Endotelina-1, proteína C reactiva ultrasensible y actividad antioxidante en pacientes con hipotiroidismo subclínico y en eutiroideos con autoinmunidad tiroidea. Efectos del tratamiento con levotiroxina / Endothelin-1, high sensitivity C reactive protein and antioxidant activity in subclinical hypothyroid patients. Effects of levothyroxine treatment

RESUMEN La Endotelina-1 (ET1) y Proteína C Reactiva ultrasensible (PCRus) como marcadores de disfunción endotelial (DE) e inflamación vascular en hipotiroidismo subclínico (HS) han mostrado resultados controvertidos. El rol del estrés oxidativo y defensa antioxidante (TRAP) es motivo de discusión. Objetivos Establecer si el HS y la autoinmunidad tiroidea (AIT), excluyendo otros factores de riesgo cardiovascular, pueden causar DE e inflamación vascular, evaluadas a través de ET1 y PCRus, respectivamente. Establecer si TRAP juega algún rol. Evaluar cambios en ET1 y PCRus luego del tratamiento con levotiroxina (LT4). Material y métodos Se evaluaron prospectivamente 70 pacientes divididos en 3 grupos: HS: 41 pacientes (T4 normal,TSH >4,2 y <10 mUI/L), AIT: 10 pacientes eutiroideos (TSH <4,2 mUI/L) con aTPO y/o aTg (+) y Control: 19 pacientes eutiroideos sin AIT. Se excluyeron otros factores de riesgo cardiovascular. Se midió basalmente ET1, PCRus y TRAP plasmáticos, y en HS bajo LT4 (n = 24): ET1 y PCRus. Resultados No hubo diferencias significativas en edad, IMC, perfil lipídico y TRAP. ET1 y PCRus fueron significativamente mayores en pacientes con HS (media ± DS 1,77 ± 0,85 pg/ml y 1,5 ± 0,6 mg/l vs. controles (0,8 ± 0,3 pg/ml y 0,5 ± 0,2 mg/l) p <0,0001 y <0,008 respectivamente. Del mismo modo en AIT (1,4 ± 0.4 pg/ml y 2,3 ± 1,3 mg/l) vs controles p <0,0001 y <0,034, respectivamente. La TSH fue mayor en el grupo AIT vs. Control 2,57 ± 0,88 vs. 1,64 ± 0,5 mUI/L; p = 0,002. En HS bajo LT4 (8,7 ± 3,8 meses) se observó descenso de ET1 (p <0,001). ET1 correlacionó con TSH (r = 0,5 p <0,0001). El punto de corte de ET1 mediante curva ROC fue 1,32 pg/ml (Sensibilidad 81,6%-Especificidad 75%). Conclusiones ET1 y PCRus resultaron marcadores útiles para evaluar DE e inflamación vascular asociadas a HS. La defensa antioxidante no ejercería un rol en estos mecanismos. El tratamiento con LT4 produjo una significativa caída de ET1, pudiendo necesitarse un período más largo de eutiroidismo para normalizarla. En AIT, niveles de TSH >2,5 mUI/L podrían sugerir un mínimo grado de hipotiroidismo justificando la elevación en ET1 y PCR, sin descartar el rol de la AIT "per se".

