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Henning Dralle,
Thomas J Musholt,
Jochen Schabram,
Thomas Steinmüller,
Andreja Frilling,
Dietmar Simon,
Peter E Goretzki,
Bruno Niederle,
Christian Scheuba,
Thomas Clerici, [......],
Andreas Zielke, Wolfram Karges,
Markus Luster,
Kurt W Schmid,
Dirk Vordermark,
Hans-Joachim Schmoll,
Reinhard Mühlenberg,
Otmar Schober,
Harald Rimmele,
Andreas Machens
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ABSTRACT: INTRODUCTION: Over the past years, the incidence of thyroid cancer has surged not only in Germany but also in other countries of the Western hemisphere. This surge was first and foremost due to an increase of prognostically favorable ("low risk") papillary thyroid microcarcinomas, for which limited surgical procedures are often sufficient without loss of oncological benefit. These developments called for an update of the previous practice guideline to detail the surgical treatment options that are available for the various disease entities and tumor stages. METHODS: The present German Association of Endocrine Surgeons practice guideline was developed on the basis of clinical evidence considering current national and international treatment recommendations through a formal expert consensus process in collaboration with the German Societies of General and Visceral Surgery, Endocrinology, Nuclear Medicine, Pathology, Radiooncology, Oncological Hematology, and a German thyroid cancer patient support organization. RESULTS: The practice guideline for the surgical management of malignant thyroid tumors includes recommendations regarding preoperative workup; classification of locoregional nodes and terminology of surgical procedures; frequency, clinical, and histopathological features of occult and clinically apparent papillary, follicular, poorly differentiated, undifferentiated, and sporadic and hereditary medullary thyroid cancers, thyroid lymphoma and thyroid metastases from primaries outside the thyroid gland; extent of thyroidectomy; extent of lymph node dissection; aerodigestive tract resection; postoperative follow-up and surgery for recurrence and distant metastases. CONCLUSION: These evidence-based recommendations for surgical therapy reflect various "treatment corridors" that are best discussed within multidisciplinary teams and the patient considering tumor type, stage, progression, and inherent surgical risk.
Langenbeck s Archives of Surgery 03/2013; · 1.81 Impact Factor
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Markus Luster, Wolfram Karges,
Katrin Zeich,
Sandra Pauls,
Frederik A. Verburg,
Henning Dralle,
Gerhard Glatting,
Andreas K. Buck,
Christoph Solbach,
Bernd Neumaier,
Sven N. Reske,
Felix M. Mottaghy
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ABSTRACT: PurposeIn detecting pheochromocytoma (PHEO), positron emission tomography (PET) with the radiolabelled amine precursor 18F-fluorodihydroxyphenylalanine (18F-DOPA) offers excellent specificity, while computed tomography (CT) provides high sensitivity and ability to localize lesions;
therefore, the combination of these modalities could be advantageous in this setting. The aim of this study was to investigate
whether combined 18F-DOPA PET/CT more accurately detects and localizes PHEO lesions than does each modality alone.
Methods
18F-DOPA PET, CT and 18F-DOPA PET/CT images of 25 consecutive patients undergoing diagnostic scanning of suspected sporadic or multiple endocrine
neoplasia type 2 syndrome-associated PHEO were reviewed retrospectively in randomized sequence. Two blinded observers scored
the images regarding the likelihood of PHEO being present and localizable. Results were correlated with subsequent clinical
history and, when available, histology.
ResultsOf the 19 lesions detected by all three modalities, PET identified each as positive for PHEO, but was unable to definitively
localize 15 of 19 (79%). CT could definitively localize all 19 lesions, but could not definitively diagnose or exclude PHEO
in 18 of 19 (95%) lesions. Furthermore, CT falsely identified as negative for PHEO one lesion which was judged to be positive
for this tumor by both PET and PET/CT. Only in PET/CT scans were all 19 lesions accurately characterized and localized. On
a per-patient basis, the sensitivity of 18F-DOPA PET/CT for PHEO was 100% and the specificity 88%, with a 100% positive predictive value and an 88% negative predictive
value.
Conclusion
18F-DOPA PET/CT more accurately diagnoses and localizes adrenal and extra-adrenal masses suspicious for PHEO than do 18F-DOPA PET or CT alone.
