentages. A comparison of age specific consultations for asthma, as an example of a common paediatric condition, was also made between two separate general practice data sets, the General Practice Research Database (GRPD) and the continuous morbidity recording (CMR) subset of GPASS.

Results

Of 214 medicines investigated for unlicensed and off‐label prescribing no unlicensed prescribing was identified. Off‐label prescribing due to age was most common among younger and older children. The most common reasons for off‐label prescriptions were, in order of frequency, lower than recommended dose, higher than recommended dose, below the recommended age, and unlicensed formulation. Age and gender specific consultations for asthma were similar in the two representative databases, GPRD and CMR, both showing disappearance of the male predominance in the teenage years.

Conclusions

Large primary care data sets available within a unified health care system such as the UK National Health Service (NHS) are likely to be broadly compatible and produce similar results. The prescribing of off‐label medicines to children is common in primary care, most commonly due to prescribing out with the recommended dosage regimen.
Should domperidone be used for the treatment of gastro‐oesophageal reflux in children? Systematic review of randomized controlled trials in children aged 1 month to 11 years old
Authors: Pritchard D. S. , Baber N. , Stephenson T.
Published: June 2005

Aim  To determine whether there is robust evidence of efficacy for domperidone in reducing the symptoms of gastro‐oesophageal reflux (GOR) and gastro‐oesophageal reflux disease (GORD) in children.

Methods  Systematic review of randomized controlled trials (RCTs). A search was made of the Cochrane Library Issue 2004 (Central Register of Controlled Trials and Database of Systematic Reviews), Medline (Pub‐med) 1966 to present and Embase from 1974 to 2004, and reference citations of the RCTs that had been found electronically.

Results  Four RCTs were identified. Only the two older trials showed any benefits of domperidone on clinical symptoms of GORD in older children, which were the primary outcome measures. In the trial undertaken by Clara, a good or excellent result was obtained in 93% of the domperidone group compared with 33% of the controls (P < 0.05). In the trial undertaken by de Loore, after 2 weeks of treatment 75% of patients treated with domperidone were found not to be vomiting, compared with 43% in the metoclopramide group and 7% in the placebo group. The trial by Corraccio gave no detailed results regarding the primary outcomes of effect of domperidone on symptoms but simply reported ‘cured’, ‘improved’ or ‘unchanged’. The secondary pH‐metric outcome of the number of reflux episodes, was reduced with domperidone.

Conclusion  From the limited evidence available, there was no robust evidence of efficacy for the treatment of GOR with domperidone in young children. Given the usually benign nature of the condition, the widespread use of unlicensed medicines for GOR is not warranted.
Monitoring adverse drug reactions in children using community pharmacies: a pilot study
Authors: Stewart Derek , Helms Peter , McCaig Dorothy , Bond Christine , McLay James
Published: June 2005

Aims  To determine the feasibility of a community pharmacy‐based parental adverse drug reaction (ADR) reporting system for children.

Design  Prospective study of parent‐reported ADRs using a questionnaire issued to the parent or guardians of children 0–11 years of age collecting prescribed medicine for amoxicillin, and/or salbutamol, and collecting prescribed medicine for, or purchasing, paracetamol or ibuprofen suspension.

Setting  Seven community pharmacies in Grampian, Scotland.

Results  During a 4‐week period 360 prescriptions or purchases for the study medications occurred. Two hundred and sixty‐seven parents (85.5%) agreed to participate in the study. One hundred and six participants (40%) returned a total of 122 questionnaires. The demographics of responders and nonresponders including medication, age of child, and social status as assessed by the Depcat score were similar. There was no evidence of under‐representation of any socio‐economic group. Possible adverse events were detected using a symptom tick list and perceived ADRs using free text entry. Using the symptom tick list approach the most commonly reported symptoms were diarrhoea (28.9%) and tiredness (31.6%) for amoxicillin. The levels of diarrhoea and tiredness reported for ibuprofen, paracetamol and salbutamol were 15% and 20%, 7.4% and 18.5%, and 20% and 0%, respectively. Using the freehand section of the questionnaire 15 specific ADRs were reported by parents (12.3%). Eight children (21.2%) reported ADRs attributed to amoxicilin [diarrhoea (n = 4), fever (n = 1), anorexia (n = 1), hyperactivity (n = 1) and nonspecific (n = 1)], five to paracetamol [diarrhoea (n = 3), anorexia, irritability, crying and very angry (n = 1) and not stated (n = 1)], two to ibuprofen [diarrhoea (n = 1), not stated (n = )]. Only one off‐label prescription was identified and this was for salbutamol syrup prescribed to a child under 2 years of age.

