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Aim: circumvallate placenta, placental abruption and acute chorioamnionitis separately are associated with unfavourable clinical outcomes. We aimed to determine the prevalence and define whether an association exists between the three abnormalities., Methods: 16,042 placenta pathology reports between 1997 and 2020 from a tertiary care centre in the Netherlands were retrospectively analysed. For the statistical analysis, the chi-square test and bootstrapping were used to evaluate an association., Results: In our cohort the prevalence of circumvallate placenta is 2.2 %, placental abruption cases 4.0 % and acute chorioamnionitis 20.6 %. We observed a statistically significant association between all three placental abnormalities: circumvallate placenta, placental abruption and acute chorioamnionitis. In addition, there was also an association between circumvallate placenta and acute chorioamnionitis., Conclusion: Our results show that combined presence of circumvallate placenta, placental abruption and acute chorioamnionitis are associated in preterm birth (p = 0.001). A remarkable finding is that the combination of all three abnormalities (circumvallate placenta, placental abruption and acute chorioamnionitis) was not observed in term pregnancies >37 weeks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate factors that cause impairment of hand function in children with an upper Neonatal Brachial Plexus Palsy (NBPP), we performed an in-depth analysis of tactile hand sensibility, especially the ability to correctly localize a sensory stimulus on their fingers., Design: A cross-sectional investigation of children with NBPP, compared with healthy controls. The thickest Semmes-Weinstein (SW) monofilament was pressed on the radial or ulnar part of each fingertip (10 regions), while a screen prevented seeing the hand., Setting: Tertiary referral center for nerve lesions in an academic hospital in The Netherlands. The control group was recruited at their school., Participants: Forty-one children with NBPP (mean age 10.0 y) and 25 controls (mean age 9.5 y; N=41)., Interventions: Not applicable., Main Outcomes Measures: Correct localization of the applied stimuli was evaluated, per region, per finger, and per dermatome with a test score. The affected side of the NBPP group was compared with the non-dominant hand of the controls., Results: The ability to localize stimuli on the tips of the fingers in children with an upper NBPP was significantly diminished in all fingers, except for the little finger, as compared with healthy controls. Mean localization scores were 6.6 (thumb) and 6.3 (index finger) in the NBPP group and 7.6 in both fingers for controls (maximum score possible is 8.0). Localization scores were significant lower in regions attributed to dermatomes C6 (P<.001) and C7 (P=.001), but not to C8 (P=.115)., Conclusion: Children with an upper NBPP showed a diminished and incorrect ability to localize sensory stimuli to their fingers. This finding is likely 1 of the factors underlying the impairment of hand function and should be addressed with sensory focused therapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Primary infection with or reactivation of Epstein-Barr virus (EBV) can occur after liver transplant (LT) and can lead to posttransplant lymphoproliferative disease (PTLD). In pediatric LT, an EBV-DNA viral load (EBV VL) monitoring strategy, including the reduction of immunosuppression, has led to a lower incidence of PTLD. For adult LT recipients with less primary infection and more EBV reactivation, it is unknown whether this strategy is effective., Objective: To examine the effect of an EBV VL monitoring strategy on the incidence of PTLD after LT in adults., Design: Cohort study., Setting: Two university medical centers in the Netherlands., Patients: Adult recipients of first LT in Leiden between September 2003 and January 2017 with an EBV VL monitoring strategy formed the monitoring group (M1), recipients of first LT in Rotterdam between January 2003 and January 2017 without such a strategy formed the contemporary control group (C1), and those who had transplants in Leiden between September 1992 and September 2003 or Rotterdam between 1986 and January 2003 formed the historical control groups (M0 and C0, respectively)., Measurements: Influence of EBV VL monitoring on incidence of PTLD., Results: After inverse probability of treatment weighting of the 4 groups to achieve a balance among the groups for important patient characteristics, differences within hospitals between the historical and recent era in cumulative incidences-expressed as the number of events per 1000 patients measured at 5-, 10-, and 15-year follow-up-showed fewer events in the contemporary era in both centers. This difference was considerably larger in the monitoring center, whereas the 95% CI included the null value of 0 for point estimates., Limitation: Retrospective, low statistical power, and incompletely balanced groups, and non-EBV PTLD cannot be prevented., Conclusion: Monitoring EBV VL may reduce PTLD incidence after LT in adults; larger studies are warranted., Primary Funding Source: None.

