RESUMO
Chronic kidney disease (CKD) is a global socioeconomic problem. It is characterised by the presence of differentiated myofibroblasts, which cause tissue fibrosis in response to TGFB1, leading to renal failure. Here, we define a novel interaction between the SET9 lysine methyltransferase (also known as SETD7) and SMAD3, the principal mediator of TGFB1 signalling in myofibroblasts. We show that SET9-deficient fibroblasts exhibit globally altered gene expression profiles in response to TGFB1, whilst overexpression of SET9 enhances SMAD3 transcriptional activity. We also show that SET9 facilitates nuclear import of SMAD3 and controls SMAD3 protein degradation via ubiquitylation. On a cellular level, we demonstrate that SET9 is broadly required for the effects of TGFB1 in diseased primary renal fibroblasts; SET9 promotes fibroblast migration into wounds, expression of extracellular matrix proteins, collagen contractility and myofibroblast differentiation. Finally, we demonstrate that SET9 is recruited to the α-smooth muscle actin gene in response to TGFB1, providing a mechanism by which SET9 regulates myofibroblast contractility and differentiation. Together with previous studies, we make the case for SET9 inhibition in the treatment of progressive CKD.
Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Miofibroblastos/metabolismo , Transdução de Sinais/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Animais , Diferenciação Celular , Linhagem Celular , Movimento Celular , Células Cultivadas , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Fibrose , Regulação da Expressão Gênica , Humanos , Rim/citologia , Camundongos , Camundongos Knockout , Miofibroblastos/citologiaRESUMO
BACKGROUND: Topical photodynamic therapy (PDT) and imiquimod 5% (IMQ) cream are established treatments for superficial basal cell carcinoma (sBCC). Both have high initial response rates and recurrence rates of up to 37%. Recent studies demonstrate that PDT and imiquimod may act on sBCCs via synergistic immunomodulatory pathways. OBJECTIVE: To describe the sequential use of MAL-PDT and imiquimod 5% cream in the treatment of sBCCs and report treatment tolerability, cosmetic outcomes, and efficacy. MATERIALS AND METHODS: This is a retrospective case series of patients presenting over a 2-year period with primary sBCC who underwent 2 cycles of topical MAL-PDT, followed by 6 weeks of imiquimod 5% cream. Outcome measures were resolution of the index lesion at 3 months, side effects, cosmetic outcome, and long-term recurrence (LTR). RESULTS: A total of 17 consecutive patients (n = 17) with a combined 21 sBCCs (n = 21) were included. The median length of follow-up was 72 months (range 24-95 months). Long-term recurrence occurred in 2/21 lesions (10%). CONCLUSION: Sequential use of PDT and imiquimod was well tolerated with good cosmetic outcomes. The 10% LTR rate is at the lower end of the range reported for single modality treatment; however, larger samples are required to evaluate efficacy differences.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Basocelular/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/efeitos adversos , Ácido Aminolevulínico/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Basocelular/patologia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Estética , Feminino , Seguimentos , Humanos , Imiquimode/administração & dosagem , Imiquimode/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fotoquimioterapia/efeitos adversos , Fármacos Fotossensibilizantes/efeitos adversos , Estudos Retrospectivos , Creme para a Pele/administração & dosagem , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: If loss of functioning nephrons predisposes to glomerular barotrauma (a "remnant nephron" effect), then glomerular permeability should increase as glomerular filtration rate (GFR) falls, as is observed in animal models of nephron loss. METHODS: Changes in net renal protein permeability, defined as proteinuria or albuminuria per mL/min of GFR, were measured in the setting of nephron loss due to kidney donation (Assessing Long Term Outcomes in Living Kidney Donors cohort) or progressive chronic kidney disease (CKD; Modification of Diet in Renal Disease [MDRD], African American Study of Kidney Disease [AASK], and Chronic Renal insufficiency Cohort [CRIC] studies). RESULTS: Following kidney donation, renal albumin permeability increased by 31% from predonation levels (p < 0.001). With progression of CKD, a 50% loss of residual GFR was accompanied by increases in proteinuria per mL/min GFR of 1.8-, 2.1-, and 1.6-fold in the MDRD, AASK, and CRIC cohorts, respectively (p < 0.001 for all), independent of changes in systolic blood pressure and ACEi/ARB use. A 70% reduction in GFR was associated with permeability increases of 3.1-, 4.4-, and 2.6-fold in the same cohorts. Among MDRD participants with progression of nonglomerular primary disease, the 75th percentile of final permeability was 141 mg/24 h proteinuria per mL/min GFR. This degree of permeability would have resulted in nephrotic range proteinuria had it been present at the baseline mean GFR of 40 mL/min, implying the development of de novo glomerular pathology as GFR fell. Increasing permeability also accompanied CKD progression in participants with nephrotic syndrome at baseline. Consequently, these participants had little improvement in 24 h proteinuria or serum albumin, despite substantial loss of functioning nephron mass across which the protein leak occurred. In the absence of a fall in GFR, there was no increase in permeability in any cohort. CONCLUSION: Nephron loss is accompanied by an increase in renal protein permeability, even in the absence of a primary glomerular disease. This is consistent with a remnant nephron effect in human CKD.
