Seven years of safety and efficacy of the recombinant human growth hormone Omnitrope in the treatment of growth hormone deficient children: results of a phase III study.

AIM: This phase III clinical study in growth hormone deficiency (GHD) children with growth retardation was designed to compare efficacy and safety of Omnitrope((R)) with Genotropin((R)) and assess the long-term safety and efficacy of Omnitrope((R)). The results of 7 years of treatment with Omnitrope((R)) are presented. PATIENTS AND METHODS: Eighty-nine treatment-naïve, prepubertal children with GHD were randomized (part 1) to Omnitrope((R)) lyophilisate (group A, n = 44) or Genotropin((R)) (group B, n = 45) for 9 months and received a subcutaneous dose of 0.03 mg/kg/day. In part 2, patients receiving Omnitrope((R))lyophilisate continued the same treatment for a further 6 months, while patients on Genotropin((R)) were switched to Omnitrope((R)) liquid for the subsequent 6 months. In part 3, patients in both groups received Omnitrope((R))liquid for a period up to 69 months. RESULTS: The development of the 4 auxological parameters (height, height SD score, height velocity and height velocity SD score) and IGF-1 and IGFBP-3 levels were comparable between both groups of patients and confirmed the well-known growth response of GHD children to recombinant human GH treatment. Omnitrope((R)) was well tolerated and safe over 7 years of treatment. CONCLUSION: The clinical comparability between Omnitrope((R)) and Genotropin((R)) was demonstrated within 9 months of treatment. Long-term safety and efficacy of 7 years of treatment with Omnitrope((R)) was proven.

Symptomatic hypoparathyroidism based on a 22q11 deletion first diagnosed in a 43-year-old woman.

Congenital hypoparathyroidism usually manifests in early childhood with hypocalcaemia with or without clinical characteristics. This report describes a Caucasian woman who, at the age of 43 years, was diagnosed with dysgenesis of the parathyroid glands due to a de novo microdeletion in chromosome 22q11 or DiGeorge syndrome. This syndrome is characterised by a considerable variability in clinical symptoms, including heart defects, thymic hypoplasia and mental retardation. Our patient presented with generalised convulsions due to extreme, symptomatic hypocalcaemia. The convulsions had been apparent for 18 months at the time of the diagnosis. Remarkably, whereas parathyroid hormone levels were undetectable, the 1,25-dihydroxy vitamin D level was normal. Chromosome 22q11 deletion was confirmed by fluorescence in situ hybridisation analysis.

Thyroid function disorders--Guidelines of the Netherlands Association of Internal Medicine.

Thyroid function disorders are common with a female to male ratio of 4 to 1. In adult women primary hypothyroidism and thyrotoxicosis have a prevalence of 3.5/1000 and 0.8/1000, respectively. This guideline is aimed at secondary care providers especially internists, but also contains relevant information for interested general practitioners and gynaecologists. A multidisciplinary working group, containing delegates of professional and patient organisations, prepared the guideline. According to principles of 'evidence-based medicine' available literature was studied and discussed. Considering the availability and quality of published studies a practical advice was formulated. For a full overview of the literature and considerations the reader is referred to the original version of the guideline (accessible through NIV-net). In this manuscript we have aimed to provide the practicing internist with practical and 'as evidence-based as possible' treatment guidelines with respect to thyroid function disorders.

[A mass in the popliteal fossa and leucocytosis caused by a paraneoplastic leukemoid reaction]. / Een massa in de knieholte en leukocytose door een paraneoplastische leukemoïde reactie.

A 65-year-old woman was referred with a mass in the right popliteal fossa, fever and leucocytosis reaching 105 x 10(9)/l. Her medical history included the excision of a melanoma from the right ankle more than 20 years before. Ultrasound, CT and positron-emission tomography showed the mass in the right knee but no other lesions. The process was drained. Histological examination ofa subcutis biopsy indicated malignancy. Due to deterioration in her clinical condition amputation of the right leg was performed after which her leucocyte count normalized. The pathology specimen revealed a high-grade undifferentiated soft tissue tumour of unclear origin. Preoperatively assessed serum levels of granulocyte-stimulating factor (G-CSF), interleukin 6 and interleukin 8 were elevated to 241, 91 and 82 pg/ml respectively. After the amputation these levels returned to almost normal. This extreme leucocyte count may be explained by a paraneoplastic leukemoid reaction. It is hypothesized that the tumour cells produce G-CSF and other cytokines causing leucocytosis. Normalisation of the cytokine levels postoperatively supports this hypothesis.