ABSTRACT The measurement of endothelin-1 (ET1) and high sensitivity C-reactive protein (hsCRP) as markers of endothelial dysfunction (ED) and vascular inflammation in subclinical hypothyroidism (SH) has shown controversial results. The role of oxidative stress and antioxidant defense (TRAP) is a matter of discussion. Objectives To establish if SH and thyroid autoimmunity (TAI), excluding other cardiovascular risk factors, may cause ED and vascular inflammation, evaluated through the measurement of ET1 and hsCRP respectively. To determine if TRAP could have some role. Additionally, changes in these parameters after treatment with levothyroxine (LT4) will be evaluated. Material and methods: 70 patients were prospectively evaluated. They were classified into: SH Group: 41 patients (normal T4, TSH> 4.2 and <10 mIU/L), TAI Group: 10 euthyroid patients (TSH <4.2 mUI/L) with positive aTPO and/or aTg and Control Group: 19 euthyroid patients without TAI. Other cardiovascular risk factors were excluded in patients and controls. Plasma ET1, hsCRP and TRAP were measured basally, and ET1 and hsCRP under LT4 therapy in the HS Group. Results There were no significant differences between the 3 groups in age, BMI, lipids and TRAP. ET1 and hsCRP were significantly higher in patients with SH (mean ± SD 1.77 ± 0.85 pg/ml and 1.5 ± 0.6 mg/l) vs. controls (0.8 ± 0.3 pg/ml y 0.5 ± 0.2 mg/l) p <0.0001 y <0.008 respectively. Similarly, in TAI patients (1.4 ± 0.4 pg/ml y 2.3 ± 1.3 mg/l) vs controls, p <0.0001 and <0.034, respectively. TSH was higher in the TAI patients versus control group (2.5 ± 0.88 versus 1.64 ± 0.5 mIU/L, p = 0.002). Twenty-four patients with SH showed a significant decrease in ET1 (p <0.001) under treatment with LT4 (8.7 ± 3.8 months). ET1 had a highly significant correlation (p <0.0001) with TSH (r = 0.5). The cut-off level of ET1 established by ROC curve was 1.32 pg/ml (Sensitivity 81.6%-Specificity 75%). Conclusions ET1 and hsCRP were useful markers to evaluate ED and vascular inflammation associated with SH. There were no differences in TRAP levels between patients and controls, so it does not appear that oxidative stress would have played any role. Treatment with LT4 produced a significant drop in ET1. Probably, a longer period of euthyroidism might be necessary to normalize ET1 levels. In TAI Group, TSH levels >2.5 mUI/L could suggest a "minimal degree" of hypothyroidism justifying the elevation in ET1 and hs CRP. The role of the TAI "per se" couldn't be completely ruled out.

False positive in the measurement of thyroglobulin induced by rheumatoid factor.

BACKGROUND: We report a case of interference in thyroglobulin (Tg) measurement in a woman with differentiated thyroid cancer and rheumatoid arthritis history. Due to discordant Tg in relation to TSH concentrations and negative images, we investigated possible interference in the measurement of Tg. METHODS: During the follow-up we measured Tg by chemiluminescence (TgQL) using Immulite 2000 immunoassay system. To investigate possible interference in Tg measurement, we made serial dilutions, re-testing of Tg by an alternative method: electrochemiluminescence, Cobas 6000 analyzer (TgEQL), recovery test of Tg and polyethylene glycol (PEG) 6000 precipitation. RESULTS: During the patient follow-up, the TgQL ranged between <0.3 and 16.1ng/ml. In the evaluated serum samples very high titers of rheumatoid factor (RF) were found. When RF titers were lowered post PEG precipitation, Tg QL concentrations became undetectable. CONCLUSION: We describe an unusual case of interference in Tg assay due to RF. When disagreement among Tg concentrations, images and clinical features is observed, we suggest taking into account the evaluation of possible Tg interference to avoid unnecessary complementary exams and inappropriate treatment.

Autoinmunidad tiroidea: Mecanismos patogénicos comunes y distintivos en tiroiditis de Hashimoto y enfermedad de Graves / Thyroid Autoimmunity: Common and Distinctive Pathogenic Mechanisms in Hashimoto's Thyroiditis and Graves' Disease

Las enfermedades tiroideas autoinmunes (ETA) son los desórdenes más frecuentes que llevan a la disfunción de la glándula tiroidea. Incluyen varias formas clínicas como Tiroiditis de Hashimoto (TH) y Enfermedad de Graves (EG). La relación entre TH y EG ha sido objeto de debate por décadas. Si bien, muy diferentes en su clínica, algunos las consideran los lados opuestos de una misma moneda. En su patogénesis tienen aspectos en común, como la predisposición genética demostrado por la ocurrencia en una misma familia y en un mismo individuo. Sin embargo, diferencias en el microambiente local determinan la diferente expresión fenotípica o el viraje de una a otra patología. El objetivo de esta monografía es investigar similitudes y diferencias entre TH y EG en las distintas etapas que llevan al desarrollo de autoinmunidad. Los autores declaran no poseer conflictos de interés.