Assuntos
Taxa de Filtração Glomerular/fisiologia , Nefrectomia/efeitos adversos , Néfrons/metabolismo , Proteinúria/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Animais , Progressão da Doença , Feminino , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Néfrons/fisiopatologia , Permeabilidade , Estudos Prospectivos , Proteinúria/etiologia , Insuficiência Renal Crônica/complicações , Fatores de Risco , Albumina Sérica Humana/metabolismo , Obtenção de Tecidos e ÓrgãosRESUMO
Leber hereditary optic neuropathy (LHON) was the first mitochondrial disease to be identified as being caused by mutations in the mitochondrial DNA (mtDNA). This disease has been studied extensively in the past two decades, particularly in Brazilian, Chinese and European populations; and many primary mutations have been reported. However, the disease is enigmatic with many unique features, and there still are several important questions to be resolved. The incomplete penetrance, the male-biased disease expression and the prevalence in young adults all defy a proper explanation. It has been reported that the development of LHON is affected by the interaction between mtDNA mutations, mtDNA haplogroup background, nuclear genes, environmental factors and epigenetics. Furthermore, with the help of new animal models for LHON that have been created in recent years, we are continuing to learn more about the mechanism of this disease. The stage has now been reached at which there is a good understanding of both the genetic basis of the disease and its epidemiology, but just how the blindness that follows from the death of cells in the optic nerve can be prevented remains to be a pharmacological challenge. In this chapter, we summarize the progress that has been made in various recent studies on LHON, focusing on the molecular pathogenic mechanisms, clinical features, biochemical effects, the pharmacology and its treatment.
Assuntos
DNA Mitocondrial/genética , Mutação , Atrofia Óptica Hereditária de Leber/genética , Animais , Edição de Genes , Terapia Genética , Humanos , Atrofia Óptica Hereditária de Leber/terapiaRESUMO
The androgen receptor (AR), a member of the nuclear receptor family, is a transcription factor involved in prostate cell growth, homeostasis, and transformation. AR is a key protein in growth and development of both normal and malignant prostate, making it a common therapeutic target in prostate cancer. AR is regulated by an interplay of multiple post-translational modifications including ubiquitination. We and others have shown that the AR is ubiquitinated by a number of E3 ubiquitin ligases, including MDM2, CHIP, and NEDD4, which can result in its proteosomal degradation or enhanced transcriptional activity. As ubiquitination of AR causes a change in AR activity or stability and impacts both survival and growth of prostate cancer cells, deubiquitination of these sites has an equally important role. Hence, deubiquitinating enzymes could offer novel therapeutic targets. We performed an siRNA screen to identify deubiquitinating enzymes that regulate AR; in that screen ubiquitin-specific protease 12 (Usp12) was identified as a novel positive regulator of AR. Usp12 is a poorly characterized protein with few known functions and requires the interaction with two cofactors, Uaf-1 and WDR20, for its enzymatic activity. In this report we demonstrate that Usp12, in complex with Uaf-1 and WDR20, deubiquitinates the AR to enhance receptor stability and transcriptional activity. Our data show that Usp12 acts in a pro-proliferative manner by stabilizing AR and enhancing its cellular function.
