A Case of Systemic Inflammatory Response Syndrome after Liposuction-assisted Abdominoplasty

A 51-year-old woman underwent liposuction-abdominoplasty. After surgery, she developed hypotension and bradycardia, attributed to iatrogenic opioid-intoxication. After discontinuing opioids, the patient had several episodes of hypotension and tachycardia, responding well to fluid resuscitation. The initial differential diagnosis of postoperative bleeding was ruled out with a CT-scan. Other potential causes of hemodynamic instability, such as pulmonary embolism and fat embolism, were considered unlikely in absence of corresponding symptoms. Based on leukocytosis and tachycardia, the patient was diagnosed with systemic inflammatory response syndrome, a disproportional inflammatory reaction to surgery. The patient was managed expectantly with intravenous fluid administration and recovered without further treatment or complications

Ethnic differences in prevalence of Dupuytren disease can partly be explained by known genetic risk variants

Dupuytren disease (DD), a fibroproliferative disorder of the palmar fascia that causes flexion contractures in the fingers, is prevalent in people of North-Western European descent and less so in other ethnicities. DD is a complex disorder, influenced by genetic risk variants. We aimed to study if the marked differences in prevalences in DD between ethnic (sub)groups could be explained by differences in allele frequencies of the 26 known genetic risk variants of DD. Therefore, genetic risk scores (GRS) composed of the 26 DD risk variants were calculated for the 26 populations from the 1000 Genomes database and correlated to observed DD prevalences from literature. For comparison, GRSs were generated for 10,000 sets of 26 random SNPs and also correlated to the observed DD prevalences to determine the significance of the observed correlation. To determine whether differences in allele frequencies between ethnicities were caused by natural selection, fixation indices (Fst) were calculated from the 26 SNPs and from the sets of 26 random SNPs for comparison. Observed prevalences could be determined from literature for 10 populations. Their correlation with the GRS composed of DD SNPs proved to be 0.60 (p = 0.0003). The Fsts between British and other populations were low for European, ad mixed American, and South-Asian populations, and moderate for East-Asians. African populations were significantly different from expected values determined from the random sets. In conclusion, the 26 known genetic risk variants associated with DD explain for a substantial part (R-2 = 0.36) the differing DD prevalences observed between ethnicities

Prevalence of Peyronie and Ledderhose Diseases in a Series of 730 Patients with Dupuytren Disease

BACKGROUND: Dupuytren, Peyronie, and Ledderhose diseases are related fibroproliferative disorders characterized by abnormalities in the connective tissue of the palm of the hand, the tunica albuginea of the penis, and the sole of the foot, respectively. Concomitant prevalence rates of these diseases have only been described in a few small populations. This article aims to report on a large population and to raise awareness in surgeons treating Dupuytren disease for concurring related fibroproliferative disorders. METHODS: Patients diagnosed as having Dupuytren disease were recruited from outpatient clinics in the northern part of the Netherlands from 2007 to 2016. Questionnaires concerning demographics, clinical characteristics, the coexistence of Ledderhose and/or Peyronie diseases, and other factors were filled in by the participants and by plastic surgeons. RESULTS: For 730 men with Dupuytren disease, the surgeons' reported prevalence rate of Peyronie disease was 7.8 percent and of Ledderhose disease was 16.1 percent. The participants themselves reported prevalence rates of 8.8 percent for Peyronie disease and of 22.0 percent for Ledderhose disease. CONCLUSIONS: In the Dupuytren patient cohort, the prevalence of Peyronie disease was lower than that described in the literature. The prevalence of Ledderhose disease corresponded with the rates from the literature. However, both were underreported by plastic surgeons, which calls for a rise in awareness, recognition, and referral to a urologist when the conditions are bothersome or symptomatic

Verteporfin ameliorates fibrotic aspects of Dupuytren's disease nodular fibroblasts irrespective the activation state of the cells

Dupuytren's disease is a chronic, progressive fibroproliferative condition of the hand fascia which results in digital contraction. So far, treatments do not directly interfere with the (myo)fibroblasts that are responsible for the formation of the collagen-rich cords and its contraction. Here we investigated whether verteporfin (VP) is able to inhibit the activation and subsequent differentiation of DD nodular fibroblasts into myofibroblasts. Fibroblasts were isolated from nodules of 7 Dupuytren patients. Cells are treated (1) for 48 h with 5 ng/ml transforming growth factor β1 (TGF-β1) followed by 48 h with/without 250 nM VP in the absence of TGF-β1, or treated (2) for 48 h with TGF-β1 followed by 48 h with/without VP in the presence of TGF-β1. mRNA levels were measured by means of Real-Time PCR, and proteins were visualized by means of Western blotting and/or immunofluorescence. Quantitative data were statistically analyzed with GraphPad Prism using the paired t-test. We found that fibroblasts activated for 48 h with TGF-β1 show a decrease in mRNA levels of COL1A1, COL3A1, COL4A1, PLOD2, FN1EDA, CCN2 and SERPINE1 when exposed for another 48 h with VP, whereas no decrease is seen for ACTA2, YAP1, SMAD2 and SMAD3 mRNA levels. Cells exposed for an additional 48 h with TGF-β1, but now in the presence of VP, are not further activated anymore, whereas in the absence of VP the cells continue to differentiate into myofibroblasts. Collagen type I, fibronectin-extra domain A, α-smooth muscle actin, YAP1, Smad2 and Smad3 protein levels were attenuated by both VP treatments. We conclude that VP has strong anti-fibrotic properties: it is able to halt the differentiation of fibroblasts into myofibroblasts, and is also able to reverse the activation status of fibroblasts. The decreased protein levels of YAP1, Smad2 and Smad3 in the presence of VP explain in part the strong anti-fibrotic properties of VP. Verteporfin is clinically used as a photosensitizer for photodynamic therapy to eliminate abnormal blood vessels in the eye to attenuate macular degeneration. The antifibrotic properties of VP do not rely on photo-activation, as we used the molecule in its non-photoinduced state

