Literatura científica selecionada sobre o tema "Najjārī family"

Background: Crigler–Najjar syndrome type I (CN-1) and type II (CN-2) are rare hereditary unconjugated hyperbilirubinemia disorders. However, there have been no reports regarding the co-existence of CN-1 and CN-2 in one family. We experienced a case of an Iranian family that included members with either CN-1 or CN-2. Genetic analysis revealed a mutation in the bilirubin UDP-glucuronosyltransferase (UGT1A1) gene that resulted in residual enzymatic activity.Case report: The female proband developed severe hyperbilirubinemia [total serum bilirubin concentration (TB) = 34.8 mg/dL] with bilirubin encephalopathy (kernicterus) and died after liver transplantation. Her family history included a cousin with kernicterus (TB = 30.0 mg/dL) diagnosed as CN-1. Her great grandfather (TB unknown) and uncle (TB = 23.0 mg/dL) developed jaundice, but without any treatment, they remained healthy as CN-2. Results: The affected cousin was homozygous for a novel frameshift mutation (c.381insGG, p.C127WfsX23). The affected uncle was compound heterozygous for p.C127WfsX23 and p.V225G linked with A(TA)7TAA. p.V225G-UGT1A1 reduced glucuronidation activity to 60% of wild-type. Thus, linkage of A(TA)7TAA and p.V225G might reduce UGT1A1 activity to 18%–36 % of the wild-type. Conclusion: Genetic and in vitro expression analyses are useful for accurate genetic counseling for a family with a history of both CN-1 and CN-2. Abbreviations: CN-1: Crigler–Najjar syndrome type I; CN-2: Crigler–Najjar syndrome type II; GS: Gilbert syndrome; UGT1A1: bilirubin UDP-glucuronosyltransferase; WT: Wild type; TB: total serum bilirubin.

Crigler-Najjar syndrome (CNS) type I and type II are inherited as autosomal recessive conditions that are caused by mutations in theUGT1A1gene. We present the analysis ofUGT1A1gene in 12 individuals from three different families. This analysis allowed us to identify one novel mutation, which was not previously described. In this study, three families with clinically diagnosed CNS referred from Khuzestan province, southwest Iran, were screened. After signing the informed consent, peripheral blood samples from the patients and their parents were collected in EDTA-containing tube followed by DNA extraction using a routine phenol-chloroform method. All five coding exons and the flanking intronic regions of the bilirubin-UGT were amplified by polymerase chain reaction (PCR) followed by DNA sequencing by Sanger method. From the first family, a 9-month-old boy was homozygous for a deletion mutation of two adjacent nucleotides including one adenosine (A) and one glutamine (G) between nucleotides 238 and 239 in exon 1 (c.238_240 del AG). In the second family, there were two affected individuals, an 11-year-old girl and a fetus, found to be homozygous for the same mutation. The third family showed a mutation at nucleotide 479 in exon 1 (Val160Glu) that has been reported previously. Molecular analysis can significantly help confirm the diagnosis of CNS, without any need for the liver biopsy, and may help the therapeutic management by ruling out more harmful causes of hyperbilirubinemia.

Crigler-Najjar syndrome type 1 (CN1) is an inherited disorder characterized by the absence of hepatic uridine diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for the conjugation and excretion of bilirubin. We performed allogenic hepatocyte transplantation (AHT) in a child with CN1, aiming to improve bilirubin glucuronidation in this condition. A 9-year-old boy with CN1 was prepared with plasmapheresis and immunosuppression with prednisolone and tacrolimus. When a graft was made available, 7.5 × 109 hepatocytes were isolated and infused into the portal vein percutaneously. After 2 weeks phenobarbitone was added to promote the enzymatic activity of UDPGT of the transplanted hepatocytes. Nocturnal phototherapy was continued throughout the studied period. Total bilirubin was considered a reliable marker of allogenic cell function. There was no significant variation of vital signs nor complications during the infusion. Mean ± SD bilirubin level was 530 ± 38 μmol/L before and 359 ± 46 μmol/L after AHT (t-test, p < 0.001). However, the introduction of phenobarbitone was followed by a drop of tacrolimus level with increase of alanine aminotransferase (ALT) and increase of bilirubin. After standard treatment of cellular rejection bilirubin fell again but from then on it was maintained at a greater level. After discharge the patient experienced a further increase of bilirubin that returned to predischarge levels after readmission to the hospital. This was interpreted as poor compliance with phototherapy. Only partial correction of clinical jaundice and the poor tolerability to nocturnal phototherapy led the parents to refuse further hepatocyte infusions and request an orthotopic liver transplant. After 24 months the child is well, with good liver function on tacrolimus and prednisolone-based immunosuppression. Isolated AHT, though effective and safe, is not sufficient to correct CN1. Maintenance of adequate immunosuppression and family compliance are the main factors hampering the success of this procedure.