Conclusions  The prospective monitoring of paediatric ADRs, using a questionnaire issued to parents or guardians in the community pharmacies, is feasible.
Modelling approaches to dose estimation in children
Authors: Johnson Trevor N.
Published: June 2005

Introduction

Most of the drugs on the market are originally developed for adults and dosage selection is based on an optimal balance between clinical efficacy and safety. The aphorism ‘children are not small adults’ not only holds true for the selection of suitable drugs and dosages for use in children but also their susceptibility to adverse drug reactions [1]. Since children may not be subject to dose escalation studies similar to those carried out in the adult population, some initial estimation of dose in paediatrics should be obtained via extrapolation approaches. However, following such an exercise, well‐conducted PK‐PD or PK studies will still be needed to determine the most appropriate doses for neonates, infants, children and adolescents.
How children's responses to drugs differ from adults
Authors: Stephenson Terence
Published: June 2005

Children are not small adults. However, the main thesis of this review will be that children's responses to drugs have much in common with the responses in adults and indeed in other mammals. Often, it is assumed that drug effects differ in children but in reality this perception often arises because the drugs have not been adequately studied in paediatric populations of different ages and with different diseases. There may also be difficulties in measuring small but significant effects because the outcome measures are more difficult to assess in children. In some cases, stage of development can alter the action of, and response to, a drug – a truly age‐dependent difference in pharmacodynamics. This may be true of both the desired action and adverse events. Examples are given. Programming by drugs is also a phenomenon almost exclusive to early life, i.e. permanent effects result from a stimulus applied at a sensitive point in development (‘critical window’), often in fetal or neonatal life. Again, examples are discussed. Different pathophysiology, different disease variants, different pharmacodynamics, different ‘host’ response and different adverse drug reactions can all explain why some drugs behave differently in children. However, we need to explore ways to avoid re‐inventing the wheel by determining how data from adult animal and human models can help inform research and practice for children.
The potential of UK clinical databases in enhancing paediatric medication research
Authors: Wong Ian C. K. , Murray Macey L.
Published: June 2005

The research potential of many UK clinical databases is not being realized. A recent report published by the Royal College of Paediatrics & Child Health stated that there is a need to build research capacity and support in the area of paediatric pharmacology, with specific emphasis on the use of clinical databases. This article presents the databases available in the UK for medication research and gives some examples of paediatric studies conducted. The databases discussed include the Prescription Pricing Authority database, the General Practice Research Database, IMS Health databases (Medical Data Index, MIDAS Prescribing Insights, Disease‐Analyser‐Mediplus) and the Yellow Card Scheme. Other databases such as the Medicines Monitoring Unit (MEMO) and the Scottish Primary Care Computer System also have research potential in paediatric pharmacoepidemiology, but their population sizes are relatively small.
Courting the expert: a clash of culture?
Authors: Caldwell P.
Published: June 2005

This article reviews the utility of expert opinion in legal proceedings and the deployment of expert witnesses in adversarial litigation. The use of expert witnesses to assist courts in making just and fair conclusions may be contrasted with the partisan interests of those who call them. An adversarial system is a bad method of scientific enquiry and undermines the court's capacity to reach the ‘right’ answer. As a consequence, courts may reach the wrong conclusion based on bad science. The role of the expert as a witness places strain on an expert to provide certainty, where in fact there may be none. Recent reforms in the civil courts have changed little and the problem is even more acute in criminal trials. The expert can rely solely on the integrity of his or her own opinion, tempered with a little humility. However, when filtered through the rhetoric and advocacy of a court arena, even this may be compromised.
Low‐dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma
Authors: Kyriakou Charalampia , Thomson Kirsty , D'Sa Shirley , Flory Angela , Hanslip Judith , Goldstone Anthony H. , Yong Kwee L.
Published: June 2005

The feasibility and efficacy of a triple regimen of oral weekly cyclophosphamide, monthly pulsed dexamethasone and low‐dose Thalidomide (CDT) was studied in 52 patients with relapsed or refractory multiple myeloma (MM). All 52 patients were evaluable for response with a median follow up of 18 (4–29) months. About 17% achieved complete response (CR), 62% partial response (PR), 11% minimal response (MR), 6% stable disease (SD) and 4% progressive disease (PD), resulting in an objective response rate (≥MR) of 90%. Subsequent to successful response, nine patients received high‐dose therapy (HDT) followed by stem cell transplantation (SCT) and 34 received thalidomide monotherapy as maintenance. Response rate was not influenced by disease status, prior HDT or age. The regimen was successfully delivered to all patients except for one patient who developed abnormal liver function at 7 weeks. Infective complications were minimal and there were no infection‐related deaths. The estimated overall and event‐free survival (EFS) at 2 years was 73% and 34%, respectively, and the median time to progression has not been reached. We conclude that the CDT regimen is safe, well tolerated and effective in patients with relapsed and refractory myeloma.
Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long‐term results in 30 patients
Authors: Cervantes Francisco , Alvarez‐Larrán Alberto , Domingo Abel , Arellano‐Rodrigo Eduardo , Montserrat Emili
Published: June 2005

Androgens are considered the treatment of choice for the anaemia of myelofibrosis with myeloid metaplasia (MMM). Good results have been reported in a few patients treated with danazol, a synthetic attenuated androgen. The long‐term efficacy and tolerability of danazol as treatment for the anaemia of MMM was evaluated in 30 patients, who received 600 mg/d, with progressive tapering to the minimum effective dose in the responders after 6 months. Complete response (CR) was defined as transfusion cessation with normal Hb and partial response (PR) as an Hb increase ≥1·5 g/dl with transfusion‐independent Hb values >10 g/dl maintained for at least 8 weeks. Median follow‐up was 20·5 months (range: 3·5–58 months). Response was achieved in 11 patients (37%), including eight CRs and three PRs. Median time to response was 5 months (range: 1–9 months). Four patients stopped responding at 6–24 months, two responders discontinued treatment because of toxicity, and five maintained response at 3·5–42 months. Pretreatment variables associated with response were lack of transfusion requirement (P= 0·001) and higher Hb at treatment start (P= 0·02). Toxicity was usually moderate, leading to treatment withdrawal in only two cases. Danazol is effective and well tolerated in a substantial proportion of MMM patients with anaemia.
Recessive congenital methaemoglobinaemia: functional characterization of the novel D239G mutation in the NADH‐binding lobe of cytochrome b5 reductase
Authors: Percy M. J. , Crowley L. J. , Davis C. A. , McMullin M. F. , Savage G. , Hughes J. , McMahon C. , Quinn R. J. M. , Smith O. , Barber M. J. , Lappin T. R. J.
Published: June 2005

