A hallmark of atopic eczema (AE) is skin barrier dysfunction. Lipids in the stratum corneum (SC), primarily ceramides, fatty acids, and cholesterol, are crucial for the barrier function, but their ...role in relation to AE is indistinct. Filaggrin is an epithelial barrier protein with a central role in the pathogenesis of AE. Nevertheless, the precise causes of AE-associated barrier dysfunction are largely unknown. In this study, a comprehensive analysis of ceramide composition and lipid organization in nonlesional SC of AE patients and control subjects was performed by means of mass spectrometry, infrared spectroscopy, and X-ray diffraction. In addition, the skin barrier and clinical state of the disease were examined. The level of ceramides with an extreme short chain length is drastically increased in SC of AE patients, which leads to an aberrant lipid organization and a decreased skin barrier function. Changes in SC lipid properties correlate with disease severity but are independent of filaggrin mutations. We demonstrate for the first time that changes in ceramide chain length and lipid organization are directly correlated with the skin barrier defects in nonlesional skin of AE patients. We envisage that these insights will provide a new therapeutic entry in therapy and prevention of AE.
Diabetic nephropathy (DN) is a complication of diabetes mellitus that can lead to proteinuria and a progressive decline in renal function. Endoglin, a co-receptor of TGF-β, is known primarily for ...regulating endothelial cell function; however, endoglin is also associated with hepatic, cardiac, and intestinal fibrosis. This study investigates whether endoglin contributes to the development of interstitial fibrosis in DN. Kidney autopsy material from 80 diabetic patients was stained for endoglin and Sirius Red and scored semi-quantitatively. Interstitial endoglin expression was increased in samples with DN and was correlated with Sirius Red staining (
< 0.001). Endoglin expression was also correlated with reduced eGFR (
= 0.001), increased creatinine (
< 0.01), increased systolic blood pressure (
< 0.05), hypertension (
< 0.05), and higher IFTA scores (
< 0.001). Biopsy samples from DN patients were also co-immunostained for endoglin together with CD31, CD68, vimentin, or α-SMA Endoglin co-localized with both the endothelial marker CD31 and the myofibroblast marker α-SMA. Finally, we used shRNA to knockdown endoglin expression in a human kidney fibroblast cell line. We found that TGF-β1 stimulation upregulated
,
, and
mRNA and α-SMA protein, and that these effects were significantly reduced in fibroblasts after endoglin knockdown. Taken together, these data suggest that endoglin plays a role in the pathogenesis of interstitial fibrosis in DN.
Aims/hypothesis
Animal models of diabetic nephropathy show increased levels of glomerular vascular endothelial growth factor (VEGF)-A, and several studies have shown that inhibiting VEGF-A in animal ...models of diabetes can prevent albuminuria and glomerular hypertrophy. However, in those studies, treatment was initiated before the onset of kidney damage. Therefore, the aim of this study was to investigate whether transfecting mice with the VEGF-A inhibitor
sFlt-1
(encoding soluble fms-related tyrosine kinase 1) can reverse pre-existing kidney damage in a mouse model of type 1 diabetes. In addition, we investigated whether transfection with
sFlt-1
can reduce endothelial activation and inflammation in these mice.
Methods
Subgroups of untreated 8-week-old female C57BL/6J control (
n
= 5) and diabetic mice (
n
= 7) were euthanised 5 weeks after the start of the experiment in order to determine the degree of kidney damage prior to treatment with sFLT-1. Diabetes was induced with three i.p. injections of streptozotocin (75 mg/kg) administered at 2 day intervals. Diabetic nephropathy was then investigated in diabetic mice transfected with
sFlt-1
(
n
= 6); non-diabetic, non-transfected control mice (
n
= 5); non-diabetic control mice transfected with
sFlt-1
(
n
= 10); and non-transfected diabetic mice (
n
= 6). These mice were euthanised at the end of week 15. Transfection with
sFlt-1
was performed in week 6.
Results
We found that transfection with
sFlt-1
significantly reduced kidney damage by normalising albuminuria, glomerular hypertrophy and mesangial matrix content (i.e. glomerular collagen type IV protein levels) (
p
< 0.001). We also found that transfection with
sFlt-1
reduced endothelial activation (
p
< 0.001), glomerular macrophage infiltration (
p
< 0.001) and glomerular TNF-α protein levels (
p
< 0.001). Finally, sFLT-1 decreased VEGF-A-induced endothelial activation in vitro (
p
< 0.001).
Conclusions/interpretation
These results suggest that sFLT-1 might be beneficial in treating diabetic nephropathy by inhibiting VEGF-A, thereby reducing endothelial activation and glomerular inflammation, and ultimately reversing kidney damage.
