Thyroid hormone resistance from newborns to adults: a Spanish experience.

OBJECTIVE: Thyroid hormone resistance (RTH ß) is a rare genetic disorder characterized by an altered response of target tissue to the action of thyroid hormone. Few studies on RTH ß have been carried out in southern European populations. We aimed to describe the clinical and genetic characteristics at the time of diagnosis in a Spanish cohort of patients with genetically confirmed RTH ß, with ages ranging from newborns to adults. METHODS: Retrospective multicenter study of 28 patients who were genetically confirmed as RTH ß. Clinical and biochemical data were collected from the reference centers, and the studied variables included age, sex, anthropometric data, clinical characteristics and biochemical results. In the Basque country, a simultaneous analysis of TSH and T4 is carried out in the program for the screening of inborn errors of metabolism. A molecular analysis of the thyroid hormone beta (THRB) gene was performed. RESULTS: The total cohort included 20 adults and eight pediatric patients (six newborns). Of the total, 5 (17.8%) were diagnosed by clinical characteristics (goiter, hypertension or tachycardia), 13 (46.4%) were analyzed in the context of a family study and 10 (35.7%) were diagnosed after obtaining an altered fT4 and/or TSH level in a biochemical analysis performed due to clinical symptoms unrelated to RTH ß. Four of the newborns included in the series were diagnosed by the result of neonatal screening, which allows us to estimate a minimum local incidence of RTH ß of 1/18,750 live newborns. The genetic analysis showed the presence of 12 different heterozygous mutations in the THRB gene. CONCLUSIONS: We report the clinical and genetic characteristics of a Spanish RTH ß cohort, from neonates to adults. We also describe one novel mutation in the THRB gene as the cause of the disease. The simultaneous analysis of TSH and T4 carried out in the program for the screening of inborn errors of metabolism facilitates the early diagnosis of RTH ß in newborns and has allowed us to estimate a minimum local incidence of RTH of 1/18,750 live newborns.

Aspectos clínicos en dos casos de seudohipoparatiroidismo ( Ia y Ib) y estudio molecular del locus GNAS / Clinical features of two cases of pseudohypoparathyroidism ( I a and I b) and molecular analysis of GNAS

El seudohipoparatiroidismo (PHP) es una entidad rara, caracterizada por resistencia tisular a la hormona paratiroidea (PTH). Los 2 subtipos principales, PHP-Ia y PHP-Ib, son causados por alteraciones en el gen GNAS (20q13.3), que codifica para la proteína Gsα, esencial para la acción de la PTH y otras hormonas. El PHP-Ia se asocia a diversas alteraciones hormonales, osteodistrofia hereditaria de Albright (AHO) y actividad reducida de Gsα. Está causado por mutaciones inactivantes del gen GNAS. El PHP-Ib presenta resistencia aislada a la PTH, sin AHO y con actividad Gsα normal o levemente baja. Se asocia a defectos en la impronta de GNAS. Se presentan 2 casos con PHP-Ia y PHP-Ib, ahondando en su clínica y en el diagnóstico diferencial frente a afecciones similares (AU)

Pseudohypoparathyroidism (PHP) is a rare disorder, characterized by a tissue resistance to parathyroid hormone (PTH). The two main subtypes of PHP, PHPIa and PHPIb, are caused by alterations in the GNAS locus (20q13.3), which encodes the Gs protein, essential for the action of PTH and other hormones. PHP-Ia is associated with several hormone resistances, Albright hereditary osteodystrophy (AHO), and reduced Gsα activity. It is caused by inactivating mutations in the GNAS gene. PHPIb presents with isolated resistance to PTH, without AHO and with normal to low Gsα activity. It is related to imprinting defects in GNAS. Two unrelated cases of PHP-Ia and PHP-Ib are presented here, focusing on their clinical aspects and in the differential diagnosis with similar pathologies (AU)

[Clinical features of two cases of pseudohypoparathyroidism (ia and ib) and molecular analysis of GNAS]. / Aspectos clínicos en dos casos de seudohipoparatiroidismo (ia y ib) y estudio molecular del locus GNAS.

Pseudohypoparathyroidism (PHP) is a rare disorder, characterized by a tissue resistance to parathyroid hormone (PTH). The two main subtypes of PHP, PHPIa and PHPIb, are caused by alterations in the GNAS locus (20q13.3), which encodes the Gsα protein, essential for the action of PTH and other hormones. PHP-Ia is associated with several hormone resistances, Albright hereditary osteodystrophy (AHO), and reduced Gsα activity. It is caused by inactivating mutations in the GNAS gene. PHP-Ib presents with isolated resistance to PTH, without AHO and with normal to low Gsα activity. It is related to imprinting defects in GNAS. Two unrelated cases of PHP-Ia and PHP-Ib are presented here, focusing on their clinical aspects and in the differential diagnosis with similar pathologies.