Efficacy and safety of a new ready-to-use recombinant human growth hormone solution.

We report 24-month interim results of two multicenter phase III studies in previously untreated children with growth failure secondary to GH deficiency (GHD) that were paramount to the development of a new recombinant human GH (rh- GH, somatropin), approved as the first 'biosimilar' in Europe. Study 1 consisted of 3 parts performed in 89 children. The objective was to compare efficacy and safety of the lyophilized formulation of the new somatropin [Somatropin Powder (Sandoz)] with a licensed reference rhGH preparation and the liquid formulation of the new somatropin [Somatropin Solution (Sandoz)] and to assess long-term efficacy and safety of this ready-to-use Somatropin Solution. Study 2 was performed in 51 children and designed to demonstrate efficacy and safety of Somatropin Powder and to confirm its low immunogenic potential; rhGH was given sc at a daily dose of 0.03 mg/kg. Primary [body height, height SD score (HSDS), height velocity, and height velocity (HV) SD score (HVSDS)] and secondary [IGF-I and IGF binding protein 3 (IGFBP-3)] efficacy endpoints and safety parameters were assessed regularly. In study 1, all treatments showed comparable increases in growth. The baseline-adjusted difference between Somatropin Powder and the reference rhGH product in mean HV was -0.20 cm/yr (95% confidence interval (CI) [-1.34;0.94]) and in mean HVSDS was 0.76 (95% CI [-0.57;2.10]) after 9 months. These very small differences demonstrate comparable therapeutic efficacy between the two treatments. The results of study 2 were consistent with those seen in study 1. Equivalent therapeutic efficacy and clinical comparability in terms of safety and immunogenicity between Somatropin Powder and the reference rhGH product and between Somatropin Powder and Somatropin Solution was demonstrated. The safety and immunogenicity profiles were similar and as expected from experience with rhGH preparations.

Fundamental state quantities and high-pressure phase transition in beryllium chalcogenides.

In this work we study the structural and electronic properties of Be chalcogenides (BeS, BeSe and BeTe) using two different methods: the full-potential linear augmented-plane wave (FP-LAPW) and the plane-wave pseudopotential (PPsPW). The exchange-correlation effects are treated in the local-density approximation (LDA) and the generalized-gradient approximation (GGA). We have evaluated the ground-state quantities such as equilibrium volume, bulk modulus and its pressure derivative as well as the elastic constants. Various structural phase transitions were considered here in order to confirm the most stable structure and to predict the phase transition under hydrostatic pressure. In addition we have studied the band structure and the density of states, which show a wide indirect band gap for these compounds. These results were in favourable agreement with previous theoretical works and the existing experimental data. To complete the fundamental characteristics of beryllium chalcogenide compounds we have analysed their bonding character in terms of charge transfer and the ionicity parameter. The latter is found to be in agreement with the charge transfer behaviour, which shows an important ionic localization.

Evaluation of cardiac ischaemia in cardiac asymptomatic newly diagnosed untreated patients with primary hypothyroidism.

