Alkaptonuria – Many questions answered, further challenges beckon

2019 ◽  
Vol 57 (2) ◽  
pp. 106-120
Author(s):  
AS Davison ◽  
AT Hughes ◽  
AM Milan ◽  
N Sireau ◽  
JA Gallagher ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Human Subjects ◽  
Clinical Manifestations ◽  
Homogentisic Acid ◽  
Common Disease ◽  
Clinical Complications ◽  
Disease Modifying Therapy ◽  
Treatment Measures ◽  
History Of ◽  
Collagenous Tissues

Alkaptonuria is an iconic rare inherited inborn error of metabolism affecting the tyrosine metabolic pathway, resulting in the accumulation of homogentisic acid in the circulation, and significant excretion in urine. Dating as far back as 1500 BC in the Egyptian mummy Harwa, homogentisic acid was shown to be central to the pathophysiology of alkaptonuria through its deposition in collagenous tissues in a process termed ochronosis. Clinical manifestations occurring as a consequence of this are typically observed from the third decade of life, are lifelong and significantly affect the quality of life. In large supportive and palliative treatment measures are available to patients, including analgesia, physiotherapy and joint replacement. Studying the natural history of alkaptonuria, in a murine model and human subjects, has provided key insights into the biochemical and molecular mechanisms underlying the pathophysiology associated with the disease, and has enabled a better understanding of the common disease osteoarthritis. In the last decade, a major focus has been on an unlicensed disease-modifying therapy called nitisinone. This has been shown to be highly efficacious in reducing homogentisic acid, and it is hoped this will halt ochronosis, thus limiting the clinical complications associated with the disease. A well-documented metabolic consequence of nitisinone therapy is hypertyrosinaemia, the clinical implications of which are uncertain. Recent metabolomic studies have helped understand the wider metabolic consequences of nitisinone therapy.

Alka Ptonuria Disorder

2021 ◽  
pp. 364-366
Author(s):  
Bhawan B. Bhende
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Homogentisic Acid ◽  
Dark Urine ◽  
Disease Modifying Therapy ◽  
Collagenous Tissue ◽  
Reduce Life Expectancy ◽  
Recent Developments ◽  
History Of

Alkaptonuria (AKU) is a rare disorder of autosomal recessive inheritance. It is caused by a mutation in a gene that results in the accumulation of homogentisic acid (HGA). Characteristically, the excess HGA means sufferers pass dark urine, which upon standing turns black. This is a feature present from birth. Over time patients develop other manifestations of AKU, due to deposition of HGA in collagenous tissue namely ochronosis and ochronotic osteoarthropathy. Although this condition does not reduce life expectancy, it significantly affects quality of life. The natural history of this condition is becoming better understood, despite gaps in knowledge. Clinical assessment of the condition has also improved along with the development of a potentially disease-modifying therapy. Furthermore, recent developments in AKU research have led to new understanding of the disease, and further study of the AKU arthropathy has the potential to influence therapy in the management of osteoarthritis.

scholarly journals Case Report of Isolated Hepatic Tuberculosis

2015 ◽  
Vol 26 (1) ◽  
pp. 43-45 ◽  
Author(s):  
Mohammad Rafiqul Islam ◽  
Maria Maksud ◽  
Prianka Baral ◽  
Mahbub Hossain ◽  
Ahmedul Kabir
Keyword(s):  
Case Report ◽  
Clinical Manifestations ◽  
Common Disease ◽  
Pulmonary Tb ◽  
Common Diseases ◽  
Hepatic Tuberculosis ◽  
History Of ◽  
Space Occupying Lesion

Tuberculosis is one of the most common diseases in Bangladesh and has variable clinical manifestations. Isolated Hepatic tuberculosis is not a common disease; in fact the presentation of hepatic tuberculosis may be without having history of any active Pulmonary TB or military TB. Patient usually present without having any typical symptoms; so it is difficult for a physician to diagnose the disease quickly. Patient presenting with space occupying lesion in liver is confused with abscess, hepatoma or metastases. Here we are presenting a case report of isolated hepatic tuberculosis.Bangladesh J Medicine Jan 2015; 26 (1) : 43-45

scholarly journals Aquaporin 9 Represents a Novel Target of Chronic Liver Injury That May Antagonize Its Progression by Reducing Lipotoxicity

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Quancheng Cheng ◽  
Huiru Ding ◽  
Jinyu Fang ◽  
Xuan Fang ◽  
Huaicun Liu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Clinical Manifestations ◽  
Chronic Liver ◽  
Common Disease ◽  
Chronic Liver Injury ◽  
Aquaporin 9 ◽  
Hepatic Lipotoxicity ◽  
Novel Target