A bedside-available transcatheter aortic valve implantation (TAVI)–dedicated prognostic risk score is an unmet clinical need. We aimed to develop such a risk score predicting 1-year mortality ...post-TAVI and to compare it with the performance of the logistic EuroSCORE (LES) I and LES-II and the Society of Thoracic Surgeons' (STS) score. Baseline variables of 511 consecutive patients who underwent TAVI that were independently associated with 1-year mortality post-TAVI were included in the “TAVI2 -SCORe.” Discrimination and calibration abilities of the novel score were assessed and compared with surgical risk scores. One-year mortality was 17.0% (n = 80 of 471). Porcelain thoracic aorta (hazard ratio HR 2.56), anemia (HR 2.03), left ventricular dysfunction (HR 1.98), recent myocardial infarction (HR 3.78), male sex (HR 1.81), critical aortic valve stenosis (HR 2.46), old age (HR 1.68), and renal dysfunction (HR 1.76) formed the TAVI2 -SCORe (all p <0.05). According to the number of points assigned (1 for each variable and 2 for infarction), patients were stratified into 5 risk categories: 0, 1 (HR 2.6), 2 (HR 3.6), 3 (HR 10.5), and ≥4 (HR 17.6). TAVI2 -SCORe showed better discrimination ability (Harrells' C statistic 0.715) compared with LES-I, LES-II, and STS score (0.609, 0.633, and 0.50, respectively). Cumulative 1-year survival rate was 54% versus 88% for patients with TAVI2 -SCORE ≥3 versus <3 points, respectively (p <0.001). Contrary to surgical risk scores, there was no significant difference between observed and expected 1-year mortality for all TAVI2 -SCORe risk strata (all p >0.05, Hosmer-Lemeshow statistic 0.304), suggesting superior calibration performance. In conclusion, the TAVI2 -SCORe is an accurate, simple, and bedside-available score predicting 1-year mortality post-TAVI, outperforming conventional surgical risk scores for this end point.
The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of ...kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN.
A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score.
The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (
<0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (
=0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively (
<0.001). These survival percentages are higher compared with the percentages in the original study.
The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost.
In light of the significant morbidity and mortality of cutaneous invasive squamous cell carcinomas (SCCs) in renal transplant recipients, we investigated whether conversion to sirolimus-based ...immunosuppression from standard immunosuppression could diminish the recurrence rate of these skin cancers.
In a 2-year randomized controlled trial, 155 renal transplant recipients with at least one biopsy-confirmed SCC were stratified according to age (< 55 v ≥ 55 years) and number of previous SCCs (one to nine v ≥ 10) and randomly assigned to conversion to sirolimus (n = 74) or continuation of their original immunosuppression (n = 81). Development of a new SCC within 2 years after random assignment was the primary end point.
After 2 years of follow-up, the risk reduction of new SCCs in the multivariable analysis was not significant, with a hazard ratio (HR) of 0.76 (95% CI, 0.48 to 1.2; P = .255), compared with a non-sirolimus-based regimen. After the first year, there was a significant 50% risk reduction, with an HR of 0.50 (95% CI, 0.28 to 0.90; P = .021) for all patients together and an HR of 0.11 (95% CI, 0.01 to 0.94; P = .044) for patients with only one previous SCC. The tumor burden of SCC was reduced during the 2-year follow-up period in those receiving sirolimus (0.82 v 1.38 per year; HR, 0.51; 95% CI, 0.32 to 0.82; P = .006) if adjusted for the number of previous SCCs and age. Twenty-nine patients stopped taking sirolimus because of various adverse events.
Conversion to sirolimus-based immunosuppression failed to show a benefit in terms of SCC-free survival at 2 years.
Chronic kidney disease (CKD) is a slow-developing, progressive deterioration of renal function. The final common pathway in the pathophysiology of CKD involves glomerular sclerosis, tubular atrophy ...and interstitial fibrosis. Transforming growth factor-beta (TGF-β) stimulates the differentiation of fibroblasts towards myofibroblasts and the production of extracellular matrix (ECM) molecules, and thereby interstitial fibrosis. It has been shown that endoglin (ENG, CD105), primarily expressed in endothelial cells and fibroblasts, can function as a co-receptor of TGF signaling. In several human organs, endoglin tends to be upregulated when chronic damage and fibrosis is present. We hypothesize that endoglin is upregulated in renal interstitial fibrosis and plays a role in the progression of CKD. We first measured renal endoglin expression in biopsy samples obtained from patients with different types of CKD, i.e., IgA nephropathy, focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN) and patients with chronic allograft dysfunction (CAD). We showed that endoglin is upregulated in CAD patients (p < 0.001) and patients with DN (p < 0.05), compared to control kidneys. Furthermore, the amount of interstitial endoglin expression correlated with eGFR (p < 0.001) and the amount of interstitial fibrosis (p < 0.001), independent of the diagnosis of the biopsies. Finally, we investigated in vitro the effect of endoglin overexpression in TGF-β stimulated human kidney fibroblasts. Overexpression of endoglin resulted in an enhanced ACTA2, CCN2 and SERPINE1 mRNA response (p < 0.05). It also increased the mRNA and protein upregulation of the ECM components collagen type I (COL1A1) and fibronectin (FN1) (p < 0.05). Our results suggest that endoglin is an important mediator in the final common pathway of CKD and could be used as a possible new therapeutic target to counteract the progression towards end-stage renal disease (ESRD).
