Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

Background: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective: To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients. Subjects and methods: The GHSR coding region was directly sequenced in 96 independent patients with ISS, 31 of them with CDGP, in 150 adults, and in 197 children with normal stature. The pharmacological consequences of GHSR non-synonymous variations were established using in vitro cell-based assays. Results: Five different heterozygous point variations in GHSR were identified (c.-6 G>C, c.251G>T (p.Ser84Ile), c.505G>A (p.Ala169Thr), c.545 T>C (p.Val182Ala), and c.1072G>A (p.Ala358Thr)), all in patients with CDGP. Neither these allelic variants nor any other mutations were found in 694 alleles from controls. Functional studies revealed that two of these variations (p.Ser84Ile and p. Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. These mutations were identified in two female patients with CDGP (at the age of 13 years, their height SDS were -2.4 and -2.3). Both patients had normal progression of puberty and reached normal adult height (height SDS of -0.7 and -1.4) without treatment. Conclusion: This is the first report of GHSR mutations in patients with CDGP. Our data raise the intriguing possibility that abnormalities in ghrelin receptor function may influence the phenotype of individuals with CDGP.

Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia

Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone marrow samples from 133 consecutive patients with acute myeloid leukemia and 198 controls for variations in TERT and TERC genes. An additional 89 patients from a second cohort, selected based on cytogenetic status, and 528 controls were further examined for mutations. A third cohort of 372 patients and 384 controls were specifically tested for one TERT gene variant. In the first cohort, 11 patients carried missense TERT gene variants that were not present in controls (P<0.0001); in the second cohort, TERT mutations were associated with trisomy 8 and inversion 16. Mutation germ-line origin was demonstrated in 5 patients from whom other tissues were available. Analysis of all 3 cohorts (n = 594) for the most common gene variant (A1062T) indicated a prevalence 3 times higher in patients than in controls (n = 1,110; P = 0.0009). Introduction of TERT mutants into telomerase-deficient cells resulted in loss of enzymatic activity by haploinsufficiency. Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability.

Constitutional Telomerase Mutations Are Genetic Risk Factors for Cirrhosis

Some patients with liver disease progress to cirrhosis, but the risk factors for cirrhosis development are unknown. Dyskeratosis congenita, an inherited bone marrow failure syndrome associated with mucocutaneous anomalies, pulmonary fibrosis, and cirrhosis, is caused by germline mutations of genes in the telomerase complex. We examined whether telomerase mutations also occurred in sporadic cirrhosis. In all, 134 patients with cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528 healthy subjects were screened for variation in the TERT and TERC genes by direct sequencing; an additional 1,472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation-containing vectors into telomerase-deficient cell lines, and telomerase activity was measured in cell lysates. Nine of the 134 patients with cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P = 0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in patients with cirrhosis (2.6%) than in 2,000 controls (0.7%; P = 0.0011). One additional patient carried a TERC mutation. The mean telomere length of leukocytes in patients with cirrhosis, including six mutant cases, was shorter than in age-matched controls (P = 0.0004). Conclusion: Most TERT gene variants reduced telomerase enzymatic activity in vitro. Loss-of-function telomerase gene variants associated with short telomeres are risk factors for sporadic cirrhosis. (HEPATOLOGY 2011;53:1600-1607)

Re McBain; ex parte Australian Catholic Bishops Conference

The case of Re McBain; ex parte Australian Catholic Bishops Conference sought to make an order under s 76 of the Constitution that the decision of the Federal Court was incorrect in law - decision was made on the basis of constitutional and procedural issues - High Court consolidated the definition of 'matter' in sections 75 and 76 of the Constitution - writ of certiorari considered - role of the Attorney-General in proceedings in which he had granted a fiat - case reiterated the role of the judiciary in Australia.

Anotação sintética, numa perspectiva de Direito Público-penal e Direito Privado-civil, ao Acórdão do Supremo Tribunal de Justiça Português, de 19 de Abril de 2012-- A poluição sonora e o direito humano ao descanso e à saúde, sem descurar a necessidade duma adequada política tributária.