Dynamic assembly of tight junction-associated proteins ZO-1, ZO-2, ZO-3 and occludin during mouse tooth development.

Tight junctions might play a role during tissue morphogenesis and cell differentiation. In order to address these questions, we have studied the distribution pattern of the tight junction-associated proteins ZO-1, ZO-2, ZO-3 and occludin in the developing mouse tooth as a model. A specific temporal and spatial distribution of tight junction-associated proteins during tooth development was observed. ZO-1 appeared discontinuously in the cell membrane of enamel organ and dental mesenchyme cells. However, endothelial cells of the dental mesenchyme capillaries displayed a continuous fluorescence at the cell membrane. Inner dental epithelium first showed an evident signal for ZO-1 at the basal pole of the cells at bud/cap stage, but ZO-1 was accumulated at the basal and apical pole of preameloblast/ameloblasts at late bell stage. Surprisingly, in the incisor ZO-1 decreased as the inner dental epithelium differentiated, and was re-expressed in secretory and mature ameloblasts. On the contrary, ZO-2 was confined to continuous cell-cell contacts of the enamel organ in both molars and incisors. The lateral cell membrane of inner dental epithelial cells was specifically ZO-2 labeled. However, ZO-3 was expressed in oral epithelium whereas dental embryo tissues were negative. In addition, occludin was hardly detected in dental tissues at the early stage of tooth development, but was distributed continuously at the cell membrane of endothelial cells of ED19.5 dental mesenchyme. In incisors, occludin was detected at the cell membrane of the secretory pole of ameloblasts. The occurrence and relation during tooth development of tight junction proteins ZO-1, ZO-2 and occludin, but not ZO-3, suggests a combinatory assembly in tooth morphogenesis and cell differentiation.

[Tissue antioxidant capacity and bacterial translocation in parenteral nutrition. Experimental study]. / Capacidad antioxidante tisular y traslocación bacteriana bajo nutrición parenteral. Estudio experimental.

Alterations in the antioxidant system (AS) has been observed during total parenteral nutrition (TPN). Light exposure or changes in the composition of TPN may affect this deleterious effect. On the other hand, bacterial translocation (BT) is frequent under TPN and may be related to AS. The aim of the study was to determine the adverse effect of standard and glutamine-enriched (GE) TPN, with or without light exposure, on the AS, and its relationship to BT. Forty-nine adult Wistar rats underwent central venous cannulation and were randomly assigned to one of five groups: Sham (n = 16): chow and water ad libitum and saline i.v. TPN (n = 10): had standard TPN. TPN(-) (n = 8): standard TPN without light-exposure. GTPN (n = 8): GE TPN. GTPN(-) (n = 7): GE TPN without light exposure. After 10 days, glutation reduced (GSH) was determined in liver and kidney. Mesenteric lymph nodes, peripheral and portal blood samples were cultured for BT. Comparing to Sham rats, TPN groups had statistically significant lower GSH levels, but there were no differences between standard or GE groups nor with or without light exposure groups. Sham animals had 12% BT. Significantly higher BT (p < 0.05) was found in TPN rats: 70% in TPN group, 88% in TPN(-) group, 86% in GTPN(-) animals and only 50% in GTPN group (p = 0.06 vs TPN group). To conclude: 1. TPN reduces antioxidant capacity and induces BT. 2. Glutamine supplementation or light protection do not improve tissue antioxidant capacity under TPN. 3. Glutamine supplementation tends to reduce BT only in the presence of light. 4. Absence of light exposure does not improve BT TPN-related.

Capacidad antioxidante tisular y traslocación bacteriana bajo nutrición parenteral. Estudio experimental / Tissue antioxidant capacity and bacterial translocation under total parenteral nutrition. An experimental study

Durante la nutrición parenteral total (NPT) aparecen alteraciones en la capacidad antioxidante (CA) que pueden depender de la propia NPT o de su exposición a la luz. La traslocación bacteriana (TB) es frecuente bajo NPT y puede estar relacionada con la CA. Se ha estudiado el efecto adverso de la NPT estándar o suplementada con glutamina (SG), con o sin exposición a la luz, sobre la CA, y su relación con la TB. Tras colocar un catéter central a 49 ratas Wistar adultas, se les randomizó para uno de los cinco grupos siguientes:* Sham (n = 16): suero salino.i.v. y dieta oral libre.* NPT (n = 10): NPT estándar expuesta a la luz.* NPT(-) (n = 8): NPT estándar sin exposición a la luz.* GNPT (n = 8): NPT expuesta a la luz y SG.* GTPN(-) (n = 7): NPT sin exposición a la luz y SG.A los diez días se determinó el glutation reducido (GSH) en hígado y riñón y se cultivaron ganglio mesentérico y sangre portal y periférica. Los grupos con NPT tuvieron niveles significativamente más bajos de GSH que el grupo Sham, pero no hubo diferencias entre los grupos con NPT estándar o, ni entre grupos con y sin exposición a la luz. En el grupo Sham la TB fue del 12 por ciento, mientras que en los que recibieron NPT fue mayor (p < 0,05): 70 por ciento en el grupo NPT, 88 por ciento en el NPT(-), 86 por ciento en el GNPT(-) y sólo 50 por ciento en el grupo GNPT (p = 0,06 vs grupo NPT).En conclusión: 1. La NPT disminuye la CA e induce TB. 2. El SG o la protección contra la luz no mejoran la CA tisular bajo NPT: 3. La ausencia de luz no disminuye la TB debida a la NPT. 4. El SG reduce la TB sólo en presencia de luz (AU)