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.</p

The Genetic Etiology Of Dupuytren’s Disease: exploring susceptibility, profiling risk, and predicting recurrence

The studies of this thesis focus on Dupuytren’s disease, a disorder characterized by proliferation of the connective tissue of the palms of the hands. In this disease, nodules and cords appear, that can cause a permanent contractures of the fingers. Although a contracture can be ameliorated with surgery (among others), over time it often returns. The causes of the development of this disease and its recurrence after treatment are largely unknown. Since Dupuytren’s disease often occurs within families, it is known to have a strong heritable (genetic) basis. In the research of this thesis we studied different aspects of heritability of Dupuytren’s disease. We showed that genetic factors explain a large part of the differences in disease prevalence between different ethnic populations and identified new genetic factors that increase the risk of Dupuytren’s disease. We zoomed in on which of these factors are likely to play major roles and studied the mechanism of action of a potential drug for Dupuytren’s disease. Furthermore, each person has a unique constitution (profile) of genetic risk factors. We therefore also studied whether patients’ genetic risk profiles have a predictive value of risk of recurrence after treatment. Although the predictive value of genetic risk profiling for Dupuytren’s disease recurrence after treatment at this time is insufficient for integration in patient care, we established that the genetic susceptibility of patients for Dupuytren’s disease can indeed help to predict risk for recurrence after treatment

Polygenic Risk Associations with Clinical Characteristics and Recurrence of Dupuytren Disease

Background: Dupuytren disease (DD) is a common complex trait, with varying severity and incompletely understood cause. Genome-wide association studies (GWAS) have identified risk loci. In this article, we examine whether genetic risk profiles of DD in patients are associated with clinical variation and disease severity and with patient genetic risk profiles of genetically correlated traits, including body mass index (BMI), triglycerides, high-density lipoproteins, type 2 diabetes mellitus, and endophenotypes fasting glucose and glycated hemoglobin.Methods: The authors used a well-characterized cohort of 1461 DD patients with available phenotypic and genetic data. Phenotype data include age at onset, recurrence, and family history of disease. Polygenic risk scores (PRSs) of DD, BMI, triglycerides, high-density lipoprotein, type 2 diabetes, fasting glucose, and hemoglobin A1c using various significance thresholds were calculated with PRSice using the most recent GWAS summary statistics. Control data from LifeLines were used to determine P value cutoffs for PRS generation explaining most variance. Results: The PRS for DD was significantly associated with a positive family history for DD, age at onset, disease onset before the age of 50, and recurrence. We also found a significant negative correlation between the PRSs for DD and BMI. Conclusions: Although GWAS studies of DD are designed to identify genetic risk factors distinguishing case/control status, we show that the genetic risk profile for DD also explains part of its clinical variation and disease severity. The PRS may therefore aid in accurate prognostication, choosing initial treatment and in personalized medicine in the future. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.</p

Polygenic Risk Associations with Clinical Characteristics and Recurrence of Dupuytren Disease

BACKGROUND: Dupuytren's disease (DD) is a common complex trait, with varying severity and incompletely understood etiology. Genome-wide association studies (GWAS) have identified risk loci. Here, we examine whether genetic risk profiles of DD in patients are associated with clinical variation and disease severity as well as with patient genetic risk profiles of genetically correlated traits, including body mass index (BMI), triglycerides (TG), high-density lipoproteins (HDL), type 2 diabetes mellitus (T2D), and endophenotypes fasting glucose (FG), and glycated hemoglobin (HbA1c).METHODS: We used a well-characterized cohort of 1,461 DD patients with available phenotypic and genetic data. Phenotype data include age of onset, recurrence, and family history of disease. Polygenic risk scores (PRSs) of DD, BMI, TG, HDL, T2D, FG, and HbA1c using various significance thresholds were calculated with PRSice using the most recent GWAS summary statistics. Control data from LifeLines were used to determine p-value cut-offs for PRSs generation explaining most variance.RESULTS: The PRS for DD was significantly associated with a positive family history for DD, age of onset, disease onset before the age of 50, and recurrence. We also found a significant negative correlation between the PRSs for DD and BMI.CONCLUSIONS: While GWAS studies of DD are designed to identify genetic risk factors distinguishing case/control status, we show that the genetic risk profile for DD also explains part of its clinical variation and disease severity. The PRS may therefore aid in accurate prognostication, choosing initial treatment and in personalized medicine in future.</p

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.</p

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.</p