Autoimmune thyroid disease (ATD) is the most common disorder that leads to thyroid gland dysfunction. ATD manifests in various clinical forms, such as Hashimoto's Thyroiditis (HT) and Graves' Disease (GD). The relation between HT and GD has been discussed for decades. Even if they greatly differ in their clinical features and treatment, some people believe they are the opposite sides of the same coin. In their pathogenesis, they share some mechanisms, such as genetic susceptibility, shown by the fact that they tend to occur both in the same person and within the same family. However, differences in the local micro-environment can determine the distinct phenotypic expression or the switch from one disease to the other. The aim of this monograph was to investigate similarities and differences between HT and GD at the diverse stages leading to the development of autoimmunity. No financial conflicts of interest exist.

Autoinmunidad tiroidea: Mecanismos patogénicos comunes y distintivos en tiroiditis de Hashimoto y enfermedad de Graves / Thyroid Autoimmunity: Common and Distinctive Pathogenic Mechanisms in Hashimotos Thyroiditis and Graves Disease

Las enfermedades tiroideas autoinmunes (ETA) son los desórdenes más frecuentes que llevan a la disfunción de la glándula tiroidea. Incluyen varias formas clínicas como Tiroiditis de Hashimoto (TH) y Enfermedad de Graves (EG). La relación entre TH y EG ha sido objeto de debate por décadas. Si bien, muy diferentes en su clínica, algunos las consideran los lados opuestos de una misma moneda. En su patogénesis tienen aspectos en común, como la predisposición genética demostrado por la ocurrencia en una misma familia y en un mismo individuo. Sin embargo, diferencias en el microambiente local determinan la diferente expresión fenotípica o el viraje de una a otra patología. El objetivo de esta monografía es investigar similitudes y diferencias entre TH y EG en las distintas etapas que llevan al desarrollo de autoinmunidad. Los autores declaran no poseer conflictos de interés.(AU)

Autoimmune thyroid disease (ATD) is the most common disorder that leads to thyroid gland dysfunction. ATD manifests in various clinical forms, such as Hashimotos Thyroiditis (HT) and Graves Disease (GD). The relation between HT and GD has been discussed for decades. Even if they greatly differ in their clinical features and treatment, some people believe they are the opposite sides of the same coin. In their pathogenesis, they share some mechanisms, such as genetic susceptibility, shown by the fact that they tend to occur both in the same person and within the same family. However, differences in the local micro-environment can determine the distinct phenotypic expression or the switch from one disease to the other. The aim of this monograph was to investigate similarities and differences between HT and GD at the diverse stages leading to the development of autoimmunity. No financial conflicts of interest exist.(AU)

Effects of diet and behavioral enrichment on free fatty acids in the aged canine brain.

Despite several recent studies suggesting that dysregulation of brain lipid metabolism might contribute to the mechanisms of aging and Alzheimer's disease (AD), lipid metabolism has not been evaluated extensively in the aging brain. Here, we use a lipidomic approach to demonstrate that antioxidants plus mitochondrial cofactors treatment, either alone or in combination with behavioral enrichment, attenuates lipid abnormalities in the frontal cortices of aged canine in a manner correlated with cognitive scores. Our analyses revealed that the levels of free palmitoleic acid and nervonic acid were decreased in frontal cortices of aged dogs (n=5-6/group) treated with antioxidant compared with the control group. The monounsaturated/saturated fatty acid ratio, also known as "desaturation index"-an ex-vivo indicator of stearoyl-CoA desaturase activity, was also reduced in the frontal cortex of dogs treated with antioxidants compared with control groups. Increased palmitoleic acid levels and desaturation index were positively correlated with increased reversal learning errors and decreased cognitive performance. In conclusion, our study indicates that the addition of antioxidants and mitochondrial cofactors to the regular diet alters the composition of free fatty acids in the aged brain. Together with data showing increased palmitoleic acid levels in AD patients, our data suggest that reducing palmitoleic acid levels and desaturation index in the brain may be associated with improved cognitive performance.

The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease.

