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American Family Physician Sep 2017Hair loss is often distressing and can have a significant effect on the patient's quality of life. Patients may present to their family physician first with diffuse or...
Hair loss is often distressing and can have a significant effect on the patient's quality of life. Patients may present to their family physician first with diffuse or patchy hair loss. Scarring alopecia is best evaluated by a dermatologist. Nonscarring alopecias can be readily diagnosed and treated in the family physician's office. Androgenetic alopecia can be diagnosed clinically and treated with minoxidil. Alopecia areata is diagnosed by typical patches of hair loss and is self-limited. Tinea capitis causes patches of alopecia that may be erythematous and scaly and must be treated systemically. Telogen effluvium is a nonscarring, noninflammatory alopecia of relatively sudden onset caused by physiologic or emotional stress. Once the precipitating cause is removed, the hair typically will regrow. Trichotillomania is an impulse-control disorder; treatment is aimed at controlling the underlying psychiatric condition. Trichorrhexis nodosa occurs when hairs break secondary to trauma and is often a result of hair styling or overuse of hair products. Anagen effluvium is the abnormal diffuse loss of hair during the growth phase caused by an event that impairs the mitotic activity of the hair follicle, most commonly chemotherapy. Physician support is especially important for patients in this situation.
Topics: Alopecia; Hair; Humans; Medical History Taking; Physical Examination; Tinea Capitis; Trichothiodystrophy Syndromes; Trichotillomania
PubMed: 28925637
DOI: No ID Found -
Cell Mar 2017The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and...
The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
Topics: Aging; Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Cycle Proteins; Cell Line; Cell Survival; Cell-Penetrating Peptides; Cellular Senescence; Doxorubicin; Female; Fibroblasts; Forkhead Transcription Factors; Humans; Inclusion Bodies; Kidney; Liver; Male; Mice; Trichothiodystrophy Syndromes; Tumor Suppressor Protein p53
PubMed: 28340339
DOI: 10.1016/j.cell.2017.02.031 -
Dermatology and Therapy Sep 2019Hair loss in early childhood represents a broad differential diagnosis which can be a diagnostic and therapeutic challenge for a physician. It is important to consider... (Review)
Review
Hair loss in early childhood represents a broad differential diagnosis which can be a diagnostic and therapeutic challenge for a physician. It is important to consider the diagnosis of a genetic hair disorder. Genetic hair disorders are a large group of inherited disorders, many of which are rare. Genetic hair abnormalities in children can be an isolated phenomenon or part of genetic syndromes. Hair changes may be a significant finding or even the initial presentation of a syndrome giving a clue to the diagnosis, such as Netherton syndrome and trichothiodystrophy. Detailed history including family history and physical examination of hair and other ectodermal structures such as nails, sweat glands, and sebaceous glands with the use of dermoscopic devices and biopsy all provide important clues to establish the correct diagnosis. Understanding the pathophysiology of genetic hair defects will allow for better comprehension of their treatment and prognosis. For example, in patients with an isolated hair defect, the main problem is aesthetic. In contrast, when the hair defect is associated with a syndrome, the prognosis will depend mainly on the associated condition. Treatment of many genetic hair disorders is focused on treating the primary cause and minimizing trauma to the hair.
PubMed: 31332722
DOI: 10.1007/s13555-019-0313-2 -
Open Biology Oct 2019Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA lesions. A major substrate for NER is DNA damage caused by environmental... (Review)
Review
Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA lesions. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human disorders caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated ageing. All three syndromes include developmental abnormalities, indicating an important role for optimal transcription and for NER in protecting against spontaneous DNA damage during embryonic development. Here, we review the current knowledge on genes that function in NER that also affect embryonic development, in particular the development of a fully functional nervous system.
Topics: Animals; Cockayne Syndrome; DNA Repair; DNA Repair Enzymes; Embryonic Development; Humans; Phenotype
PubMed: 31662099
DOI: 10.1098/rsob.190166 -
DNA Repair Dec 2023The heterodecameric transcription factor IIH (TFIIH) functions in multiple cellular processes, foremost in nucleotide excision repair (NER) and transcription initiation... (Review)
Review
The heterodecameric transcription factor IIH (TFIIH) functions in multiple cellular processes, foremost in nucleotide excision repair (NER) and transcription initiation by RNA polymerase II. TFIIH is essential for life and hereditary mutations in TFIIH cause the devastating human syndromes xeroderma pigmentosum, Cockayne syndrome or trichothiodystrophy, or combinations of these. In NER, TFIIH binds to DNA after DNA damage is detected and, using its translocase and helicase subunits XPB and XPD, opens up the DNA and checks for the presence of DNA damage. This central activity leads to dual incision and removal of the DNA strand containing the damage, after which the resulting DNA gap is restored. In this review, we discuss new structural and mechanistic insights into the central function of TFIIH in NER. Moreover, we provide an elaborate overview of all currently known patients and diseases associated with inherited TFIIH mutations and describe how our understanding of TFIIH function in NER and transcription can explain the different disease features caused by TFIIH deficiency.