The colorectal cancer ranks high among the malignant tumours in incidence and mortality and irinotecan is standardly used in palliative treatment of metastatic disease in every therapeutic line. Unfortunately, the treatment with irinotecan is often associated with severe toxicities, especially neutropenia and diarrhea. The majority of the toxic manifestation is caused by the insufficient deactivation (glucuronidation) of irinotecan active metabolite SN-38 by UGT1A enzyme. The elevated SN-38 plasma concentration is responsible for the hematological and gastrointestinal toxicity that can become life-threatening. The patients carrying the mutation of the gene encoding UGT1A enzyme lack the ability of bilirubin glucuronidation, and suffer from the inherited un-conjugated hyperbilirubinemia (Gilbert syndrome, Crigler- Najjar type 1 and 2 syndrome). The mutations in other enzyme systems also play role in the etiopathogenesis of the irinotecan toxicity: CYP3A (cytochrome P-450), ABC family of transmembrane transporters (adenosine-triphosphate binding cassette). The goal of the contemporary research is to determine the predictive factors that will enable the individual adjustment of the individual drug dosage while minimising the adverse effects and maintaining the treatment benefit.

<p><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">What is the core purpose of Islamic banking? Why is the existence of Islamic banking so important? It can not be denied, the answer of the crucial question about the purpose of establishing Islamic banking is still a fragmentary discussion.</span><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">If studied more deeply, Islamic banking is an entity that has its own unique characteristics, especially when compared with conventional banking. Therefore, Islamic banking, both in theory and practice, should make paradigm shifts, especially in terms of performance measurement that is not only limited to financial parameters.</span><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">This study aims to explore the extent to which the revitalization of the concept of <em>maqāṣid</em> in Islamic finance, especially banking.</span><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;"> The result shows that the revitalization of the concept of <em>maqāṣid</em> defined by Muhammad Abu Zahrah and Abdul Majid Najjar can be used to measure the performance of sharia banking in a more measurable way.</span></p><p><span style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt; line-height: 115%;" lang="IN">Apakah sebenarnya tujuan inti dari perbankan syariah? Kenapa eksistensi perbankan syariah begitu penting? Tidak dapat dipungkiri, jawaban dari pertanyaan krusial mengenai tujuan pendirian perbankan syariah masih berupa diskusi sepotong-sepotong. Jika dikaji lebih dalam, perbankan syariah adalah entitas yang mempunyai karakteristik unik dan tersendiri, khususnya saat dibandingkan dengan perbankan konvensional. Oleh karena itu, </span><span class="longtext" style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt;"><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Cambria',serif; mso-ascii-theme-font: major-latin; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-latin; mso-bidi-font-family: 'Times New Roman'; mso-bidi-theme-font: major-bidi; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">perbankan syariah, baik secara teori </span></span><span class="longtext" style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt;"><span style="font-size: 10pt; line-height: 115%; letter-spacing: 0.3pt;" lang="IN">maupun</span></span><span class="longtext" style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt;"><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Cambria',serif; mso-ascii-theme-font: major-latin; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-latin; mso-bidi-font-family: 'Times New Roman'; mso-bidi-theme-font: major-bidi; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN"> praktik, harus melakukan pergeseran paradigma (</span></span><em style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt;"><span style="font-size: 10pt; line-height: 115%; letter-spacing: 0.3pt;" lang="IN">shifting paradigm</span></em><span style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt; line-height: 115%;" lang="IN">), khususnya </span><span class="longtext" style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt;"><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Cambria',serif; mso-ascii-theme-font: major-latin; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: major-latin; mso-bidi-font-family: 'Times New Roman'; mso-bidi-theme-font: major-bidi; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">dalam hal pengukuran kinerja yang tidak hanya terbatas pada parameter keuangan.</span></span><span style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt; line-height: 115%;" lang="IN"> Penelitian ini bertujuan untuk menelusuri sejauh mana revitalisasi konsep <em>maqāṣid</em> dalam keuangan </span><span style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt; line-height: 115%;">s</span><span style="font-family: Calibri, sans-serif; font-size: 10pt; letter-spacing: 0.3pt; line-height: 115%;" lang="IN">yariah, khususnya perbankan. Hasil penelitian menunjukkan bahwa revitalisasi konsep maqāṣid Muhammad Abu Zahrah dan Abdul Majid Najjar dapat digunakan untuk melakukan pengukuran kinerja perbankan syariah secara lebih terukur.</span></p><em><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">Beyond Banking: </span><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;"><br /> </span></em><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-ascii-theme-font: minor-latin; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: minor-latin; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">Revitalisasi <em>Maqā</em></span><em><span style="font-size: 12.0pt; line-height: 115%; font-family: 'Tahoma',sans-serif; mso-fareast-font-family: 'Times New Roman'; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">ṣ</span><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-ascii-theme-font: minor-latin; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: minor-latin; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN">id</span></em><span style="font-size: 10.0pt; mso-bidi-font-size: 11.0pt; line-height: 115%; font-family: 'Calibri',sans-serif; mso-ascii-theme-font: minor-latin; mso-fareast-font-family: 'Times New Roman'; mso-hansi-theme-font: minor-latin; mso-bidi-font-family: Arial; letter-spacing: .3pt; mso-ansi-language: IN; mso-fareast-language: EN-US; mso-bidi-language: AR-SA;" lang="IN"> dalam Perbankan Syariah</span>