Activation of cannabinoid receptors (CBs) by endocannabinoids impacts on a number of gastrointestinal functions. Recent data indicate that CB1 agonists improve 2,4-dinitrobenzene sulfonic acid-induced colitis in mice, thus suggesting a role for the endocannabinoid agonist anandamide (AEA) in protecting the gut against inflammation. We here examined the gut endocannabinoid system in inflammatory bowel disease (IBD) patients, and investigated the ex vivo and in vitro effects of the non-hydrolysable AEA analog methanandamide (MAEA) on the mucosal proinflammatory response. The content of AEA, but not of 2-arachidonoyl-glycerol and N-palmitoylethanolamine, was significantly lower in inflamed than uninflamed IBD mucosa, and this was paralleled by lower activity of the AEA-synthesizing enzyme N-acyl-phosphatidylethanolamine-specific phospholipase D and higher activity of the AEA-degrading enzyme fatty acid amide hydrolase. MAEA significantly downregulated interferon-γ and tumor necrosis factor-α secretion by both organ culture biopsies and lamina propria mononuclear cells. Although these results are promising, further studies are needed to determine the role of cannabinoid pathways in gut inflammation.

[Stapled hemorrhoidopexy in the treatment of hemorroidal prolapse]. / Mucoprolassectomia con suturatrice meccanica nel trattamento della patologia emorroidaria.

In the treatment of hemorroidal prolapse, stapled hemorrhoidopexy, according to the Longo's technique, represents an innovative and interesting procedure. The Authors consider own experience in the years 2001-2002, estimating preliminary results in the treatment of 50 patients affected by hemorrhoidal disease classified as III-IV grade, associated with mucosal prolapse, rectocystocele in 5 cases, anal fissures in 6 and hyperplastic polyp in 1. The patients were submitted to mucosal prolapsectomy with mechanical stapler (PPH 01-33 Ethicon), applying haemostatic stitch on suture line, apart from intraoperative bleeding, associated to closed anal sphincterotomy in 6 cases, and resection of anal hyperplasic polyp in 1. In 5 cases of rectocystocele a Burch's culposuspension was associated to a stapled transanal rectal resection (STARR). After 3 and 12 months the Authors performed ano-rectoscopy, anal manometry and defecography. Mean operative time was 45 minutes (range 20'-130') and mean hospital stay was 3 days (range 2-6 days). In the early postoperative course urinary ritention in 4 cases, treated with temporary catheterization in 3 and permanent for 72 hours in 1, was observed. Only 1 patient, was reoperated in day-surgery and with loco-regional anesthesia for residual fibrous hemorroid. Bleeding, severe pain, anal stenosis, impairment of continence were not observed. According to the Literature data, our experience confirm that mucoprolapsectomy represents an innovative, safe, simple and definitive operation in the treatment of hemorrhoids disease. In case of rectal prolapse associated to external fibrous hemorroids, a combined surgical treatment is requested in order to achieve better results.

[Treatment for microcarcinoma of the thyroid. Clinical experience]. / Il trattamento dei microcarcinomi della tiroide. Esperienza clinica.

According to WHO, small papillary cancer represents a papillary carcinoma < or = 1 cm in greatest dimension. The autoptic incidence is more elevated showing a low aggressivity. In fact lower mortality and local relapse have been reported. The AA report their results of 17 pt operated on for benign thyroid pathology in last three years. The diagnosis has been "incidental cancer" with 7 mm of mean diameter. Surgical treatment consisted of 9 total thyroidectomy, 3 near total thyroidectomy, 3 subtotal thyroidectomy, 2 lobo-isthmusectomy, with completion on the fifteenth day. Radioiodine therapy was administered in the case of uptake > 3.5%. There were no significant complications. Only in parathyroidectomy for secondary hyperparathyroidism, we have definitive hypoparathyroidism. Age, capsular infiltration, multifocality and lymphonodal dissemination represent main prognostic factors. In the treatment of SPC we recommend a total thyroidectomy or a near total in association with iodine-131 radioiodine therapy.

