Systematic review of publicity interventions to increase awareness amongst healthcare professionals and the public to promote earlier diagnosis of type 1 diabetes in children and young people.

BACKGROUND: Children with new onset type 1 diabetes (T1D) are at risk of developing the life-threatening condition ketoacidosis if they have a delayed diagnosis. The rate of children presenting in ketoacidosis remains high in a number of countries worldwide. To ensure interventions to raise awareness of symptoms are effective a systematic review was conducted to evaluate previous publicity campaigns. METHODS: A range of databases was searched using search terms relating to T1D, publicity campaigns, and symptom awareness. Identified articles were checked against the inclusion criteria, ensuring interventions were designed to target individuals prior to diagnosis of T1D. Papers were independently assessed under the criteria specified within the Critical Appraisal Skills Programme checklist. RESULTS: The initial search retrieved 1537 papers and following screening 20 were identified for full consideration. Thirteen did not meet the inclusion criteria, leaving 7 to be assessed. Of these 7, 2 observational case-control studies reported a reduction in the rate of ketoacidosis following a publicity campaign using posters and providing glucose testing equipment to primary healthcare professionals. Four observational cohort studies, utilized posters, and media campaigns; 2 reported a reduction in the rate of ketoacidosis and 2 reported no difference following their interventions. A feasibility study, not designed to evaluate effectiveness, reported some anecdotal evidence of a more timely diagnosis. CONCLUSION: Due to the methodological limitations of the studies identified, it is not possible to make a definitive conclusion on the effectiveness of the interventions reported.

Establishing the feasibility of a community and primary health care intervention to raise awareness of symptoms of Type 1 Diabetes-The Early Detection of Type 1 Diabetes in Youth (EDDY) study.

AIMS: To design, develop, and evaluate the feasibility of delivering a multi-component community based intervention to parents and primary health care professionals to raise awareness of the symptoms of Type 1 diabetes (T1D) in childhood in 3 adjoining borough counties of South Wales. MATERIALS AND METHODS: Parent and primary health care advisory groups were established to design the intervention. Qualitative interviews with stakeholders and parents assessed the acceptability, feasibility and any potential impact of the intervention. RESULTS: The parent component of the intervention developed was a re-useable shopping bag with the 4 main symptoms of T1D illustrated on the side, based on the road traffic system of red warning triangles and an octagon "stop" sign stating "Seek Medical Help". Accompanying the bag was an A5 leaflet giving further information. Both were overwrapped with clear plastic and delivered to 98% (323/329) schools, equating to 101 371 children. The primary health care professional component was a dual glucose/ketone meter, single use lancets, stickers, the A5 parent leaflet displayed as a poster and an educational visit from a Community Diabetes Liaison Nurse. 87% (73/84) of GP practices received the intervention, 100% received the materials. The intervention was delivered within Cardiff, the Vale of Glamorgan and Bridgend. Qualitative analyses suggest that the intervention raised awareness and had some impact. CONCLUSION: This study showed that it is feasible and acceptable to design, develop and deliver a community based intervention to raise awareness of T1D. There is some suggestion of impact but a definitive evaluation of effectiveness is still required.

Family preferences for home or hospital care at diagnosis for children with diabetes in the DECIDE study.

AIMS: A diagnosis of Type 1 diabetes in childhood can be a difficult life event for children and families. For children who are not severely ill, initial home rather than hospital-based care at diagnosis is an option although there is little research on which is preferable. Practice varies widely, with long hospital stays in some countries and predominantly home-based care in others. This article reports on the comparative acceptability and experience of children with Type 1 diabetes and their parents taking part in the DECIDE study evaluating outcomes of home or hospital-based treatment from diagnosis in the UK. METHODS: Semi-structured interviews with 11 (pairs of) parents and seven children were conducted between 15 and 20 months post diagnosis. Interviewees were asked about adaptation to, management and impact of the diabetes diagnosis, and their experience of initial post-diagnosis treatment. RESULTS: There were no differences between trial arms in adaptation to, management of or impact of diabetes. Most interviewees wanted to be randomized to the 'home' arm initially but expressed a retrospective preference for whichever trial arm they had been in, and cited benefits relating to learning about diabetes management. CONCLUSIONS: The setting for early treatment did not appear to have a differential impact on families in the long term. However, the data presented here describe different experiences of early treatment settings from the perspective of children and their families, and factors that influenced how families felt initially about treatment setting. Further research could investigate the short-term benefits of both settings.