In recent years, chronic liver injury has become a common disease that harms human health. Its clinical manifestations are hepatic steatosis and secondary chronic steatohepatitis, which can quickly transform into liver fibrosis and cirrhosis if not treated in time. Therefore, this study is aimed at searching for new therapeutic targets of chronic liver injury and clarifying the molecular mechanisms of the new targets involved in chronic liver injury. After aquaporin 9 was identified as a target by proteomics, Aqp9-/- mice were constructed using the CRISPR/Cas9 system. Biochemical and morphological tests were used to verify the effect of Aqp9 knockout on early chronic liver injury. Proteomics, molecular biology, and morphology experiments were used to screen and verify the effects of Aqp9 knockout on its downstream pathway. Through the above experiments, we demonstrated that aquaporin 9 could be used as an intervention target for antagonizing the development of early chronic liver injury and its gene knockout affected downstream inflammation, oxidative stress, apoptosis, and pyroptosis by alleviating hepatic lipotoxicity.

scholarly journals Molecular Mechanisms of Curcumin in COVID-19 Treatment and Prevention: A Global Health Perspective

2020 ◽  
Vol 8 (10) ◽  
Author(s):  
Nathan Roberts ◽  
Robert Brown ◽  
L. Buja ◽  
Priya Weerasinghe
Keyword(s):  
Molecular Mechanisms ◽  
Curcuma Longa ◽  
Clinical Manifestations ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Respiratory Disorder ◽  
Therapeutic Effects ◽  
Electron Transfer Mechanism ◽  
Treatment And Prevention ◽  
History Of

Turmeric (Curcuma Longa) has a near 4000-year history of extensive medical use in South Asia. Its main physiologically active phytochemical is curcumin (diferuloylmethane), derived from the rhizome of turmeric. Curcumin is a hydrophobic polyphenol with a diketone moiety connecting two phenoxy rings. It is widely available, and exerts systemic and pleiotropic effects via several key mechanisms. Most famously, it is known to inhibit pro-inflammatory pathways such as PI3k/akt/NF-kB activation. It is also a potent antioxidant and free radical scavenger via a sequential proton loss electron transfer mechanism in ionizing solvents due to its extended conjugating ability across the entire molecule, and its ability to induce NRF-2. It has been implicated in the treatment of diseases ranging from asthma to various cancers, and is also a broad spectrum anti-microbial. COVID-19 is a novel beta-coronavirus that was declared a pandemic by the WHO in March, 2020. It is primarily a respiratory disorder, but it can spread hematogenously and effect many other organs such as the heart, nervous system, and kidneys. There is a significant intersection between the clinical manifestations of COVID-19 and curcumin’s therapeutic effects. In addition, curcumin has been shown to inhibit initial viral infectivity. Thus, there is potential for curcumin to safely both prevent and treat COVID-19 infection across the globe.

Sickle Cell Diseases: Diagnosis and Management in Infancy and Childhood

1987 ◽  
Vol 9 (4) ◽  
pp. 121-130
Author(s):  
Howard A. Pearson
Keyword(s):  
Sickle Cell ◽  
Molecular Mechanisms ◽  
The United States ◽  
Western Hemisphere ◽  
Black America ◽  
Clinical Complications ◽  
History Of ◽  
Sickle Cell Disorders ◽  
Hb S ◽  
Considerable Morbidity

From their basic genetic and molecular mechanisms to their clinical expression, the sickle cell hemoglobinopathies are among the best understood of human diseases. However, advances in clinical management have not progressed as rapidly: sickle cell anemia, as of 1987, is still largely incurable and its treatment is empiric and symptomatic. Despite this, today we have a better understanding of the natural history of the sickle hemoglobinopathies and many of their clinical complications. This has led to improved diagnostic, prophylactic, and therapeutic strategies which have reduced the considerable morbidity and mortality of these diseases. The sickle cell disorders will be reviewed from genetic, biochemical, and clinical perspectives. Particular emphasis will be given to the rationale and strategies for neonatal testing and comprehensive clinical follow-up. Although it is widely believed that the gene for Hb S is almost exclusively, African, it has, in fact, a much wider geographic distribution. There is a broad periequatorial sickle cell belt in Africa. From Africa, the sickle gene was introduced into the Western hemisphere by the 16th and 17th century slave trade. In the United States today, sickle cell disorders are particularly prevalent in the South and in the urban North, reflecting the demography of black America. In the Carribean and Latin America, relatively high frequencies are seen in Purto Rico, Cuba, Jamaica, Haiti, Panama, Guyana, and Brazil, but not in Mexico and most of South America.

