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Background and objective Approximately 24•40% of patients with type 2 diabetes mellitus (T2DM) develop kidney damage. Our objective was to evaluate the long-term evolution of renal function using isotopic determination of GFR and urinary albumin excretion (UAE) in patients with T2DM undergoing intensive treatment for renal and cardiovascular risk factors. Patients and methods This was a single-center, prospective study of 201 patients with T2DM and UAE who initiated intensive treatment. They were followed for 17.2 ± 6.5 years. Patients were divided into three groups, according to renal function: 167(85.6%) had stable renal function, 16(8.2%) had creatinine levels that doubled and 12(6.2%) began renal replacement therapy (RRT). We performed periodic isotopic determinations of GFR using 125 I-iothalamate. Results There were significant differences between the three groups with respect to age, duration of T2DM at baseline, years of follow-up in the study and systolic blood pressure, serum creatinine, isotopic GFR, and UAE at baseline. Renal function evolution slopes were ∧1.55 mL/min/1.73 m 2 /year in patients with stable creatinine, ∧2.49 mL/min/1.73 m 2 /year in those with doubled creatinine, and ∧8.16 mL/min/1.73 m 2 /year in those requiring RRT. We also found that differences in renal events were determined by delayed initiation of intensive treatment. Conclusion Patients with glomerular hyperfiltration who were undergoing treatment with renin angiotensin aldosterone system blockers exhibited a better evolution in renal function, possibly because these patients initiated intensive treatment earlier. Although diabetic nephropathy is associated with classic risk factors, early initiation of intensive treatment should be a priority in order to prevent worsening renal function.

SummaryObjective Pregnancy-associated plasma protein-A (PAPP-A) is a protease promoting IGF1 tissue availability and considered as a new biomarker of cardiovascular disease. Aim To evaluate the relationship between PAPP-A concentrations and anthropometric variables, physical activity, smoking status, glucose homoeostasis and adipocytokines in healthy adults. Design and methods One hundred and forty-nine subjects (77 women; mean age 39·7 ± 14 years; mean BMI 23·7 ± 1·9 kg/m2) were randomly selected from 8000 adults of The Health Survey of Catalonia. Possible effects of gender, age, body composition, smoking status, physical activity, glucose homoeostasis and adipocytokines on PAPP-A concentrations were assessed. Results Pregnancy-associated plasma protein-A was significantly higher in men than in women [ 1·04 (0·61–0·44) vs 0·61 (0·41–0·90) μIU/ml; P

Context One of the side effects of interferon-alpha therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT melanoma patients remains to be defined. Objective Our objective was to assess different peripheral blood lymphocyte subpopulations, mainly regulatory T cells (Tregs), in melanoma patients who developed IIT. Design, patients and methods From 30 melanoma patients receiving high-dose interferon (HDI)-alpha 2b (IFN-α2b) treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-MM) and healthy controls (Co-H). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment and at appearance of IIT (TT). Results Nine patients developed IIT (30%): four Hashimoto's thyroiditis and five destructive thyroiditis. An increase in Tregs was observed in both melanoma groups during HDI treatment. A decrease in CD3(+) , NKT lymphocyte subpopulations and Bcl2 expression on B cells was also observed in both groups. However, no changes were observed in the percentage of CD4(+) , CD8(+) , CD3(+) γδ(+) , CD19(+) , transitional B cells (CD24(high) CD38(high) CD19(+) CD27(-) ), natural killer (NK), invariant NKT (iNKT) lymphocytes and Th1/Th2 balance when BT was compared with ET. At TT, IIT patients had a higher Tregs percentage than Co-MM (P = 0·012) and Co-H (P = 0·004), a higher iNKT percentage than Co-MM (P = 0·011), a higher transitional B cells percentage than Co-H (P = 0·015), a lower CD3(+) percentage than Co-H (P = 0·001) and a lower Bcl2 expression on B cells than Co-H (P Conclusions Our results point to the immunomodulatory effects of IFN-α on different lymphocyte subpopulations and a possible role of Tregs in melanoma patients who developed IIT.

Resumen Introduccion La incidencia de cancer de tiroides ha aumentado en las ultimas decadas en todo el mundo. Objetivo Aportar evidencias sobre la eficiencia diagnostica y asistencial si la atencion al nodulo tiroideo se realiza en una consulta monografica que integre exploracion clinica, estudio ecografico y citologia con valoracion in situ. Pacientes y metodos Pacientes que acudieron a la consulta monografica de nodulo tiroideo entre enero 2004 y junio 2010. Basado en la disposicion del ecografo en el momento de la visita 2 periodos son definidos: primer periodo (P1: 01/2004-09/2007) sin ecografo en la consulta, PAAF por palpacion; y segundo periodo (P2: 10/2007-06/2010) con ecografo, PAAF eco-guiada. Resultados Un total de 1.036 pacientes [P1: 537 (52%), P2: 499 (48%)] fueron consultados e incluidos. Eficiencia diagnostica (P1 vs P2): numero de pacientes visitados/ano fue 143 vs 181, p Eficiencia asistencial: tiempo medio (rango) entre primera visita e indicacion de cirugia: 332 (0-2177) vs 108 (0-596) dias, p Conclusion La consulta monografica del nodulo tiroideo, que integra exploracion clinica, ecografia y citologia con valoracion in situ, aumenta la eficiencia diagnostica y asistencial del nodulo tiroideo.

INTRODUCTION Worldwide incidence of thyroid cancer has increased in recent decades. OBJECTIVE To provide evidence of the diagnostic and care efficiency of a monographic thyroid nodule clinic integrating clinical examination, ultrasound examination, and cytology with on site evaluation. PATIENTS AND METHODS Patients attending the monographic thyroid nodule clinic from January 2004 to June 2010. Two periods may be distinguished based on availability of ultrasound equipment at the time of the visit: a first period (P1: 01/2004-09/2007) where no ultrasound equipment was available at the clinic and FNA by palpation was performed, and a second period (P2: 10/2007-06/2010) where this equipment was available and ultrasound-guided FNA was performed. RESULTS A total of 1036 patients [P1: 537 (52%), P2: 499 (48%)] were seen and enrolled. Diagnostic efficiency (P1 vs P2): 143 vs 181 patients were seen annually, p

One salient feature of autoimmune thyroid disease is the inappropriate expression of human leukocyte antigen (HLA) class II molecules by thyroid follicular cells. Metallothioneins (MT) are small proteins induced by tissue stress that can contribute to restoring homeostasis of tissue inflammation and have been found to be increased in a transcriptomic analysis of Graves' disease (GD) glands.To assess the role of MT in the pathogenesis of GD, we analyzed MT-I and -II expression and distribution in GD-affected thyroid glands (n = 14) compared with other thyroid diseases (n = 20) and normal thyroid glands (n = 5). Two-color indirect immunofluorescence and semiquantitative morphometry were applied. The relationship between MT and HLA class II expression was analyzed by their degree of colocalization in GD sections, and in vitro induction kinetics and expression of these molecules on the HT93 thyroid cell line were compared by quantitative RT-PCR and flow cytometry using interferon-γ and zinc as stimuli.MT were clearly overexpressed in nine of 14 GD glands. MT expression distribution in GD was almost reciprocal to that of HLA class II. In vitro analysis of MT and HLA class II demonstrated that MT is induced more slowly and at a lower level than HLA. Moreover, the main MT inducer, zinc, reduces interferon-γ-induced class II expression.These findings show that MT and HLA class II play very different roles in the autoimmune process by affecting the thyroid gland, thereby pointing to the possible role of MT as a marker of cell stress and homeostasis restoration in GD.