Prevalence of ketoacidosis at diagnosis of childhood onset Type 1 diabetes in Wales from 1991 to 2009 and effect of a publicity campaign.

AIMS: To determine the proportion of cases of childhood Type 1 diabetes that present with ketoacidosis and any temporal trend. To assess the impact of a publicity campaign promoting earlier diagnosis. METHODS: We used an all-Wales register of incident cases with data on 2046 children from 1991 to 2009. The proportion with ketoacidosis at diagnosis was compared with the Yorkshire Childhood Diabetes Register. On World Diabetes Day posters were sent to every pharmacy, school and general practitioner surgery across Wales and radio interviews given. A questionnaire survey was conducted in Gwent to assess penetrance of the campaign. RESULTS: Annually, in 1991-2009 the proportion presenting with ketoacidosis varied between 20% and 33% (mean 25%) with no change over time. Similar proportions occurred in Yorkshire. Ketoacidosis was more common before age 5 years (37% of cases) than at age 5-9 years (20%) or 10-14 years (23%) (P < 0.001). From November 2006-2007 30% of cases presented with ketoacidosis and from November 2007-2008 25% cases presented with ketoacidosis. After the campaign (November 2008-2009) 26% presented with ketoacidosis (P = 0.72). The information had reached a low proportion of families. General practitioners referred immediately cases that presented to them. CONCLUSIONS: Over 20 years in Wales there has been no change in the proportion of children with Type 1 diabetes initially presenting with ketoacidosis. This presentation occurs in a higher proportion of new cases aged under 5 years. Publicity to increase awareness did not reduce the proportion with ketoacidosis at diagnosis in Wales. We need to get the educational message through to parents to reduce ketoacidosis at presentation.

Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.

AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to ß subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only.

The experiences of children and their parents in paediatric diabetes services should inform the development of communication skills for healthcare staff (the DEPICTED Study).

AIMS: The aims of this study were to describe users' experience of paediatric diabetes services to inform development of an intervention to improve communication between staff and patients in secondary care within a wider study (the DEPICTED Study). METHODS: Methods adapted for paediatric settings were used to set up six audio-recorded focus discussion groups with a total of 32 participants. Transcriptions and notes were coded thematically (supported by NVivo software) and analytic themes developed with discussion between researchers. RESULTS: Three main themes developed: the lack of two-way conversation about glycaemic control in clinic settings; the restricting experience of living with diabetes; and the difficult interactions around diabetes the children had with their schools. Doctors in particular were seen as struggling to link these themes of everyday life in their consultations with children and their parents. Children felt marginalized in clinics, despite active involvement in their own blood glucose management at home. CONCLUSIONS: Health professionals need to balance a requirement for good glycaemic control with realism and appreciation of their patients' efforts. There is a need for a systematic approach to consulting, in particular using agenda setting to ensure that the issues of both the patient and the professional are addressed. A framework for a conceptual approach is discussed. How a patient is involved is as important as what is communicated during a consultation.

The changing incidence of childhood-onset type 1 diabetes in Wales: Effect of gender and season at diagnosis and birth.

