Modular Label-Free Electrochemical Biosensor Loading Nature-Inspired Peptide toward the Widespread Use of COVID-19 Antibody Tests.

Limitations of the recognition elements in terms of synthesis, cost, availability, and stability have impaired the translation of biosensors into practical use. Inspired by nature to mimic the molecular recognition of the anti-SARS-CoV-2 S protein antibody (AbS) by the S protein binding site, we synthesized the peptide sequence of Asn-Asn-Ala-Thr-Asn-COOH (abbreviated as PEP2003) to create COVID-19 screening label-free (LF) biosensors based on a carbon electrode, gold nanoparticles (AuNPs), and electrochemical impedance spectroscopy. The PEP2003 is easily obtained by chemical synthesis, and it can be adsorbed on electrodes while maintaining its ability for AbS recognition, further leading to a sensitivity 3.4-fold higher than the full-length S protein, which is in agreement with the increase in the target-to-receptor size ratio. Peptide-loaded LF devices based on noncovalent immobilization were developed by affording fast and simple analyses, along with a modular functionalization. From studies by molecular docking, the peptide-AbS binding was found to be driven by hydrogen bonds and hydrophobic interactions. Moreover, the peptide is not amenable to denaturation, thus addressing the trade-off between scalability, cost, and robustness. The biosensor preserves 95.1% of the initial signal for 20 days when stored dry at 4 °C. With the aid of two simple equations fitted by machine learning (ML), the method was able to make the COVID-19 screening of 39 biological samples into healthy and infected groups with 100.0% accuracy. By taking advantage of peptide-related merits combined with advances in surface chemistry and ML-aided accuracy, this platform is promising to bring COVID-19 biosensors into mainstream use toward straightforward, fast, and accurate analyses at the point of care, with social and economic impacts being achieved.

The phenotypic spectrum associated with OTX2 mutations in humans.

Objective: The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development. Design: We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods: We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results: Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions: OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.

Genetic diagnosis of congenital hypopituitarism by a target gene panel: novel pathogenic variants in GLI2, OTX2 and GHRHR.

AIM: Congenital hypopituitarism has an incidence of 1:3500-10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism. METHODS: Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel. RESULTS: We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];[c.109+1G>A]. CONCLUSIONS: Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.

Androgen receptor mRNA analysis from whole blood: a low-cost strategy for detection of androgen receptor gene splicing defects.

Androgen insensitivity syndrome (AIS) is caused by defects in the androgen receptor (AR) gene and is the most common aetiology of 46,XY disorders of sex development. Allelic variants in the AR gene are found in 90% of complete AIS (CAIS), but in only 28% to 50% of cases of partial AIS. Even a single nucleic acid change can disrupt splicing sites or splicing regulatory sequences, resulting in inadequate exon and intron recognition, ultimately leading to an aberrant transcript. Therefore, we tested the feasibility of conducting AR cDNA analysis from whole blood and from gonadal tissue in a patient with CAIS due to AR synonymous mutation (c.1530C > T, p.Ser510Ser; NM_000044.3), which led to an aberrant splicing site causing deletion of 92 nucleotides resulting in a very short transcript. AR cDNA sequencing was similar in the whole blood and in the gonadal tissue, with similar evidence of a consequent altered AR transcript. We propose that analysis of AR RNA extracted from whole blood with AR DNA sequencing can help to improve the frequency of molecular diagnosis, particularly for partial AIS.

Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: a long term follow-up of patients from a single center.

BACKGROUND: Children initially diagnosed with isolated GH deficiency (IGHD) have a variable rate to progress to combined pituitary hormone deficiency (CPHD) during follow-up. OBJECTIVE: To evaluate the development of CPHD in a group of childhood-onset IGHD followed at a single tertiary center over a long period of time. PATIENTS AND METHODS: We retrospectively analyzed data from 83 patients initially diagnosed as IGHD with a mean follow-up of 15.2 years. The Kaplan-Meier method and Cox regression analysis was used to estimate the temporal progression and to identify risk factors to development of CPHD over time. RESULTS: From 83 patients initially with IGHD, 37 (45%) developed CPHD after a median time of follow up of 5.4 years (range from 1.2 to 21 years). LH and FSH deficiencies were the most common pituitary hormone (38%) deficiencies developed followed by TSH (31%), ACTH (12%) and ADH deficiency (5%). ADH deficiency (3.1 ± 1 years from GHD diagnosis) presented earlier and ACTH deficiency (9.3 ± 3.5 years) presented later during follow up compared to LH/FSH (8.3 ± 4 years) and TSH (7.5 ± 5.6 years) deficiencies. In a Cox regression model, pituitary stalk abnormalities was the strongest risk factor for the development of CPHD (hazard ratio of 3.28; p = 0.002). CONCLUSION: Our study indicated a high frequency of development of CPHD in patients initially diagnosed as IGHD at childhood. Half of our patients with IGHD developed the second hormone deficiency after 5 years of diagnosis, reinforcing the need for lifelong monitoring of pituitary function in these patients.

PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation.

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n=10), somatotrophinomas (n=8), and nonfunctioning adenomas (n=6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r=0.49, p=0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation.

PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation. .

Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly.

OBJECTIVE: GLI2 is a downstream transcription factor in Sonic Hedgehog signalling, acting early in ventral forebrain and pituitary development. Heterozygous nonsense GLI2 mutations have been reported in patients with isolated or combined pituitary hormone deficiency (CPHD), with or without holoprosencephaly. The aim of this study was to screen for GLI2 mutations in a large cohort of patients with congenital GH deficiency. DESIGN AND PATIENTS: The GLI2 coding region of 41 patients with severe isolated GH deficiency (IGHD) and 136 patients with CPHD was amplified by PCR using intronic primers and sequenced. The frequency of GLI2 variants was verified in up to 155 Brazilian controls and in the 1000 Genomes database. The consequences of allelic variants were analysed by the Polyphen, SIFT, Mutationtaster and SNAP prediction sites. RESULTS: Eighteen different heterozygous non-synonymous GLI2 variants were identified in 24 patients. Twenty-three patients had CPHD and one had IGHD. Two patients had additional diabetes insipidus, indicating deficiencies of anterior and posterior pituitary lobes. The posterior pituitary lobe on MRI was ectopic in 16, not visible in 4, normally placed in 2 and imaging was not available in two patients, but there were no signs of holoprosencephaly. Sixteen GLI2 variants were considered deleterious in at least one of the prediction sites. CONCLUSIONS: A relatively high frequency of non-synonymous GLI2 variants was identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with CPHD and an ectopic posterior pituitary lobe. In vitro functional assays may contribute to ascertain the deleterious consequences of these variants.

PROP1 and CTNNB1 expression in adamantinomatous craniopharyngiomas with or without ß-catenin mutations.

INTRODUCTION: Activating mutations in exon 3 of the ß-catenin gene are involved in the pathogenesis of adamantinomatous craniopharyngiomas. Recently, the interaction between ß-catenin and PROP1 has been shown to be responsible for pituitary cell lineage determination. We hypothesized that dysregulated PROP1 expression could also be involved in the pathogenesis of craniopharyngiomas OBJECTIVES: To determine whether dysregulated gene expression was responsible for tumor pathogenesis in adamantinomatous craniopharyngiomas, the ß-catenin gene was screened for mutations, and the expression of the ß-catenin gene and PROP1 was evaluated. ß-catenin gene was amplified and sequenced from 14 samples of adamantinomatous craniopharyngiomas. PROP1 and ß-catenin gene expression was assessed by real-time RT-PCR from 12 samples, and ß-catenin immunohistochemistry was performed on 11 samples. RESULTS: Mutations in the ß-catenin gene were identified in 64% of the adamantinomatous craniopharyngiomas samples. Evidence of ß-catenin gene overexpression was found in 71% of the tumors with ß-catenin mutations and in 40% of the tumors without mutations, and ß-catenin immunohistochemistry revealed a nuclear staining pattern for each of the analyzed samples. PROP1 expression was undetectable in all of the tumor samples. CONCLUSION: We found evidence of ß-catenin gene overexpression in the majority of adamantinomatous craniopharyngiomas, and we also detected a nuclear ß-catenin staining pattern regardless of the presence of a ß-catenin gene mutation. These results suggest that WNT signaling activation plays an important role in the pathogenesis of adamantinomatous craniopharyngiomas. Additionally, this study was the first to evaluate PROP1 expression in adamantinomatous craniopharyngiomas, and the absence of PROP1 expression indicates that this gene is not involved in the pathogenesis of this tumor, at least in this cohort.

Absence of GH-releasing hormone (GHRH) mutations in selected patients with isolated GH deficiency.