Summary Objective One of the side effects of interferon-alpha (IFN-α) therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT remains to be defined. The aim of this study was to assess different peripheral blood lymphocyte subpopulations, mainly CD4+CD25+CD127low/-FoxP3+ regulatory T cells (Tregs), in patients with chronic hepatitis C virus (HCV) infection who developed IIT. Design, patients and methods From 120 patients with chronic HCV who started antiviral treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-HCV). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment (PT) and at appearance of IIT (TT). Results Eleven patients developed IIT: three Hashimoto’s thyroiditis, one Graves’disease, one positive antithyroidal antibodies, one nonautoimmune hypothyroidism and five destructive thyroiditis. During antiviral treatment, an increase in CD8+ and in Tregs was observed in both groups. A decrease in CD3+, CD19+ and NKT lymphocyte subpopulations was also observed (all P

Resolution of hepatitis C virus (HCV) infection requires a complex interplay between innate and adaptative immune responses. The role of lymphocyte subpopulations during combined antiviral treatment remains to be defined. This study was conducted to assess the effect of pegylated interferon-alpha2a (pegIFN-α2a) and ribavirin treatment on peripheral blood lymphocytes, mainly on CD81 expression on B cells and CD4(+) CD25(+) CD127(low/-) FoxP3(+) regulatory T cells (Tregs) in patients with chronic HCV infection. Thirty-five patients with chronic HCV infection who started pegIFN-α2a and ribavirin treatment were enrolled. Peripheral blood mononuclear cells (PBMC) were obtained at baseline before treatment (BT), mid-treatment (MT), the end of treatment (ET) and 24weeks post-treatment (PT). During combined antiviral treatment, a significant decrease in the percentage of CD3(+) , CD8(+) , CD3(+) gamma/delta (γδ)(+) , CD19(+) lymphocyte subpopulations and Tregs was observed. There was also a significant increase in the percentage of the CD4(+) lymphocyte subpopulation and in CD81 expression levels on CD19(+) B cells when BT was compared with ET (all P

Resumen Antecedentes y objetivo Existe escasa literatura nacional de series descriptivas de pacientes con carcinoma diferenciado de tiroides (CDT) y seguimiento a largo plazo en Espana. El objetivo de nuestro estudio ha sido describir las series de CDT de dos hospitales de tercer nivel (Hospital Clinic de Barcelona [HC] i Hospital Germans Trias i Pujol de Badalona [HGTiP]) y compararlas con las descritas en la National Cancer Data Base (NCDB), y la Clinica Mayo (CM), las series internacionales mas destacadas por numero de pacientes y tiempo de seguimiento. Material y metodo Estudio retrospectivo de revision de historias clinicas de pacientes diagnosticados de CDT en dos hospitales de tercer nivel del area de Barcelona. Revision y comparacion con los resultados publicados por la NCDB y la CM. Resultados Se revisaron 480 historias clinicas de pacientes con CDT diagnosticados entre 1973 y 2006 y con un tiempo de seguimiento de 16±8 anos. No hubo diferencias significativas entre la serie conjunta HC/HGTiP y la NCDB respecto a las caracteristicas clinicas, los factores de riesgo y la forma de presentacion mas frecuente. La ecografia y la citologia fueron los metodos diagnosticos mas utilizados en todas las series y el principal tipo de cirugia fue una tiroidectomia total o casi total, sin diferencias entre los grupos estudiados. Se administro con mas frecuencia tratamiento postoperatorio con i 131 en la serie HC/HGTiP (83,9%) que en la de la NCDB (55,1%) o la CM (46%). En los pacientes de la serie conjunta la recidiva tumoral fue del 9,3% y la mortalidad especifica del 1,8%. Conclusiones Las series del HC y HGTiP fueron comparables entre si con similitud de las diferentes tecnicas diagnosticas y terapeuticas. El estudio pone en evidencia evolucion historica respecto al uso de exploraciones de imagen, y diferencias respecto a las grandes series americanas referentes a ciertas exploraciones (p.ej. laringoscopia) o al uso de tratamiento ablativo con i 131 .

Background and aim: To determine the temporal evolution of serum markers of autoimmune gastritis, mainly pepsinogen I (PI) and parietal cell antibodies (PCA), in patients with Type 1 diabetes mellitus (DM1). Materials and methods: A 5-yr prospective follow-up study of 168 DM1 patients (87 men, aged 31±9.3 yr) attending the endocrinology outpatient clinic of a university hospital evaluated in 2001 and 2006. Serum PI, gastrin, hemoglobin, cobalamin concentrations, PCA and antibodies to intrinsic factor were measured. Results: In 2001, 11 patients had low PI concentrations and positive PCA (group I), 11 had only low PI concentrations (group II), and 33 had only positive PCA (group III). After 5 yr, PI remained low and PCA positive in all patients from group I. In group II, PI remained low in 4 and normalized in 7. In group III, 4 patients presented low PI concentrations after 5 yr, which remained normal in the other 29 subjects. PCA became negative in 17 patients from group III. In 2001, 3 of the 11 patients of group I had low cobalamin concentrations. In 2006, 2 additional patients from this group presented low cobalamin concentrations. Conclusions: These results show the importance of determining PI together with PCA, since the presence of abnormal results in both tests, that is low PI and positive PCA, is the association that best identifies patients with a higher risk to decrease cobalamin concentrations during follow-up.

Resumen Fundamento y objetivo La pulsioximetria se ha propuesto como metodo de cribado de la vasculopatia periferica. Dado que la arteriosclerosis afecta a todo el territorio vascular, estudiamos su eficacia para detectar pacientes con diabetes mellitus tipo 2 (DM2) con arteriosclerosis carotidea. Pacientes y metodo Se incluyeron 105 pacientes con DM2 sin historia previa de vasculopatia periferica. Se realizo historia clinica, exploracion fisica, medicion del indice tobillo-brazo (ITB) y de la saturacion de oxigeno en el pie y la mano mediante pulsioximetria, analisis sanguineo y ecografia carotidea (medicion del grosor intima-media carotideo y de placas carotideas [PC]). Se consideraron patologicos los valores de ITB inferiores a 0,9 y un descenso en la pulsioximetria de la saturacion de oxigeno superior al 2% en los pies respecto de la mano o tras la elevacion de la extremidad inferior respecto del decubito supino. Resultados Sesenta pacientes eran varones (edad media de 62,1 anos [desviacion estandar de 7,1] y hemoglobina glucosilada media del 6,9% [1,0]). Un 58,1% presentaba PC. Los datos antropometricos y analiticos fueron homogeneos entre los pacientes con y sin PC. El ITB fue inferior a 0,9 en el 49% y en el 25% de los pacientes con y sin PC, respectivamente. No hubo diferencias en la pulsioximetria en funcion de la presencia de PC ni del ITB patologico. Tampoco el grosor intima-media fue diferente en funcion de la pulsioximetria, aunque fue mayor en los pacientes con PC y con ITB inferior a 0,9 que en aquellos sin alteraciones. Estos resultados fueron independientes de la historia de macroangiopatia clinica. Conclusiones La pulsioximetria no es util en el cribado de la aterosclerosis carotidea en pacientes con DM2.