KeywordsPheochromocytoma-Multiple endocrine neoplasia type 2 (MEN2)-
18F-fluorodihydroxyphenylalanine (18F-DOPA)-Positron emission tomography (PET)-Computed tomography (CT)-Staging
European journal of nuclear medicine and molecular imaging 04/2012; 37(3):484-493. · 4.99 Impact Factor
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ABSTRACT: Disturbances of zinc homeostasis have been observed in several diseases, including diabetes mellitus. To further characterize the association between zinc and diabetes, we recruited 75 patients with type 1 or type 2 diabetes and 75 nondiabetic sex-/age-matched control subjects in order to analyze differences concerning human zinc transporter 8 (hZnT-8) expression, single nucleotide polymorphisms (SNPs) in the genes of hZnT-8 as well as metallothionein 1A and serum/intracellular zinc. Furthermore, we investigated the relation between insulin and zinc homeostasis in type 2 diabetic subjects and consolidated our results by in vitro analysis of the effect of insulin on cellular zinc status and by analysis of the modulation of insulin signal transduction by intracellular zinc homeostasis. Concerning the expression of hZnT-8 and the SNPs analyzed, we did not observe any differences between diabetic and control subjects. Serum zinc was significantly lower in diabetic patients compared to controls, and intracellular zinc showed the same tendency. Interestingly, type 2 diabetes patients treated with insulin displayed lower serum zinc compared to those not injecting insulin. In vitro analyses showed that insulin leads to an increase in intracellular zinc and that insulin signaling was enhanced by elevated intracellular zinc concentrations. In conclusion, we show that type 1 and type 2 diabetic patients suffer from zinc deficiency, and our results indicate that zinc supplementation may qualify as a potential treatment adjunct in type 2 diabetes by promoting insulin signaling, especially in zinc-deficient subjects.
The Journal of nutritional biochemistry 03/2012; 23(11):1458-66. · 4.29 Impact Factor
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Jürgen Kratzsch,
Anne Petzold,
Friedhelm Raue,
Walter Reinhardt,
Martina Bröcker-Preuss,
Rainer Görges,
Klaus Mann, Wolfram Karges,
Nils Morgenthaler,
Markus Luster,
Christoph Reiners,
Joachim Thiery,
Henning Dralle,
Dagmar Fuhrer
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ABSTRACT: Calcitonin (CT) is a sensitive marker for evaluation of medullary thyroid cancer (MTC). However, CT measurement can vary with assay- and nonassay-dependent factors, and procalcitonin (PCT) measurement has been proposed for evaluating questionable increases in CT.
We tested 2 fully automated CT assays (Immulite [IL] and Liaison [LIA]) and 1 nonautomated CT assay (IRMA, Medipan) and compared these results with PCT (Brahms Kryptor). We evaluated preanalytical conditions and PCT cross-reactivity in sera of 437 patients with clinical conditions associated with hypercalcitoninemia. Additionally, we determined the true "nil" CT concentration in 60 thyroidectomized patients and defined CT cutoff concentrations for pentagastrin stimulation testing in 13 chronic kidney disease (CKD) patients and 10 MTC patients.
Markedly decreased CT concentrations were found after storage of sera for >2 h at room temperature and >6 h at 4 °C. Cutoff concentrations for basal and stimulated CT were disease and assay dependent. Proton pump inhibitor therapy was the most frequent reason for increased CT. PCT concentrations were higher in patients with MTC than in patients with CKD without infections (P<0.001). Whereas IL and LIA demonstrated comparable analytical quality, the IRMA gave increased CT concentrations in nil sera and showed cross-reactivity with PCT in patients with concomitant bacterial infection.
IL, LIA, and IRMA detected increased CT concentrations in non-MTC patients and discriminated MTC from CKD patients in pentagastrin tests. PCT assessment may be helpful in the diagnostic work-up of increased CT concentrations in questionable clinical circumstances.