scholarly journals Associative relationship between atopy, HLA complex genes and other genes

2019 ◽  
Vol 16 (3) ◽  
pp. 5-25
Author(s):  
N G Astafyeva ◽  
B A Shamgunova ◽  
D Yu Kobzev ◽  
I Ae Michailova
Keyword(s):  
Molecular Mechanisms ◽  
Complex Structure ◽  
Clinical Manifestations ◽  
Current Data ◽  
Genetic Determinants ◽  
Genetic Characteristics ◽  
Hla Genes ◽  
Histocompatibility Complex ◽  
History Of

This review presents current data on the associative relationships of genes of the major histocompatibility complex (HLA) and other genes with atopy. Despite the long history of studying the role of HLA class genes in atopy and the introduction of modern technologies and methods, many unresolved issues remain, including the difficulties caused by the heterogeneity of the human population, the complex structure and disequilibrium of linkage between different HLA genes. Although phenotypic heterogeneity is considered as the main limitation in understanding the genetic determinants of atopy, only a few studies have examined the relationships of its typical clinical manifestations induced by aeroallergens with certain HLA genes. The identified molecular mechanisms and genetic characteristics open up the possibility of using new therapeutic targets and modifying existing drugs.

scholarly journals Arguments for Human Therapeutic Cloning

2008 ◽  
Vol 4 (1) ◽  
pp. 15-18 ◽  
Author(s):  
Krešimir Pavelić
Keyword(s):  
Molecular Mechanisms ◽  
Human Subjects ◽  
Scientific Work ◽  
Modern Medicine ◽  
Molecular Medicine ◽  
Genetic Diagnostics ◽  
Modern Biology ◽  
Ethical Violations ◽  
History Of ◽  
Short Time

For over 30 years, many Western governments have regulated scientific research involving human subjects. According to Knoppers (1) implementation of regulation followed a long and checkered history of research abuse. The regulations evolved largely in response to ethical violations. The Nuremberg Codex exemplifies the progression. It was adopted in 1947. At the conclusion of Nazi Doctors Trial.Spectacular technical and conceptual advances in modern biology and molecular medicine have solved many problems in a short time. Genetic diagnostics extended well beyond simple inheritance testing, and is now moving into all areas of pathology. Gene therapy, although in a phase of consolidation after an exuberant youth, holds real promise. Understanding of the molecular basis of tissue differentiation, perhaps with the use of nuclear transfer techniques, may allow creation of histocompatible tissue for transplantation purposes (2).Scientific work will have propounds long-term consequences for medicine, leading to the elucidation of the underlying molecular mechanisms of disease and thereby facilitating the design of rational diagnostics and therapeutics targeted at those mechanisms.All molecular medicine must operate within a social and ethical context.Prominence of ethical controversy (i.e. presymptomatic genetical testing, or human therapeutically cloning) will very likely diminish with time, as the products of molecular medicine range further away from establishing pure diagnostic and into therapy.One of the major issues of today’s modern medicine is therapeutically cloning. The main practical purpose of cloning is to generate genetically modified animals to serve as bioreactors. The cloning of mammals is fascinating biological problem, although it is difficult to perform and attempts are rarely successful. The reproductive cloning of humans is likely to cause more individual concern than real social effects, as it is unlikely to became a widespread method of reproduction even if possible and safe.

АССОЦИАТИВНЫЕ СВЯЗИ МЕЖДУ АТОПИЕЙ, ГЕНАМИ КОМПЛЕКСА HLA И ДРУГИМИ ГЕНАМИ

2019 ◽  
pp. 5-25
Author(s):  
N.G. Astafyeva ◽  
B.A. Shamgunova ◽  
D.Yu. Kobzev ◽  
I.Ae. Michailova
Keyword(s):  
Molecular Mechanisms ◽  
Complex Structure ◽  
Clinical Manifestations ◽  
Current Data ◽  
Genetic Determinants ◽  
Genetic Characteristics ◽  
Hla Genes ◽  
Histocompatibility Complex ◽  
History Of