Type I recessive congenital methaemoglobinaemia (RCM), caused by the reduced form of nicotinamide adenine dinucleotide (NADH)‐cytochrome b5 reductase (cytb5r) deficiency, manifests clinically as cyanosis without neurological dysfunction. Two mutations, E255‐ and G291D, have been identified in the NADH‐binding lobe of cytb5r in previously reported patients, and we have detected a further novel mutation, D239G, in this lobe in two unrelated Irish families. Although one family belongs to the genetically isolated Traveller Community, which separated from the general Irish population during the 1845–48 famine, the D239G mutation was present on the same haplotype in both families. Three known cytb5r mutations were also identified, including the R159‐ mutation, which causes loss of the entire NADH‐binding lobe and had previously been reported in an individual with type II RCM. Characterization of the three NADH‐binding lobe mutants using a heterologous expression system revealed that all three variants retained stoichiometric levels of flavin adenine dinucleotide with spectroscopic and thermodynamic properties comparable with those of native cytb5r. In contrast to the E255‐ and G291D variants, the novel D239G mutation had no adverse impact on protein thermostability. The D239G mutation perturbed substrate binding, causing both decreased specificity for NADH and increased specificity for NADPH. Thus cytb5r deficient patients who are heterozygous for an NADH‐binding lobe mutation can exhibit the clinically less severe type I phenotype, even in association with heterozygous deletion of the NADH‐binding lobe.
Thromboembolism in children with acute lymphoblastic leukaemia treated on Dana‐Farber Cancer Institute protocols: effect of age and risk stratification of disease
Authors: Athale Uma H. , Siciliano Sabrina A. , Crowther Mark , Barr Ronald D. , Chan Anthony K. C.
Published: June 2005

Children with acute lymphoblastic leukaemia (ALL) are at increased risk for thromboembolism (TE). Identification of a susceptible population is crucial for effective thromboprophylaxis. However, the risk factors for ALL‐associated TE are unclear. Concomitant asparaginase (ASP) and steroid therapy has been shown to increase the incidence of TE. Dana‐Farber Cancer Institute (DFCI)‐ALL protocols use a combination of ASP and steroids during the postinduction intensification phase when high‐risk (HR) patients receive thrice the steroid‐dose given to standard‐risk (SR) patients. We studied prospectively assembled cohorts of children treated on two consecutive DFCI‐ALL protocols to define the risk factors for symptomatic TE. Ten (11%) of 91 patients developed symptomatic TE; eight (seven HR) during intensification. Seven (44%) of 16 older patients (≥10 years) compared with three of 75 (4%) younger patients developed TE (P < 0·0001). Nine of 35 (26%) HR and one of 56 (2%) SR patients developed TE (P = 0·0006). Gender, ALL‐immunophenotype, steroid‐type or ASP dosing schedule did not alter the risk but older age and HR‐disease were factors predisposing to TE associated with DFCI‐ALL protocols. Age‐related risk may partly reflect the effect of ALL‐risk stratification. Higher dose steroids combined with ASP may lead to an increased risk of TE in HR patients.
Hepatitis C virus‐related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura
Authors: Rajan Sandeep K. , Espina Byron M. , Liebman Howard A.
Published: June 2005

Thrombocytopenia can be a complication of hepatitis C viral (HCV) infection. However, there is little published data regarding the clinical and laboratory manifestations of HCV‐related thrombocytopenia (HCV‐TP) compared with adult chronic immune thrombocytopenic purpura (CITP). We reviewed the medical records for all patients evaluated for chronic thrombocytopenia by the Haematology Service between January 1996 and June 2000. All patients were screened for HCV infection at the time of initial diagnosis. Of 250 patients who fulfilled American Society of Hematology criteria for CITP, 76 (30%) were HCV seropositive. HCV‐TP patients were older [mean age (±SD) 54·9 ± 8 years vs. 40·3 ± 8 years, P ≤ 0·001] and equally distributed between both sexes. HCV‐TP patients had less severe thrombocytopenia, defined as platelet count ≤10 × 109/l (4% vs. 46% for CITP, P ≤ 0·001). However, 56 (74%) had a platelet count ≤50 × 109/l. Symptoms and signs of thrombocytopenia were less frequent in HCV‐TP, but major bleeding was more frequent (25% vs. 10%, P = 0·0059). Serum cryoglobulins and anticardiolipin antibodies were more frequent in HCV‐TP (90% and 62% respectively), but rare in CITP (7% and 15%, P ≤ 0·001 compared with HCV‐TP). HCV infection can be associated with significant thrombocytopenia and appears to be a distinct clinical entity.
The effect of atorvastatin on serum lipoproteins in acromegaly
Authors: Mishra Manoj , Durrington Paul , Mackness Mike , Siddals Kirk W. , Kaushal Kalpana , Davies Rob , Gibson Martin , Ray David W.
Published: June 2005

Objective Acromegaly is associated with long‐term adverse effects on cardiovascular mortality and morbidity. Reducing growth hormone secretion improves well‐being and symptoms, but may not significantly improve the lipoprotein profile. An additional approach to cardiovascular risk reduction in acromegaly may therefore be to target lipoprotein metabolism directly. In this study we investigated the effect of statin treatment.

