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1.
Aesthetic Plast Surg ; 44(3): 855-861, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32157376

RESUMO

INTRODUCTION: Multiple symmetric lipomatosis (MSL) (syn.: Launois-Bensaude Syndrome, benign symmetric lipomatosis) is a rare disease of fatty tissue. The pathophysiology of MSL still remains unclear, although several approaches have been described in order to understand it. Beside morphological characteristics and some molecular cell biological approaches, little is known about the histological and immunohistochemical characterization of adipose tissue from patients with MSL. METHODS: From the 45 patients with MSL in our database, 10 were included in the study. Fat tissue samples were collected from affected and unaffected areas. The forearm served as a control area as this area is not affected in MSL. The specimens were analyzed after selected stainings were taken (hematoxylin-eosin = HE, Elastica van Gieson, Ladewig, CD200, CIDEA, myf5, p107, Prdm16, Sca-1, syndecan, UCP1, MAC387, Glut4). RESULTS: In patients suffering from MSL, no macroscopic or microscopic morphological difference could be found between affected and unaffected adipose tissue in HE stainings. The majority of samples showed positivity for UCP1 (9/10 clinically affected tissues, 7/10 clinically unaffected tissues) and CD200. CONCLUSION: Marker profiles support the hypothesis that affected adipose tissue derives from brown or beige adipose tissue rather than from white fat. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.


Assuntos
Tecido Adiposo Bege , Lipomatose Simétrica Múltipla , Tecido Adiposo , Humanos , Lipomatose Simétrica Múltipla/cirurgia
2.
Exp Dermatol ; 26(2): 127-132, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27623507

RESUMO

Dysregulation of pH is a feature of both tumor growth and tissue repair. In tumors, microenvironmental changes, like in lactate metabolism, lead to altered intra- and extracellular pH (pHi , pHe ) and vice versa. In wounds, barrier disruption results in extensive variations in pHe on the wound surface. It is known that altered extracellular proton concentrations have a major impact on cell turnover and migration as well as on the metabolic activity of cells involved in tumor spread and wound closure. The proton-sensing G protein-coupled receptors (GPCRs) GPR4, GPR65 (TDAG8), GPR68 (OGR1) and GPR132 (G2A) are activated via a decrease in pHe and transduce this signal to molecular intracellular pathways. Based on the current knowledge, we speculate on the role of proton-sensing GPCRs in wound healing and on their potential as mechanistic linkers of tumor growth and tissue repair.


Assuntos
Movimento Celular , Proliferação de Células , Neoplasias/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Cicatrização/fisiologia , Animais , Proteínas de Ciclo Celular/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Neoplasias/patologia , Microambiente Tumoral
3.
Exp Dermatol ; 26(2): 124-126, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27249231

RESUMO

Wound repair is an orchestrated process, encompassing the phases of inflammation, proliferation and tissue remodeling. In this context, sodium hydrogen exchanger 1 (NHE1) is crucial to epidermal barrier integrity and acidification. Recently, we found that extracellular pH (pHe) on wound surfaces is dramatically increased initially after barrier disruption, and that pHe decreases gradually during physiological healing. Additionally, we have shown that spatial NHE1-patterns account for pHe-gradients on surfaces of chronic wounds. Here, we show that NHE1-expression is very low at margins initially after wounding and that it increases massively during the time-course of physiolgical healing. This finding is in accordance with the decrease of pHe on wound surfaces, which we reported on in previous works. Thus, we show that NHE1 is an interesting target when it comes to modification of surface pHe on wounds, both acute and chronic, and that NHE1 is time-dependently regulated in physiological healing.


Assuntos
RNA Mensageiro/metabolismo , Trocador 1 de Sódio-Hidrogênio/genética , Trocador 1 de Sódio-Hidrogênio/metabolismo , Cicatrização , Epiderme/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Fatores de Tempo
4.
Am J Hum Genet ; 93(1): 181-90, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23830518

RESUMO

Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.


