Tripeptidyl-peptidase I in health and disease

2006 ◽  
Vol 387 (8) ◽  
pp. 1091-1099 ◽  
Author(s):  
Adam A. Golabek ◽  
Elizabeth Kida
Keyword(s):  
Disease Process ◽  
Underlying Disease ◽  
Laboratory Animals ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Tripeptidyl Peptidase ◽  
Cell Components ◽  
Health And Disease ◽  
Secondary Lysosomes ◽  
Turn Over

AbstractThe lysosomal lumen contains numerous acidic hydrolases involved in the degradation of carbohydrates, lipids, proteins, and nucleic acids, which are basic cell components that turn over continuously within the cell and/or are ingested from outside of the cell. Deficiency in almost any of these hydrolases causes accumulation of the undigested material in secondary lysosomes, which manifests itself as a form of lysosomal storage disorder (LSD). Mutations in tripeptidyl-peptidase I (TPP I) underlie the classic late-infantile form of neuronal ceroid lipofuscinoses (CLN2), the most common neurodegenerative disorders of childhood. TPP I is an aminopeptidase with minor endopeptidase activity and Ser475 serving as an active-site nucleophile. The enzyme is synthesized as a highly glycosylated precursor transported by mannose-6-phosphate receptors to lysosomes, where it undergoes proteolytic maturation. This review summarizes recent progress in understanding of TPP I biology and molecular pathology of the CLN2 disease process, including distribution of the enzyme, its biosynthesis, glycosylation, transport and activation, as well as catalytic mechanisms and their potential implications for pathogenesis and treatment of the underlying disease. Promising data from gene and stem cell therapy in laboratory animals raise hope that CLN2 will be the first neurodegenerative LSD for which causative treatment will become available for humans.

Tripeptidyl-peptidase 1 in neuronal ceroid lipofuscinoses and other lysosomal storage disorders

2001 ◽  
Vol 5 ◽  
pp. 73-79 ◽  
Author(s):  
Krystyna E. Wisniewski ◽  
Elizabeth Kida ◽  
Mariusz Walus ◽  
Peter Wujek ◽  
Wojciech Kaczmarski ◽  
...  
Keyword(s):  
Lysosomal Storage Disorders ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Tripeptidyl Peptidase ◽  
Storage Disorders

Drug-Induced Movement Disorders

2015 ◽  
Vol 25 (2) ◽  
pp. 70-77
Author(s):  
Amy Lustig ◽  
Cesar Ruiz
Keyword(s):  
Movement Disorders ◽  
Medical Management ◽  
Disease Process ◽  
Underlying Disease ◽  
Extrapyramidal Symptoms ◽  
Drug Induced ◽  
General Overview ◽  
Management Approaches ◽  
Broad Understanding ◽  
Underlying Disease Process

The purpose of this article is to present a general overview of the features of drug-induced movement disorders (DIMDs) comprised by Parkinsonism and extrapyramidal symptoms. Speech-language pathologists (SLPs) who work with patients presenting with these issues must have a broad understanding of the underlying disease process. This article will provide a brief introduction to the neuropathophysiology of DIMDs, a discussion of the associated symptomatology, the pharmacology implicated in causing DIMDs, and the medical management approaches currently in use.

Measuring Disease Modification in Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 11-14
Author(s):  
Jeffrey L. Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Modification ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β -amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

scholarly journals Sphingolipid lysosomal storage diseases: from bench to bedside

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Muna Abed Rabbo ◽  
Yara Khodour ◽  
Laurie S. Kaguni ◽  
Johnny Stiban
Keyword(s):  
Basic Research ◽  
Lysosomal Storage Diseases ◽  
Therapeutic Strategies ◽  
Clinical Applications ◽  
Late Nineteenth Century ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
The Past ◽  
Health And Disease ◽  
General Aspects

AbstractJohann Ludwig Wilhelm Thudicum described sphingolipids (SLs) in the late nineteenth century, but it was only in the past fifty years that SL research surged in importance and applicability. Currently, sphingolipids and their metabolism are hotly debated topics in various biochemical fields. Similar to other macromolecular reactions, SL metabolism has important implications in health and disease in most cells. A plethora of SL-related genetic ailments has been described. Defects in SL catabolism can cause the accumulation of SLs, leading to many types of lysosomal storage diseases (LSDs) collectively called sphingolipidoses. These diseases mainly impact the neuronal and immune systems, but other systems can be affected as well. This review aims to present a comprehensive, up-to-date picture of the rapidly growing field of sphingolipid LSDs, their etiology, pathology, and potential therapeutic strategies. We first describe LSDs biochemically and briefly discuss their catabolism, followed by general aspects of the major diseases such as Gaucher, Krabbe, Fabry, and Farber among others. We conclude with an overview of the available and potential future therapies for many of the diseases. We strive to present the most important and recent findings from basic research and clinical applications, and to provide a valuable source for understanding these disorders.