Design Double blind, placebo‐controlled, crossover study of the effects on circulating lipoproteins of atorvastatin 10 mg daily vs. placebo. Each treatment was given for 3 months in random order.

Subjects Eleven patients with acromegaly.

Measurements Lipids, lipoproteins, apolipoproteins, enzyme activity and calculated cardiovascular risk.

Results Atorvastatin treatment compared to placebo resulted in a significant decrease in serum cholesterol (5·85 ± 1·04 mmol/l vs. 4·22 ± 0·69 mmol/l; mean ± SD; P < 0·001), low‐density lipoprotein (LDL) cholesterol (2·95 ± 1·07 mmol/l vs. 1·82 ± 0·92 mmol/l; P < 0·001), very low‐density lipoprotein (VLDL) cholesterol (0·31 (0·21–0·47) mmol vs. 0·23 (0·13–0·30) mmol/l median (interquartile range); P < 0·05), apolipoprotein B (111 ± 28 mg/dl vs. 80 ± 18 mg/dl; P < 0·001), and calculated coronary heart disease risk (6·8 (3·3–17·9) vs. 2·8 (1·5–5·7)% over next 10 years; P < 0·01). Serum triglyceride was 1·34 (1·06–1·71) mmol/l on placebo and 1·14 (0·88–1·48) mmol/l on atorvastatin (ns). HDL cholesterol, apolipoprotein A1 and Lp(a) concentrations and cholesteryl ester transfer protein and lecithin: cholesterol acyl transferase activities were also not significantly altered.

Conclusion Atorvastatin treatment was safe, well tolerated and effective in improving the atherogenic lipoprotein profile in acromegaly.
The pattern of growth hormone secretion during the menstrual cycle in normal and depressed women
Authors: Kasa‐Vubu Josephine Z. , Dimaraki Eleni V. , Young Elizabeth A.
Published: June 2005

Objective  Major depression is associated to altered hypothalamic‐pituitary function. Stress is linked to elevated cortisol as well as menstrual cycle disturbance; however, there is no known relationship between depression and menstrual cycle disruption. The aim of this study was to investigate changes of growth hormone (GH) secretion during the menstrual cycle in normal and depressed women.

Design  Case‐control study.

Patients and methods  Nineteen women affected with depression and 24 normal controls were included. The two groups had comparable body mass index (BMI), and age (29·4 ± 9·8 vs. 28·6 ± 9·7 years). Nine depressed and 10 controls were studied in the follicular phase, while 10 depressed and 14 controls were studied in the luteal phase of the cycle. GH was sampled every 10 min for 24 h, and the data were analysed by the cluster pulse detection method.

Results  There was no difference in 24‐h mean GH concentrations between depressed and control subjects (P = 0·93), even after accounting for menstrual cycle phase (P = 0·38). GH pulse frequency was higher during the follicular phase of the cycle (P = 0·032), and nocturnal GH was higher in the follicular phase of the cycle (P = 0·05, and after adjusting for 24‐h GH, P = 0·0138) regardless of whether the subjects were depressed or healthy.

Conclusions  In studies of GH secretion in women with or without depression, it is necessary to control for the phase of menstrual cycle.
Morning cortisol does not mediate the association of size at birth with blood pressure in children born from full‐term pregnancies
Authors: Koupil Ilona , Mann Vera , Leon David A. , Lundberg Ulf , Byberg Liisa , Vågerö Denny
Published: June 2005

Objective It had been suggested that programming of the hypothalamo‐pituitary‐adrenal axis may underlie the associations of reduced size at birth with raised blood pressure in later life. We investigated whether morning salivary cortisol mediates the inverse association of birthweight with systolic blood pressure in children.

Design Subjects and measurements – a historical cohort study involving 1152 Swedish children aged 5–14 years, who took part in a family study comprised of mother, father, and two full‐sibs delivered in 1987–1995 after 38–41 weeks gestation within 36 months of each other. Birthweight and gestational age were available from obstetric records. Blood pressure, weight, height and puberty stage were measured at a clinic. Cortisol was measured by radioimmunoassay in morning salivary samples taken at home, within 30 min of waking.

Results Morning cortisol showed a weak negative association with length of gestation in siblings, was not related to birthweight or to systolic or diastolic blood pressure. There was no change in the strength of the negative association between birthweight and systolic blood pressure on adjustment for cortisol (−1·4 mmHg/kg, 95% CI −2·7, −0·2; adjusted for age, sex, puberty stage, weight and height, and cortisol).