CONTEXT: Although numerous reports of mutations in GH1 and GHRHR (GHRH receptor) causing isolated GH deficiency (IGHD) have been published, mutations in GHRH itself have not been hitherto reported but are obvious candidates for GH deficiency. OBJECTIVE: The aim of this study was to identify mutations in GHRH in a large cohort of patients with IGHD. PATIENTS AND METHODS: DNA was isolated from 151 patients diagnosed with IGHD at national and international centers. Seventy-two patients fulfilled all the following criteria: severe short stature (height sd score ≤ -2.5), low peak GH after stimulation (peak ≤ 5 ng/ml), eutopic posterior pituitary lobe, and absence of mutations in GH1 and GHRHR and therefore were strong candidates for GHRH mutations. The coding sequence and splice sites of GHRH were amplified by PCR with intronic primers and sequenced. RESULTS: In five of 151 patients (four of 42 from Brazil), the GHRH c.223 C>T, p.L75F change was identified in heterozygosity. This variant has been previously reported as a polymorphism and is more frequent in African than European and Asian populations. Six allelic variants (five novel) that do not predict change of amino acids or splice sites were identified in five patients: c.147 C>T, p.S49S, IVS1 -70 G>A, IVS1 -74 T>C, IVS3 -47 del1, and IVS3 +7 G>A /IVS3+41 G>A. No functional mutations were found in this cohort. CONCLUSIONS: GHRH mutations were not identified in a selected cohort of patients with IGHD, suggesting that, if they exist, they may be an extremely rare cause of IGHD. Other, as-yet-unidentified genetic factors may be implicated in the genetic etiology of IGHD in our cohort.

PROP1 and CTNNB1 expression in adamantinomatous craniopharyngiomas with or without β-catenin mutations

INTRODUCTION: Activating mutations in exon 3 of the β-catenin gene are involved in the pathogenesis of adamantinomatous craniopharyngiomas. Recently, the interaction between β-catenin and PROP1 has been shown to be responsible for pituitary cell lineage determination. We hypothesized that dysregulated PROP1 expression could also be involved in the pathogenesis of craniopharyngiomas OBJECTIVES: To determine whether dysregulated gene expression was responsible for tumor pathogenesis in adamantinomatous craniopharyngiomas, the β-catenin gene was screened for mutations, and the expression of the β-catenin gene and PROP1 was evaluated. β-catenin gene was amplified and sequenced from 14 samples of adamantinomatous craniopharyngiomas. PROP1 and β-catenin gene expression was assessed by real-time RT-PCR from 12 samples, and β-catenin immunohistochemistry was performed on 11 samples. RESULTS: Mutations in the β-catenin gene were identified in 64 percent of the adamantinomatous craniopharyngiomas samples. Evidence of β-catenin gene overexpression was found in 71 percent of the tumors with β-catenin mutations and in 40 percent of the tumors without mutations, and β-catenin immunohistochemistry revealed a nuclear staining pattern for each of the analyzed samples. PROP1 expression was undetectable in all of the tumor samples. CONCLUSION: We found evidence of β-catenin gene overexpression in the majority of adamantinomatous craniopharyngiomas, and we also detected a nuclear β-catenin staining pattern regardless of the presence of a bcatenin gene mutation. These results suggest that WNT signaling activation plays an important role in the pathogenesis of adamantinomatous craniopharyngiomas. Additionally, this study was the first to evaluate PROP1 expression in adamantinomatous craniopharyngiomas, and the absence of PROP1 expression indicates that this gene is not involved in the pathogenesis of this tumor, at least in this cohort.

Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly.

CONTEXT: GLI2 is a transcription factor downstream in Sonic Hedgehog signaling, acting early in ventral forebrain and pituitary development. GLI2 mutations were reported in patients with holoprosencephaly (HPE) and pituitary abnormalities. OBJECTIVE: The aim was to report three novel frameshift/nonsense GLI2 mutations and the phenotypic variability in the three families. SETTING: The study was conducted at a university hospital. PATIENTS AND METHODS: The GLI2 coding region of patients with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency was amplified by PCR using intronic primers and sequenced. RESULTS: Three novel heterozygous GLI2 mutations were identified: c.2362_2368del p.L788fsX794 (family 1), c.2081_2084del p.L694fsX722 (family 2), and c.1138 G>T p.E380X (family 3). All predict a truncated protein with loss of the C-terminal activator domain. The index case of family 1 had polydactyly, hypoglycemia, and seizures, and GH, TSH, prolactin, ACTH, LH, and FSH deficiencies. Her mother and seven relatives harboring the same mutation had polydactyly, including two uncles with IGHD and one cousin with GH, TSH, LH, and FSH deficiencies. In family 2, a boy had cryptorchidism, cleft lip and palate, and GH deficiency. In family 3, a girl had hypoglycemia, seizures, excessive thirst and polyuria, and GH, ACTH, TSH, and antidiuretic hormone deficiencies. Magnetic resonance imaging of four patients with GLI2 mutations and hypopituitarism showed a hypoplastic anterior pituitary and an ectopic posterior pituitary lobe without HPE. CONCLUSION: We describe three novel heterozygous frameshift or nonsense GLI2 mutations, predicting truncated proteins lacking the activator domain, associated with IGHD or combined pituitary hormone deficiency and ectopic posterior pituitary lobe without HPE. These phenotypes support partial penetrance, variable polydactyly, midline facial defects, and pituitary hormone deficiencies, including diabetes insipidus, conferred by heterozygous frameshift or nonsense GLI2 mutations.