Clinical Chemistry 03/2011; 57(3):467-74. · 7.91 Impact Factor
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Thomas J Musholt,
Thomas Clerici,
Henning Dralle,
Andreja Frilling,
Peter E Goretzki,
Michael M Hermann,
Jochen Kussmann,
Kerstin Lorenz,
Christoph Nies,
Jochen Schabram, [......],
Christian Scheuba,
Dietmar Simon,
Thomas Steinmüller,
Arnold W Trupka,
Robert A Wahl,
Andreas Zielke,
Andreas Bockisch, Wolfram Karges,
Markus Luster,
Kurt W Schmid
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ABSTRACT: Benign thyroid disorders are among the most common diseases in Germany, affecting around 15 million people and leading to more than 100,000 thyroid surgeries per year. Since the first German guidelines for the surgical treatment of benign goiter were published in 1998, abundant new information has become available, significantly shifting surgical strategy towards more radical interventions. Additionally, minimally invasive techniques have been developed and gained wide usage. These circumstances demanded a revision of the guidelines.
Based on a review of relevant recent guidelines from other groups and additional literature, unpublished data, and clinical experience, the German Association of Endocrine Surgeons formulated new recommendations on the surgical treatment of benign thyroid diseases. These guidelines were developed through a formal expert consensus process and in collaboration with the German societies of Nuclear Medicine, Endocrinology, Pathology, and Phoniatrics & Pedaudiology as well as two patient organizations. Consensus was achieved through several moderated conferences of surgical experts and representatives of the collaborating medical societies and patient organizations.
The revised guidelines for the surgical treatment of benign thyroid diseases include recommendations regarding the preoperative assessment necessary to determine when surgery is indicated. Recommendations regarding the extent of resection, surgical techniques, and perioperative management are also given in order to optimize patient outcomes.
Evidence-based recommendations for the surgical treatment of benign thyroid diseases have been created to aid the surgeon and to support optimal patient care, based on current knowledge. These recommendations comply with the Association of the Scientific Medical Societies in Germany requirements for S2k guidelines.
Langenbeck s Archives of Surgery 03/2011; 396(5):639-49. · 1.81 Impact Factor
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ABSTRACT: Neuroendocrine tumors (NET) have several distinct pathophysiological features that can be addressed by specific radiolabeled probes. An overview on the different radiopharmaceuticals that have been developed for positron emission tomography (PET) of NET are presented. The focus is on fluordeoxyglucose (F-18 FDG), biogenic amine precursors, somatostatin analogs, and hormone syntheses markers. Due to the highly specific tracers lacking any clear anatomical landmarking, the advantages of integrated functional and morphological imaging systems such as PET-CT are obvious. Based on the up to now published literature and one's own experience, it is concluded that amine precursors (e.g. fluor-dihydroxyphenylalanin and hydroxytryptophane) should be employed in most gastroenteropancreatic NET, whereas F-18 FDG should be preserved for more aggressive less-differentiated NETs. Hormone syntheses markers have up to now only been used in few centers and their broad clinical value remains uncertain. The different available somatostatin analogs are the most promising tracers, since they can improve dosimetry in cases where peptide receptor radiotherapies are planned. Of specific interest are the somatostatin analogs addressing several subtypes of the somatostatin receptor (e.g. DOTANOC) that allow detecting also subtypes not expressing the "classically" addressed subtype 2 and 5. Since NET have a high variety of different features, the individual diagnostic approach using PET or integrated PET-CT should be tailored, depending on the histological classification and the differentiation of the tumor.
Methods in molecular biology (Clifton, N.J.) 01/2011; 727:105-22.
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ABSTRACT: A commercial biotyping system (Taxa Profile™, Merlin Diagnostika) testing the metabolization of various substrates by bacteria was used to determine if a set of phenotypic features will allow the identification of members of the genus Brucella and their differentiation into species and biovars.