В настоящем обзоре представлены современные данные об ассоциативных связях генов главного ком плекса гистосовместимости (HLA) и других генов с атопией. Несмотря на длительную историю изучения роли генов класса HLA при атопии и внедрение современных технологий и методов, остается много не решенных вопросов, в том числе трудности, обусловленные гетерогенностью человеческой популяции, сложной структурой и неравновесностью сцепления между различными генами HLA. Хотя фенотипиче ская гетерогенность рассматривается как основное ограничение в понимании генетических детерминант атопии, лишь в немногих работах изучались связи ее типичных клинических проявлений, индуцированных аэроаллергенами, с определенными генами HLA. Идентифицированные молекулярные механизмы и генетические характеристики открывают возможности использования новых терапевтических мишеней и модификации существующих лекарственных средств.This review presents current data on the associative relationships of genes of the major histocompatibility complex (HLA) and other genes with atopy. Despite the long history of studying the role of HLA class genes in atopy and the introduction of modern technologies and methods, many unresolved issues remain, including the difficulties caused by the heterogeneity of the human population, the complex structure and disequilibrium of linkage between different HLA genes. Although phenotypic heterogeneity is considered as the main limitation in understanding the genetic determinants of atopy, only a few studies have examined the relationships of its typical clinical manifestations induced by aeroallergens with certain HLA genes. The identified molecular mechanisms and genetic characteristics open up the possibility of using new therapeutic targets and modifying existing drugs.

Electron Microscopic and Isozyme Study of a Case of Ochronosis

1972 ◽  
Vol 30 ◽  
pp. 88-89
Author(s):  
Jay W. Cha ◽  
Perry J. Melnick
Keyword(s):  
Benzene Ring ◽  
Enzyme System ◽  
Homogentisic Acid ◽  
Degenerative Changes ◽  
Acid Oxidase ◽  
Electron Microscopic ◽  
Tyrosine Metabolism ◽  
Collagenous Tissues

Hereditary ochronosis in very few cases has been examined electron microscopically or histochemically. In this disease homogentisic acid, a normal intermediary of tyrosine metabolism, forms in excessive amounts. This is believed to be due to absence or defective activity of homogentisic acid oxidase, an enzyme system necessary to break the benzene ring and to further break it down to fumaric and acetoacetic acids. Ochronotic pigment, a polymerized form of homogentisic acid, deposits mainly in mesenchymal tissues. There has been a question whether the pigment originates from the collagenous tissues, or deposits passively, where in contrast to melanin it induces degenerative changes.

The Diagnostic Value of Pericardial Fluid and Pericardial Biopsy: Single Center Experiences

2016 ◽  
Vol 19 (1) ◽  
pp. 023 ◽  
Author(s):  
Mehmet Yildirim ◽  
Recep Ustaalioglu ◽  
Murat Erkan ◽  
Bala Basak Oven Ustaalioglu ◽  
Hatice Demirbag ◽  
...  
Keyword(s):  
Pericardial Effusion ◽  
Thoracoscopic Surgery ◽  
Pericardial Tamponade ◽  
Pericardial Fluid ◽  
Pathological Examination ◽  
Common Disease ◽  
Pericardial Window ◽  
Surgical Interventions ◽  
History Of ◽  
Recurrent Pericardial Effusion

<strong>Background:</strong> Patients with recurrent pericardial effusion and pericardial tamponade are usually treated in thoracic surgery clinics by VATS (video-assisted thoracoscopic surgery) or open pericardial window operation. The diagnostic importance of pathological evaluation of the pericardial fluid and tissue in the same patients has been reported in few studies. We reviewed pathological examination of the pericardial tissue and fluid specimens and the effect on the clinical treatment in our clinic, and compared the results with the literature. <br /><strong>Methods:</strong> We retrospectively analyzed 174 patients who underwent pericardial window operation due to pericardial tamponade or recurrent pericardial effusion. For all patients both the results of the pericardial fluid and pericardial biopsy specimen were evaluated. Clinicopathological factors were analyzed by using descriptive analysis. <br /><strong>Results:</strong> Median age was 61 (range, 20-94 years). The most common benign diagnosis was chronic inflammation (94 patients) by pericardial biopsy. History of malignancy was present in 28 patients (16.1%) and the most common disease was lung cancer (14 patients). A total of 24 patients (13.8%) could be diagnosed as having malignancy by pericardial fluid or pericardial biopsy examination. The malignancy was recognized for 12 patients who had a history of cancer; 9 of 12 with pericardial biopsy, 7 diagnosed by pericardial fluid. Twelve of 156 patients were recognized as having underlying malignancy by pericardial biopsy (n = 9) or fluid examination (n = 10), without known malignancy previously. <br /><strong>Conclusion:</strong> Recurrent pericardial effusion/pericardial tamponade are entities frequently diagnosed, and surgical interventions may be needed either for diagnosis and/or treatment, but specific etiology can rarely be obtained in spite of pathological examination of either pericardial tissue or fluid. For increasing the probability of a specific diagnosis both the pericardial fluid and the pericardial tissues have to be sent for pathologic examination.

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