Assuntos
Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Doenças Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Deleção de Sequência , Proteínas de Transporte Vesicular/metabolismo , Adolescente , Adulto , Ataxia/genética , Mapeamento Cromossômico , Consanguinidade , Creatina Quinase/sangue , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Exoma , Feminino , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Complexo de Golgi/patologia , Homozigoto , Humanos , Proteína 2 de Membrana Associada ao Lisossomo , Proteínas de Membrana Lisossomal/genética , Proteínas de Membrana Lisossomal/metabolismo , Lisossomos/metabolismo , Masculino , Transtornos dos Movimentos/patologia , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Doenças Musculares/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Linhagem , Ligação Proteica , Transporte Proteico , Sítios de Splice de RNA , Síria , Proteínas de Transporte Vesicular/genética , Adulto Jovem
5.
Hum Mol Genet ; 22(2): 398-407, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23077215

RESUMO

Functional loss of SMN1 causes proximal spinal muscular atrophy (SMA), the most common genetic condition accounting for infant lethality. Hence, the hypomorphic copy gene SMN2 is the only resource of functional SMN protein in SMA patients and influences SMA severity in a dose-dependent manner. Consequently, current therapeutic approaches focus on SMN2. Histone deacetylase inhibitors (HDACi), such as the short chain fatty acid VPA (valproic acid), ameliorate the SMA phenotype by activating the SMN2 expression. By analyzing blood SMN2 expression in 16 VPA-treated SMA patients, about one-third of individuals were identified as positive responders presenting increased SMN2 transcript levels. In 66% of enrolled patients, a concordant response was detected in the respective fibroblasts. Most importantly, by taking the detour of reprograming SMA patients' fibroblasts, we showed that the VPA response was maintained even in GABAergic neurons derived from induced pluripotent stem cells (iPS) cells. Differential expression microarray analysis revealed a complete lack of response to VPA in non-responders, which was associated with an increased expression of the fatty acid translocase CD36. The pivotal role of CD36 as the cause of non-responsiveness was proven in various in vitro approaches. Most importantly, knockdown of CD36 in SMA fibroblasts converted non- into pos-responders. In summary, the concordant response from blood to the central nervous system (CNS) to VPA may allow selection of pos-responders prior to therapy. Increased CD36 expression accounts for VPA non-responsiveness. These findings may be essential not only for SMA but also for other diseases such as epilepsy or migraine frequently treated with VPA.


Assuntos
Antígenos CD36/metabolismo , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/metabolismo , Ácido Valproico/uso terapêutico , Antígenos CD36/genética , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Perfilação da Expressão Gênica , Humanos , Atrofia Muscular Espinal/genética , Ácido Valproico/farmacologia
6.
Hum Mol Genet ; 22(7): 1328-47, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23263861

RESUMO

F-actin bundling plastin 3 (PLS3) is a fully protective modifier of the neuromuscular disease spinal muscular atrophy (SMA), the most common genetic cause of infant death. The generation of a conditional PLS3-over-expressing mouse and its breeding into an SMA background allowed us to decipher the exact biological mechanism underlying PLS3-mediated SMA protection. We show that PLS3 is a key regulator that restores main processes depending on actin dynamics in SMA motor neurons (MNs). MN soma size significantly increased and a higher number of afferent proprioceptive inputs were counted in SMAPLS3 compared with SMA mice. PLS3 increased presynaptic F-actin amount, rescued synaptic vesicle and active zones content, restored the organization of readily releasable pool of vesicles and increased the quantal content of the neuromuscular junctions (NMJs). Most remarkably, PLS3 over-expression led to a stabilization of axons which, in turn, resulted in a significant delay of axon pruning, counteracting poor axonal connectivity at SMA NMJs. These findings together with the observation of increased endplate and muscle fiber size upon MN-specific PLS3 over-expression suggest that PLS3 significantly improves neuromuscular transmission. Indeed, ubiquitous over-expression moderately improved survival and motor function in SMA mice. As PLS3 seems to act independently of Smn, PLS3 might be a potential therapeutic target not only in SMA but also in other MN diseases.