A total of 191 different amines, amides, amino acids, other organic acids and heterocyclic and aromatic substrates (Taxa Profile™ A), 191 different mono-, di-, tri- and polysaccharides and sugar derivates (Taxa Profile™ C) and 95 amino peptidase- and protease-reactions, 76 glycosidase-, phosphatase- and other esterase-reactions, and 17 classic reactions (Taxa Profile™ E) were tested with the 23 reference strains representing the currently known species and biovars of Brucella and a collection of 60 field isolates. Based on specific and stable reactions a 96-well "Brucella identification and typing" plate (Micronaut™) was designed and re-tested in 113 Brucella isolates and a couple of closely related bacteria.Brucella species and biovars revealed characteristic metabolic profiles and each strain showed an individual pattern. Due to their typical metabolic profiles a differentiation of Brucella isolates to the species level could be achieved. The separation of B. canis from B. suis bv 3, however, failed. At the biovar level, B. abortus bv 4, 5, 7 and B. suis bv 1-5 could be discriminated with a specificity of 100%. B. melitensis isolates clustered in a very homogenous group and could not be resolved according to their assigned biovars.
The comprehensive testing of metabolic activity allows cluster analysis within the genus Brucella. The biotyping system developed for the identification of Brucella and differentiation of its species and biovars may replace or at least complement time-consuming tube testing especially in case of atypical strains. An easy to handle identification software facilitates the applicability of the Micronaut™ system for microbiology laboratories.
BMC Microbiology 10/2010; 10:269. · 3.04 Impact Factor
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Markus Luster, Wolfram Karges,
Katrin Zeich,
Sandra Pauls,
Frederik A Verburg,
Henning Dralle,
Gerhard Glatting,
Andreas K Buck,
Christoph Solbach,
Bernd Neumaier,
Sven N Reske,
Felix M Mottaghy
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ABSTRACT: 18-Fluorine-fluorodihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET) is a sensitive method for detecting medullary thyroid carcinoma (MTC). The advent of PET/computed tomography (CT) has enabled more sensitive and specific lesion identification using various tracers in many other tumors. The aim of this study was therefore to test the hypothesis that combined (18)F-DOPA PET/CT more accurately detects MTC lesions than each modality does alone.
Twenty-eight consecutive (18)F-DOPA PET, CT, and (18)F-DOPA PET/CT scans of patients followed up for sporadic MTC or multiple endocrine neoplasia 2 syndrome-associated MTC were reviewed retrospectively in randomized sequence by two blinded readers, one a nuclear medicine physician and the other a radiologist, with extensive experience interpreting such images.
Of 18 lesions detected concurrently by the three modalities, PET identified all as positive for MTC, but was unable to definitively localize 4 (22%) lesions. CT could definitively localize all 18 lesions, but could not definitively diagnose or exclude MTC in 6 (33%) lesions. Further, CT falsely identified as MTC-negative one lesion that was judged to be MTC-positive by both PET and PET/CT. Only PET/CT scans accurately characterized and localized all 18 lesions. On a per patient basis, the sensitivity of (18)F-DOPA PET/CT for MTC was 74% and the specificity, 100%. In the present series, no truly MTC-positive (18)F-DOPA PET/CT case was found in patients with basal human calcitonin (hCt) levels under 60 pg/mL, and conversely, no truly MTC-negative PET/CT case was found in patients with basal hCt over 120 pg/mL. Between hCt concentrations of 60 and 150 pg/mL true-negative, false-negative, and true-positive scans all were obtained. (18)F-DOPA PET/CT had 100% sensitivity and specificity when hCt at the time of scanning was over 150 pg/mL, the threshold at which the 2009 American Thyroid Association guidelines recommend performing additional imaging including (18)F-DOPA PET/CT.
(18)F-DOPA PET/CT allows for a more accurate diagnosis and localization of MTC lesions than do (18)F-DOPA PET or CT alone. Supporting the recent American Thyroid Association recommendations on additional imaging in MTC, (18)F-DOPA PET/CT appears to have 100% sensitivity in patients with hCt over 150 pg/mL.