Assuntos
Proliferação de Células , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Animais , Células COS , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/genética , Estabilidade Proteica , Receptores Androgênicos/genética , Ubiquitina Tiolesterase/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Since the determination in 1981 of the sequence of the human mitochondrial DNA (mtDNA) genome, the Cambridge Reference Sequence (CRS), has been used as the reference sequence to annotate mtDNA in molecular anthropology, forensic science and medical genetics. The CRS was eventually upgraded to the revised version (rCRS) in 1999. This reference sequence is a convenient device for recording mtDNA variation, although it has often been misunderstood as a wild-type (WT) or consensus sequence by medical geneticists. Recently, there has been a proposal to replace the rCRS with the so-called Reconstructed Sapiens Reference Sequence (RSRS). Even if it had been estimated accurately, the RSRS would be a cumbersome substitute for the rCRS, as the new proposal fuses--and thus confuses--the two distinct concepts of ancestral lineage and reference point for human mtDNA. Instead, we prefer to maintain the rCRS and to report mtDNA profiles by employing the hitherto predominant circumfix style. Tree diagrams could display mutations by using either the profile notation (in conventional short forms where appropriate) or in a root-upwards way with two suffixes indicating ancestral and derived nucleotides. This would guard against misunderstandings about reporting mtDNA variation. It is therefore neither necessary nor sensible to change the present reference sequence, the rCRS, in any way. The proposed switch to RSRS would inevitably lead to notational chaos, mistakes and misinterpretations.
Assuntos
DNA Mitocondrial/genética , Bases de Dados de Ácidos Nucleicos/normas , Análise de Sequência de DNA/normas , Feminino , Humanos , Masculino , Padrões de ReferênciaRESUMO
BACKGROUND: A large body of genetic research has focused on the potential role that mitochondrial DNA (mtDNA) variants might play on the predisposition to common and complex (multi-factorial) diseases. It has been argued however that many of these studies could be inconclusive due to artifacts related to genotyping errors or inadequate design. METHODS: Analyses of the data published in case-control breast cancer association studies have been performed using a phylogenetic-based approach. Variation observed in these studies has been interpreted in the light of data available on public resources, which now include over >27,000 complete mitochondrial sequences and the worldwide phylogeny determined by these mitogenomes. Complementary analyses were carried out using public datasets of partial mtDNA sequences, mainly corresponding to control-region segments. RESULTS: By way of example, we show here another kind of fallacy in these medical studies, namely, the phenomenon of SNP-SNP interaction wrongly applied to haploid data in a breast cancer study. We also reassessed the mutually conflicting studies suggesting some functional role of the non-synonymous polymorphism m.10398A>G (ND3 subunit of mitochondrial complex I) in breast cancer. In some studies, control groups were employed that showed an extremely odd haplogroup frequency spectrum compared to comparable information from much larger databases. Moreover, the use of inappropriate statistics signaled spurious "significance" in several instances. CONCLUSIONS: Every case-control study should come under scrutiny in regard to the plausibility of the control-group data presented and appropriateness of the statistical methods employed; and this is best done before potential publication.
Assuntos
Neoplasias da Mama/genética , DNA Mitocondrial , Alelos , Estudos de Casos e Controles , Epistasia Genética , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/genética , Viés de Publicação , RiscoRESUMO
A commentary of the paper 'Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology' that appeared recently in Aging Cell. The possible association of a mitochondrial haplogroup with a disease is frequently discussed. The Humanin peptide encoded by the mtDNA has been shown to play an important regulatory role in cell metabolism. There are variants of Humanin caused by different mutations and it is known that the potent form of Humanin, termed S14G, is found naturally in the people of haplogroup U6a7a1a because they have the mutation m.A2672G; however it has not been shown that having this mutation is indeed beneficial. In their paper, the authors suggest that the mitochondrial DNA mutation, m.C2639T, may be beneficial in people who are in haplogroup N1b and also carry APOE4. The mutation changes the common form of Humanin to Humanin P3S. In the study, the researchers looked at a group of Ashkenazi women who were over the age of 95, and found that a higher proportion of them carried APOE4, suggesting that Humanin P3S protected them against the adverse effects of APOE4. A study in a mouse model supported this finding by showing treatment with Humanin P3S reduced APOE4-induced brain pathology. In the world population, there are about 500,000 Ashkenazi in haplogroup N1b, predominantly in the subgroup N1b1b1; and there are about 9.5 million non-Ashkenazi people with the mutation m.C2639T and are therefore also in haplogroup N1b and have Humanin P3S. However, the researchers have yet to show Humanin P3S is of benefit in non-Ashkenazi people. This paper raises the possibility of a therapeutic use of Humanin P3S in the treatment of Alzheimer's disease.