SummaryTo determine the genotype distributions of the polymorphisms in platelet glycoproteins (GP) Ib-alpha, Ia/IIa and IIb/IIIa and their association with clinical arterial thrombosis and preclinical carotid atherosclerosis in type 2 diabetes we studied 229 patients with type 2 diabetes and 229 controls matched by age, gender and ethnicity. Biochemical and haemostasis analyses were performed. The GP Ib-alpha VNTR, GP Ia 807 C/T and GP IIIa Pl(A) polymorphisms were determined by PCR. Thrombotic events were registered and carotid atherosclerosis was evaluated by ultrasound examination. A total of 107 patients had clinical atherothrombosis (CA), 65 subclinical atherosclerosis (SA), and 57 had no evidence of atherosclerosis (NA). There were no differences in allele frequencies and the genotype distribution of platelet GP polymorphisms between diabetic patients and controls. The VNTR Ib-alpha polymorphism was not associated with CA. We found a significant association between CA and the 807T (odds ratio [OR]: 2.86, confidence interval [CI]: 1.65–4.93; p

ObjectivePregnancy-associated plasma protein-A (PAPP-A) has been implicated in the atherosclerotic process through regulation of local expression of IGF1. In type 2 diabetes mellitus, glycaemic control has been involved in PAPP-A expression. We compared PAPP-A, IGF1, inflammatory markers and adiponectin concentrations in type 2 diabetic patients with and without carotid plaques and evaluated the relationship between these serum parameters and ultrasound carotid markers of atherosclerosis.MethodsWe studied 125 consecutive type 2 diabetic patients. Clinical data, metabolic variables, hemostatic factors (plasma type-1 plasminogen activator inhibitor, fibrinogen), high-ultrasensitive C reactive protein (hsCRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6, adiponectin, IGF1 and PAPP-A were determined. Patients were classified into two groups according to the presence of carotid plaques on ultrasound. Carotid intima–media thickness (IMT) and morphology of carotid plaques were evaluated.ResultsThe mean age was 61.5±7.3 years and the mean glycated hemoglobin of 6.8±0.9%. A total of 60% presented carotid plaques. Both groups were homogeneous in anthropometric data, biochemical determinations and hemostatic factors. Adiponectin, hsCRP, TNF-α and IL-6 were similar in both groups. No differences were observed in serum PAPP-A (0.46 (0.22–0.86) vs 0.38 (0.18–0.66) mIU/l and in SDS IGF1 (−0.34±1.38 vs −0.67±1.35)) in patients with and without carotid plaques respectively. PAPP-A and IGF1 were not correlated with IMT.ConclusionsSerum PAPP-A and IGF1 do not appear to be useful serum biomarkers for carotid atherosclerosis in type 2 diabetic patients with stable glycemic control, despite scientific evidence of their local role in atherosclerosis.

ObjectiveGH deficiency (GHD) in adults is associated with adverse effects on metabolism and increased cardiovascular risk. Pregnancy-associated plasma protein-A (PAPP-A) is a protease that promotes IGF-I availability in vascular tissues. PAPP-A levels appear to correlate with carotid intima-media thickness and have been proposed as an early predictor of cardiac events. The aim of our study was to evaluate PAPP-A levels in GHD adults at baseline and after GH replacement and correlate them with changes in body composition, lipid profile, glucose homeostasis, inflammatory markers and in leptin and adiponectin.Patients and methodsFourteen GHD adults were evaluated at baseline and after 1 year of GH therapy. All patients were compared at baseline with 28 age-, sex- and body mass index (BMI)-matched control subjects.ResultsAt baseline, GHD adults showed higher PAPP-A levels (P=0.03) and higher leptin (P=0.04), fibrinogen (P=0.002) and highly sensitive C-reactive protein (P=0.01) values than controls. Therapy with GH reduced PAPP-A (P=0.03) and fibrinogen levels (P=0.002) while increased BMI (P=0.01) and reduced waist-hip ratio (WHR; P=0.05) were observed. Insulin and homeostasis model assessment of insulin resistance index increased after treatment (PP=0.007), without changes in leptin or adiponectin levels. PAPP-A values correlated positively with BMI and WHR and negatively with adiponectin before and after treatment, with no correlation with glucose homeostasis parameters, lipid profile or leptin.ConclusionsOur study suggests that PAPP-A expression is increased in GHD adults, and that 1 year of GH replacement therapy is able to reduce PAPP-A levels in this population. However, further studies are required to determine whether this decrease correlates with an improvement in atherosclerosis.

ObjetivosDetectar pacientes con diabetes tipo LADA (latent autoinmune diabetes of adult) tipo 1 en diabéticos adultos con sobrepeso y describir las variaciones metabólicas tras administrar metformina.DiseñoEstudio observacional, multicéntrico, basado en una serie de casos.EmplazamientoAtención primaria, provincia de Barcelona.ParticipantesDiabéticos con sobrepeso u obesidad, con diagnóstico de diabetes < 2 años, entre 35 y 65 años de edad, sin complicaciones microvasculares o macrovasculares ni tratamiento farmacológico inicial antidiabético.IntervenciónAdministración de metformina, 1.700 mg/día.MedicionesLa variable de control metabólico fue la hemoglobina glucosilada (HbA1c); otras variables fueron el índice de masa corporal (IMC), la glucemia en ayunas, la insulinemia, el péptido C y la valoración de la insulinorresistencia (HOMA-IR). Para el diagnóstico de diabetes tipo LADA se determinaron los anticuerpos ICA, anti-GAD y anti-IA2.ResultadosEn la muestra de diabéticos estudiada (n=103) se detectaron 3 casos de LADA tipo 1 (prevalencia del 2,9%; intervalo de confianza del 95%, 0,6-8,3%). Estos pacientes presentaron valores basales más elevados de HbA1c, insulina y sobre todo de HOMA-IR. El tratamiento con metformina mejoró la HbA1c en ambos grupos de pacientes (con o sin LADA de tipo 1). El descenso de la insulinemia al cabo de un año en los pacientes con LADA de tipo 1 fue más marcado que en el resto de diabéticos.ConclusionesDada su frecuencia, hay que reflexionar sobre si deberían buscarse con más frecuencia anticuerpos frente a células β pancreáticas en atención primaria. Los pacientes con LADA de tipo 1 presentaron buen control de la HbA1c en tratamiento con metformina y un drástico descenso de la insulina. Faltan estudios que evalúen si la metformina mejora el control glucémico, aunque tal vez no proteja la reserva insulínica, y confrontarla con otros fármacos.ObjectivesTo detect type-1 LADA (latent auto-immune diabetes in adults) in adults with overweight.To describe the metabolic variations in these patients after metformin treatment.DesignObservational, multi-centre study based on a series of cases.SettingHealth centres in Barcelona province, Spain.ParticipantsDiabetic patients with overweight or obesity, diagnosed with diabetes for

The effect of subclinical hyperthyroidism on bone mineral density is controversial and could be significant in patients with differentiated thyroid carcinoma who receive suppressive doses of levothyroxine (LT4). To ascertain whether prolonged treatment with LT4 to suppress thyrotropin had a deleterious effect on bone mineral density and/or calcium metabolism in patients thyroidectomized for differentiated thyroid cancer we have performed a cross-sectional study in a group of 88 women (mean ± SD age: 51 ± 12 years) treated with LT4 after near-total thyroidectomy and in a control group of 88 healthy women (51 ± 11 years) matched for body mass index and menopausal status. We determined calcium metabolism parameters, bone turnover marker N-telopeptide and bone mass density by dual-energy X-ray absorptiometry. No differences were found between patients and controls in calcium metabolism parameters or N-telopeptide except for PTH, which was significantly increased in controls. No differences were found between groups in bone mineral density in femoral neck (0.971 ± 0.148 gr/cm2 vs 0.956 ± 0.130 gr/cm2 in patients and controls respectively, P = 0.5). In lumbar spine, bone mineral density values were lower in controls than in patients (1.058 ± 0.329 gr/cm2 vs 1.155 ± 0.224 gr/cm2 respectively, Pn = 44) and postmenopausal (n = 44) patients were compared with their respective controls, bone mineral density was similar both in femoral neck and lumbar spine. The proportion of women with normal bone mass density, osteopenia and osteoporosis in patient and control groups was similar in pre- and postmenopausal women. In conclusion, long-term suppressive LT4 treatment does not appear to affect skeletal integrity in women with differentiated thyroid carcinoma.