Thyroid: official journal of the American Thyroid Association 05/2010; 20(5):527-33. · 2.60 Impact Factor
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ABSTRACT: Zinc is an essential trace element crucial for the function of more than 300 enzymes and it is important for cellular processes like cell division and apoptosis. Hence, the concentration of zinc in the human body is tightly regulated and disturbances of zinc homeostasis have been associated with several diseases including diabetes mellitus, a disease characterized by high blood glucose concentrations as a consequence of decreased secretion or action of insulin. Zinc supplementation of animals and humans has been shown to ameliorate glycemic control in type 1 and 2 diabetes, the two major forms of diabetes mellitus, but the underlying molecular mechanisms have only slowly been elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of insulin and by reducing the production of cytokines, which lead to beta-cell death during the inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might play a role in the development of diabetes, since genetic polymorphisms in the gene of zinc transporter 8 and in metallothionein (MT)-encoding genes could be demonstrated to be associated with type 2 diabetes mellitus. The fact that antibodies against this zinc transporter have been detected in type 1 diabetic patients offers new diagnostic possibilities. This article reviews the influence of zinc on the diabetic state including the molecular mechanisms, the role of the zinc transporter 8 and MT for diabetes development and the resulting diagnostic and therapeutic options.
The Journal of nutritional biochemistry 07/2009; 20(6):399-417. · 4.29 Impact Factor
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ABSTRACT: Inappropriate signaling of the RET receptor tyrosine kinase causes different forms of human thyroid malignancy. We have previously identified the adaptor Grap-2 as RET binding protein. To verify involvement of Grap-2 in RET oncogenic signaling we performed sequence and expression analysis of Grap-2 in 15 human MTC samples. All tumors displayed marked Grap-2 mRNA and protein expression without a linear correlation. Beyond one conservative base pair substitution we detected no further alteration in genomic Grap-2 sequence. Consistent Grap-2 expression suggests a specific role for this adaptor in human MTC, while qualitative alterations do not appear to influence RET signaling.
Cancer letters 12/2008; 275(2):194-7. · 4.86 Impact Factor
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ABSTRACT: A 2-D DIGE approach allowed the characterization of the intramacrophagic proteome of the intracellular pathogen Brucella suis at the late stage of in vitro infection by efficient discrimination between bacterial and host cell proteins. Using a subtraction model, a total of 168 proteins showing altered concentrations in comparison with extracellularly grown, stationary-phase bacteria were identified. The majority of the 44 proteins significantly regulated at this stage of infection were involved in bacterial metabolism and 40% were present in lowered concentrations, supporting the hypothesis of an adaptive response by quantitative reduction of processes participating in energy, protein, and nucleic acid metabolism. In the future, the 2-D DIGE-based approach will permit to decipher specifically and quantitatively the intracellular proteomes of various pathogens during adaptation to their specific host cell environments.
Proteomics 09/2008; 8(18):3862-70. · 4.43 Impact Factor
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ABSTRACT: Insulinomas are rare endocrine disorders. Pre-operatively, conventional imaging techniques often fail to localise the tumor. In addition, due to the lack of quick insulin assays, intra-operative confirmation of complete resection was impossible until recently.
Six patients with biochemical evidence of an insulinoma underwent pre-operative localisation studies and selective arterial calcium injection (SACI). In addition, insulin was measured before surgery and every 10-15 min after resection of the tumor using a quick insulin assay.
Pre-operative localisation studies identified the tumor correctly as follows: endosonography: three of four, magnetic resonance imaging: two of four and SACI: six of six. Tumors in the head and body were enucleated while those in the tail were resected (n = 2, each). Those three patients, in whom magnetic resonance imaging and/or endosonography could localise the tumors pre-operatively, underwent laparoscopic surgery while the remaining three patients underwent open surgery. Intra-operatively, insulin dropped to normal levels within 20 min in all cases. After a follow-up of 0.8-3 years, all patients remained biochemically cured.
Pre-operatively, SACI appears to be a very sensitive localisation technique and may be most helpful in guiding the surgeon if conventional imaging techniques fail to localise the tumor. Complete removal of an insulinoma can be reliably predicted using a quick insulin assay.
Langenbeck s Archives of Surgery 12/2007; 392(6):679-84. · 1.81 Impact Factor
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ABSTRACT: In multiple endocrine neoplasia type 1 (MEN1), age-related tumour penetrance according to the type of MEN1 germline mutation has not been investigated in-depth. This study was conducted to examine whether carriers of out-of-frame/truncating and in-frame MEN1 mutations differ in age-related tumour penetrance.
A multicentre study with biochemical, hormonal and radiological screening for MEN1-associated tumours.
A total of 258 MEN1 carriers from six major German tertiary referral centres averaging 43 years of age at last follow-up.