BACKGROUND: Hypothyroidism is regarded as a risk factor for coronary artery disease. Possible factors involved in this association are hyperlipidaemia and hypertension, both occurring with increased frequency in hypothyroid patients. The aim of our study was to evaluate signs/symptoms of cardiac ischaemia in untreated hypothyroid patients without angina pectoris, since this has never been performed before. METHODS: 51 consecutive cardiac asymptomatic patients (mean age 47, range 22 to 86 years) were studied by dobutamine stress echocardiography and bicycle ergometry. RESULTS: Mean values of body mass index, resting heart rate and blood pressure were 28.5 kg/m2, 68 beats/min and 129/81 mmHg, respectively. Median TSH was 51.9 mU/l, mean FT4 7.3 +/- 2.9 pmol/l (mean +/- SD), TT3 1.6 +/- 0.6 nmol/l and total cholesterol was 5.8 +/- 1.6 mmol/l. None of the patients had symptoms of angina pectoris during dobutamine stress echocardiography or bicycle ergometry and no evidence of myocardial ischaemia was demonstrated. Exercise tolerance, assessed by dividing the maximum achieved workload by the target performance (depending on body height, sex and age), was diminished in 38% of patients, and significantly related to the degree of hypothyroidism. CONCLUSION: No angina pectoris or cardiac ischaemia at exercise or stress was found in cardiac asymptomatic hypothyroid patients. The precise role of hypothyroidism as a risk factor for coronary artery disease should be further elucidated.

No clear effect of diabetes education on glycaemic control for Turkish type 2 diabetes patients: a controlled experiment in general practice.

BACKGROUND: In Turkish immigrant diabetics, problems with communication and cultural differences may hinder delivery of diabetes care. METHODS: In a prospective controlled study, the effect of an ethnic-specific diabetes education programme on glycaemic control and cardiovascular risk factors in Turkish type 2 diabetes patients was assessed, by comparing Turkish diabetics who were offered the education programme with Turkish diabetics offered routine care only (control group). From 16 general practices (31 GPs) in Rotterdam, 104 Turkish type 2 diabetes patients were recruited, 85 of whom could be assessed at one-year follow-up. Glycaemic control, lipid concentrations, blood pressure and body mass index were measured. RESULTS: Compared with the control group, mean HbA(1C) in the intervention group decreased by 0.3% (95% CI -0.8 to 0.2). A significant decrease in HbA(1C) was observed in women with HbA(1C) >7% at baseline (-0.9%; 95% CI -1.73 to -0.09) but not in the other subgroups studied. serum lipid concentrations, blood pressure and body mass index remained unchanged in the intervention group. CONCLUSION: Ethnic-specific diabetes education by Turkish female educators has no obvious beneficial effect on glycaemic control or cardiovascular risk profile. More focus on specific patient selection and gender equality between educators/patients may prove worthwhile.

[A pregnant woman with autoimmune thyroiditis and recurrent goiter]. / Een zwangere met auto-immuunthyreoïditis en recidiverend struma.

A 27-year-old woman was first referred at the age of 14 with cosmetic complaints due to an echographically diffuse, euthyroid goitre. Tests for antibodies against thyroid peroxidase and thyroglobulin were positive. Thyroid-suppression therapy with levothyroxine resulted in regression of the goitre. At the age of 26 there was a transitory recurrence of the goitre during a pregnancy, during which time the thyroid peroxidase antibodies became strongly positive. Six months post partum the goitre recurred again, accompanied by pain in the throat and fever. The C-reactive protein level was strongly elevated. Serology established the diagnosis of viral thyroiditis due to a Coxsackie-B virus. The size of the goitre decreased after treatment with acetylsalicylic acid and prednisone. Two months later the goitre again showed further growth, now in association with cervical lymphadenopathy and an enlarged left parotid gland. Histology revealed a non-Hodgkin lymphoma of the type diffuse large B-cell (stage II), very likely a primary thyroid lymphoma. The lymphoma was refractory to cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP); this was followed by intensive chemotherapy and autologous stem-cell transplantation, resulting finally in a complete remission. The goitre disappeared and thyroid peroxidase antibodies were no longer detectable. Primary thyroid lymphoma is a rare disease, but autoimmune thyroiditis appears to be an important predisposing factor.

[Continuous subcutaneous insulin infusion in diabetes mellitus type 1 and 2: lower HbA1c-values and a high level of patient satisfaction]. / Continue subcutane insuline-infusie bij diabetes mellitus type 1 en 2: lagere HbA1c-waarden en grote patiëntentevredenheid.