Assuntos
Glicoproteínas de Membrana/fisiologia , Proteínas dos Microfilamentos/fisiologia , Placa Motora/fisiopatologia , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/patologia , Actinas/metabolismo , Animais , Potencial Evocado Motor , Expressão Gênica , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência , Placa Motora/metabolismo , Placa Motora/patologia , Neurônios Motores/patologia , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/fisiopatologia , Fenótipo , Propriocepção , Transporte Proteico , Receptores Colinérgicos/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Sinapses/metabolismo , Vesículas Sinápticas/metabolismo
7.
Retrovirology ; 12: 27, 2015 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-25886562

RESUMO

BACKGROUND: The human genome contains multiple LTR elements including human endogenous retroviruses (HERVs) that together account for approximately 8-9% of the genomic DNA. At least 40 different HERV groups have been assigned to three major HERV classes on the basis of their homologies to exogenous retroviruses. Although most HERVs are silenced by a variety of genetic and epigenetic mechanisms, they may be reactivated by environmental stimuli such as exogenous viruses and thus may contribute to pathogenic conditions. The objective of this study was to perform an in-depth analysis of the influence of HIV-1 infection on HERV activity in different cell types. RESULTS: A retrovirus-specific microarray that covers major HERV groups from all three classes was used to analyze HERV transcription patterns in three persistently HIV-1 infected cell lines of different cellular origins and in their uninfected counterparts. All three persistently infected cell lines showed increased transcription of multiple class I and II HERV groups. Up-regulated transcription of five HERV taxa (HERV-E, HERV-T, HERV-K (HML-10) and two ERV9 subgroups) was confirmed by quantitative reverse transcriptase PCR analysis and could be reversed by knock-down of HIV-1 expression with HIV-1-specific siRNAs. Cells infected de novo by HIV-1 showed stronger transcriptional up-regulation of the HERV-K (HML-2) group than persistently infected cells of the same origin. Analysis of transcripts from individual members of this group revealed up-regulation of predominantly two proviral loci (ERVK-7 and ERVK-15) on chromosomes 1q22 and 7q34 in persistently infected KE37.1 cells, as well as in de novo HIV-1 infected LC5 cells, while only one single HML-2 locus (ERV-K6) on chromosome 7p22.1 was activated in persistently infected LC5 cells. CONCLUSIONS: Our results demonstrate that HIV-1 can alter HERV transcription patterns of infected cells and indicate a correlation between activation of HERV elements and the level of HIV-1 production. Moreover, our results suggest that the effects of HIV-1 on HERV activity may be far more extensive and complex than anticipated from initial studies with clinical material.


Assuntos
Retrovirus Endógenos/fisiologia , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Transcrição Gênica , Ativação Viral , Linhagem Celular , Retrovirus Endógenos/genética , Perfilação da Expressão Gênica , Humanos , Análise em Microsséries
8.
Hum Genet ; 133(1): 29-39, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23982343

RESUMO

Proteoglycan (PG) synthesis begins with the sequential addition of a "linker chain", made up of four sugar residues, to a specific region of a core protein. Defects in the enzymes catalyzing steps two to four of the linker chain synthesis have been shown to cause autosomal recessive human phenotypes while no mutation has yet been reported in humans for the xylosyltransferases 1 and 2 (XT1 and XT2), the initiating enzymes in the linker chain formation. Here, we present a consanguineous Turkish family with two affected individuals presenting with short stature, distinct facial features, alterations of fat distribution, and moderate intellectual disability. X-rays showed only mild skeletal changes in the form of a short femoral neck, stocky and plump long bones and thickened ribs. Using a combination of whole-exome sequencing (WES), determination of homozygous stretches by WES variants, and classical linkage analysis, we identified the homozygous missense mutation c.C1441T in XYLT1, encoding XT1, within a large homozygous stretch on chromosome 16p13.12-p12.1. The mutation co-segregated with the phenotype in the family, is not found in over 13,000 alleles in the exome variant server and is predicted to change a highly conserved arginine at position 481 (p.R481W) located in the putative catalytical domain. Immunostaining of primary patient fibroblasts showed a loss of predominance of Golgi localization in mutant cells. Moreover, western blot analysis of decorin in cell culture supernatant demonstrated glycosylation differences between patient and control cells. Our data provide evidence that functional alterations of XT1 cause an autosomal recessive short stature syndrome associated with intellectual disability.