Objective: To evaluate clinical symptoms, health-related quality of life (HRQL) and biochemical parameters in patients with primary adrenal insufficiency under treatment with two different hydrocortisone regimens (20mg- 0mg-10mg/day and 10mg-5mg-5mg/day), each maintained for 3 months and compare results obtained with those in healthy controls. Design, Patients and Methods: Twelve patients with primary adrenal insufficiency were studied. Clinical symptoms and HRQL with the Nottingham Health Profile (NHP) were evaluated and Na, K and serum cortisol determined at 09:00 h, 12:30 h and 17:30 h and urinary free cortisol (UFC) throughout the day. Control group comprised 19 healthy subjects. Results: No differences in specific adrenal insufficiency symptoms were detected between the two regimens. HRQL was worse in energy dimension assessed by the NHP compared to the general population, regardless of 20mg-0mg-10mg/day or 10mg-5mg-5mg/day treatment (p=0.03 and p=0.013). The total NHP score was only adversely affected when patients were on the 10mg-5mg-5mg/day hydrocortisone replacement regimen (p=0.008). Serum cortisol concentrations were higher than controls at 09:00 h, and lower at 17:30 h with both regimens, whereas serum cortisol at 12:30 h and UFC were within the 5th-95th percentile normal range only with the 10mg-5mg-5mg/day regimen. Conclusions: Patients with primary adrenal insufficiency had worse HRQL in the NHP energy dimension compared with the general population, regardless of the hydrocortisone regimen although total score for HRQL was worse only with the 10mg-5mg-5mg/day regimen. Patients on the thrice-daily hydrocortisone regimen showed a more physiological cortisol profile, leading us to recommend initially treating patients with this dose and increasing it in the case of impaired HRQL.

Objective: Type 2 diabetes mellitus (DM-2) is an important cardiovascular risk factor, although hardly any data are available in our country. Therefore, we decided to study the incidence of cardiovascular disease (CVD) and the related variables with its appearance in a group of patients with DM-2. Research design and methods: 176 DM-2 patients without CVD at baseline (63.6% women, mean age 54±8.9), mean follow-up 6.3 years. We collected data at 6-month intervals concerning new micro- and macrovascular complications, glucose, HbA 1C , lipid profile, and renal function. We analyzed values at baseline and at the end of follow-up. For numeric variables, the mean value during follow-up was calculated. In renal function variables, we also worked out the difference between baseline and final values, considering the time until the first episode of CVD as the independent variable. Kaplan–Meier analysis was used in categorical variables and Cox regression tests for numeric data and also for multivariate analysis. In multivariate analysis, we included significant data in the univariate analysis, excluding those from the end of the follow-up with the aim of having some predictive meaning in our results. Results: New episodes of CVD were detected in 28 patients (15.9%). These events were statistically related with baseline diagnosed hypertension, presence of diabetic nephropathy and retinopathy, HbA 1C , and total cholesterol. Among mean values during follow-up, the association was with HbA 1C , cholesterol, urinary albumin excretion rate (UAER), glomerular filtration rate (GFR), and systolic arterial pressure. There was also a relationship of CVD events with the new appearance or worsening of diabetic retinopathy or nephropathy, creatinine and UAER increase and the decrease of GFR and effective renal plasma flow (ERPF), during follow-up. In the multivariate analysis, we found an independent association with the appearance of CVD and mean HbA 1C , mean UAER and the presence of proliferative diabetic retinopathy at baseline. Conclusions: We have a rather low incidence of CVD in our patients with DM-2. The appearance of CVD is independently related with HbA 1C , the level of UAER, and the presence at baseline of diabetic retinopathy.

Objective/Hypothesis Fine-needle aspiration biopsy is the most accurate diagnostic test for thyroid nodules, its only limitation being the diagnosis of follicular neoplasm that does not distinguish between benign and malignant follicular lesions. Study Design To determine the utility of intraoperative frozen-section analysis in cases of a cytological diagnosis of follicular neoplasm, a retrospective review of 66 patients with a solitary thyroid nodule and follicular neoplasm who underwent thyroid surgery was carried out. Methods Fine-needle aspiration was classified following the Papanicolaou Society of Cytopathology Classification, and frozen section was defined as malignant or “deferred.” If a malignant diagnosis was made by frozen-section analysis, a total thyroidectomy was carried out. The extension of thyroid surgery in the deferred cases was based on the definitive histological diagnosis. Results Sixty-four cases were classified as deferred, and two as suspect for malignancy. Among the 64 deferred cases, 15 were malignant in the final pathological findings, and 49 were benign. The two suspect cases were papillary carcinoma. Frozen-section analysis classified 2 of 17 (11.7%) cases as follicular variant of papillary carcinoma that could not be diagnosed by cytological study. However, these two cases had a strong clinical evidence of malignancy. Conclusion The routine use of frozen-section analysis is useless in cases of cytological diagnosis of follicular neoplasm on fine-needle aspiration biopsy, because of the low probability of achieving the diagnosis of follicular carcinoma and the inability to provide additional information apart from the clinical and the cytological data.

En este articulo se especifica el protocolo unificado de utilizacion de hormona de crecimiento en pacientes adultos deficitarios: indicaciones para el inicio de tratamiento, diagnostico bioquimico de la deficiencia de GH, contraindicaciones al tratamiento, dosis recomendadas y seguimiento.

En esta revision se repasan algunos aspectos del tratamiento sustitutivo con glucocorticoides en pacientes con enfermedad de Addison. Segun opinion de algunos autores, la dosis tradicional de 30 mg/dia de hidrocortisona, repartida en dos tomas, podria ser excesiva para la mayoria de los enfermos, por lo que deberia administrarse en tres tomas. Asi, se ha senalado que la sobreexposicion prolongada a los glucocorticoides podria aumentar el riesgo de padecer osteoporosis. Por otra parte, aunque los pacientes con enfermedad de Addison tratados pueden llevar una vida normal, muchos de ellos aquejan fatiga, cansancio y disminucion de la tolerancia al estres, y en varios estudios se demuestra que presentan una alteracion significativa de la calidad de vida relacionada con la salud (CVRS). Una explicacion para este hallazgo podria ser el deficit de deshidroepiandrosterona (DHEA) que presentan y que tambien justificaria, al menos en parte, la peor CVRS observada en las mujeres. El tratamiento de este deficit de DHEA mejora algunos aspectos psicologicos. Tampoco resulta facil establecer una pauta de tratamiento que imite el perfil fisiologico de secrecion de cortisol, en los pacientes con enfermedad de Addison, si se consideran criterios bioquimicos. Por todo ello, como recomendacion general proponemos iniciar el tratamiento sustitutivo de estos enfermos con 10-5-5 mg/dia de hidrocortisona y aumentar esta dosis en los casos en que se detecte alteracion de la CVRS.