AIMS: Determinants of the changing incidence of childhood-onset type 1 diabetes remain uncertain. We determined the recent time-trend of type 1 diabetes incidence in Wales and explored the role of vitamin D by evaluating the influence of season both at diagnosis and at birth. METHODS: Data from all Welsh paediatric units 1990-2019, and from primary care to determine ascertainment. RESULTS: Log-linear modelling indicated a non-linear secular trend in incidence with peak and subsequent decline. The peak occurred around June 2010: 31∙3 cases/year/100,000 children aged < 15y. It occurred earlier in children younger at diagnosis and earlier in boys. There were more cases in males aged <2y and >12y but more in females aged 9-10 y. More were diagnosed in winter. Also, children born in winter had less risk of future diabetes. CONCLUSIONS: The risk of developing type 1 diabetes before age 15y in Wales is no longer increasing. The data on season are consistent with a preventative role for vitamin D both during pregnancy and later childhood. Metereological Office data shows increasing hours of sunlight since 1980 likely to increase vitamin D levels with less diabetes. Additional dietary supplementation with vitamin D might further reduce the incidence of type 1 diabetes.

Meeting the psychosocial needs of children with diabetes within routine clinical practice.

AIMS: There is little guidance for paediatric diabetes teams on how best to meet their patients' psychosocial needs. The aims of conducting this survey of practitioners were to examine the challenges they face in delivering routine care, elicit their approaches to encouraging behaviour change and to inform the development of a training package to be evaluated in the Development and Evaluation of a Psychosocial Intervention with Children and Teenagers Experiencing Diabetes (DEPICTED) Study. METHODS: A semi-structured telephone interview was completed with 44 doctors and seven paediatric diabetes specialist nurses and emergent themes identified. RESULTS: The key challenges for practitioners were categorized as engagement and communication, meeting the needs of different ages and helping patients and their families integrate diabetes into their everyday life. Approaches to behaviour change were described in terms of education, advice and listening. CONCLUSIONS: The survey demonstrates the complexities of communication with such a heterogeneous patient group and the range of approaches taken by practitioners in addressing behaviour change within routine care.

Communication skills of healthcare professionals in paediatric diabetes services.

AIMS: To identify training needs in communication skills and to assess training preferences of staff working in paediatric diabetes services, which will inform the development of a learning programme in behaviour change counselling for healthcare professionals. METHODS: Three hundred and eighty-five staff in 67 UK paediatric diabetes services were sent questionnaires to determine their previous communication skills training, to measure their self-reported view of the importance of and confidence in addressing common clinical problems and to assess the perceived feasibility of training methods to improve skillfulness. RESULTS: Two hundred and sixty-six questionnaires (69%) were returned from 65 services. Sixteen per cent of doctors, nurses and dietitians reported no previous training in communication skills and 47% had received no training since graduating. Respondents rated psychosocial issues as more important to address than medical issues within consultations (t = 8.93, P < 0.001), but felt less confident addressing such issues (t = 15.85, P < 0.001). One-day workshops and monthly team meetings were the most popular of the training options considered (65% and 77%, respectively). CD ROM and web-based learning were considered feasible for 54% and 56% of respondents, respectively, although lack of time (55%) and privacy (34%) were potential barriers. CONCLUSIONS: Addressing psychosocial issues is an important component of consultations involving young people with diabetes, but healthcare professionals find it easier to address medical issues. This represents a key training need in communication skills for diabetes professionals. The survey will inform the development of a tailored learning programme for health professionals in UK paediatric diabetes clinics.

Response to growth hormone treatment and final height in Noonan syndrome in a large cohort of patients in the KIGS database.

BACKGROUND: Noonan syndrome (NS) is an autosomal dominant inherited disease, characterized by a distinctive facial appearance, congenital heart defects, and short stature. Treatment with growth hormone (GH) is an option to enhance height, but long-term effects are still unclear. PATIENTS AND METHODS: A cohort of 402 patients (269 males, 133 females), mean age 9.7 years at start with GH, was studied within the KIGS International growth database with respect to long-term response to GH therapy and final height after GH therapy. RESULTS: At the start of GH therapy median height was -2.61 SDS (Tanner 1966 standards). Seventy-three patients who were followed longitudinally for 3 years had an increment in height SDS (Ht SDS) over the first 3 successive years of 0.54, 0.13 and 0.13, respectively. Twenty-four patients had reached their final height after 4-12 years of GH treatment. Their Ht SDS increased from a median of -3.28 to a median of -2.41 at final height. CONCLUSION: This group of patients with NS showed an early response to GH treatment, with an attenuation of this effect thereafter. At final height the median increment of final height was 0.61 SDS according to Tanner standards and 0.97 SDS according to Noonan standards. No serious side effects were reported.