Main outcome measure was time to first diagnosis of MEN1-associated tumours.
Independent of the year of birth and observation period, time to first tumour diagnosis did not vary much by the type of MEN1 germline mutation or endocrine organ system, and perhaps not even by the type of endocrine tumour when the amount of time was considered by which the diagnosis probably has been advanced through the manifestation of hormonal symptoms. Parathyroid hyperplasia and adenomas developed almost twice as often as enteropancreatic and pituitary tumours (77%vs. 49-32%), and more than five to sevenfold as often as adrenal cortical tumours and carcinoids (77%vs. 15-10%), reaching penetrance rates of up to 90%, 60%, 40%, 26% and 17%, respectively. The heterogeneity of tumour penetrance was marked, ranging from 9 years to 25 years for the earliest, and from 68 years to 77 years for the latest tumour manifestation.
Because of our inability of predicting tumour penetrance and malignant transformation individually, life-long follow-up of MEN1 carriers is warranted to prevent tumour morbidity.
Clinical Endocrinology 11/2007; 67(4):613-22. · 3.17 Impact Factor
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ABSTRACT: Type 1 diabetes mellitus can result from the specific destruction of pancreatic beta cells by autoreactive T cells. As shown here, experimental autoimmune diabetes (EAD) is efficiently induced in RIP-B7.1 mice by preproinsulin (ppins)-encoding DNA vaccines. EAD develops in RIP-B7.1 mice within 3-4 wk after a single immunization with ppins-encoding plasmid DNA. RIP-B7.1 mice develop insulitis, insulin deficiency and hyperglycemia after vaccination with plasmids encoding murine ppins-I or murine ppins-II or human hu-ppins. EAD induction critically depends on CD8 T cells and is independent of CD4 T cells. To be diabetogenic, ppins-specific CD8 T cells had to express IFN-gamma. Neither expression of perforin nor signaling through the type I IFN receptor is an essential component of this pathogenic CD8 T cell phenotype. Using plasmids encoding truncated ppins variants, we show that EAD is only induced by DNA vaccines encoding the insulin A-chain. Diabetogenic CD8 T cells specifically recognize the Kb-restricted A12-21 epitope of the insulin A-chain. The RIP-B7.1 model hence represents an attractive model for the characterization of cellular and molecular events involved in the CD8 T cell-mediated immune pathogenesis of diabetes.
European Journal of Immunology 09/2007; 37(8):2097-103. · 5.10 Impact Factor
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Diabetes care 07/2007; 30(6):1613-4. · 8.09 Impact Factor
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Beate Karges,
Rainer Muche,
Ina Knerr,
Waldemar Ertelt,
Thomas Wiesel,
Regine Hub,
Andreas Neu,
Albrecht Klinghammer,
Julia Aufschild,
Andrea Rapp,
Andreas Schirbel,
Bernhard O Boehm,
Klaus M Debatin,
Eberhard Heinze, Wolfram Karges
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ABSTRACT: Patients with type 1 diabetes (T1D) have an increased risk of autoimmune thyroiditis (AIT).
Our objective was to determine whether levothyroxine (l-T(4)) treatment prevents the clinical manifestation of AIT in euthyroid subjects with T1D.
We conducted a prospective, randomized, open, controlled clinical trial at six tertiary care centers for pediatric endocrinology and diabetes.
Of 611 children and adolescents with T1D, 89 individuals (14.5%) were identified with positive thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), or both. Of these, 30 patients (age, 13.3 +/- 2.1 yr) met the inclusion criteria and were randomized to receive l-T(4) (n = 16 patients) or no treatment (n = 14 patients).
l-T(4) (1.3 microg/kg daily) was given for 24 months in the treatment group, followed by an additional observation period of 6 months in both groups.
Thyroid gland volume (as determined by ultrasound), serum levels of TSH, thyroid hormones, TPOAb, and TgAb were assessed every 6 months for 30 months.
Mean thyroid volume decreased in the treatment group after 24 months (-0.60 sd score) and increased in the observation group (+ 1.11 sd score; P = 0.0218). Serum thyrotropin, free T(4), TPOAb, and TgAb levels were not significantly different in both groups during the entire study period. Hypothyroidism developed in three individuals treated with l-T(4) and in four untreated patients (conversion rate, 9.3% per year).