Conclusions Morning cortisol was not associated with size at birth, and did not mediate the birthweight–blood pressure association in children born from full‐term pregnancies. It is possible that basal cortisol levels are of more importance in explaining associations of size at birth with later blood pressure in older subjects, or in populations with more varied length of gestation. Alternatively, our results may be caused by misclassification of the hypothalamo–pituitary‐adrenal activity.
Higher bone mineral density in Caucasian, hirsute patients of reproductive age. Positive correlation of testosterone levels with bone mineral density in hirsutism
Authors: Glintborg Dorte , Andersen Marianne , Hagen Claus , Hermann Anne Pernille
Published: June 2005

Objective  The mechanisms leading to higher bone mineral density (BMD) in hirsute patients than in healthy controls have seldom been examined. We compared the metabolic, hormonal and bone metabolic parameters in hirsute patients and female controls and correlated BMD and bone metabolic parameters with testosterone, oestradiol and metabolic parameters.

Patients  Fifty‐one Caucasian, reproductive‐aged, hirsute patients referred to the outpatient clinic of an academic tertiary‐care medical centre and 63 healthy, female Caucasian controls matched for season, weight and age.

Measurements  BMD (hip, neck, lumbar and total BMD), bone metabolic parameters (osteocalcin, alkaline phosphatase, PTH, ionized calcium, phosphate and 25‐hydroxyvitamin D (25OHD)) and endocrine profiles (androgen status, oestradiol and insulin) were evaluated during follicular phase. Oestradiol measurement was repeated during cycle days 8–12.

Results  Lumbar and neck BMD levels were significantly higher in hirsute patients than in controls: (mean ± SD): lumbar BMD 1·10 ± 0·12 vs. 1·06 ± 0·10 g/cm2 and neck BMD 0·91 ± 0·11 vs. 0·87 ± 0·12 g/cm2, P < 0·05. Fasting insulin and free testosterone levels were significantly higher in hirsute patients than in controls. Free testosterone correlated positively with neck and hip BMD levels in hirsute patients. During multiple regression analysis, testosterone, oestradiol and waist/hip ratio (WHR) were found to have positive effects on BMD levels independent of body mass index (BMI). 25OHD levels were significantly lower in hirsute patients [42 (13–131)] than in controls [72 (27–196)] nmol/l (geometric mean ± 2SD), P < 0·001].

Conclusion  Hirsute patients demonstrated significantly higher bone mineral density levels than controls, which could be explained by hyperinsulinaemia and higher testosterone levels in hirsute patients compared with controls. The pathogenesis for significantly lower 25‐hydroxyvitamin D levels in hirsute patients compared with controls needs to be evaluated in future studies.
Adult growth hormone replacement therapy and neuroimaging surveillance in brain tumour survivors
Authors: Jostel Andreas , Mukherjee Annice , Hulse Paul A. , Shalet Stephen M.
Published: June 2005

Objective  Systematic collections of neuroimaging data are nonexistent in brain tumour survivors treated with adult growth hormone replacement therapy (AGHRT). We present our surveillance data.

Design  In 1993, our unit implemented a policy of performing brain scans on every brain tumour survivor before starting AGHRT, with repeat neuroimaging at least once after 12–18 months’ treatment. Reports for baseline scans and most recent scans were analysed for this retrospective study.

Patients  All brain tumour survivors who received AGHRT (60 patients) were included in the analysis.

Measurements  Evidence and extent of residual tumour, tumour progression, tumour recurrence, and secondary neoplasms (SN) on baseline scan and latest follow‐up scan.

Results  All patients had baseline scans performed. Follow‐up scans were available in 41/45 (91%) patients who received AGHRT for more than 1 year (mean duration ± SD of GHRT was 6·7 ± 3·6 years). Sixteen patients had residual tumours, and SNs (all meningiomas) were demonstrated in three patients on baseline scans. Appearances remained stable in 34 (83%) patients during follow‐up (extending to 17·4 ± 8·3 years after tumour diagnosis). Of the 16 residual primary tumours, an incurable ependymoma continued to grow, and one meningioma progressed slightly in size over 7·7 years. Follow‐up scans also revealed continued growth of the SNs detected at baseline, and five additional meningiomas (two in patients with a previous SN, confirming an excess risk in this subgroup, P = 0·02). All SNs occurred on average 22·8 (range 17–37) years after radiotherapy.

Conclusions  Our data do not suggest an increased rate of recurrence or progression of childhood brain tumours during AGHRT. Nonetheless, vigilance and long‐term surveillance are needed in these patients in order to detect and monitor SNs, in particular in patients with a previous history of a SN. We endorse a proactive neuroimaging policy, preferably as part of a larger, controlled trial in the future.
Overproduction of an amino‐terminal form of PTH distinct from human PTH(1–84) in a case of severe primary hyperparathyroidism: influence of medical treatment and surgery
Authors: Räkel Agnès , Brossard Jean‐Hugues , Patenaude Jean‐Victor , Albert Caroline , Nassif Edgard , Cantor Tom , Rousseau Louise , D’Amour Pierre
Published: June 2005

Objective  Rare patients with severe primary hyperparathyroidism present with large parathyroid tumours, severe hypercalcaemia, very high PTH levels and osteitis fibrosa cystica. Some of these patients display a large amount of C‐PTH fragments in circulation and present with a higher C‐PTH/I‐PTH ratio than seen in less severe cases of primary hyperparathyroidism. We wanted to determine how PTH levels and circulating PTH high‐performance liquid chromatography (HPLC) profiles analysed with PTH assays having different epitopes could be affected by medical and surgical treatment in such patients.