Resumo: 1 – Sumário do Acórdão do Supremo Tribunal de Justiça, de 19 de Abril de 2012; 2 – Texto completo do Acórdão do Supremo Tribunal de Justiça, de 19 de Abril de 2012: cfr. http://www.dgsi.pt/jstj.nsf/954f0ce6ad9dd8b980256b5f003fa814/fc664c231f3e73cf802579ea003d91d2?OpenDocument&Highlight=0,polui%C3%A7%C3%A3o , 2 de Junho de 2012; 3 – Anotação sintética; 3.1 – Introdução à anotação sintética e suas características neste caso concreto; 4 – Algumas referências constitucionais centrais em relação a Direitos humanos e, nomeadamente, a um Direito humano a um meio-ambiente sadio, saudável em todas as suas vertentes e sentidos – o exemplo central do artigo 9.º da CRP; 4.1 – Algumas referências constitucionais centrais em relação a Direitos humanos e, nomeadamente, a um Direito humano a um meio-ambiente sadio, saudável em todas as suas vertentes e sentidos – o exemplo central do artigo 66.º da CRP e o Regime Geral do Ruído; 5 – O direito humano ao descanso e à saúde, rectius o direito ao ambiente sadio vs o direito ao lazer e/ou exploração económica de indústrias de diversão, rectius o direito à liberdade de iniciativa económica privada; 6 – A violação do direito humano, de personalidade, ao descanso e à saúde, rectius o direito a um ambiente sadio, numa perspectiva de Direito privado e Direito civil; 7 – A criminalização da poluição, designadamente a criminalização da poluição sonora – uma perspectiva de Direito público e Direito penal; 8 - A necessidade duma adequada política tributária que compatibilize desenvolvimento sustentado com a protecção dum meio ambiente sadio e com qualidade de vida; 9 – Conclusões. § Abstract: 1 - Summary of the Judgment of the Supreme Court of April 19, 2012, 2 - Complete text of the Judgment of the Supreme Court of April 19, 2012: cf. http://www.dgsi.pt/jstj.nsf/954f0ce6ad9dd8b980256b5f003fa814/fc664c231f3e73cf802579ea003d91d2?OpenDocument&Highlight=0,polui%C3%A7%C3%A3o , June 2, 2012, 3 - Synthetic Note: 3.1 - Introduction to synthetic annotation and its characteristics in this case 4 - Some references constitutional power over human rights and in particular to a human right to a healthy environment, healthy in all its forms and meanings - the central example of Article 9. of CRP; 4.1 - Some references constitutional power over human rights and in particular to a human right to a healthy environment, healthy in all its forms and meanings - the central example of Article 66. No of CRP and the General Noise; 5 - the human right to rest and health, rectius the right to healthy environment vs. the right to leisure and / or economic exploitation of industries fun, rectius the right to freedom of private economic initiative; 6 - the violation of human personality, to rest and health, rectius the right to a healthy environment, a perspective of private law and civil law; 7 - criminalization of pollution, including the criminalization of noise - a perspective of public law and criminal law; 8 - the need for appropriate tax policy that reconciles sustainable development with the protection of a healthy environment and quality of life; 9 - Conclusions.

Vir sapiens dominabitur astris: astrological knowledge and practices in the Portuguese medieval court (king João I to king Afonso V)

Dissertação apresentada para cumprimento dos requisitos necessários à obtenção do grau de Mestre em História Medieval