In this study in euthyroid patients with AIT and T1D, l-T(4) treatment reduced thyroid volume but had no effect on thyroid function and serum autoantibody levels.
Journal of Clinical Endocrinology & Metabolism 06/2007; 92(5):1647-52. · 6.50 Impact Factor
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ABSTRACT: Pain resulting from injections has a potential influence on the acceptance and thus on the success of insulin treatment. Systematic investigation in humans has suggested that individuals perceive more pain during SC injection of acidic solutions than neutral solutions. Insulin glargine is a long-acting (up to 24-hour duration of effect), parenteral blood glucose-lowering agent. Unlike other insulins, it is injected as an acidic solution (pH 4).
The aim of this study was to assess whether the SC injection of insulin glargine is more painful than neutral insulin in a clinical setting.
This single-center, prospective, controlled, noninterventional study was performed in consecutively enrolled male and female pediatric patients (7-21 years) with type 1 diabetes mellitus who self-injected insulin >or=3 times per day and who had diabetes duration of >or=6 months. The study was conducted from September 1, 2005, to December 30, 2005, at the Diabetes Clinic, University Children's Hospital, Ulm, Germany. No changes to the patients' current insulin regimen were made. Based on their existing insulin treatment, patients were assigned to 1 of 2 treatment groups: (1) the acidic insulin group, which injected insulin glargine, and (2) the neutral insulin group, which injected neutral protamine Hagedorn or Semilente insulin. All patients also injected shortacting regular insulin or insulin analogs. Pain during SC insulin injection and during self-monitoring of blood glucose (SMBG) (the internal control) was assessed using a standardized, noninterventional protocol and optimized combined 10-cm visual analog scale and 5-point verbal rating scale (minimum = I cannot feel it at all; maximum = it hurts me). Patients were instructed to document pain immediately after insulin injection and SMBG at home 3 times a day on 3 different days.
A total of 112 patients (mean [SD] age, 14.6 [3.0] years; sex, 60 [53.6%] male; mean [SD] glycosylated hemoglobin [HbA(1c)], 8.0% [1.4%]; mean [SD] diabetes duration, 6.1 [3.9] years) completed the study. Pain scores reported by the acidic group (n = 76) were not significantly different when compared with those of the neutral group (n = 36) (4.0 [2.0] vs 4.2 [1.9]). Pain scores were also similar for the injection of short-acting insulin in those from the acidic group when compared with those from the neutral group (3.7 [1.7] vs 4.1 [2.1]). Insulin injections were generally perceived as more painful than SMBG (3.9 [1.7] vs 2.9 [1.8]; P < 0.001). Using the Spearman rank correlation coefficient, pain perception was determined to be independent of age, gender, HbA(1c) level, and duration of diabetes.
Despite its acidic formulation (pH 4), insulin glargine was not perceived as more painful during SC injection than neutral long-acting or shortacting insulin in these pediatric patients with type 1 diabetes mellitus.
Clinical Therapeutics 01/2007; 28(12):2094-101. · 2.32 Impact Factor
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Ivana Durinovic-Belló,
Silke Rosinger,
Jennifer A Olson,
Mauro Congia,
Regina C Ahmad,
Mathias Rickert,
Johannes Hampl,
Hubert Kalbacher,
Jan W Drijfhout,
Elizabeth D Mellins, [......],
Thomas Kamradt,
Markus J Maeurer,
Carol Nhan,
Bart O Roep,
Bernhard O Boehm,
Constantin Polychronakos,
Gerald T Nepom, Wolfram Karges,
Hugh O McDevitt,
Grete Sønderstrup
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ABSTRACT: Recently, we have identified proinsulin (P-Ins)(73-90) as an immunodominant T cell epitope of HLA-DRB1*0401 (DR4) subjects with beta-islet cell autoimmunity and of HLA-DR4/CD4 double-transgenic mice immunized with human P-Ins. We have compared the fine specificities of one human CD4 T cell clone and two mouse T cell hybridoma clones recognizing this epitope, and, although these three clones all recognized the same core region (LALEGSLQK), there were major differences in how they interacted with the peptide (p)/HLA complex, reflecting the fact that human P-Ins is a foreign antigen in the mouse and an autoantigen in the type 1 diabetes patient. The human T cell clone was forkhead transcription factor 3 (Foxp3)-positive, a marker for regulatory T cell lineages, and secreted predominantly IL-5, IL-10, and low levels of IFNgamma in response to P-Ins(73-90). This finding is compatible with the previously detected regulatory cytokine pattern in subjects with beta-cell autoimmunity. However, added N- or C-terminal amino acids drastically changed HLA and tetramer binding capacity as well as T cell reactivity and the cytokine phenotype of the P-Ins(73-90)-specific human CD4 T cell clone, suggesting a potential for this P-Ins epitope as a target for therapeutic intervention in HLA-DR4-positive humans with beta-islet cell autoimmunity or recent-onset type 1 diabetes.