Summary objective To investigate the GH response to glucagon in adult patients with GH deficiency and in controls compared with the GH response to the insulin tolerance test (ITT) in patients with GH deficiency and to determine whether the use of glucagon results in a diagnostic utility test. patients and design Seventy-three patients with adult GH deficiency and organic hypothalamic-pituitary disease were recruited, along with 46 controls. The patients were divided into five groups according to the number of associated hormone deficiencies present. measurements Hypopituitary subjects underwent assessment of GH secretory status by the ITT, the glucagon test and measurement of serum IGF-I concentration. Controls underwent the glucagon test. After the ITT, glucose and GH levels were measured at baseline, 30, 60 and 90 minutes, and after glucagon at baseline, 90, 120, 150, 180, 210 and 240 minutes. results The highest GH value after the ITT in the patient group was 3 µg/l (0·76 ± 0·82 µg/l), and after the glucagon test the highest GH peak value was 2·9 µg/l (0·64 ± 0·79 µg/l). A correlation was found between the GH peak and the progressive number of hormone deficiencies. After the glucagon test, the GH peak obtained in the controls at 180 minutes was 9·8 ± 4·6 µg/l and, on an individual basis, none of the 46 controls failed to achieve peak GH levels higher than 3 µg/l. In the controls, a negative correlation was observed between the GH response to glucagon and age (r = –0·389, P = 0·0075) and body mass index (r = –0·329, P = 0·0254). The accuracy of the glucagon test for differentiating patients from controls, estimated by receiver operating characteristics (ROC) curve methodology, showed that the cut-off of 3 µg/l for the GH peak provides 100% sensitivity and 100% specificity and is a reliable decision threshold. conclusions The glucagon GH test is reliable and provides a clear separation between GH-deficient and normal adults. A single glucagon test with a cut-off of 3 µg/l for the GH peak is diagnostic of GH deficiency in adults and could be considered and studied as an alternative to the ITT.

OBJECTIVE Postpartum has been considered as a period of risk for developing postpartum depression (PD) by some but not all authors, and this PD has been linked with postpartum thyroid dysfunction (PPTD). The major aim of this study was to evaluate the relation between the presence of PPTD and PD. DESIGN and PATIENTS Six hundred and forty-one healthy Caucasian women recruited between their 36th week of pregnancy and fourth day postpartum underwent clinical and laboratory evaluation and were checked again at 1 (n = 605), 3 (n = 552), 6 (n = 574), 9 (n = 431), and 12 (n = 444) months postpartum. MEASUREMENTS At baseline and at each clinical evaluation, Beck Depression Inventory (BDI) was administered to screen PD. The definitive diagnoses of PD was performed by a psychiatrist according to the DSM-III-R criteria. At each visit, we determined serum free T4 and TSH concentrations. Thyroperoxidase and thyroglobulin antibodies were determined only in patients with abnormal hormone concentrations. Postpartum thyroiditis (PPT) was considered to be present in women with overt or subclinical transient hyperthyroidism between 1 and 3 months postpartum and/or overt or subclinical hypothyroidism between 3 and 6 months postpartum. RESULTS Fifty-six women developed postpartum thyroid dysfunction (PPTD), corresponding to an incidence rate of 11%: 45 with PPT [incidence rate 7·8%; confidence interval (CI) 5·6–10%], eight with Graves' disease (incidence rate 1·5%; CI 0·5–2·5%) and three with nonpalpable toxic thyroid adenoma (incidence rate 0·5%; CI 0–1·5%). Five hundred and eighty of the evaluated women (incidence rate 90·5%; CI 95% 88·2–92·8) presented BDI scores below 21 and therefore the PD diagnoses was excluded. In 50 cases (incidence rate 7·8%; CI 95% 5·7–9·8), we detected a BDI score over 21 in some evaluations, but the PD diagnosis was not confirmed. Another 11 (incidence rate 1·7%; CI 95% 0·7–2·7) were diagnosed as having PD and required psychiatric treatment. None of the PPTD was diagnosed as having PD. The BDI scores frequency over 21 was similar between healthy women and those with PPTD. Patients with a previous history of depression developed PD more often (P

to define the prevalence of inducible myocardial ischaemia in asymptomatic Type 2 diabetic patients and its relation to urinary albumin excretion rate (AER).98 Type 2 diabetic patients aged 56+/-7 years, and 20 non-diabetic volunteers were recruited. Dypiridamole plus exercise thallium-201 myocardial single photon emission computed tomography (SPECT) was performed in all participants. Exclusion criteria were: age30 or70 years, evidence of cardiovascular disease, anomalous ECG, autonomic neuropathy or serum creatinine level177 micromol/l.36 out of 98 diabetic patients (37%) showed abnormal thallium SPECT (considered as inducible myocardial ischaemia), versus one out of 20 (5%) in control group (odds ratio 7.3 (95% CI 1.1-50.5), P0.005). Among diabetic patients, prevalence of inducible ischaemia was greater in those with higher urinary AER (AER30:30-300:300 mg/24 h: 26: 53: 88%, and greater in the normoalbuminuric group compared to the control group (26 vs. 5%; P0.05). An AER30 mg/24 h was the only independent factor associated with inducible myocardial ischaemia in the multivariate analysis (P=0.009).raised urinary AER in asymptomatic diabetic patients is a risk factor for present myocardial ischaemia demonstrated by thallium dypiridamole tomography. The prevalence of inducible myocardial ischaemia in asymptomatic diabetic patients without known coronary disease is much higher than in non-diabetic population.

OBJECTIVE: The aim of the present study was to assess the socio-economic impact at baseline and after one year of follow-up of clinical and health status characteristics and laboratory tests of adult-onset GH deficiency (AGHD), a well-known clinical entity, in a large group of Spanish hypopituitary patients with untreated AGHD. DESIGN AND METHODS: A total of 926 eligible patients with GHD (GH

OBJECTIVE The aim of the study was to evaluate the impact on health-related quality of life (HRQoL) in untreated GHD patients using the disease-specific Assessment of Growth Hormone Deficiency in Adults (AGHDA) questionnaire. DESIGN AND PATIENTS A cohort of 356 consecutive adult GHD patients, diagnosed after the age of 18 years, from the endocrinology units of 37 Spanish hospitals were included over a 6-month period in a longitudinal observational quality-of-life study. In addition, patients' HRQoL scores were compared to those obtained from a random sample of 963 subjects from the general population recruited by trained interviewers in a 6-month period and matched by age and sex to figures of the 1991 Spanish census. MEASUREMENTS Patients were evaluated at baseline and after 12-months. Socio-demographic and health variables such as age,sex, level of education, income level, number of chronic diseases and self-reported health status were recorded at baseline and follow-up visits. Patients underwent physical and analytical examination and completed the AGHDA questionnaire. A survey including socio-demographic, self-reported health status and the AGHDA questionnaire was administered at the individuals' homes. RESULTS Mean score for patients at baseline was 9.4 (CI = 8.4–10.4) and at 12 months 10 (CI = 8.8–11). HRQoL was worse in the case of older patients with a low level of education, lower income levels, reporting having an associated chronic disease and poor self-reported health status (P

The aim of this work was to assess the relationship between GH-binding protein (GHBP) and leptin. Both peptides are nutritionally regulated, but the recent implication of a role for leptin in the GH axis requires further study. To avoid the sexual dimorphism in leptin values, we performed leptin standardization according to gender (sd score-leptin). The relationship between sd score-leptin and GHBP was studied in 128 adults with different nutritional status [8 groups according to body mass index (BMI)], ranging from severely underweight anorexia nervosa to highly morbid obesity. Both GHBP and sd score-leptin significantly increased according to BMI within the range from 18–27 kg/m2, whereas no significant differences were found among underweight groups (BMI, 27 kg/m2). We found a strong correlation between GHBP and sd score-leptin (r = 0.8; P < 0.0001). Multiple regression analysis revealed sd score-leptin to be a significant determinant of GHBP, accounting for 64...