Topics: Humans; Transcription Factor TFIIH; Xeroderma Pigmentosum Group D Protein; DNA Repair; Xeroderma Pigmentosum; DNA
PubMed: 37977600
DOI: 10.1016/j.dnarep.2023.103568 -
Muscle & Nerve Feb 2023Repair of genomic DNA is a fundamental housekeeping process that quietly maintains the health of our genomes. The consequences of a genetic defect affecting a component... (Review)
Review
Repair of genomic DNA is a fundamental housekeeping process that quietly maintains the health of our genomes. The consequences of a genetic defect affecting a component of this delicate mechanism are quite harmful, characterized by a cascade of premature aging that injures a variety of organs, including the nervous system. One part of the nervous system that is impaired in certain DNA repair disorders is the peripheral nerve. Chronic motor, sensory, and sensorimotor polyneuropathies have all been observed in affected individuals, with specific physiologies associated with different categories of DNA repair disorders. Cockayne syndrome has classically been linked to demyelinating polyneuropathies, whereas xeroderma pigmentosum has long been associated with axonal polyneuropathies. Three additional recessive DNA repair disorders are associated with neuropathies, including trichothiodystrophy, Werner syndrome, and ataxia-telangiectasia. Although plausible biological explanations exist for why the peripheral nerves are specifically vulnerable to impairments of DNA repair, specific mechanisms such as oxidative stress remain largely unexplored in this context, and bear further study. It is also unclear why different DNA repair disorders manifest with different types of neuropathy, and why neuropathy is not universally present in those diseases. Longitudinal physiological monitoring of these neuropathies with serial electrodiagnostic studies may provide valuable noninvasive outcome data in the context of future natural history studies, and thus the responses of these neuropathies may become sentinel outcome measures for future clinical trials of treatments currently in development such as adeno-associated virus gene replacement therapies.
Topics: Humans; Peripheral Nervous System Diseases; DNA Repair; Xeroderma Pigmentosum; Cockayne Syndrome; Polyneuropathies
PubMed: 36190439
DOI: 10.1002/mus.27721 -
Photochemistry and Photobiology 2015Ultraviolet (UV) radiation from sunlight is a major etiologic factor for skin cancer, the most prevalent cancer in the United States, as well as premature skin aging. In... (Review)
Review
Ultraviolet (UV) radiation from sunlight is a major etiologic factor for skin cancer, the most prevalent cancer in the United States, as well as premature skin aging. In particular, UVB radiation causes formation of specific DNA damage photoproducts between pyrimidine bases. These DNA damage photoproducts are repaired by a process called nucleotide excision repair, also known as UV-induced DNA repair. When left unrepaired, UVB-induced DNA damage leads to accumulation of mutations, predisposing people to carcinogenesis as well as to premature aging. Genetic loss of nucleotide excision repair leads to severe disorders, namely, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS), which are associated with predisposition to skin carcinogenesis at a young age as well as developmental and neurological conditions. Regulation of nucleotide excision repair is an attractive avenue to preventing or reversing these detrimental consequences of impaired nucleotide excision repair. Here, we review recent studies on molecular mechanisms regulating nucleotide excision repair by extracellular cues and intracellular signaling pathways, with a special focus on the molecular regulation of individual repair factors.
Topics: Aging; Carcinogenesis; Cockayne Syndrome; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Gene Expression Regulation; Humans; RNA Polymerase II; Signal Transduction; Skin Neoplasms; Trichothiodystrophy Syndromes; Ultraviolet Rays; Xeroderma Pigmentosum
PubMed: 25534312
DOI: 10.1111/php.12406 -
Cells Jun 2019The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and... (Review)
Review
The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in rRNA transcription and processing translate to ribosomal malfunction. Nucleolar malfunction has recently been described in the classical progeria of childhood, Hutchinson-Gilford syndrome (HGPS), which is characterized by severe signs of premature aging, including atherosclerosis, alopecia, and osteoporosis. A deregulated ribosomal biogenesis with enlarged nucleoli is not only characteristic for HGPS patients, but it is also found in the fibroblasts of "normal" aging individuals. Cockayne syndrome (CS) is also characterized by signs of premature aging, including the loss of subcutaneous fat, alopecia, and cataracts. It has been shown that all genes in which a mutation causes CS, are involved in rDNA transcription by RNA Pol I. A disturbed ribosomal biogenesis affects mitochondria and translates into ribosomes with a reduced translational fidelity that causes endoplasmic reticulum (ER) stress and apoptosis. Therefore, it is speculated that disease-causing disturbances in the process of ribosomal biogenesis may be more common than hitherto anticipated.
Topics: Aging, Premature; Cell Nucleolus; Child; Cockayne Syndrome; Endoplasmic Reticulum Stress; Humans; Mitochondria; Progeria; RNA Polymerase I; Ribosomes
PubMed: 31167386
DOI: 10.3390/cells8060534