Response to letter to editor: 'Comment on Arch et al., Trials. 2016;17:517'.

In October 2015 we published the paper 'Measurement of HbA1c in multicentre diabetes trials - should blood samples be tested locally or sent to a central laboratory: an agreement analysis'. Chatterjee and Pradhan have submitted a letter to the editor asking critical questions regarding the methods we used. We offer this letter in response. TRIAL REGISTRATION: Eudract No. 2010-023792-25. Registered on 4 November 2010. ISRCTN No. ISRCTN29255275 . Registered on 12 November 2010.

A new form of familial multi-nodular goitre with progression to differentiated thyroid cancer.

We report a kindred with euthyroid multi-nodular goitre (MNG) of adolescent onset. Two of the seven subjects with MNG have progressed to papillary thyroid cancer. One affected male had nodular kidney disease, and breast cancer occurred in one affected female. Genes that were candidates on the basis of the associated kidney (PAX8) and breast diseases (sodium iodide symporter (NIS)), were sequenced. No mutations were found in the coding region, intron/exon splice sites or in the promoter sequences (from -1248 relative to the translation initiation codon) of PAX8. Similar results were obtained for NIS. Subsequently, microsatellite analyses were performed on 14 informative family members. We used 2 to 3 markers per locus for 6 loci (on chromosomes 1,2,3,14,19,X) previously reported to predispose to MNG and/or familial non-medullary thyroid cancer (FNMTC). On the basis of non-significant logarithm of the odds ratio (LOD) scores or inheritance of different alleles in affected individuals, all loci have been excluded. Thyroidectomy specimens from three members of the kindred show multiple benign lesions, with papillary cancer in two. The morphological features do not resemble those seen in familial adenomatous polyposis, Cowden syndrome, or in multiple oxyphil lesions. From these findings and from the absence of any linkage to any of the known loci associated with MNG or FNMTC, we suggest that this represents a new form of inherited MNG with a significant risk of progression to papillary carcinoma.

Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear. PATIENTS AND METHODS: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia. RESULTS: Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy. CONCLUSIONS: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.

Are factors at diagnosis of growth hormone deficiency in childhood associated with persistence of growth hormone deficiency into adult life?

A proportion of children with growth hormone deficiency (GHD) have persistence of GHD as young adults. To date, no markers have been shown in childhood to have predictive value in determining persistence of GHD into adult life. We examined the hypothesis in 31 patients that variables present at the time of diagnosis of childhood-onset GHD, or those related to the early response to growth hormone (GH) therapy, are associated with the likelihood of persistence of GHD. The results show that, as previously demonstrated, children with GHD are more likely to have persistent severe GHD in adult life when the diagnosis is associated with other pituitary hormone deficiencies (p = 0.02), abnormal pituitary neuroimaging (p = 0.003), induced puberty (p = 0.001), early age of diagnosis (p = 0.03) and lower peak GH response at the first dynamic GH test in childhood (p = 0.02). However, there are no associations of persistent severe GHD with the pattern of pretreatment growth or growth response to GH treatment in the initial phase.

Visual function in young IDDM patients over 8 years of age. A 4-year longitudinal study.