Abstract The genetic diagnosis of inherited anaemias is an important aspect of the diagnostic pathway for patients with haematological disorders, allowing discrimination between conditions of overlapping phenotypes therefore enabling more effective clinical treatment. Next Generation sequencing platforms are now in widespread use in diagnostic settings and are facilitating more rapid, accurate and cost-effective molecular diagnosis. The Red Cell Gene Panel developed by the Viapath Molecular Pathology laboratory based at King's College Hospital, London has harnessed this technology with the aim of identifying genetic diagnoses of rare inherited causes of anaemia. Although originally setup to diagnose inherited red cell disorders, clinical demand has led to the inclusion of inherited bone marrow failure syndromes and other related conditions such that the panel now consists of 194 genes, divided into 16 subpanels (see table 1). Here we present the data from the first 1000 diagnostic cases reported under the following referral groups: 462 cases of unexplained anaemia (including haemolytic anaemia, sideroblastic anaemia, congenital dyserythropoietic anaemia, Diamond-Blackfan Anaemia), 232 cases of inherited bone marrow failure syndromes (including thrombocytopenia and neutropenia), 163 cases of congenital erythrocytosis and 143 other cases (including but not limited to iron regulation, haemophagocytic lymphohistiocytosis (HLH) and Criggler-Najjar ). Of these 1000 cases, we have achieved an overall diagnostic yield of approximately 25%. A diagnosed case is defined here as one in which a clear pathogenic or likely pathogenic variant that explains the phenotype has been detected. The unexplained anaemia cases have achieved the highest percentage of cases diagnosed with 47% diagnostic yield and data will be presented outlining the gene-by-gene breakdown of diagnoses made. Our bespoke bioinformatics pipeline has also allowed the detection of novel disease-causing structural variants in 20 cases, contributing 2% of our diagnostic yield. These are detected using three different methods; read-depth analysis, split-read mapping and discordant insert-size analysis. All reported structural variants have been confirmed with a second method, either breakpoint mapping or dosage-sensitive PCR. A significant proportion of cases (28%) have been reported with variants of uncertain clinical significance, highlighting the need for family studies and functional characterisation to be able to accurately ascertain the significance of these variants. Future developments of the service include functional characterisation of membrane disorders using next generation ektacytometry and preliminary data from this work will be presented here. Disclosures Kulasekararaj: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Pagliuca:Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

An international symposium entitled Pharmacogenetics in clinical pharmacology and toxicology: a tribute to Werner Kalow was held in Toronto, Ontario, July 20, 1994. This subject was particularly important to discuss in the presence of Werner Kalow, 77 years young, who is considered as one of the grandfathers of this unique combination of medical research fields. It has become increasingly appreciated that dozens of human drug metabolism polymorphisms exist. The interindividual variabilities in drug metabolism discussed at this symposium do not represent small differences such as 50% or 3-fold but, rather, represent 10- to greater than 1000-fold differences. When attributed to a single gene, dramatic differences can be seen among family members, just as blue and brown eyes can occur in siblings. These differences can result in acute drug toxicity. In addition, there are chronic effects: over one's lifetime, striking differences in the metabolism of drugs, occupationally hazardous chemicals, and other environmental pollutants can lead to interindividual differences in the buildup of DNA damage (e.g., mutations, chromosomal breaks, rearrangements) leading to toxicity and tumor initiation, as well as leading to a buildup in nongenotoxic signals (signal transduction pathways without DNA damage) important for toxicity, tumor promotion, and tumor progression. The human UDP glucuronosyltransferase (UGT superfamily is known to comprise more than 10 genes in humans, and probably in other mammalian species. Breakthroughs in UGT gene mutations responsible for the Crigler-Najjar syndrome and Gilbert's disease have recently been reported. The human cytochrome P450 termed CYP3A4 is a major P450 enzyme in the liver and gastrointestinal tract, and the full impact of the CYP3A4 polymorphism has yet to be fully appreciated. CYP3A4 metabolism of cyclosporin A, commonly prescribed to organ transplant recipients, the induction of CYP3A4 by rifampicin, and inhibition of CYP3A4 metabolism by erythromycin or ketoconazole are now quite well understood. The field of ethnopharmacology, or pharmacoanthropology, has recently emerged, pioneered at least in part by Kalow. Differences in debrisoquine–sparteine metabolism, S-mephenytoin hydroxylation, diazepam clearance, and omeprazole clearance in various Caucasian and Oriental subpopulations in a number of countries have been extensively reported. After a number of inconclusive studies, it has now been shown unequivocally that the human S-mephenytoin 4′-hydroxylase polymorphism represents at least two distinct mutations (one involving a splice site) in the CYP2C19 gene. Finally, the implications and clinical significance of a number of human polymorphisms (CYP2D6, CYP2C19, N-acetylation (NAT2), S-methylation by thiopurine methyltransferase (TPMT), and ester hydrolysis by plasma cholinesterase) were carefully reviewed at this symposium.Key words: pharmacology, toxicology, drug metabolism, pharmacogenetic polymorphism.