[Growth hormone (GH) deficiency treatment in children: comparison between uses of pen versus bottles/syringes on GH administration]. / Tratamento da deficiência do hormônio de crescimento (GH) em crianças: comparação entre o uso de canetas versus frascos/seringas para a aplicação do GH.

The aim of this study was to compare two preparations of recombinant human GH (rGH) in the treatment of GH deficient patients. Ten prepubertal GH-deficient children were followed during 6 months. They received injections with syringe for 3 months, followed by pen administration for the subsequent 3 months. Acceptability was evaluated through a questionnaire. Waste of medication was calculated by the difference between the number of used bottles or refills and the calculated amount for the period. Treatment response was evaluated by SDS gain of height measured each 3 months. After 6 months, 90% of patients/family members declared they preferred the pen regarding technical facility and local pain, and all patients considered the pen easier to transport and store. The waste of medication was lower with pen administration, as was the final cost. We concluded that pen-administered rGH treatment is more convenient, better accepted by the patients, and leads to less waste of medication when compared to the syringe administration.

Tratamento da deficiência do hormônio de crescimento (GH) em crianças: comparação entre o uso de canetas versus frascos/seringas para a aplicação do GH / Growth hormone (GH) deficiency treatment in children: comparison between uses of pen versus bottles/syringes on GH administration

O objetivo deste estudo foi comparar as duas apresentações de GH recombinante humano (rGH) para tratamento da deficiência de GH (DGH). Dez crianças pré-púberes portadoras de DGH foram acompanhadas durante 6 meses. Elas receberam, por 3 meses, injeções com seringa e, a seguir, com canetas por mais 3 meses. A aceitabilidade foi avaliada através de questionário. O desperdício foi calculado através da diferença entre o número de frascos/refis utilizados e o previsto para o período. A resposta ao tratamento foi avaliada pelo ganho em desvio-padrão (DP) de altura medido a cada 3 meses. Após 6 meses, 90 por cento dos pacientes/familiares afirmaram preferir a caneta em termos de facilidade técnica e dor local, e todos consideraram a caneta melhor em termos de facilidade de transporte e armazenamento. O desperdício foi menor com a caneta, assim como o custo. Concluímos que a administração de rGH através de caneta é mais conveniente, melhor aceita pelos pacientes e resulta em menor desperdício quando comparada com o tratamento por seringa.

The aim of this study was to compare two preparations of recombinant human GH (rGH) in the treatment of GH deficient patients. Ten prepubertal GH-deficient children were followed during 6 months. They received injections with syringe for 3 months, followed by pen administration for the subsequent 3 months. Acceptability was evaluated through a questionnaire. Waste of medication was calculated by the difference between the number of used bottles or refills and the calculated amount for the period. Treatment response was evaluated by SDS gain of height measured each 3 months. After 6 months, 90 percent of patients/family members declared they preferred the pen regarding technical facility and local pain, and all patients considered the pen easier to transport and store. The waste of medication was lower with pen administration, as was the final cost. We concluded that pen-administered rGH treatment is more convenient, better accepted by the patients, and leads to less waste of medication when compared to the syringe administration.