To assess gripforce in children with a C5 and C6 neonatal brachial plexus palsy, as it may affect hand use. Applying classic innervation patterns, gripforce should not be affected, as hand function ...is not innervated by C5 or C6. This study compares gripforce in children with a neonatal brachial plexus palsy with that in a healthy control group, and assesses correlations with hand sensibility, bimanual use and external rotation.
A total of 50 children with neonatal brachial plexus palsy (mean age 9.8 years) and 25 controls (mean age 9.6 years) were investigated. Nerve surgery had been performed in 30 children, and 20 children had been treated conservatively. Gripforce of both hands was assessed using a Jamar dynamometer. Sensibility of the hands was assessed with 2-point discrimination and Semmes-Weinstein monofilaments. External rotation was assessed using the Mallet score. Bimanual use was measured by using 1 of 3 dexterity items of the Movement Assessment Battery for Children-2. The affected side of the neonatal brachial plexus palsy group was compared with the non-dominant hand of the control group using 1-way analysis of variance (ANOVA), χ2 and Mann-Whitney tests.
The mean gripforce of the affected non-dominant hand of children with neonatal brachial plexus palsy was reduced compared with healthy controls (95 N and 123 N, respectively, with p = 0.001). The mean gripforce of the non-dominant hand in the control group was 92% of that of the dominant hand, while it was only 76% in the neonatal brachial plexus palsy group (p = 0.04). There was no relationship between gripforce reduction and sensibility, bimanual use or shoulder external rotation.
The gripforce in neonatal brachial plexus palsy infants with a C5 and C6 lesion is lower than that of healthy controls, although classic interpretation of upper limb innervation excludes this finding. The reduction in gripforce in upper neonatal brachial plexus palsy lesions is not widely appreciated as a factor inherently compromising hand use. The reduction in gripforce should be taken into consideration in planning the type of rehabilitation and future activities.
Values for level- (apical, mid, and basal) and layer-based (endocardial, mid-myocardial, and epicardial) left ventricular (LV) longitudinal strain across age are scarce. The present study evaluates ...the effect of aging on level- and layer-specific LV longitudinal strain in subjects without structural heart disease. A total of 408 subjects (mean age 58 years range 16 to 91; 49% men) were evaluated retrospectively. Subjects were divided into equal groups based on age and gender. Subjects with evidence of structural heart disease or arrhythmias were excluded. Mean LV ejection fraction was 62 ± 6.2%. A gradual increase in magnitude of level LV longitudinal strain was observed from basal to mid and apical levels (−16.7 ± 2.1%, −18.8 ± 2.0%, −22.6 ± 3.8%; p <0.001, respectively). Across age groups, there was a borderline significant decrease in magnitude of basal longitudinal strain in older subjects, whereas the magnitude in the apical level significantly increased. On layer-based analysis, the magnitude of longitudinal strain increased from epicardium to endocardium across all age groups. On multivariable analysis, only diabetes mellitus was associated with more impaired longitudinal strain in the endocardium, and male gender was associated with more impaired longitudinal strain at the epicardium layer. In conclusion, with increasing age, the magnitude of LV longitudinal strain at the basal level declines while the apical LV longitudinal strain increases. In contrast, layer-specific LV longitudinal strain remains unchanged with aging. The presence of diabetes mellitus modulated the effect of age on the LV endocardial layer, and male gender was associated with more impaired longitudinal strain at the epicardial layer.
The hypothesis that elimination of facultative and strict anaerobic microorganisms from the gastro-intestinal tract by antimicrobial drugs in the period of time around allogeneic bone marrow ...transplantation (BMT) prevents acute graft-versus-host disease (GVHD), was examined in a cohort of 112 children grafted between 1989 and 2002 for hematological malignancies. All patients received T-cell replete marrow from human leukocyte antigens (HLA) matched sibling donors under identical transplantation conditions. To eliminate microorganisms from the gastro-intestinal tract, total gastro-intestinal decontamination (GID) was applied by high doses of non-absorbable antimicrobial drugs while the graft recipient was maintained in strict protective isolation. About half of the children (51%) proved to be successfully decontaminated, and about half (49%) unsuccessfully. One recipient got acute GVHD in the first group and 8 in the second group (p = 0.013). The degree of success of total GID was decisive for the occurrence of acute GVHD, irrespective of the presence of other risk factors such as higher age of recipient and/or donor, female donor for male recipient and carriership or reactivation of herpesviruses. Our results demonstrate that successful total GID of the graft recipient prevents moderate to severe acute GVHD. We suppose that substantial translocation of gastro-intestinal microorganisms or parts of these, functioning as microbial-associated molecular patterns (MAMP's), triggering macrophages/dendritic cells via pattern recognizing receptors (PRR's) is prohibited. As a consequence the initiation and progression of an inflammatory process leading to acute GVHD is inhibited.
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