scholarly journals Clinical Features and Outcomes of a Racially Diverse Population with Fibrillary Glomerulonephritis

2017 ◽  
Vol 45 (3) ◽  
pp. 248-256 ◽  
Author(s):  
Fernanda Payan Schober ◽  
Meghan A. Jobson ◽  
Caroline J. Poulton ◽  
Harsharan K. Singh ◽  
Volker Nickeleit ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Disease Process ◽  
Signs And Symptoms ◽  
Patient Characteristics ◽  
Underlying Disease ◽  
Fibrillary Glomerulonephritis ◽  
Black Patients ◽  
End Stage ◽  
20 Nm ◽  
The University

Background: Fibrillary glomerulonephritis is characterized by randomly arranged fibrils, approximately 20 nm in diameter by electron microscopy. Patients present with proteinuria, hematuria and kidney insufficiency, and about half of the reported patients progress to end-stage kidney disease within 4 years. The dependence of patient characteristics and outcomes on race has not been explored. In this study, we describe a cohort of patients with fibrillary glomerulonephritis and compare their clinical characteristics and outcomes with those of patients previously described. Methods: The University of North Carolina (UNC) Nephropathology Database was used to retrospectively identify patients diagnosed with fibrillary glomerulonephritis between 1985 and 2015. Of these patients, those treated at UNC were selected. Their demographic and clinical characteristics - including signs and symptoms, comorbidities, laboratory values, treatments and outcomes - were compared with those of patients described earlier. Results: Among the 287 patients identified, 42 were treated at the UNC Kidney Center. When compared to earlier cohorts, a higher frequency of black race, hepatitis C virus (HCV) infection and use of hemodialysis were noted in both black and HCV-positive patients. Autoimmune diseases, infections and malignancies were frequently observed, present in over half of all cases. Conclusion: According to this study, fibrillary glomerulonephritis represents a secondary glomerular disease process (associated with autoimmune disease, infection or malignancy) in many cases and hence screening is essential. As the screening for comorbidities increased over time, more underlying causes were identified. We noted a high frequency of HCV among black patients, suggesting a possible causative association. Treatment of underlying disease is essential for patients for the best outcome.

Human Immunodeficiency Virus-Associated Thrombocytopenia

DICP ◽  
1989 ◽  
Vol 23 (2) ◽  
pp. 157-160 ◽  
Author(s):  
Dennis M. Hoffman ◽  
Rocco F. Caruso ◽  
Timothy Mirando
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Globulin ◽  
Disease Process ◽  
Underlying Disease ◽  
Asymptomatic Patients ◽  
Increased Risk ◽  
Immunodeficiency Virus ◽  
Acquired Immunodeficiency ◽  
A New Technique ◽  
Immunodeficiency Syndrome

Thrombocytopenia has emerged as a major hematological manifestation associated with AIDS (acquired immunodeficiency syndrome) and human immunodeficiency virus (HIV)-positive patients. A study of homosexual patients with thrombocytopenia indicates 93 percent had serological evidence of HIV exposure whereas only 33 percent of homosexuals without thrombocytopenia exhibited this finding. Thrombocytopenia in patients with hemophilia has been identified as an increased risk factor for AIDS development and has been observed in about one-third of children with AIDS. The management of thrombocytopenia in HIV-infected patients poses a therapeutic dilemma for clinicians since many of the traditional modalities for treating immune thrombocytopenia may adversely affect the underlying disease process or further compromise the immune system. Splenectomy, corticosteroids, danazol, intravenous immune globulin, vincristine, and RHo(D) immune globulin have all been used with variable results. A new technique that physically removes antibodies and immune complexes associated with thrombocytopenia is under investigation. Due to either toxicity or the high incidence of transient response, asymptomatic patients may not be candidates for treatment.

Lysosomal Storage Disorders Including Neuronal Ceroid Lipofuscinoses

2014 ◽  
pp. 399-435
Author(s):  
Carla Hollak ◽  
Matthias Kettwig ◽  
Lars Schlotawa ◽  
Robert Steinfeld
Keyword(s):  
Lysosomal Storage Disorders ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Storage Disorders

Pharmacologic and Technological Innovations in Pain Medicine

2016 ◽  
Author(s):  
Anita Gupta ◽  
Hawa Abubakar
Keyword(s):  
Pain Management ◽  
Disease Process ◽  
Multimodal Analgesia ◽  
Underlying Disease ◽  
Antiinflammatory Drug ◽  
Treatment Modalities ◽  
Technological Innovations ◽  
Duration Of Action ◽  
Key Words Pain ◽  
Opioid Receptor Antagonists