Assuntos
Doença de Alzheimer , Haplótipos , Doença de Alzheimer/genética , Humanos , Haplótipos/genética , Animais , Camundongos , Feminino , DNA Mitocondrial/genética , Apolipoproteína E4/genética , Mutação , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
This paper reports the discovery of a m.C1494T pedigree in the east of England made during a search for matrilineal relations of King Richard III. The mitochondrial DNA variant m.C1494T has been associated with aminoglycoside-induced deafness. This variant is very uncommon. although pedigrees with this variant have previously been found in China and Spain. The members of the newly identified pedigree all belong to the mitochondrial haplogroup J1c2c3, which is also the haplogroup of King Richard III. The presence of a few people in the USA from the same haplogroup has previously been noted, and it is now known that one of the people can show his descent from a couple who lived in Nottinghamshire, England, in the late 1700's. The mitochondrial DNA sequence of this man, at present living in the USA, and of his 4th cousin, twice removed, living in Lincoln, England, has shown they belong to haplogroup J1c2c3 and both have the variant m.C1494T; thereby, allowing the production of a multi-generational pedigree originating in the east of England. Fortunately, deafness has not been found in any living member of this large pedigree. It was also noted that the link to the family of King Richard III has not been firmly defined; however the circumstantial evidence is strong as many of his family members lived in this part of England.
Assuntos
DNA Mitocondrial , Linhagem , Humanos , DNA Mitocondrial/genética , Masculino , Inglaterra , Feminino , Haplótipos , Surdez/genéticaRESUMO
A precise diagnosis in medicine allows appropriate disease-specific management. Kidney failure of unknown aetiology remains a frequent diagnostic label within the haemodialysis unit and kidney transplant clinic, accounting for 15-20% of these patients. Approximately 10% of such cases may have an underlying monogenic cause of kidney failure. Modern genetic approaches can provide a precise diagnosis for patients and their families. A search for extra-renal disease manifestations is also important as this may point to a specific genetic diagnosis. Here, we present two patients where molecular genetic testing was performed because of kidney failure of unknown aetiology and associated retinal phenotypes. The first patient reached kidney failure at 16 years of age but only presented with a retinal phenotype at 59 years of age and was found to have evidence of rod-cone dystrophy. The second patient presented with childhood kidney failure at the age of 15 years and developed visual difficulties and photophobia at the age of 32 years and was diagnosed with cone dystrophy. In both cases, genetic tests were performed which revealed a homozygous whole-gene deletion of NPHP1-encoding nephrocystin-1, providing the unifying diagnosis of Senior-Løken syndrome type 1. We conclude that reviewing kidney and extra-renal phenotypes together with targeted genetic testing was informative in these cases of kidney failure of unknown aetiology and associated retinal phenotypes. The involvement of an interdisciplinary team is advisable when managing such patients and allows referral to other relevant specialities. The long time lag and lack of diagnostic clarity and clinical evaluation in our cases should encourage genetic investigations for every young patient with unexplained kidney failure. For these and similar patients, a more timely genetic diagnosis would allow for improved management, a risk assessment of kidney disease in relatives, and the earlier identification of extra-renal disease manifestations. Supplementary Information: The online version contains supplementary material available at 10.1007/s44162-024-00031-4.
RESUMO
BACKGROUND: orthostatic hypotension (OH) affects up to 30% of adults over 65 and frequently contributes to falls and syncopal episodes. Current guidelines suggest a wide range of treatments, but systematic reviews of the evidence base for such recommendations are lacking. METHODS: we performed a systematic review to assess the evidence for all non-pharmacological and pharmacological interventions for OH. Our search included the following databases: MEDLINE; EMBASE; CINAHL; and the Cochrane library. We searched grey literature and references from included studies and other reviews. We included randomised, placebo-controlled trials, which measured postural drop as an outcome. Study quality was assessed using pre-specified measures of bias. RESULTS: overall, 36 trials (21 interventions) were included. We identified a heterogeneous population and a wide variety of study methods, precluding meta-analysis. Most trials were of poor quality with high risk of bias. Changes in postural drop and symptoms were frequently inconsistent. Compression bandages, indomethacin, oxilofrine, potassium chloride and yohimbine improved the postural drop. Several vasoactive drugs-including midodrine and pyridostigmine-improved the standing blood pressure, but overall worsened the postural drop. CONCLUSIONS: many commonly recommended interventions for OH have a limited evidence base supporting their use. High quality, randomised, controlled trials are needed to underpin clinical practice for this condition.