Clinical transplantation of human islets has a disappointingly low rate of success. We report here the identification of a possible causative factor: endotoxin present in the collagenase preparations used to disperse the pancreatic tissue before islet purification and transplantation. Supporting evidence includes (1) detection of unexpectedly high levels of endotoxin in most collagenase solutions currently used to digest human pancreases; (2) demonstration that supernatants generated during islet separation are able to induce the inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) in macrophages; and (3) induction of IL-1, IL-6, and TNF-α in the islets during the separation procedure. Cytokine expression was assessed by reverse transcription-polymerase chain reaction and, for TNF-α, confirmed by enzyme-linked immunoabsorbent assay. It is proposed that endotoxin and locally induced cytokines carried over with the graft activate the endothelium and promote lymphomonocytic infiltration of grafted islets and surrounding liver tissue favoring primary nonfunction and early rejection. These results also have implications for the numerous experimental procedures that use collagenase, and they point to possible ways to improve islet preparation and transplantation protocols.

Vascular complications are the main cause of morbidity in diabetes mellitus. To evaluate lipoprotein and hemostatic parameters and their relationship with clinically detectable microangiopathy, we studied 58 insulin-dependent diabetes mellitus patients and 60 controls matched for age, sex, and body mass index. Thirteen patients presented clinically detectable microangiopathy (8 retinopathy and 5 both retinopathy and microalbuminuria). A cross-sectional study of lipid profile, coagulation parameters, and a flow-cytometric evaluation of tissue factor expression in normal monocytes induced by patient plasma were performed. Patients were re-evaluated for microangiopathy in a 3-year median follow-up. Patients showed triglyceride enrichment in low (P = 0.00002) and high density lipoproteins (P = 0.004) and increased levels of D-dimer (P < 0.00001), prothrombin fragment 1 + 2 (P < 0.00001), and thrombin-antithrombin III complex (P = 0.0001). Patients with clinically detectable microangiopathy had increased type 1 plasminogen activator inhibitor (P = 0.00001), thrombomodulin (P = 0.02), and induced monocyte tissue factor expression (P < 0.00001). Nine patients developed clinically detectable microangiopathy in the follow-up and the only predictive variable was increased induced tissue factor expression. In conclusion, in these patients elevated thrombin and fibrin generation reflects a hypercoagulable state but clinically detectable microangiopathy seems related to endothelial cell injury markers and to increased induced tissue factor expression on monocytes.

Human islet transplantation has a high rate of failure, often due to primary nonfunction, which suggests that islets are damaged during the processing of the pancreas. The preparation of human islets for transplantation is still a complex process that requires large teams of surgical and laboratory personnel. To overcome this problem, we have adopted the use of the IBM 2991 COBE cell separator and a metrizamide/Ficoll density medium that is easy to prepare. Twenty-seven pancreatic glands have been processed using the COBE cell separator, 23 of which were purified in metrizamide/Ficoll gradients and 4 in bovine serum albumin gradients. The results show an improvement of recovery and viability in these preparations when compared retrospectively with manual gradients. More importantly, the time required for purification was shortened to one fourth the usual time and total processing time is about half as long. Moreover, a team of two laboratory staff was regularly able to prepare islets for transplantation, reducing the separation time from 7 hr to 3.5 hr. We conclude that the automatic cell separator and metrizamide-based separation medium are useful modifications of current islet purification methods.

Lucas A, Llatjós M, Salinas I, Reverter J, Pizarro E, Sanmarti A. Fine-needle aspiration cytology of benign nodular thyroid disease. Value of re-aspiration. Eur J Endocrinol 1995;132:677–80. ISSN 0804–4643 Fine-needle aspiration cytology (FNAC) has become a widespread procedure for the study of thyroid nodules (TN). Some authors recommend the practice of repeated punctures for their follow-up. This study was done to determine the usefulness of repeated FNAC in patients with benign nodular thyroid disease. We have studied 251 fine-needle re-aspirations performed on 116 females aged 45.6 ± 14 years with benign nodular thyroid disease. The time elapsed between each consecutive FNAC was 1 year. No patients presented any changes in the size or consistency of their nodular goiters during this period; all FNACs were carried out by the same physician in the same thyroid area according to the Löwhagen technique, with a minimum of two or three aspirations of each nodule, and processed in the same way and valued by the same cytologist without any knowledge of previous cytological diagnoses. These were done using strictly classical criteria (Löwhagen). One hundred and five out of 116 patients (90.51%) with two consecutive FNACs (210) showed identical cytological diagnoses in the two specimens studied. The remaining 11 patients (9.48%) with two FNACs were diagnosed with colloid goiter and cyst alternately. Fifteen out of 19 patients (78.94%) with three FNACs showed identical cytological diagnoses in the three samples and the rest (21%) also demonstrated alternate diagnoses of colloid goiter and cyst. Our results show that the routine performance of repeated FNAC in the follow-up of females with benign nodular thyroid disease, without any clinical changes, is of limited usefulness. A Lucas, Endocrinology Service, Hospital Universitari "Germans Trias i Pujol", Ctra. de Canyet s/n, 08916 Badalona, Barcelona, Catalonia, Spain

Lipoproteins, including intermediate density lipoproteins and lipoprotein(a), and apolipoproteins A-I, B, C-II, C-III and E, were studied in 13 newly-diagnosed type I diabetic patients with severe insulinopenia without dehydration or acidosis. At baseline, the main finding was a significant increase in serum triglycerides due to raised triglyceride concentrations in all lipoproteins, particularly triglyceride-rich lipoproteins. Cholesterol concentrations were slightly increased in lipoproteins and led to a significant increase in serum cholesterol. Two days after the start of insulin therapy, lipoprotein profiles had normalized except for the LDL triglyceride contents, which remained significantly increased on the fifth day of treatment. No significant modifications were observed in lipoprotein(a), apolipoproteins A-I and E concentrations throughout the study. However, serum apolipoproteins B, C-II and C-III were increased at baseline and fell to normal levels 2 days after the start of insulin therapy. On the other hand, apolipoprotein C-II/C-III ratios in high and very low density lipoprotein, showed no significant differences at baseline compared with controls, suggesting that an apolipoprotein C-II deficiency or apolipoproteins Cs imbalance can be ruled out. In conclusion, significant lipoprotein abnormalities were observed in the insulin-deficient state of type I diabetes mellitus; insulin therapy normalizes the lipoprotein profile in two days, except for low density lipoprotein triglyceride contents which remain increased at the fifth day.

Background and objective: To study Chlamydophila pneumoniae DNA (CP-DNA) in leukocytes measured by real-time polymerase chain reaction (PCR) in patients with type 2 diabetes mellitus (DM2) with different degrees of atherosclerosis, a cross-sectional protocol was performed. Patients and methods: We included 135 patients with DM2. Clinical, metabolic and inflammatory variables were measured. Previous clinical macrovascular disease was recorded and carotid ultrasound and real-time PCR for CP-DNA were performed. Results: Mean age was 62 (7) years and mean diabetes duration 16 (9) years; 40.7% of patients presented clinical atherosclerosis, 32.5% subclinical atherosclerosis and 26.6% no evidence of atherosclerosis. Anthropometric data were homogeneous in the three groups. Patients with clinical atherosclerosis had greater carotid intima-media thickness compared to the other two groups. No CP-DNA was detected in any patient. Conclusions: The lack of detection of CP-DNA in blood leukocytes suggests that C. pneumoniae plays no active, systemic role in the pathogenesis of atherosclerosis in DM2 patients and is not a reliable marker of atherosclerosis in high-risk patients.