The experience of pain is subjective, and treatment modalities should aim at providing the greatest amount of pain relief while minimizing adverse effects. Pharmacologic and technological innovations are making this possible. By taking advantage of new manufacturing processes, the pharmaceutical industry is retooling old and effective drugs. SoluMatrix diclofenac uses nanotechnology to address the need for an effective nonsteroidal antiinflammatory drug at the lowest possible dose to minimize risks associated with cardiac, renal, and gastrointestinal side effects. Intravenous acetaminophen provides an additional alternative in multimodal analgesia in instances when the oral or rectal route of delivery is not desirable. Liposomal bupivacaine uses liposomal encapsulated, resulting in a local anesthetic with a prolonged duration of action that can be used effectively in the management of postoperative pain. With the recognition that opioid therapy still remains a mainstay in pain management, advances in science have allowed for the development of peripherally acting mu opioid receptor antagonists such as naloxegol, which minimize the bothersome side effect of opioid-induced constipation. In terms of interventional pain management, advances in radiofrequency ablation (RFA) technology have resulted in cooled RFA, which allows for the creation of larger spherical lesions, thereby alleviating pain by interfering with neurotransmission. Advances in stem cell research have led to the application of multipotent cells with the aim of treating the underlying disease process and thereby eliminating pain. Finally, pharmacogenetics testing and smart drugs provide an avenue via which issues surrounding how medication is consumed, determination of effectiveness, and ensuring compliance and adherence can be optimized. Key words: Pain, Pharmacology, Medications, Technology, Innovation, Smart Pills, Personalized Medicine, Biotechnology, Device, Surgery, Multimodal

Delayed Puberty

2020 ◽  
Author(s):  
Amanda French
Keyword(s):  
Pubertal Timing ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Disease Process ◽  
Optimal Growth ◽  
Underlying Disease ◽  
Delayed Puberty ◽  
Hypergonadotropic Hypogonadism ◽  
Pubertal Delay ◽  
Constitutional Delay

Although common, delayed puberty can be distressing to patients and families.   Careful assessment is necessary to ensure appropriate physical and social development in patients that require intervention to reach pubertal milestones and achieve optimal growth.  Most pubertal delay is from lack of activation of the hypothalamic-pituitary-gonadal axis which then results in a functional or physiologic GnRH deficiency.  The delay may be temporary or permanent.  Constitutional delay (CDGP), also referred to as self-limited delayed puberty (DP), describes children on the extreme end of normal pubertal timing and is the most common cause of delayed puberty, representing about one third of cases.  Hypergonadotropic hypogonadism (primary hypogonadism) results from a failure of the gonad itself, and hypogonadotropic hypogonadism (secondary hypogonadism) results from a failure of the hypothalamic-pituitary axis, which is usually caused by another process, often systemic.  Diagnosis is based on history and examination.  Treatment is based on the underlying cause of pubertal delay and may include hormone replacement.  Involving a pediatric endocrinologist should be considered.  Appropriate counseling and ongoing support are important for all patients and families, regardless of underlying disease process.   This review contains 4 figures, 4 tables, and 32 references. Keywords: puberty, delayed puberty, hypogonadism, hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, menarche, thelarche, constitutional delay and growth in puberty, Turner syndrome

Surgical Management of Benign and Malignant Colorectal Disease in the Immunocompromised Patient

2017 ◽  
Author(s):  
Cindy Kin ◽  
Amy Lightner ◽  
Mark Welton
Keyword(s):  
Preoperative Evaluation ◽  
Disease Process ◽  
Underlying Disease ◽  
Colorectal Disease ◽  
Immunosuppressed Patient ◽  
Neutropenic Enterocolitis ◽  
Anal Squamous Cell Carcinoma ◽  
Benign Colorectal Disease ◽  
Immunosuppressed Patients ◽  
Inflammatory Bowel

Patients who are immunosuppressed either due to an underlying disease process or medications to treat a disease require important perioperative considerations. Preoperative evaluation mandates a higher index of suspicion for pathology given that peritoneal and systemic markers of illness may be masked. Intraoperatively, consideration should be given for diversion more frequently than in a nonimmunosuppressed patient. Postoperatively, patients should be managed in a multidisciplinary fashion. This review largely focuses on the immunosuppressive mediations used for the treatment of inflammatory bowel disease, benign colorectal disease in an immunosuppressed patient, and colorectal malignancies in immunosuppressed patients to highlight important considerations for this patient population. This review contains 4 figures, 5 tables, and 78 references. Key words: anal squamous cell carcinoma, appendicitis versus typhlitis, biologic therapy, corticosteroids, human papillomavirus, immunosuppression, neutropenic enterocolitis 

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