Assuntos
Pressão Sanguínea/fisiologia , Hipotensão Ortostática/fisiopatologia , Hipotensão Ortostática/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Bandagens Compressivas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêuticoRESUMO
BACKGROUND: Pleomorphic dermal sarcoma (PDS) describes rare dermal-based malignant tumours that are morphologically similar to atypical fibroxanthoma (AFX). PDS may be differentiated from AFX by the presence of one or more of the following histologic features: subcutaneous invasion, tumour necrosis, lymphovascular invasion (LVI), and/or perineural infiltration (PNI). AIMS: To further define the clinicopathological features, surgical management, and outcomes of PDS primary tumours. METHODS AND RESULTS: This study was a retrospective observational case series using a database search from 2012 to 2017. Inclusion criteria required all cases to meet the histopathologic criteria for PDS as confirmed by a specialist soft-tissue histopathologist. A total of n = 17 cases were included with a median age of 78 years (range 66-85). All tumours were located on the head and neck, with 13/17 located on the scalp. Primary treatment was with wide local excision (WLE) in all cases. Median follow-up was 48 months. Local recurrence occurred in 4/17 cases (24%) and distant metastasis in 2/17 cases (12%). CONCLUSION: PDS behaves more aggressively than atypical fibroxanthoma with which it shares a biologic continuum. The optimal surgical management approach is yet to be determined.
Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Sarcoma , Neoplasias Cutâneas , Humanos , Idoso , Idoso de 80 Anos ou mais , Feminino , Sarcoma/diagnóstico , Sarcoma/cirurgia , Estudos Retrospectivos , Centros de Atenção Terciária , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgiaRESUMO
Here we define an important role for heat shock factor 1 (HSF1) in the cellular response to genotoxic agents. We demonstrate for the first time that HSF1 can complex with nuclear p53 and that both proteins are co-operatively recruited to p53-responsive genes such as p21. Analysis of natural and synthetic cis elements demonstrates that HSF1 can enhance p53-mediated transcription, whilst depletion of HSF1 reduces the expression of p53-responsive transcripts. We find that HSF1 is required for optimal p21 expression and p53-mediated cell-cycle arrest in response to genotoxins while loss of HSF1 attenuates apoptosis in response to these agents. To explain these novel properties of HSF1 we show that HSF1 can complex with DNA damage kinases ATR and Chk1 to effect p53 phosphorylation in response to DNA damage. Our data reveal HSF1 as a key transcriptional regulator in response to genotoxic compounds widely used in the clinical setting, and suggest that HSF1 will contribute to the efficacy of these agents.
Assuntos
Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Ciclo Celular , Linhagem Celular , Quinase 1 do Ponto de Checagem , Fatores de Transcrição de Choque Térmico , Humanos , Fosforilação , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Reactive perforating collagenosis is commonly recognised as an unusual form of transepithelial elimination of collagen and elastin fibres which are extruded through the epidermis in patients with a genetic predisposition or underlying diseases, such as diabetes mellitus or renal diseases. We present the unusual case of an 87-year-old diabetic male with a giant form of reactive perforating collagenosis and review the available literature.
RESUMO
Ipilimumab and nivolumab are immune checkpoint inhibitors used in the treatment of metastatic melanoma. The authors report the case of a 62-year-old white male individual with metastatic choroidal melanoma who had commenced adjuvant systemic treatment with combination checkpoint inhibitor therapy of intravenous ipilimumab (anti-cytotoxic T-lymphocyte antigen-4) and nivolumab (anti-programmed cell death-1) at 3-week cycle intervals. On day 4 after the second cycle, he developed an acute widespread rash. On examination there was confluent erythema with bullae and epidermal loss over 60% of the body surface area, with severe oral mucosal ulceration. A clinical diagnosis of toxic epidermal necrolysis (TEN) was made and he was transferred to the intensive care unit. Despite active treatment, he deteriorated systemically and died from multiorgan failure. This is the first reported case of TEN associated with nivolumab and ipilimumab dual therapy for metastatic uveal melanoma. Monotherapy improves survival in metastatic melanoma, but dual therapy has shown a greater mortality benefit at 3 years. Although the literature demonstrates case reports of Stevens-Johnson syndrome and TEN in association with nivolumab, ipilimumab has generally been regarded as a "safe" treatment with regard to severe cutaneous adverse reactions. With the increased use of immunotherapies, it is important to plan the management and early recognition of drug-related skin toxicity. This is of greatest concern during treatment initiation and with the higher risk associated with combination therapy. Reporting of adverse events and infrequently encountered complications with systemic biologic treatments will augment pharmacovigilance and improve the stratification of patients to treatments.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Melanoma/complicações , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/métodos , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/administração & dosagem , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Pele/patologia , Síndrome de Stevens-Johnson/terapia , Resultado do TratamentoRESUMO