Assuntos
Nanismo/genética , Deficiência Intelectual/genética , Pentosiltransferases/genética , Consanguinidade , Exoma , Feminino , Genes Recessivos , Ligação Genética , Homozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Pentosiltransferases/metabolismo , Fenótipo , Proteoglicanas/metabolismo , Análise de Sequência de DNA , Síndrome , Turquia , Raios X , UDP Xilose-Proteína Xilosiltransferase
9.
Clin Case Rep ; 12(5): e8881, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38721567

RESUMO

Key Clinical Message: Keratosis palmoplantaris striata type I (SPPK-I) is a rare autosomal-dominant type of hereditary epidermolytic palmoplantar keratoderma, which can be caused by mutations in desmoglein-1 (DSG-1). Patients suffer from hyperkeratotic plaques and painful palmoplantar fissures. Unfortunately, treatment options including salicylic vaseline, topical corticosteroids, phototherapy, and retinoids are inefficient. Abstract: Hereditary palmoplantar keratodermas (PPKs) represent a heterogeneous group of rare skin disorders with epidermal palmoplantar hyperkeratosis. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate PPKs. We report a patient with keratosis palmoplantaris striata type I (SPPK-I) with a specific pathogenic variant [c.349C>T, p.(Arg117*)] in DSG1. Despite increased understanding, effective treatment options for PPK, including SPPK-I, remain limited.

10.
Hum Mol Genet ; 20(22): 4334-44, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21840928

RESUMO

Low levels of full-length survival motor neuron (SMN) protein cause the motor neuron disease, spinal muscular atrophy (SMA). Although motor neurons undoubtedly contribute directly to SMA pathogenesis, the role of muscle is less clear. We demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic severe SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomic data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. Robust upregulation of voltage-dependent anion-selective channel protein 2 (Vdac2) and downregulation of parvalbumin in severe SMA mice was confirmed in a milder SMA mouse model and in human patient muscle biopsies. Molecular pathology of skeletal muscle was ameliorated in mice treated with the FDA-approved histone deacetylase inhibitor, suberoylanilide hydroxamic acid. We conclude that intrinsic pathology of skeletal muscle is an important and reversible event in SMA and also suggest that muscle proteins have the potential to act as novel biomarkers in SMA.


Assuntos
Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Proteínas do Complexo SMN/metabolismo , Animais , Western Blotting , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Imuno-Histoquímica , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular Espinal/tratamento farmacológico , Proteínas do Complexo SMN/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo , Vorinostat
11.
Med Genet ; 33(1): 13-19, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38836198

RESUMO

Counseling recurrence risks for monogenic disorders is one of the mainstays of human genetics. However, in practice, consultations concerning autosomal recessive disorders exceed the simple conveyance of a 25 % recurrence risk for future offspring. Medical geneticists should be aware of the multifaceted way in which autosomal recessive disorders can pose a diagnostic and counseling challenge in their daily lives and of the pitfalls they might encounter. Although the intentional or incidental detection of carrier states for autosomal recessive diseases happens more and more frequently, our current practice when clarifying their associated reproductive risks remains unsystematic and often subjectively guided. We question whether the approach of focusing on small recurrence risks for a single familial disease with extensive single-gene tests in the partner of a known carrier truly addresses the counseling needs of a couple seeking preconceptional genetic advice. Different perspectives between patients and medical practitioners (or between different medical practitioners) on "acceptable risks" or the extent to which such risks must be minimized raise the question of whether existing professional guidelines need to be clarified.