Design  A 55‐year‐old man with severe hypercalcaemia (Ca2+: 2·01 mmol/l), very high PTH levels (CA‐PTH 82·1 and T‐PTH 72 pmol/l) caused by a large parathyroid tumour (7·35 g) and accompanied by significant bone involvement (alkaline phosphatase of 185 UI/l and subperiostal bone resorption of hands) was referred to us. Blood was obtained at various time points during his medical treatment, before and after surgery, to measure parameters of calcium and phosphorus metabolism, and of bone turnover. HPLC separations of circulating PTH molecular forms were performed and analysed with PTH assays having 1–4 (CA), 12–18 (T), 26–32 (E) and 65–84 (C) epitopes.

Results  Before surgery, serum Ca2+ was nearly normalized with hydratation, intravenous (IV) pamidronate and oral vitamin D administration. Despite a decrease in Ca2+ to 1·31 mmol/l, CA‐PTH and T‐PTH levels decreased by half in relation to a threefold increase in basal 1,25‐dihydroxyvitamin D [1,25(OH)2D] level (94 to 337 pmol/l). After this initial positive response, hypercalcaemia and elevated CA‐ and T‐PTH levels recurred even if 1,25(OH)2D levels remained elevated. The tumour was removed surgically and proved to be poorly differentiated with nuclear atypia and mitosis. After surgery, the Ca2+ level and PTH secretion normalized. The higher CA‐PTH level relative to the T‐PTH level observed before surgery in this patient was related to the oversecretion of an amino‐terminal (N) form of PTH recognized by PTH assays with (1–4) or (26–32) epitopes but not by the T‐PTH assay with a (12–18) epitope. This molecular form represented 50% of CA‐PTH measured in this patient, but only 7% in less severe cases of primary hyperparathyroidism. It was unaffected by medical therapy and disappeared after surgery.

Conclusion  The relationship between the overexpression of this N‐PTH molecular form and severe primary hyperparathyroidism remains unclear. Further studies will be required in these rare patients to see whether N‐PTH is a marker of less well differentiated parathyroid tumours and/or relates to the overproduction of C‐PTH fragments in the presence of severe hypercalcaemia.
Could associations between breastfeeding and insulin‐like growth factors underlie associations of breastfeeding with adult chronic disease? The Avon Longitudinal Study of Parents and Children
Authors: Martin Richard M. , Holly Jeff M. P. , Smith George Davey , Ness Andrew R. , Emmett Pauline , Rogers Imogen , Gunnell David ,   for the ALSPAC Study Team
Published: June 2005

Objective  The influence of infant feeding method (breast/formula) on growth factor levels could underlie associations of breastfeeding with childhood growth and risk factors for cardiovascular disease. We investigated associations of having been breastfed with serum IGF‐I and IGFBP‐3 in childhood.

Methods  Prospective birth cohort study (subsample of the Avon Longitudinal Study of Parents and Children, UK) based on 871 children born in 1991/1992 who underwent clinical follow‐up and blood tests at age 7–8 years. A total of 488 (56%) children had complete data.

Results  In children with complete data, the age‐ and sex‐standardized IGF‐I levels of those who were partially or exclusively breastfed were 6·1 and 13·8 ng/ml higher, respectively, than those who were never breastfed (increase in IGF‐I levels per category of breastfeeding exclusivity: 7·1 ng/ml; 95% CI: 0·3–13·9; P = 0·04). In models also controlling for birthweight, gestational age, mother's age, and socioeconomic and dietary factors, the breastfeeding–IGF‐I association was attenuated (regression coefficient: 3·3 ng/ml; −4·2–10·7; P = 0·4); further adjustment for IGFBP‐3 made little difference (regression coefficient: 4·1 ng/ml; −2·8–10·9; P = 0·2). There was little evidence for an association between breastfeeding and IGFBP‐3 or the molar ratio IGF‐I/IGFBP‐3.

Conclusions  The positive association between breastfeeding and IGF‐I could be due to residual confounding or to chance. Nevertheless, the magnitude of the fully adjusted effect estimate and the novelty of the association suggest that larger studies should now be conducted to confirm or refute the hypothesis that variations in IGF‐I by infant feeding mode explain associations of breastfeeding with health in later life.
Relationship between fasting serum glucose, age, body mass index and serum 25 hydroxyvitamin D in postmenopausal women
Authors: Need Allan G. , O'Loughlin Peter D. , Horowitz Michael , Nordin B. E. Christopher
Published: June 2005

Objective  Because it has been reported that vitamin D, given to mother or infant, can prevent type I diabetes in children, that diabetes is more common in adults with low serum vitamin D and that insulin secretion and action are related to vitamin D levels in healthy young adults we examined the relationship between serum vitamin D metabolites and fasting serum glucose in patients attending our outpatient clinics.

Design  Retrospective examination of convenience sample of postmenopausal women attending our osteoporosis clinics.

Patients  A total of 753 postmenopausal women attending a university hospital outpatient clinic and not on any treatment known to affect glucose metabolism.

Measurements  Body weight and height, serum 25‐hydroxyvitamin D [25(OH)D], serum 1,25‐dihydroxyvitamin D [1,25(OH)2D], serum PTH and fasting serum glucose.