Investigation for secondary causes is recommended in early onset hypertension. However, obesity is associated with higher blood pressure (BP), so investigation for alternative secondary causes may not be necessary in all obese patients. We sought to define a rational approach to investigation across strata of age, body mass index (BMI) sex and race, based on BP distributions in the US National Health and Nutrition Examination Surveys 2005 to 2016. The majority (71% [95% CI, 59%-79%] and 64% [95% CI, 57%-69%] by European and US definitions respectively) of early onset hypertension cases were attributable to BP distribution shifts accompanying obesity and male sex. Male versus female sex, BMI>40 versus 18.2Assuntos
Idade de Início
, Hipertensão
, Obesidade
, Adulto
, Negro ou Afro-Americano
, Pressão Sanguínea/fisiologia
, Índice de Massa Corporal
, Comorbidade
, Etnicidade
, Feminino
, Fatores de Risco de Doenças Cardíacas
, Humanos
, Hipertensão/diagnóstico
, Hipertensão/epidemiologia
, Masculino
, Inquéritos Nutricionais/métodos
, Inquéritos Nutricionais/estatística & dados numéricos
, Obesidade/diagnóstico
, Obesidade/epidemiologia
, Prevalência
, Projetos de Pesquisa
, Fatores Sexuais
, Estados Unidos/epidemiologia
RESUMO
OBJECTIVE: Medical treatment (serial closed-needle aspiration) and surgical treatment (arthroscopy/arthrotomy combined with joint washout) are well-recognized methods to treat septic arthritis (SA) of native joints. We compared the outcome of proven SA based on the method of treatment. METHODS: We reviewed case notes of adult patients who were admitted to our institution from January 2001 to December 2006 with proven SA (Newman Grade A organism isolated from the joint). RESULTS: Thirty-two episodes were treated medically and 19 surgically (4 with arthrotomy, 15 with arthroscopy) in the study period. All had mono-articular SA. No significant difference in the age, symptom duration before treatment and duration of intravenous antibiotic therapy was present between the two groups. Medical treatment resulted in complete recovery in more patients (69 vs 53%, P = 0.24) but longer period of hospitalization [median (interquartile range), 16.5 (14-19) vs 15 (11-17), P = 0.34], although the difference between the groups was not significant. More surgically treated patients had deterioration in functional status at the time of discharge from the hospital (29 vs 44%, P = 0.27), but the difference between the groups was not statistically significant. Surgically treated patients required significantly more sessions of physiotherapy (mean +/- S.D., 7 +/- 2 vs 10 +/- 3, P = 0.002). Mortality was similar (one in each group). CONCLUSION: Results from this study show that for the native joint SA, surgical treatment was not superior to the medical treatment and, therefore, highlight the need for careful case selection for surgical intervention.
Assuntos
Artrite Infecciosa/terapia , Infecções Bacterianas/terapia , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/microbiologia , Artrite Infecciosa/cirurgia , Artroscopia , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Infecções Bacterianas/cirurgia , Biópsia por Agulha , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Fatores de Risco , Staphylococcus/isolamento & purificação , Streptococcus/isolamento & purificação , Resultado do TratamentoRESUMO
The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer.
Assuntos
Inibidores de Histona Desacetilases , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Transcrição Gênica , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proliferação de Células , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1 , Humanos , Masculino , Antígeno Prostático Específico/genética , Neoplasias da Próstata/patologia , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Ubiquitina/metabolismoRESUMO
The colors reflected from the skin are important indicators of dermatologic and systemic disorders. Incident light is subject to absorption by chromophores in the skin and scattering. Chromophores associated with yellow light reflection include the carotenoids and bilirubin. Various pathophysiologic mechanisms associated with these and other chromophores manifest with a yellow hue on examination. This review describes these mechanisms and the clinical features of yellow skin disorders by morphology. A brief summary of the differential diagnosis, laboratory investigations, and treatments are presented. Yellow skin disorders are a heterogenous group composed of abnormalities in keratin, elastic and connective tissue, lipid metabolism, and other states of metabolic, inflammatory, or organ dysfunction. Patients will present through different routes, and skin disease may precede or follow systemic disease. Dermatologists have an essential role in identifying those with malignant or systemic associations to ensure early diagnosis and treatment.