OBJECTIVE: To carry out a longitudinal study of visual functions in young patients over the age of 8 years with IDDM and to assess the impact of metabolic control on the presence of diabetic retinopathy. RESEARCH DESIGN AND METHODS: There were 37 young IDDM patients from the Paediatric and Adolescent Clinic at the University Hospital of Wales studied annually for 4 years, with a control group of 24 healthy subjects observed over a 2-year period. Assessment of visual functions included visual acuity, color vision, and contrast sensitivity. Ophthalmoscopy and retinal photography were used to determine the presence or absence of diabetic retinopathy. In addition, pubertal status and metabolic control (glycosylated hemoglobin) were determined at each visit. RESULTS: Patients with IDDM demonstrate abnormal color vision and contrast sensitivity compared with the control group (P < 0.05), but visual acuity was unaffected. Visual functions were not significantly different between those IDDM patients with and without retinopathy. After 4 years, diabetic retinopathy was present in 43% of the group and was related to diabetes duration and metabolic control (P < 0.05). CONCLUSIONS: Visual function testing could not distinguish between those IDDM patients with and without retinopathy, but the color vision and contrast sensitivity in those with IDDM were significantly impaired compared with the control group. The presence of retinopathy was related to the duration of diabetes and metabolic control. It is important to ensure that good glycemic control and regular attendance for retinopathy screening is encouraged in the adolescent patients.

Morphological determinants of femoral strength in growth hormone-deficient transgenic growth-retarded (Tgr) rats.

UNLABELLED: The extent to which childhood GHD affects adult fracture risk is unclear. We measured femoral strength in adult transgenic growth-retarded rats as a model of GHD. Long-term, moderate GHD was accompanied by endocrine and morphometric changes consistent with a significant reduction in femoral strength. INTRODUCTION: Childhood growth hormone deficiency (GHD) is associated with osteopenia, but little is known about its effects on subsequent adult bone strength and fracture risk. MATERIALS AND METHODS: We have therefore measured femoral strength (failure load measured by three-point bending) in a new model of moderate GHD, the transgenic growth-retarded (Tgr) rat at 15, 22-23, and 52 weeks of age, and have quantified potential morphological and endocrine determinants of bone strength. RESULTS: Skeletal growth retardation in Tgr rats was accompanied by a sustained reduction in the anterior-posterior diameter of the femoral cortex, whereas mid-diaphyseal cortical wall thicknesses were largely unaltered. Total femoral strength was significantly impaired in Tgr rats (p < 0.01), and this impairment was more pronounced in males than females. Compromised bone strength in Tgr rats could not be accounted for by the reduction in mechanical load (body weight) and was not caused by impairment of the material properties of the calcified tissue (ultimate tensile stress), despite marked reductions in femoral mineral density (areal bone mineral density; p < 0.001). Microcomputerized tomographical analysis revealed significant modification of the architecture of trabecular bone in Tgr rats, with reductions in the number and thickness of trabeculae (p < 0.05) and in the degree of anisotropy (p < 0.01). The marked reduction in plasma insulin-like growth factor-1 in Tgr rats was accompanied by the development of high circulating leptin levels (p < 0.01). CONCLUSION: These results show that the changes in endocrinology and bone morphology associated with long-term moderate GHD in Tgr rats are accompanied by changes consistent with a significant reduction in the threshold for femoral fracture.

The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population.

Congenital hypothyroidism (CH) occurs in approximately 1 in 3000 births and can be caused by mutations in 9 known genes, including that encoding the TSH receptor (TSHR). We report on two Welsh siblings, detected by neonatal screening, who had normal sized and placed glands but negative isotope uptake. Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically. Both siblings were homozygous for a previously described G to A transition producing a missense mutation, W546X, in the fourth membrane spanning region of the TSHR, rendering it unresponsive to TSH. Both parents were heterozygous and unrelated; furthermore, the W546X has been described in three further families (one of which is Welsh), suggesting that it may be a relatively common mutation. We genotyped 368 euthyroid Welsh individuals using single nucleotide primer extension, and found 366 homozygous wild-type (G:G) and 2 heterozygous (G:A) for the mutation. In conclusion, CH in the siblings is due to the missense mutation, W546X, in their TSHR gene. The W546X allele was detected in approximately 1 in 180 individuals and may be a major contributor to hypothyroidism in the Welsh population.