OBJECTIVE: To determine the HbA1c-values and the degree of satisfaction of patients who had switched from multiple subcutaneous insulin injections to continuous subcutaneous insulin infusion (CSII). DESIGN: Retrospective. METHOD: Data were collected and evaluated from all patients with type 1 or 2 diabetes mellitus who started treatment with CSII in the period from 1 January 1999 to 31 December 2001 in the Rijnmond-Zuid Medical Centre, Zuider site, Rotterdam, the Netherlands. The data included the insulin dosage and HbA1c-percentages before and three months after the start of CSII, and the degree of satisfaction of the patients on a scale from 1 (poor) to 10 (good). RESULTS: Of the 57 patients who started CSII, two resumed multiple daily subcutaneous injections within a few months. Of the other 55 patients, 36 (including 15 men) had type-1 diabetes, with an average age of 36.1 years, and 19 (including 8 men) had type-2 diabetes, with an average age of 49.7 years. Poor regulation of the blood glucose levels was the main reason (n = 40; 73%) for switching to CSII. In the 36 patients with type-1 diabetes, there was no significant change in the total dose of insulin before and during CSII, while the mean HbA1c-level decreased from 8.2 (SD: 1.2) to 7.3% (SD: 1.0; p = 0.0005). In the 19 patients with type-2 diabetes, there was also no significant change in insulin dosage, while the HbA1c-level decreased from 8.1 (SD: 1.0) to 7.6% (SD: 1.1; p = 0.056). All 47 interviewed patients were satisfied with the treatment. The mean score was 8.3 in type-1 diabetes mellitus and 8.1 in type-2 diabetes mellitus. CONCLUSION: Following three months on CSII, the average HbA1c-percentages were lower than during the previous treatment with multiple subcutaneous insulin injections. The patients were satisfied with the convenience of the treatment.

Consequences of autoimmune thyroiditis before, during and after pregnancy.

Autoimmune thyroiditis has important consequences for fertility, the occurrence of pregnancy complications, pregnancy outcome. Moreover autoimmune thyroiditis can aggravate during the postpartum period. Finally, the sequelae of autoimmune thyroiditis might have important consequences for the offspring. Several studies have shown an association between thyroid autoimmunity in earlyas opposed to beforepregnancy and subsequent "incidental" miscarriage. With respect to habitual abortion available data are more conflicting perhaps mild degrees of thyroid insufficiency - not detectable by routine thyroid testing - and not thyroid autoimmunity per se is causal in the association between the presence of thyroid antibodies and recurrent abortion. Autoimmune hypo- and hyperfunction during pregnancy are both related to obstetrical complications. It is important to note that treatment can - at least in part - reduce this excess risk associated with untreated hypo- or hyperthyroidism. Considering pregnancy outcome there are now data providing evidence that not only overt but also relatively mild and hitherto unrecognized states of thyroid failure are associated with persistent and significant impairment in neuropsychological performance of the offspring. Postpartum thyroiditis is clearly associated with the presence of TPO antibodies (i.e. autoimmune thyroiditis). Autoimmune thyroiditis is thus clearly associated with clinically relevant events, occurring before, during and after pregnancy. Screening should be considered; however further research is urgently needed.

Cardiac and metabolic effects in patients who present with a multinodular goitre.

Twenty-six consecutive patients who presented with clinically euthyroid multinodular goitre were studied for an overnight fasting serum lipid profile and 24 h Holter monitoring. Mean serum TSH was 0.6 +/- 0.4 vs 2.4 +/- 1.3 mU/l (p < 0.0001) and mean TT3 2.4 +/- 0.4 vs 2.0 +/- 0.5 nmol/l (p = 0.009) in patients vs controls (n = 15) while mean FT4 was not different from controls. Total serum HDL, LDL cholesterol and triglycerides were lower in patients but creatinine, ferritin and SHBG levels did not differ between patients and controls. The 24-hour ambulatory continuous ECG recordings did not demonstrate significant differences in mean, minimal and maximal heart rate between the study and the control group. Nocturnal heart rate, measured between 23.00 and 06.00 hours, also showed no differences between the two groups. Atrial fibrillation was absent in both the study and the control group. Premature atrial and ventricular complexes occurred equally frequently in both groups. Comparison of patients with a serum TSH below 0.4 mU/l (n = 11) and patients with a TSH above 0.4 mU/l revealed no differences. In conclusion, in consecutive patients who present with multinodular goitre, effects were found on the lipid profile, but not on the heart. It is argued that in this type of patients, cardiac effects depend on the degree of subclinical hyperthyroidism.