12.
Eur J Med Genet ; 64(3): 104144, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33486103

RESUMO

BACKGROUND: Mutations in NFKB1(nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) are associated with a variety of clinical symptoms, including lymphadenopathy, splenomegaly, hepatomegaly, autoimmune haemolytic anaemia, arthralgia, recurrent respiratory tract infections and post-operative necrotizing cellulitis. CASE PRESENTATION: We describe a case of a 47-year-old man, who presented with deep necrotizing cellulitis after incision of a submucous abscess by a dentist. Surgical intervention led to a massive progress. Pyoderma gangraenosum (PG) was diagnosed clinically and confirmed histopathologically. High dose corticosteroids and intravenous immunoglobulins (IVIG) improved wound healing dramatically. Until now, immune mediated inflammation events not only affected the skin, but also multiple inner organs, i.e. the heart, lungs and gut. Sequencing of all coding exons of NFKB1 revealed a heterozygous 1bp deletion in exon 23 predicting a frameshift starting at codon Ala891 and resulting in a subsequent stop codon at position 6 in the new reading frame: NM_003998.4: c.2671del; p.(Ala891Glnfs*6) Acute episodes were always successfully treated with corticosteroids, IVIG and concomitant antibiotics. To prevent further exacerbations, the patient receives IVIG once a month, low-dose corticosteroids and methotrexate. CONCLUSION: This is the first case of a patient with recurrent necrotizing cellulitis and immune mediated multi-organ involvement (heart, lungs, intestine) carrying the novel frameshift mutation c.2671del (p.Ala891Glnfs*6) in NFKB1 effectively treated with IVIG, low-dose corticosteroids and methotrexate.


Assuntos
Doenças Autoimunes/genética , Celulite (Flegmão)/genética , Mutação da Fase de Leitura , Subunidade p50 de NF-kappa B/genética , Doenças da Imunodeficiência Primária/genética , Pioderma Gangrenoso/genética , Doenças Autoimunes/diagnóstico , Celulite (Flegmão)/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária/diagnóstico , Pioderma Gangrenoso/diagnóstico , Síndrome
13.
Sci Rep ; 9(1): 8444, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186450

RESUMO

Little is known on the causes and pathogenesis of the adipose tissue disorder (familial) Multiple Symmetric Lipomatosis (MSL). In a four-generation MSL-family, we performed whole exome sequencing (WES) in 3 affected individuals and 1 obligate carrier and identified Calcyphosine-like (CAPSL) as the most promising candidate gene for this family. Screening of 21 independent patients excluded CAPSL coding sequence variants as a common monogenic cause, but using immunohistochemistry we found that CAPSL was down-regulated in adipose tissue not only from the index patient but also in 10 independent sporadic MSL-patients. This suggests that CAPSL is regulated in sporadic MSL irrespective of the underlying genetic/multifactorial cause. Furthermore, we cultivated pre-adipocytes from MSL-patients and generated 3T3-L1-based Capsl knockout and overexpressing cell models showing altered autophagy, adipogenesis, lipogenesis and Sirtuin-1 (SIRT1) expression. CAPSL seems to be involved in adipocyte biology and perturbation of autophagy is a potential mechanism in the pathogenesis of MSL. Downregulation of CAPSL and upregulation of UCP1 were common features in MSL fat while the known MSL genes MFN2 and LIPE did not show consistent alterations. CAPSL immunostainings could serve as first diagnostic tools in MSL clinical care with a potential to improve time to diagnosis and healthcare options.


Assuntos
Adipogenia/genética , Predisposição Genética para Doença , Lipomatose Simétrica Múltipla/genética , Sirtuína 1/genética , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Idade de Início , Animais , Autofagia/genética , Diferenciação Celular/genética , Feminino , GTP Fosfo-Hidrolases/genética , Regulação da Expressão Gênica/genética , Humanos , Lipomatose Simétrica Múltipla/patologia , Masculino , Camundongos , Proteínas Mitocondriais/genética , Mutação/genética , Linhagem , Sequenciamento do Exoma
14.
Curr Med Chem ; 25(13): 1538-1548, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28618994