Polyunsaturated fatty acid deficiency during dietary treatment of very long-chain acyl-CoA dehydrogenase deficiency. Rescue with soybean oil.

Nutritional management of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is based on the avoidance of fasting and substitution of medium-chain triglycerides for long- and very long-chain triglycerides. We report two cases of this disease, which developed omega-6 essential fatty acid deficiency after three and five months from the beginning of nutritional therapy (SHS product: Monogen). This alteration could be especially dangerous in these patients owing to their possible susceptibility to the development of pigmentary retinopathy. The incorporation of linoleic acid as 3-4% of total caloric intake supported as soybean oil ameliorates this deficiency. We wish to remark on this early complication in the nutritional management of VLCAD deficiency and the possibility of rescue by the incorporation of soybean oil into the diet.

Tissue antioxidant capacity and bacterial translocation under total parenteral nutrition.

Alterations in the antioxidative system have been observed during total parenteral nutrition (TPN). Light exposure or changes in the composition of TPN formulas may affect this system. Bacterial translocation (BT) is frequent under TPN and may be related to oxidative status. The aim of this study was to determine the adverse effects of standard and glutamine-enriched TPN, with or without light exposure, on oxidative status (liver and kidney-reduced glutathione, GSH) and its relationship to BT. Thirty-three adult Wistar rats underwent central-venous cannulation and were randomly assigned to one of four groups receiving different TPN regimes for 10 days. The TPN group (n = 10) had standard TPN, the TPN(-) group (n = 8) standard TPN without light exposure, the GTPN group (n = 8) glutamine-enriched TPN, and the GTPN(-) group (n = 7) glutamine-enriched TPN without light exposure. A sham group (n = 16) receiving chow and water ad libitum and saline i.v. served as controls. At the end of the experiment, GSH was determined in liver and kidney tissue. Mesenteric lymph nodes and peripheral and portal blood samples were cultured for BT. Compared to sham rats, TPN groups had statistically significant lower GSH levels, but there were no differences between standard or glutamine-enriched groups or light-exposure groups. Sham animals had 12% BT. Significantly higher BT (P < 0.05) occurred in TPN rats: 70% in the TPN group, 88% in the TPN(-) group, 86% in GTPN (-) animals, and only 50% in the GTPN group (P = 0.06 vs TPN group). In conclusion, (1) TPN reduces antioxidant capacity; (2) glutamine supplementation or light protection does not improve tissue antioxidant capacity under TPN; (3) the absence of light exposure does not improve TPN-related BT; and (4) glutamine supplementation tends to reduce BT only in the presence of light.

FGFs-1 and -2, and TGF beta 1 as inductive signals modulating in vitro odontoblast differentiation.

We have studied the expression of FGF1 and FGF2 during mouse odontogenesis by immunohistochemistry. FGF1 was detected in differentiated odontoblasts and at the secretory pole of ameloblasts. Localization of FGF2 was mainly observed within the basement membrane interposed between dental epithelium and dental mesenchyme. These findings indicate that FGF1 and FGF2 may participate in the control of odontoblast and ameloblast differentiation. Thereafter, we studied the ability of FGF1 and FGF2, alone or in combination with TGF beta 1, to induce polarization and/or functional differentiation of preodontoblasts. Dental papillae (DP) obtained from first lower molars of 17-day-old mouse embryo were cultured in the presence or the absence of growth factors. DP cultured with FGF1 + TGF beta 1 showed gradients of odontoblast-like cell differentiation, which displayed alkaline phosphatase reactivity. DP treated with FGF2 + TGF beta 1 exhibited pre-odontoblast cell polarization, and the cell bodies displayed long cytoplasm processes. However, following this treatment we did not observe extracellular matrix secretion, and alkaline phosphatase activity was completely inhibited. In summary, our results show that exogenous addition of FGF1 to pre-odontoblasts induces their terminal differentiation, by synergistically acting with TGF beta 1. In contrast, FGF2 may regulate the effect of TGF beta 1, permitting cell polarization but restraining pre-odontoblast functions.