Results  On simple correlation fasting serum glucose was a positive function of age (P < 0·05), weight (P < 0·001) and body mass index (BMI) (P < 0·001) and a negative function of serum 25(OH)D (P < 0·001), but it was not significantly related to either serum 1,25(OH)2D, PTH or creatinine. When fasting serum glucose was regressed simultaneously on age, BMI and 25(OH)D, glucose was still an inverse function of 25(OH)D (P = 0·006).

Conclusions  Fasting serum glucose increased as 25(OH)D levels fell throughout the range of serum 25(OH)D measured but the greatest increase was observed in those with 25(OH)D below 40 nmol/l.
Age‐related thymic activity in adults following chemotherapy‐induced lymphopenia
Authors: Sfikakis P. P. , Gourgoulis G. M. , Moulopoulos L. A. , Kouvatseas G. , Theofilopoulos A. N. , Dimopoulos M. A.
Published: June 2005

Background  The potential role of the adult thymus in T‐cell homeostasis subsequent to lymphopenia remains the subject of debate. We examined whether thymic activity contributes to reconstitution of the peripheral T‐cell pool, a critical process for patients recovering from antineoplastic therapy.

Methods  In selected patients with various neoplastic diseases we assessed peripheral blood lymphocyte subsets by flow‐cytometry, including thymus‐derived, CD4+ T cells expressing the CD45RA molecule, and thymic size rebound by CT scan before, and 3, 6 and 12 months after completion of cytotoxic therapy.

Results  Adult patients (n = 21, mean age of 30 years, range 18–49) had higher baseline numbers of B and lower numbers of NK cells than elderly patients (n = 15, mean age of 79 years, range 70–91), while total T‐cell numbers did not differ. Despite the reduction of lymphocyte counts being comparable in the adult (mean of 45%) and elderly (mean of 49%) groups, occurring at, or near, completion of treatment, an enlargement of the previously atrophic thymus was evident in 63% of the adult, but in none of the elderly, subjects. In 22 patients who remained active disease‐free during the following year, B cells and NK cells recovered to pretreatment levels as soon as at 3 months, whereas overall T‐cell recovery occurred at 6 months post‐treatment. Thymic rebound, observed in 11 of 22 patients who were of younger age, correlated significantly with a faster and more complete recovery of CD45RA+ CD4+ (mainly helper‐naïve) T cells.

Conclusion  The adult thymus appears capable of regeneration, at least up to middle age, contributing significantly to the reconstitution of the peripheral T‐cell pool following chemotherapy‐induced lymphopenia. In advanced age, however, although peripheral homeostatic pathways appear intact, regeneration of the naïve repertoire is incomplete.
Five cardiac hormones decrease the number of human small‐cell lung cancer cells
Authors: Vesely B. A. , Song S. , Sanchez‐Ramos J. , Fitz S. R. , Alli A. A. , Solivan S. M. , Gower W. R. , Vesely D. L.
Published: June 2005

Background  Four peptide hormones of a family of six hormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C‐natriuretic peptide (CNP), long acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide, significantly decrease the number of adenocarcinoma cells in culture. The present investigation was designed to determine whether these peptide hormones’ effects are specific to adenocarcinomas or whether they might decrease the number of cancer cells of a different type of cancer, i.e. small‐cell lung cancer.

Methods and materials  These six hormones were evaluated for their ability to decrease the number and/or proliferation of human small‐cell lung cancer cells in culture for 24, 48, 72, and 96 h.

Results  Within 24 h, vessel dilator, LANP, kaliuretic peptide, ANP and their intracellular mediator cyclic GMP, each at 1 µM, decreased the number of small‐cell lung cancer cells by 63% (P < 0·001), 21% (P < 0·05), 30% (P < 0·05), 39% (P < 0·05), and 31% (P < 0·05), respectively. There was no proliferation in the 3 days following this decrease in cell number. These same hormones decreased DNA synthesis 68% to 82% (P < 0·001). Brain natriuretic peptide and CNP did not decrease the number of small‐cell lung cancer cells or inhibit their DNA synthesis at 1 µM or 10 µM concentrations. Dose‐response curves revealed that at 100 µM, the vessel dilator decreased 92% of the cancer cells in 24 h while BNP had no effect, but CNP caused a 39% decrease. Western blots revealed that the natriuretic peptide receptors A‐ and C‐ were present in these cancer cells.

Conclusions  Five peptide hormones significantly decrease the number of human small‐cell lung cancer cells within 24 h and inhibit their proliferation for at least 96 h. Their mechanism of doing so involves inhibition of DNA synthesis mediated in part by cyclic GMP.
Treatment of osteoporotic ovariectomized rats with 24,25(OH)2D3
Authors: Gal‐Moscovici A. , Gal M. , Popovtzer M. M.
Published: June 2005

Background  Antiresorptive therapeutic regimens are the mainstay of current management of osteoporosis. Treatments that are promoting new bone formation are less available and less affordable. Previous studies have suggested that 24,25(OH)2D3 could enhance bone formation. The effect of 24,25(OH)2D3 on bone formation in ovariectomized osteopenic rats (OVX) was evaluated in this study.