RESUMO

Statin intolerance is usually defined as the inability of a patient to tolerate statintreatment due to muscle-related complaints. While randomised trials show that these complaints occure with similar frequency in patients receiving placebo, namely in up to ~5% of the subjects, and data from registries as well as clinical experience indicate a much higher frequency of up to ~30%. The lack of standard definition or of a diagnostic marker of statin intolerance confounds the problem. The diagnosis remains subjective based on the symptoms the patient reports. Therefore, a large number of patients who need a statin are not receiving it, or receiving only very-low and/or intermittent doses unable to achieve a robust decrease in low-density lipoprotein cholesterol (LDL-C), leaving patients at high or very high risk for cardiovascular events requiring an alternative form of lipid-lowering therapy. Until recently, the only available alternatives were niacin, ezetimibe, bile-acid sequestrants and fibrates that decrease LDL-C concentrations by up to 15-20%. Recently the fully human monoclonal antibodies against proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab (Praluent®) and evolocumab (Repatha®), which have been shown to decrease LDL-C by up to 70% have been approved in Europe for use in patients with primary hypercholesterolemia not at LDL-C target while on maximally tolerated lipid-lowering therapy and specifically for patients with statin intolerance and in the USA for patients with atherosclerotic cardiovascular disease or familial hypercholesterolemia requiring additional LDL-C lowering. Ongoing large clinical trials with cardiovascular endpoints will provide a definitive answer for the role of anti-PCSK9 antibodies in clinical practice.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pró-Proteína Convertase 9/imunologia , Anticorpos Monoclonais Humanizados , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/metabolismo , Aprovação de Drogas , Europa (Continente) , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico
15.
JAMA Dermatol ; 159(10): 1133-1134, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37703032

RESUMO

A woman in her 50s presented with bluish, keratotic papules and nodules on the lower legs and lipolymphedema of the lower legs. What is your diagnosis?


Assuntos
Neoplasias Cutâneas , Malformações Vasculares , Feminino , Humanos , Pessoa de Meia-Idade , Malformações Vasculares/complicações , Malformações Vasculares/diagnóstico
17.
Plast Reconstr Surg Glob Open ; 6(4): e1722, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29876171

RESUMO

BACKGROUND: Multiple symmetric lipomatosis (MSL) is defined as a disorder of nonencapsulated adipose tissue growth. Its prevalence is indicated as 1:25,000 and affects, as stated in the literature, mainly Mediterranean males (male:female ratio of 15:1). Phenotypes are still classified as defined by Donhauser in 1991. We report clinical and phenotypic data of the largest patient cohort investigated in Germany so far. METHODS: Forty-five patients diagnosed with MSL at the University Hospital Regensburg between 2007 and 2017 were photographed, clinically examined, and blood samples were taken. Based on the photographs (n = 33), 11 independent observers assessed patients using the Donhauser classification. Furthermore, the bodies of all patients were subdivided into 12 body areas, and the viewers had to indicate all MSL-affected areas per patient. Prevalence was calculated, comorbidities were assessed, and blood samples were analyzed. RESULTS: According to the established Donhauser classification, less than 50% of the patients could be classified. Therefore, based on the constellations of MSL-affected body areas, a new classification that divides phenotypes of MSL into 5 types (Ia, Ib, Ic, II, and III) was set up and was able to cover 100% of our patients. The male to female ratio was found to be 1:2.5 (male:female). Prevalence of MSL in the catchment area was found to be 1:25,000. Hypercholesterinemia and hypothyroidism were frequent comorbidities, and blood analyses were normal besides a hypercholesterinemia. DISCUSSION: The new proposed classification system describes 5 subtypes and allowed to classify all assessed patients. Male to female ratio (1:2.5) contradicted most previous publications.