Studies on the effect of exogenous subclinical thyrotoxicosis on bone mineral density (BMD) in male patients treated with suppressive doses of levothyroxine for differentiated thyroid carcinoma (DTC) are not conclusive. In order to evaluate BMD (in femoral neck, lumbar spine, and distal radius) and bone fractures in men under long-term suppressive treatment with levothyroxine for DTC, we conducted a cross-sectional, retrospective study in 33 Caucasian men (mean ± SD age: 56 ± 14 years) under treatment for DTC. The control group comprised 33 healthy age- and body mass index-matched male volunteers. BMD was assessed by dual-energy X-ray absorptiometry (DXA). Bone turnover biomarkers (calcium, phosphate, alkaline phosphatase, PTH, vitamin D, urinary calcium, and N-Telopeptide/creatinine index) and testosterone were determined. Previous bone fractures were evaluated with a questionnaire and X-ray images of thoracic and lumbar vertebrae. Patients were treated for a mean duration of 15 ± 5 years. No differences were found between patients and controls in bone turnover biomarkers or areal BMD, T-scores or Z-scores in all sites evaluated. No earlier fractures or pain episodes were registered in either group and the incidence of asymptomatic vertebral fractures did not differ significantly between patient (18.8%) and control groups (16.7%), (P = 0.9). In conclusion, long-term suppressive treatment with levothyroxine in men with DTC does not appear to exert deleterious effects on bone mineral density or increase the prevalence of fracture.

Since their demonstration in 1975, ICSAs have been proposed as serological markers and pathogenic elements in IDDM. ICSAs are detected in the sera of most newly diagnosed IDDM patients by indirect IFL that uses viable preparations of rat islet or insulinoma cells as substrate, but they also can be detected by using human insulinoma or fetal islet cells. We have tried to demonstrate ICSAs in the sera of 31 newly diagnosed diabetic patients, including 6 positive samples on human fetal islet cells, which used their natural target for the first time: normal human islet cells. In spite of using different types of preparations of these cells (i.e., freshly dispersed cell suspensions, monolayer cultures, or dispersed islets after culture), ICSAs could not be detected by IFL under the UV microscope, nor by flow cytometry. In contrast, 9 of 29 of the sera gave a positive staining on the RIN rat insulinoma cells. In an attempt to establish whether the putative ICSA autoantigen is present in the surface of human islet cells in the diabetic pancreas, the insulitis microenvironment was emulated by exposing the islets to three types of stress: 1) cytokines (IFN-γ and TNF-α); 2) heat shock; and 3) hyperglycemia. However, diabetic sera failed again to recognize membrane antigens on the islet cells after either of these treatments. Neither were islet cells from a newly diagnosed diabetic patient stained by its autologous serum (ICA titer >80 JDF U). These results suggest that ICSA autoantigen is not expressed in the membrane of human islet cells and therefore raises doubts about their proposed pathogenic role.

Our study compared the effects of an angiotensin-converting enzyme inhibitor (captopril) versus a calcium antagonist (nifedipine) on proteinuria and renal function in patients with diabetic nephropathy. A randomized follow-up study was designed. Type 2 diabetic patients, with established diabetic nephropathy (proteinuria>0.5 g24 h), were treated with nifedipine (10 patients, group A) or captopril (10 patients, group B) for 6 months. Arterial blood pressure, metabolic parameters, proteinuria and renal function were measured and compared. Mean percentage differences for glomerular filtration rate, renal plasma flow and filtration fraction between the two groups were calculated. No significant differences were observed in serum glucose, glycosylated hemoglobin (hemoglobin A1c), Na+, K+ or albumin in either group or between groups. Blood pressure decreased significantly with both treatments and mean blood pressure was significantly lower in group A compared with group B at 6 months (Mann-Whitney U-test, P = 0.03). Proteinuria was similar in both groups at randomization, but after 3 and 6 months of treatment significant reductions were observed only in the group treated with captopril (P < 0.01). A significant decrease in filtration fraction was observed in group B with an increase in group A (Mann-Whitney U-test, P = 0.03). Multiple regression analysis identified the therapeutic agent administered as an independent variable for decrease in proteinuria. It is concluded that antihypertensive treatment with captopril, but not with nifedipine, reduced proteinuria in patients with diabetic nephropathy, although a better mean blood pressure was obtained with nifedipine. The difference in filtration fraction variation between the two groups suggests an opposite pharmacological action on glomerular hemodynamics and perhaps an explanation for the results on proteinuria of the different drugs.

The presence of intercellular adhesion molecule-1 (ICAM-1) on epithelial cells facilitates their recognition by specific T lymphocytes. To assess the possible role of ICAM-1 in the recognition of thyroid follicular cells by T cells in thyroid autoimmune disease, we investigated the expression of ICAM-1 in thyrocytes from thyroid glands affected by Graves' disease, in glands with non-autoimmune pathology and normal glands using immunofluorescence staining on cryostat sections and on dispersed cell preparations. Sequential tissue sections from glands affected by Graves' disease (n = 15), multinodular goitre (MNG, n = 26), benign nodules (n = 11), primary carcinomas (n = 12) and control thyroid glands (n = 5) were stained for ICAM-1, HLA class I, HLA class II, CD3 and thyroid peroxidase (TPO). Weak and patchy ICAM-1 expression was found in the thyrocytes of 4/15 (27%) Graves' disease and of 1/26 (4%) multinodular goitre glands. In contrast, ICAM-1 expression was detected in the thyrocytes of 5/11 (45%) benign nodules and of 8/12 (67%) thyroid carcinomas in which it was sometimes strong. Thyrocytes in the five control glands were negative. These results correlated well with flow cytometry data from 23 of these glands which showed that ICAM-1 expression in thyrocytes from Graves' patients was, when present, 'dull', while in some malignant thyrocytes it was 'bright'. In preparations of thyrocytes from Graves' disease glands we found a striking discordance between the high levels of expression of HLA class I and HLA class II and the low expression of ICAM-1. This is surprising since in vitro the expression of these three molecules is equally induced by IFN-gamma and TNF-alpha. These results suggest that additional factors are involved in the induction of the inappropriate HLA class II expression observed in the thyrocytes of glands affected by Graves' disease.

Summary objective To evaluate the effect of treatment with TSH suppressive dose of levothyroxine In patients with benig nthyroid nodules. design Prospective randomized study. Group A (n= 20) patients received levothyroxine and group B (n= 20) patients did not. The dose of levothyroxine was adjusted to obtain an effective suppression of TSH. A clinical, analytical and morphological (with ultrasound) review was performed every 3 months. The mean ± SD follow-upperiod was 6·10±2·2 months. patients Forty euthyrold women with solitary thyroid nodule on palpation, cold on sclntlgraphy and cytologically benign without contraindication participated. measurements At entry: biochemical and hormonal parameters, thyroid sclntigraphy and thyroid ultrasonography. Every 3 months additional determinations of thyroid hormones and TSH levels were carried out, if necessary, to verify effective TSH suppression. Every 6 months thyroid ultrasound imaging was performed. results Patients were euthyroid at entry into the study. The mean dose of levothyroxine necessary to obtain TSH suppression was 2·82±0·6 μg/kg/day. No significant modification in the thyroid nodule diameter (mean ± SD 2·6±1·2 vs 2·5±1·2 cm) or in the thyroid nodule volume(10·3±11·9 vs 10·1±12·2 ml) were observed in group A. In group B the results were similar (2·8±0·9 vs 2·7±1·8 cm and 9·2±6·4 vs 9·2±9·5 ml, respectively). No differences were found in either group in the number of nodules that reduced significantly their volume (four and three, respectively). conclusions The suppressive therapy with levothyroxine was not effective In reducing nodule sizes in patients withsolitary benign thyroid nodules.