Total parathyroidectomy with or without autoimplantion in the therapy of secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (HPTs) in patients with chronic renal failure is related to a reduction of absorption of calcium with hyperplasia of main cells and an increase of PTH levels: this often leads to complications in dialysis. METHODS: Data from 10 patients (mean age 55 years) with HPTs who underwent total parathyroidectomy from November 1999 to November 2001 were retrospectively collected. Surgical indications included: persistent hypercalcemia, bone fractures, fatigue, joint pain and itching. Median preoperative PTH level was 800 pg/ml. Presurgical work-up included: serum PTH, calcium and alkaline phospha-tases. Thyroid ultrasound and scintigraphy, 99Tc sestamibi scintigraphy, CBM, FNB were also performed. In 5 patients 2 hours prior to the operation 2 MCu of sestamibi 99Tc had been injected. Patients underwent cervical exploration radioguided in 5 cases under general anesthesia. The operation consisted in the removal of all glands with subcutaneous forearm implant in 4 cases. PTH dosage at starting time of operation (time 0) was performed; it was repeated after the removal of each parathyroid gland and postoperatively on days 1 and 3 and then every month for 6 months. RESULTS: Twenty-four hours postoperatively 9 patients showed a great reduction of PTH levels with improved symptoms already on day 1 postoperative. In the patient with persistent HPT an autoimplant had been performed. CONCLUSIONS: Secondary HPT still shows unclear aspects. Parathyroidectomy determines an immediate improvement in symptoms. In all observed patients PTH was significantly reduced, serum calcium returned to normal and in any case hypoparathyroidism was detected.

Ni(2+), a double-acting inhibitor of neuronal nitric oxide synthase interfering with L-arginine binding and Ca(2+)/calmodulin-dependent enzyme activation.

Ni(2+), a toxic and carcinogenic pollutant and one of the leading causes of contact dermatitis, is shown to inhibit neuronal nitric oxide synthase (nNOS) in a competitive, reversible manner with respect to the substrate l-arginine (K(i) = 30 +/- 4 microM). The IC(50) values were dependent on calmodulin (CaM) concentration, but proved independent of Ca(2+), tetrahydrobiopterin (BH(4)) and other essential cofactors. Ni(2+) also inhibited CaM-dependent cytochrome c reduction, NADPH oxidation, and H(2)O(2) production by nNOS. Overall, the action profile of Ni(2+) was suggestive of an unusual, double-acting inhibitor of nNOS affecting l-arginine-binding and Ca(2+)/CaM-dependent enzyme activation.

Inhibition of neuronal nitric oxide synthase by 6-nitrocatecholamines, putative reaction products of nitric oxide with catecholamines under oxidative stress conditions.

6-Nitrodopamine and 6-nitronoradrenaline (6-nitronorepinephrine), putative products of the nitric oxide (NO)-dependent nitration of dopamine and noradrenaline, are reported to be reversible, competitive inhibitors of neuronal nitric oxide synthase (nNOS) with K(i) values of 45 and 52 microM respectively. The nitrocatecholamines inhibited H(2)O(2) production in the absence of L-arginine and tetrahydrobiopterin (BH(4)) (the IC(50) values for 6-nitrodopamine and 6-nitronoradrenaline were 85 and 55 microM respectively) but without affecting cytochrome c reduction. The apparent K(i) values for nitrocatecholamine inhibition of enzyme activation by BH(4) were 18 microM for 6-nitrodopamine and 40 microM for 6-nitronoradrenaline. Both nitrocatecholamines antagonized the dimerization of nNOS induced by BH(4) and by L-arginine, the effect being reversed by BH(4) (more than 10 microM) and L-arginine (e.g. 100 microM). Overall, these results suggest that nitrocatecholamines interfere with nNOS activity by binding to the enzyme in the proximity of the substrate and BH(4)-binding sites near the haem group.

CT indications for surgery and evaluation of prognosis in patients with spontaneous intracerebral haematomas.

This study retrospectively analyzes the CT findings of 50 patients with spontaneous intracerebral haematomas and correlates them with the clinical condition at admission and the outcome. The volume of the haematoma was well correlated with the outcome and was a very useful indicator for surgery. In patients with haematoma volume lower than 25 ml and above 80 ml there was no indication for surgery; in patients with haematoma volume between 25 and 50 ml the operation does not significantly modify the survival rate, but favours a more rapid and complete recovery of the neurological deficits, whereas a haematoma volume between 50 and 80 ml favours the rate of survival.