18.
Curr Pharm Des ; 23(10): 1562-1570, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28128058

RESUMO

BACKGROUND: Lipoprotein(a) [Lp(a)] is a particle similar to LDL that contains an additional protein called apolipoprotein(a) [apo(a)]. Recent epidemiologic and Mendelian randomization studies have provided evidence that Lp(a) may be causally related to the pathogenesis of atherosclerosis and cardiovascular disease (CVD). While the risk association between Lp(a) concentrations and CVD is weak it seems to be continuous in shape and without an obvious threshold for Lp(a) levels. METHODS: Circulating concentrations of Lp(a) are genetically determined and desirable levels are < 50 mg/dl. A plasma concentration of 60 mg/dl is associated with an odds ratio for coronary heart disease of about 1.5 after adjustment for other cardiovascular risk factors. RESULTS: Extended-release niacin is the pharmacologic means of choice for decreasing elevated Lp(a) levels by ~20-30% but it is often poorly tolerated due to adverse reactions. Diet, exercise and lipid-lowering drugs such as statins, fibrates and ezetimibe are without effect. In patients with severe progressive CVD and very high Lp(a) levels, lipoprotein apheresis may be used to decrease Lp(a) concentrations. However, it is an expensive and impractical treatment for most patients and its feasibility depends on the healthcare reimbursement system of the respective country. Since no established treatment reduces Lp(a) without influencing other lipoproteins, there has been no trial examining whether decreasing Lp(a) concentrations translates to clinical benefits. CONCLUSION: Recently, an antisense oligonucleotide against apo(a), IONIS-APO(a)Rx, has been shown to selectively decrease Lp(a) by ~80%. A phase 2 study with this drug has been completed in late 2015 and results are expected to be published soon.


Assuntos
Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/tratamento farmacológico , Lipoproteína(a)/sangue , Oligonucleotídeos Antissenso/uso terapêutico , Animais , Humanos , Fatores de Risco
19.
Case Rep Dermatol ; 8(1): 19-21, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26933410

RESUMO

A 50-year-old man presented with congenital scaling and hyperkeratosis on his palms, the soles of his feet and the extensor areas of his joints. The flexural areas were unaffected. His maternal grandmother, questionably his maternal uncle, his mother, all three brothers, one of his two sisters as well as two nephews and three nieces have or had similar skin changes. A punch biopsy was taken from the left palm. Clinical and histological signs led to the diagnosis of erythrodermia congenitalis ichthyosiformis bullosa of Brocq. We confirmed this genetically and found a heterozygous duplication (c.1752dupT) in the keratin 1 gene (KRT-1). To our knowledge, this is the first case of this skin condition reported in the literature with a heterozygous duplication (c.1752dupT) in KRT-1.

20.
Plast Reconstr Surg ; 137(4): 1181-1190, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27018673

RESUMO

BACKGROUND: The cause of the rare fat distribution disorder multiple symmetric lipomatosis is unknown. Independent reports suggest a higher proliferative activity, hormone resistance, and involvement of mitochondrial function in the disease. METHODS: The authors performed morphologic comparison of affected and unaffected tissues in five unrelated patients and generated adipose-derived stem cell cultures from the tissue samples and characterized them as a possible cellular model of multiple symmetric lipomatosis evolution. The authors investigated proliferative activity and the expression of genes relevant to disease processes. RESULTS: There was no difference in the morphologic appearance and the surface marker profile. Stem cells from lipomatous tissue showed significantly higher proliferative activity. Polymerase chain reaction arrays showed marked changes in genes associated with proliferation, hormonal regulation, and mitochondria. The authors show that multiple symmetric lipomatosis tissue is morphologically and histologically different from regular subcutaneous fat. CONCLUSIONS: This study indicates an involvement of mesenchymal stem cells in the pathogenesis of multiple symmetric lipomatosis and that the evolution of multiple symmetric lipomatosis tissue is a process driven by an inherent defect of the respective cell clone(s). Further molecular genetics and functional analysis will be required to unravel the pathogenetic mechanism underlying the derailment in fat cell metabolism and proliferation. Here, the authors show for the first time that adipose-derived stem cells exhibit many characteristics previously described for native multiple symmetric lipomatosis fat tissue and propose that they are therefore an excellent tool for further functional investigations in multiple symmetric lipomatosis and other disorders of the fat tissue. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V.


Assuntos
Lipomatose Simétrica Múltipla/genética , Células-Tronco Mesenquimais/fisiologia , Gordura Subcutânea/fisiopatologia , Transcriptoma , Idoso , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Humanos , Lipomatose Simétrica Múltipla/patologia , Lipomatose Simétrica Múltipla/fisiopatologia , Masculino , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Gordura Subcutânea/patologia
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