Proceedings of the National Academy of Sciences 09/2006; 103(31):11683-8. · 9.68 Impact Factor
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ABSTRACT: T-cell-mediated loss of pancreatic beta-cells is the crucial event in the development of type 1 diabetes. The phenotypic characteristics of disease-associated T-cells in type 1 diabetes have not yet been defined. The negative results from two intervention trials (the Diabetes Prevention Trial-Type 1 Diabetes and the European Nicotinamide Diabetes Intervention Trial) illustrate the need for technologies to specifically monitor ongoing autoimmune reactions. We used fluorescence-activated cell sorter analysis to study surface marker expression on T-cell lines specific for two major type 1 diabetes autoantigens, GAD65 and proinsulin. We then applied this knowledge in a cross-sectional approach to delineate the phenotype of circulating memory T-cells. The autoreactive T-cells of patients could be distinguished from those of control subjects by their coexpression of CD25 and CD134. Autoantigen-specific T-cells that recognized multiple GAD65- and preproinsulin-derived peptides and coexpressed CD25(+)CD134(+) were confined to patients (n = 32) and pre-diabetic probands (n = 5). Autoantigen-reactive T-cells in control subjects (n = 21) were CD25(+)CD134(-) and recognized fewer autoantigen-derived peptides. Insulin therapy did not induce CD25(+)CD134(+) T-cells in type 2 diabetic patients. The coexpression of CD25 and the costimulatory molecule CD134 on memory T-cells provides a novel marker for type 1 diabetes-associated T-cell immunity. The CD134 costimulatory molecule may also provide a novel therapeutic target in type 1 diabetes.
Diabetes 02/2006; 55(1):50-60. · 8.29 Impact Factor
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ABSTRACT: A variable number of tandem repeats (VNTR) polymorphism upstream of the insulin promoter is strongly associated with type 1 diabetes. The short class I alleles are predisposing and the long class III alleles are protective. As a possible mechanism for this effect, we previously reported a two- to threefold higher insulin transcription from class III than from class I chromosomes in thymus where insulin is expressed at low levels, presumably for the purpose of self-tolerance. In this article, we confirm this finding with independent methodology and report studies testing the hypothesis that class III alleles are associated with T-cell tolerance to (pro)insulin. Cytokine release in vitro after stimulation with 21 overlapping preproinsulin epitopes was assessed in blood mononuclear cells as well as naive and memory CD4+ T-cell subsets from 33 individuals with the high-risk DRB1*04, DQ8 haplotype (12 type 1 diabetic patients, 11 healthy control subjects, and 10 autoantibody-positive subjects). No significant differences between genotypes (24 I/I subjects versus 10 I/III or III/III subjects) were observed for gamma-interferon, tumor necrosis factor-alpha, or interleukin (IL)-4. By contrast, the I/III + III/III group showed a significant threefold higher IL-10 release in memory T-cells for whole proinsulin and the immunodominant region. Given that IL-10 is a marker of regulatory function, our data are consistent with the hypothesis that higher insulin levels in the thymus promote the formation of regulatory T-cells, a proposed explanation for the protective effect of the class III alleles.
Diabetes 01/2006; 54 Suppl 2:S18-24. · 8.29 Impact Factor