A intervenção dos orgãos de polícia criminal em sede de julgamento

Currently, Portugal assumes itself as a democratic rule of substantive law State, sustained by a legal system seeking the right balance between the guarantee of fundamental rights and freedoms constitutional foreseen in Portugal’s Fundamental Law and criminal persecution. The architecture of the penal code lies with, roughly speaking, a accusatory basic structure, “deliberately attached to one of the most remarkable achievements of the civilizational democratic progress, and by obedience to the constitutional commandment”, in balance with the official investigation principle, valid both for the purpose of prosecution and trial. Regarding the principle of non self-incrimination - nemo tenetur se ipsum accusare, briefly defined as the defendant’s right of not being obliged to contribute to the self-incrimination, it should be stressed that there isn’t an explicit consecration in the Portuguese Constitution, being commonly accepted in an implicit constitutional prediction and deriving from other constitutional rights and principles, first and foremost, the meaning and scope of the concept of democratic rule of Law State, embedded in the Fundamental Law, and in the guidelines of the constitutional principles of human person dignity, freedom of action and the presumption of innocence. In any case, about the (in) applicability of the principle of the prohibition of self-incrimination to the Criminal Police Bodies in the trial hearing in Court, and sharing an idea of Guedes Valente, the truth is that the exercise of criminal action must tread a transparent path and non-compliant with methods to obtain evidence that violate the law, the public order or in violation of democratic principles and loyalty (Guedes Valente, 2013, p. 484). Within the framework of the penal process relating to the trial, which is assumed as the true phase of the process, the witness represents a relevant figure for the administration of criminal justice, for the testimonial proof is, in the idea of Othmar Jauernig, the worst proof of evidence, but also being the most frequent (Jauernig, 1998, p. 289). As coadjutant of the Public Prosecutor and, in specific cases, the investigating judge, the Criminal Police Bodies are invested with high responsibility, being "the arms and eyes of Judicial Authorities in pursuing the criminal investigation..." which has as ultimate goal the fulfillment of the Law pursuing the defense of society" (Guedes Valente, 2013, p. 485). It is in this context and as a witness that, throughout operational career, the Criminal Police Bodies are required to be at the trial hearing and clarify the Court with its view about the facts relating to occurrences of criminal context, thus contributing very significantly and, in some cases, decisively for the proper administration of the portuguese criminal justice. With regards to the intervention of Criminal Police Bodies in the trial hearing in Court, it’s important that they pay attention to a set of standards concerning the preparation of the testimony, the very provision of the testimony and, also, to its conclusion. Be emphasized that these guidelines may become crucial for the quality of the police testimony at the trial hearing, thus leading to an improvement of the enforcement of justice system. In this vein, while preparing the testimony, the Criminal Police Bodies must present itself in court with proper clothing, to read before and carefully the case files, to debate the facts being judged with other Criminal Police Bodies and prepare potential questions. Later, while giving his testimony during the trial, the Criminal Police Bodies must, summing up, to take the oath in a convincing manner, to feel comfortable, to start well by convincingly answering the first question, keep an attitude of serenity, to adopt an attitude of collaboration, to avoid the reading of documents, to demonstrate deference and seriousness before the judicial operators, to use simple and objective language, to adopt a fluent speech, to use nonverbal language correctly, to avoid spontaneity responding only to what is asked, to report only the truth, to avoid hesitations and contradictions, to be impartial and to maintain eye contact with the judge. Finally, at the conclusion of the testimony, the Criminal Police Bodies should rise in a smooth manner, avoiding to show relief, resentment or satisfaction, leaving a credible and professional image and, without much formality, requesting the judge permission to leave the courtroom. As final note, it’s important to stress that "The intervention of the Police Criminal Bodies in the trial hearing in Court” encloses itself on a theme of crucial importance not only for members of the Police and Security Forces, who must welcome this subject with the utmost seriousness and professionalism, but also for the proper administration of the criminal justice system in Portugal.

O processo sumário e a reforma do Código do Processo Penal de 2013

The present work aims to develop the theme "The summary procedure and the reform of 2013". The purpose of its analysis serves the interest to understand the virtues and disadvantages of the changes introduced by Act n.º 20/2013 to our Code of Criminal Procedure, and the main focus of the present reflection is to further the impact of the measures taken by the legislator to the summary proceedings. The opening of the most serious crimes to summary procedure is a reform measure duly highlighted because it is a true innovation in the Portuguese penal system. Therefore, it urges to analyse not only the consequences of this measure, as well as if the objectives of its introduction in the summary procedure system are met. It should be noted that the legislator intends to promote speedy trial, and at the same time, ensure compliance with the Constitutional rights associated to the accused. At this point it is important to realize if there is a restriction of the accused essential guarantees. On the other hand, it should be noted that the typical characteristics of summary proceedings might have been invariably modified, due to the innovative aspect of the reform. That said, the changes might have fostered a mischaracterization of the typical format of the summary procedure, both in terms of the nature of the proceedings and in terms of its space and objectives within the penal system. Reflecting on the above will provide a deeper understanding of the volatile balance between the Portuguese governing prosecution efficiency and the Constitution, as well as the future of the criminal policy in Portugal.