Materials and methods  Mature Sabra rats were divided into two groups: sham‐operated and OVX. Three months after surgery the OVX and sham‐operated rats were divided into the following subgroups: (1) sham rats injected with vehicle, (2) sham rats injected with 24,25(OH)2D3, (3) OVX rats injected with vehicle, and (4) OVX rats injected with 24,25(OH)2D3. After 2 weeks’ treatment, histomorphometry of the right tibiae was performed.

Results  Ovariectomy resulted in a decrease in total bone volume (TBV/TV) and in bone formation (BFR/BS), P < 0·005 and P < 0·05 respectively, when compared with the sham‐operated rats. Beside the decrease in TBV and BFR, the OVX rats showed an increase in osteoclastic bone resorption (P < 0·001 vs. sham). Administration of 24,25(OH)2D3 was followed by an increase in all static and dynamic bone‐forming parameters. The TBV/BV (P < 0·025), osteoblast surface (Ob.S/BS) (P < 0·001), as well as the BFR/BS (P < 0·005), increased in the OVX‐treated group when compared with the OVX‐untreated and sham‐operated rats. This increment in bone formation was associated with a decrease in bone resorption (P < 0·001 in OVX‐treated vs. OVX‐untreated rats).

Conclusions  This study shows that 24,25(OH)2D3 may be of benefit in experimental osteopenia following ovariectomy, both by suppressing osteoclastic hyperactivity and by stimulating bone formation.
WNK4 regulates Na+ transport in airways
Authors: Farfel Z. , Mayan H. , Yaacov Y. , Mouallem M. , Shaharabany M. , Pauzner R. , Kerem E. , Wilschanski M.
Published: June 2005

Background  WNK [With No K (lysine)] kinases are essential for regulation of blood pressure and potassium homeostasis. WNK4 expression was recently found not only in the distal nephron but also in chloride‐transporting epithelia. To establish a physiological role for this distribution we studied patients with familial hyperkalaemia and hypertension (FHH), [pseudohypoaldosteronism type II (PHAII)], which is caused by mutations in WNK4.

Design  Measurement of nasal potential difference (NPD) and sweat electrolytes were performed in controls, in six subjects with FHH and ten subjects with cystic fibrosis (CF).

Results  Basal NPD was higher in FHH compared with controls (n = 20): 22·8 ± 5·7 vs. 16·2 ± 5·3 mV, respectively (P = 0·014). Maximal response to amiloride was also higher in FHH compared with controls: 14·8 ± 3·5 vs. 10·0 ± 4·8 mV, respectively (P = 0·03). In CF these values were 42·9 ± 9·3 and 29·9 ± 7·4 mV, respectively. The kinetics of the amiloride effect were faster in FHH, and as first reported here also in CF, compared with controls. At 30 s, amiloride‐inhibitable residual PD in FHH was 50 ± 30 vs. 81 ± 9% in controls (P = 0·0003) and 56 ± 7% in CF. The response to chloride‐free and isoproterenol solutions, which determines chloride transport activity, was similar in FHH compared with controls [16·0 ± 8·6 vs. 10·4 ± 5·9 mV (P = 0·08)]. Sweat conductivity in FHH was 49·7 ± 7·3 vs. 38·2 ± 8·1 mmol (NaCl eq) L−1 in 16 controls (P = 0·007) and 94·0 ± 19·3 in CF.

Conclusions  Mutant WNK4 increases Na+ transport in airways, and therefore it is regulated by wild‐type WNK4. This may be caused by a regulation of ENaC or a K+ channel.
Heightened levels of circulating 20S proteasome in critically ill patients
Authors: Roth G. A. , Moser B. , Krenn C. , Roth‐Walter F. , Hetz H. , Richter S. , Brunner M. , Jensen‐Jarolim E. , Wolner E. , Hoetzenecker K. , Boltz‐Nitulescu G. , Ankersmit H. J.
Published: June 2005

Background  Recently, circulating proteasome core particles (20S proteasome) have been suggested as a marker of cell damage and immunological activity in autoimmune diseases. Aberrant leucocyte activation and increased lymphocyte apoptosis with consecutive T‐cell unresponsiveness is deemed to play a pivotal role in the sepsis syndrome. Moreover sepsis‐induced muscle proteolysis mainly reflects ubiqutin proteasome‐dependent protein degradation. We therefore sought to investigate serum levels of 20S proteasome in critical ill patients.

Material and methods  Case–control‐study at a university hospital intensive care unit; 15 patients recruited within 24–48 h of diagnosis of sepsis, 13 trauma patients recruited within 24 h of admission to the ICU, a control group of 15 patients who underwent abdominal surgery, and 15 healthy volunteers. ELISA was used to measure the concentration of 20S proteasome in the sera of the patients and controls. Data are given as mean ± SEM. Mann–Whitney U‐test was used to calculate significance and a P‐value of 0·05 was considered to be statistically significant.

Results  Marked increase of 20S proteasome was detected in the sera of septic patients (33 551 ± 10 034 ng mL−1) as well as in trauma patients (29 669 ± 5750 ng mL−1). In contrast, significantly lower concentrations were found in the abdominal surgery group (4661 ± 1767 ng mL−1) and in the healthy control population (2157 ± 273 ng mL−1).

Conclusion  Detection of 20S proteasome may represent a novel marker of immunological activity and muscle degradation in sepsis and trauma patients, and may be useful in monitoring the clinical effect of proteasome‐inhibitors.