Effects of chemotherapeutic agents on the function of primary human osteoblast-like cells derived from children.

Studies in children treated with chemotherapy suggest that chemotherapeutic agents have deleterious effects on bone metabolism. We therefore evaluated the in vitro effects of clinically relevant concentrations of chemotherapeutic agents on the synthesis of type I collagen, alkaline phosphatase (AP) activity, and mineralization by primary human osteoblast-like (HOB) cells derived from children. Because serum 1,25-dihydroxyvitamin D(3) concentrations may be reduced during treatment with chemotherapy, the effect of chemotherapeutic agents on HOB cells cultured in the presence or absence of 1,25-dihydroxyvitamin D(3) was also evaluated. Type I collagen synthesis was reduced by all agents (P < 0.01) other than methotrexate, whereas the relative AP activity was increased (P < 0.01) by all agents. The relative number of cells staining intensely for AP after culture with agents increased (P < 0.05), and AP mRNA expression was increased (P < 0.01) with vincristine. 1,25-Dihydroxyvitamin D(3) ameliorated (P < 0.01) the depletion of HOB cell numbers by chemotherapeutic agents. Furthermore, vincristine and daunorubicin inhibited 1,25-dihydroxyvitamin D(3)-mediated AP activity (P < 0.01). We conclude that chemotherapeutic agents can adversely affect HOB cell function, and we speculate that this observation may account, in part, for the osteopenia observed during and after treatment of children with chemotherapy.

Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH.

The TSH receptor is a G protein-coupled receptor that mediates the effects of TSH in thyroid development, growth, and synthetic function. We report here that a child with features of TSH resistance, including markedly increased serum TSH concentrations and low normal thyroid hormone levels, is a compound heterozygote for two novel mutations in the TSH receptor gene. One allele has a G to A transition corresponding to an arginine to glutamine change at codon 109 (R109Q) in the extracellular domain of the receptor. The other allele has a G to A transition corresponding to a premature termination codon at tryptophan 546 (W546X) in the fourth transmembrane segment. Each parent is heterozygous for one mutation, and both parents have normal thyroid function. Cells transiently transfected with the R109Q mutant exhibited reduced membrane binding of [125I]TSH and impaired signal transduction in response to TSH. In contrast, the W546X mutant was nonfunctional, with negligible membrane radioligand binding. Our findings indicate that a single normal TSH receptor allele is sufficient for normal thyroid function, but that the compound abnormality in the proband leads to TSH resistance.

In vitro effects of combination chemotherapy on osteoblasts: implications for osteopenia in childhood malignancy.

Clinical studies suggest that combination chemotherapy adversely affects bone metabolism and in vitro studies have demonstrated that a reduction in osteoblast numbers results in diminished bone formation. The aim of this study was to investigate the in vitro effects of combinations of chemotherapeutic agents on primary human osteoblast-like (hOB) cell numbers and apoptosis, and to assess the ability of hOBs and osteoprogenitor (HCC1) cells to recover from prior treatment with chemotherapy. As glucocorticoids are frequently administered during treatment with cytotoxic agents, we evaluated whether glucocorticoids influence the chemosensitivity of hOB and human osteosarcoma (MG63) cells. Culture with clinically relevant concentrations of the individual chemotherapeutic agents reduced hOB cell numbers compared with control (p < 0.01) and also increased the numbers of apoptotic cells (p < 0.05). Potentiation of cytotoxicity was observed when agents were given in combination, thus further reducing cell numbers, and this effect was greatest when vincristine was given in combination with asparaginase. Following culture with a chemotherapeutic agent, there was greater recovery of hOB compared with HCC1 cell numbers (p < 0.01). Pretreatment with glucocorticoids ameliorated the adverse effects of chemotherapeutic agents on hOB and MG63 cell numbers and apoptosis (p < 0.05). We conclude that the use of combination chemotherapy contributes to osteopenia in childhood malignancy by a reduction in osteoblast numbers. However, this effect may be attenuated by the concomitant use of glucocorticoids.