[Clinical thinking and decision making in practice. A young woman with fever, arthralgia and exanthema]. / Klinisch denken en beslissen in de praktijk. Een jonge vrouw met koorts, artralgie en exantheem.

A 19-year-old woman was admitted because of high fever, rash, arthralgia and sore throat. On physical examination a diffuse skin rash was observed, leaving a facial mask unaffected. C-reactive protein and erythrocyte sedimentation rate were raised (114 mg/l and 26 mm in the first hour, respectively); white blood cell count was normal (6.2 x 10(9)/l) with an increased count of immature forms. An infective, metabolic or haematological cause was excluded. Serum ferritin turned out to be extremely elevated (4318 micrograms/l), so adult-onset Still's disease was diagnosed. The patient fulfilled the criteria of Cush et al. for adult-onset Still's disease. She was first treated with non-steroidal anti-inflammatory drugs (NSAIDs) and, at a later stage in the disease, with corticosteroids. All symptoms disappeared and blood test results normalised.

[Cardiovascular effects of hyperthyroidism and their treatment]. / Cardiovasculaire effecten van hyperthyreoïdie en de behandeling daarvan.

The most striking clinical effects of hyperthyroidism are on the heart. These effects concern both heart rate and function. The increased contractility is mainly based on the indirect inotropic effect of peripheral vasodilation as a consequence of hyperthyroidism. Although contractility at rest is enhanced in hyperthyroidism, cardiac reserve is decreased due to diminished chronotropic, inotropic and vasodilatory reserve. In hyperthyroid patients, the clinical impression is often that of a hyperadrenergic circulation. However, the sensitivity of the heart for catecholamines is not increased. The diminution of palpitations by beta-adrenergic blockers in hyperthyroid patients is due to both a decrease in heart rate and atrial extrasystoles, and is not the consequence of a normalisation of cardiac contractility. Heart failure is almost exclusively found in patients with pre-existing cardiac disease. In the case of serious heart failure a rapid reduction of circulating thyroid hormone by means of thyreostatics is important as well. There is no consensus as to whether patients with thyrotoxic atrial fibrillation should be treated with oral anticoagulants. However, most experts recommend oral anticoagulants for elderly patients (> 60 years) or patients with additional risk factors for embolism.

Ischaemic heart disease in Turkish migrants with type 2 diabetes mellitus in The Netherlands: wait for the next generation?

OBJECTIVE: To study the prevalence of ischaemic heart disease in Turkish and Surinam-Asian migrants with type 2 diabetes mellitus in the Netherlands as compared with Europeans. METHODS: In a consecutive case-control study, 59 Turkish and 62 Surinam-Asian patients were compared with 185 Europeans referred to a diabetes clinic for treatment of type 2 diabetes in the period 1992 to 1998. Main outcome measures were ischaemic heart disease and its associated risk factors. RESULTS: The prevalence of ischaemic heart disease was lower (9%) in the Turks (p < 0.02), but higher (29%) in the Surinam-Asians compared with the Europeans (23%). The Turks (52 +/- 10 years) and Surinam-Asians (46 +/- 12 years) were younger than the Europeans (64 +/- 11 years, p < 0.001). Body mass index was 32 +/- 5 (p < 0.001) in the Turks, 27 +/- 5 in the Surinam-Asians (p < 0.05) and 29 +/- 5 in the Europeans. Turkish patients smoked less (23%, p < 0.05) and used less alcohol (4%, p < 0.05) than the Europeans. Proteinuria was found in 24% of the Turks (p < 0.05), 37% of the Surinam-Asians (NS) and 46% of the Europeans. In univariate analysis ischaemic heart disease was related to Turkish origin, OR 0.34 (0.14-0.83) p < 0.02, to Surinam-Asian origin, OR 1.84 (1.00-3.38) p = 0.05, and smoking, OR 1.78 (1.18-2.68) p < 0.01. Other variables were not related to ischaemic heart disease. Multivariate analysis in a model with ethnicity and smoking showed significant relations between ischaemic heart disease and Turkish ethnicity, OR 0.19 (0.06-0.65) p = 0.007, Surinam-Asian origin, OR 2.77 (1.45-5.28) p = 0.002, and smoking, OR 1.79 (1.20-2.66) p = 0.004. CONCLUSION: Type 2 diabetes mellitus in different ethnic groups results in a significant difference in incidence of ischaemic heart disease. The most remarkable finding is a low incidence of ischaemic heart disease in the Turkish patients with type 2 diabetes, independent of smoking. The high prevalence of ischaemic heart disease in young migrant Asians with diabetes is confirmed.

Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care.

Postpartum thyroiditis is a syndrome of transient or permanent thyroid dysfunction occurring in the first year after delivery and based on an autoimmune inflammation of the thyroid. The prevalence ranges from 5-7%. We discuss the role of antibodies (especially thyroid peroxidase antibodies), complement, activated T cells, and apoptosis in the outbreak of postpartum thyroiditis. Postpartum thyroiditis is conceptualized as an acute phase of autoimmune thyroid destruction in the context of an existing and ongoing process of thyroid autosensitization. From pregnancy an enhanced state of immune tolerance ensues. A rebound reaction to this pregnancy-associated immune suppression after delivery explains the aggravation of autoimmune syndromes in the puerperal period, e.g., the occurrence of clinically overt postpartum thyroiditis. Low thyroid reserve due to autoimmune thyroiditis is increasingly recognized as a serious health problem. 1) Thyroid autoimmunity increases the probability of spontaneous fetal loss. 2) Thyroid failure due to autoimmune thyroiditis-often mild and subclinical-can lead to permanent and significant impairment in neuropsychological performance of the offspring. 3) Evidence is emerging that as women age subclinical hypothyroidism-as a sequel of postpartum thyroiditis-predisposes them to cardiovascular disease. Hence, postpartum thyroiditis is no longer considered a mild and transient disorder. Screening is considered.

An abnormal adherence of monocytes to fibronectin in thyroid autoimmunity has consequences for cell polarization and the development of veiled cells.

Blood monocytes of patients with thyroid autoimmune disease (TAID) display defects in rearranging their cortical actomyosin cytoskeleton ('polarize') in response to chemoattractants. Such rearrangements also take place after the adherence of monocytes to the extracellular matrix (ECM). It is therefore not surprising that monocytes are primed after fibronectin (FN) adherence, displaying an enhanced polarization toward chemoattractants. We investigated the integrin expression and chemoattractant-induced polarization of monocytes of TAID patients before and after FN adherence. Since cytoskeletal rearrangements are also required during the transition of monocytes into veiled antigen-presenting cells (VCs), we investigated such transition of FN-adherent monocytes of TAID patients. Adherent and nonadherent monocyte populations from TAID patients and healthy controls were subjected to a polarization test with the chemoattractant fMLP (or MCP-1), FACS analyses (FITC-labelled FN, CD29, CD49e, d, b and a) and tested for their capability to develop into veiled APC. Monocytes of healthy individuals showed an improved chemoattractant-induced cell polarization after FN adherence, not reflected by TAID monocytes, in which chemoattractant-induced polarization worsened. Monocytes of healthy individuals up-regulated CD49e and d integrins and their capability to bind FITC-labelled FN after adherence to a FN-coated plate, as well as enhancing their capability to generate T cell-stimulatory VCs. Monocytes of TAID patients did not. These data indicate that integrin- (and chemokine-) mediated functions are hampered in monocytes of TAID patients. Because integrin action is pivotal to processes such as monocyte adherence to endothelial cells, uropod formation, migration into tissues and differentiation into APC and macrophages, these defects might underly immune dysbalances important in thyroid autoimmune development.