Pulse oximetry of the toes has been suggested in the screening of peripheral arterial disease. We studied the uselfuness of pulse oximetry in detection of type 2 diabetic patients with carotid atherosclerosis.105 patients with type 2 diabetes mellitus (DM) without previous clinical peripheral arterial disease were enrolled. All patients had (1) ankle-brachial index (ABI) measurement, (2) pulse oximetry to measure SaO(2) of their index fingers and big toes in the supine position and at elevated 30cm and (3) a carotid ultrasound [carotid artery intima-media thickness (IMT) and carotid plaques (CP) measurements]. The ABI was considered abnormal when it was0.9 and when the pulse oximetry showed a decrease in SaO(2) of2% of the finger compared to foot or to 30cm foot elevation.60 patients were men (age of 62+/-7 years, HbA(1c) of 6.9+/-1.0); 58.1% had CP. There were no differences in anthropometric and biochemical results between patients with or without CP. The ABI was0.9 in 49% and 25% of patients with and without CP, respectively. Neither were there differences in pulse oximetry in patients with CP or in those with ABI0.9. The IMT did not change in relation to pulse oximetry, but it was higher in patients with CP and with ABI0.9 than in patients without alterations. These results were independent of the presence of previous clinical macroangiopathy.Pulse oximetry is not a useful screening method of carotid atherosclerosis in type 2 DM.

Type A chronic atrophic gastritis (CAG) is increased in type 1 diabetic patients (DM1). To address this issue, we determined and analyzed the number of peripheral blood regulatory T cells (Tregs) in 15 DM1-CAG patients, 15 DM1 patients without associated autoantibodies (DM1) and 15 healthy controls by flow cytometry and compared gastric Tregs expression (CD4+Foxp3+/CD4+) in DM1-CAG patients with that observed in 10 control Helicobacter pylori CAG-infected biopsies. The percentage of peripheral Tregs was higher in DM1-CAG patients compared to DM1 and controls (CD4+Foxp3+: 7.67 +/- 1.91% vs. 5.38 +/- 1.57% and 5.65 +/- 1.76%, P0.001, respectively), with no differences between DM1 and controls. Gastric mucosal Tregs were higher in H. pylori CAG than in DM1-CAG patients (31.31 +/- 5.52% vs. 7.68 +/- 3.70%; P0.001). Data suggest that Tregs are stimulated in patients with more than one autoimmune disease (DM1 + CAG) in an ineffectual attempt to control autoimmune response and that the number of Tregs in gastric mucosa implicated in the chronification of gastritis differs according to the etiology.

Forty-eight children, referred for evaluation of short stature, underwent 24-hour spontaneous growth hormone (GH) secretion studies. The GH level in pooled sera was assessed for each child, using up to 11 commercial immunoassays. In a group of 15 children, the mean GH values obtained by nine of the assays were compared with the mean value given by a polyclonal radioimmunoassay (RIA) from Sorin: four gave higher results (p < 0.0001), three gave comparable results and two gave lower results (p < 0.001). The assay yielding the highest results (Nichols: 5.9 ± 2.3 ng/ml, mean ± SD) gave values that were approximately triple those obtained by the assay yielding the lowest results (Hybritech: 1.8 ± 0.8 ng/ml; p < 0.0001); both of these are monoclonal immunoradiometric assays (IRMAs). The GH concentrations measured in 24-hour pools from 32 children using a monoclonal IRMA from Biomerieux were similar to those obtained using a polyclonal RIA from Farmos (2.8 ± 1.1 ng/ml and 2.9 ± 1.4 ng/ml, respectively) but significantly lower than those measured by another polyclonal RIA from Sorin (3.5 ±1.5 ng/ml). Two polyclonal assays (Biomerieux and Sorin) were then used to measure the GH levels in all of the 30-minute samples and in the day, night and 24-hour pools from the secretion studies of 22 children. The ratio of the results of the two assays remained fairly constant for a given child (although the GH levels in different 30-minute samples differed considerably). However, the ratios between different children showed quite wide variation (from 2.03 to 1.04). It was concluded that the GH assay must be taken into account when evaluating data from GH secretion studies, and the disparity in the GH level measured by two or more assays may differ from child to child.

ObjectiveType 1 diabetes mellitus patients (DM1) show increased prevalence of pernicious anaemia, the histological substrate of which is type A chronic atrophic gastritis (CAG) in the stomach corpus, the main source of ghrelin. We aimed to compare plasma ghrelin concentrations in DM1 patients with type A CAG (DM1-CAG), DM1 patients without type A CAG and healthy controls and in DM1-CAG group, to ascertain a possible relationship between ghrelin and biochemical markers of gastric mucosa atrophy and/or neuroendocrine (NE) cell hyperplasia and histological gastric biopsy findings.Design and methodsFifteen DM1-CAG patients were matched for age, sex and body mass index with 15 DM1 patients without type A CAG and 15 controls. Pepsinogen I, pepsinogen II, gastrin, parietal cell antibodies, chromogranin A (CgA) and ghrelin were determined in all subjects. In DM1-CAG patients, immunohistochemical analysis of gastric biopsies using antibodies to CgA and ghrelin was performed.ResultsGhrelin concentrations differed among groups; however, paired comparisons between groups were not significant. In DM1-CAG, no correlation was found between ghrelin and gastric body atrophy markers, pepsinogen I and the pepsinogen I/II ratio. Immunohistochemical studies of DMI-CAG patients showed CgA staining in 12 and ghrelin staining in 6, which was confined to the foci of NE cell hyperplasia. Those patients who stained positive for ghrelin had higher ghrelin concentrations when compared with the negative patients.ConclusionsGhrelin concentrations are not decreased in DM1-CAG patients; thus, our data suggest that ghrelin is not a good marker of gastric mucosa atrophy in these patients, given the possible ghrelin synthesis in hyperplastic gastric endocrine/enterochromaffin-like cells.

Background Abnormalities in glucose homeostasis (AGH) frequently occur in kidney transplantation and favor vascular lesions. The purpose of this study was to analyze whether C-reactive protein (CRP), adiponectin, and ghrelin are markers of AGH and indicators of carotid atherosclerosis in kidney transplant patients with fasting plasma glucose below 126 mg/dL. Methods This was a cross-sectional study of 85 kidney transplant patients (59 men; mean age: 52.4 +/- 11.6 years; median posttransplant follow-up 31 (range 3-61) months). All patients underwent an oral glucose tolerance test. Abnormalities in glucose homeostasis were diagnosed following American Diabetes Association criteria. CRP, adiponectin, and ghrelin levels were determined. Doppler ultrasound of the carotid artery was performed to determine intima media thickness (IMT) and atheromatous plaque. Results A total of 50.5% of patients had AGH (12.9% were diagnosed with new-onset diabetes mellitus after transplantation and 37.7% had impaired glucose tolerance or impaired fasting glucose), whereas 49.4% were normoglycemic. Patients with AGH were older (P=0.002), had greater carotid IMT (P=0.022), and lower ghrelin concentrations (P=0.017) than normoglycemic patients. Logistic regression analyses showed ghrelin to be an independent marker for AGH (P=0.012) and AGH to be related to greater IMT (P=0.041). No differences in adiponectin or CRP were found in relation to AGH or atherosclerosis; however, there was a positive correlation between adiponectin levels and prednisone dose (r=0.240; P=0.044). Conclusions A total of 50.5% of the study patients had abnormalities in glucose homeostasis. Patients with AGH had a higher percentage of preclinical atherosclerosis (greater carotid IMT). Ghrelin is an independent marker for abnormalities in glucose homeostasis.