Bases genéticas dos distúrbios de crescimento / Genetic bases of growth disorders

A integridade do eixo GHRH-GH-IGF-I é fundamental para o crescimento normal de um indivíduo. Mutações nos genes responsáveis por cada uma das etapas deste eixo resultam em baixa estatura grave. Podemos dividir os distúrbios de crescimento em: 1. Deficiência de GH associada a deficiências de outros hormônios hipofisários por alterações em fatores de transcriçäo envolvidos na organogênese hipofisária (HESX1/RPX, LHX3 e LHX4, PROP-1, PIT-1); 2. Deficiência isolada de GH (receptor do GHRH:GHRHR, GH-1, GH bioinativo); e 3. Insensibilidade ao GH (receptor de GH:GHR, gene da IGF-I e receptor da IGF-I:IGFR). Seräo discutidos também os genes implicados na baixa estatura da Síndrome de Turner (SHOX) e Síndrome de Noonan (PTPN11). Atualmente estamos analisando no Laboratório de Hormónios e Genética Molecular da Disciplina de Endocrinologia da FMUSP - LIM 42 os genes HESX-1, LHX3, LHX4, PROP-1, GHRHR, GH-1, GHR, SHOX e PTPN11 em pacientes com baixa estatura e características clínicas e laboratoriais que sugerem o envolvimento destes genes.

Telarca reversível espontaneamente em meninas pré-púberes durante o tratamento com hormônio de crescimento recombinante humano / Reversible thelarche spontaneously in pre-puberal girls during of the treatment with human recombinant growth hormone

OBJETIVO: Descriçäo de 4 casos de desenvolvimento transitório de mamas em meninas pré-púberes tratadas com hormônio de crescimento recombinante humano (rhGH). CASUíSTICA E MÉTODOS: Quatro meninas pré-púberes com baixa estatura, duas com síndrome de Turner (ST) e duas com deficiência de hormônio de crescimento (DGH). O desenvolvimento das mamas (Tanner II e III) ocorreu com idade cronológica (IC) de 5,6 e 7,7 anos e idade óssea (10) de 5,7 a 6,9 anos, 2 a 60 meses após o inicio do tratamento com rhGH na dose de 0,1 - 0,15U/kg/d. Todas as pacientes apresentaram regressäo espontânea da telarca num período de 8 a 15 meses. Três pacientes foram submetidas ao teste de estímulo com GnRH apresentando resposta pré-puberal de LH. DISCUSSäO: O desenvolvimento de mamas após o início do tratamento com rhGH tem sido relatado em meninos, mas näo em meninas pré-púberes. Concluímos que o rhGH pode induzir ao desenvolvimento transitório das mamas, também em meninas, sem a ativaçäo do eixo hipotálamo-hipófise-gonadal, näo se fazendo necessária a supressäo da puberdade.

Descompensaçäo cardíaca pós-intoxicaçäo exógena por estricnina: relato de caso / Cardiac descompensation from exogenous intoxication by strychnine: case report

Apresentamos o caso de um paciente intoxicado por estricnina que evoluiu com Insuficiência Cardíaca Congestiva diagnosticada através de ecocardiograma e parâmetros hemodinâmicos conseguidos através de cateter de Swan-Ganz. A intoxicaçao por estricnina nao é comumente encontrada devido à proibiçao de sua comercializaçao, especial atençao tem sido dada a esta droga devido ao seu uso na manufatura de drogas como a cocaína. Alguns autores mostram que a estricnina age sobre centros vasomotores alterando pressao arterial durante as convulsoes, outros mostraram arritmias durante as convulsoes, mas nao comprovaram a existência de cardiotoxidade pela estricnina. A monitorizaçao hemodinâmica foi de bastante auxílio neste caso nao só no sentido de guiar a terapêutica mas também no diagnóstico diferencial do edema pulmonar que, em se tratando de paciente hígido e jovem poderia facilmente ser rotulado como edema "nao cardiogênico". Embora a intoxicaçao por estricnina seja de altíssima mortalidade, com o suporte hemodinâmico e respiratório adequado proporcionamos uma recuperaçao total do paciente, sem seqüela neurológica, renal e pulmonar.

Bócio uninodular tóxico em uma criança de 11 anos de idade: relato de caso / Uninodular toxic goiter in an 11 year-old child: case report

A disfunção da glândula tiróide na infância é uma entidade rara e de significado clínico importante, já que aproximadamente dos nódulos nesta faixa etária expresam característica de malignidade, relatamos um caso de bócio nodular tóxico em uma criança de 11 anos de idade que apresentava história clínica de 3 anos de evolução caracterizada por um nódulo palpável em região cervical anterior e um quadro leve de tirotoxicose. Após a confirmação da autonomia do nódulo e descartada a hipótese de hemiagenesia da glândula tiróide, a paciente foi submetida a tiroidectomia subtotal (lobectomia direita), uma vez que este é o tratamento de escolha nesta faixa etária. No pós-operatório, a paciente evoluiu clinicamente eutiroidiana e permanece em acompanhamento no nosso serviço