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).

Objectives: We aimed to determine the presence, amount and origin of microchimerism in peripheral blood of pregnant and non-pregnant parous women with systemic lupus erythematosus (SLE) as compared to control subjects., Methods: We performed a comparative study in which peripheral blood was drawn from eleven female non-pregnant SLE-patients and 22 control subjects, and from six pregnant SLE-patients and eleven control subjects during gestation and up to six months postpartum. Quantitative PCR for insertion-deletion polymorphisms and null alleles was used to detect microchimerism in peripheral blood mononuclear cells and granulocytes., Results: Microchimerism was detected more often in non-pregnant SLE-patients than control subjects (54.4% vs. 13.6%, respectively; p=0.03). When present, the median total number of foetal chimeric cells was 5 gEq/106 in patients and 2.5gEq/106 in control subjects (p=0.048). Microchimerism was mostly foetal in origin; maternal microchimerism was detected in one patient and one control subject. In control subjects, microchimerism was always derived from only one source whereas in 50% of patients it originated from multiple sources. The pregnant patients had a significantly higher median number of foetal chimeric cells in the granulocyte fraction just after delivery than control subjects (7.5 gEq/106 vs. 0 gEq/106, respectively; p=0.02)., Conclusions: Just after delivery, SLE-patients had more microchimerism than control subjects. Three months post-partum, microchimerism was no longer detectable, only to reappear many years after the last pregnancy, more often and at higher levels in SLE-patients than in control subjects. This suggests that these chimeric cells may originate from non-circulating foetal chimeric stem cells.

(1) Background: Soluble Fms-like tyrosine kinase 1 (sFLT1) is an endogenous VEGF inhibitor. sFLT1 has been described as an anti-inflammatory treatment for diabetic nephropathy and heart fibrosis. However, sFLT1 has also been related to peritubular capillary (PTC) loss, which promotes fibrogenesis. Here, we studied whether transfection with sFlt1 aggravates experimental AKI-to-CKD transition and whether sFLT1 is increased in human kidney fibrosis. (2) Methods: Mice were transfected via electroporation with sFlt1 . After confirming transfection efficacy, mice underwent unilateral ischemia/reperfusion injury (IRI) and were sacrificed 28 days later. Kidney histology and RNA were analyzed to study renal fibrosis, PTC damage and inflammation. Renal sFLT1 mRNA expression was measured in CKD biopsies and control kidney tissue. (3) Results: sFlt1 transfection did not aggravate renal fibrosis, PTC loss or macrophage recruitment in IRI mice. In contrast, higher transfection efficiency was correlated with reduced expression of pro-fibrotic and pro-inflammatory markers. In the human samples, sFLT1 mRNA levels were similar in CKD and control kidneys and were not correlated with interstitial fibrosis or PTC loss. (4) Conclusion: As we previously found that sFLT1 has therapeutic potential in diabetic nephropathy, our findings indicate that sFLT1 can be administered at a dose that is therapeutically effective in reducing inflammation, without promoting maladaptive kidney damage.

Introduction: Lupus nephritis (LN) class III or IV is strongly related to patient mortality and morbidity. The interobserver agreement of endocapillary hypercellularity by routine light microscopy, one of the most important lesions determining whether class III or IV is present, is moderate. In IgA nephropathy (IgAN), the presence of glomerular CD68+ cells was found to be a good surrogate marker for endocapillary hypercellularity. We investigated whether the presence of glomerular CD68+ cells could serve as a surrogate marker for endocapillary hypercellularity as well in LN., Methods: A total of 92 LN biopsies were scored for the number of glomerular CD68+ cells using CD68 staining, including endocapillary hypercellularity and the activity index (AI). A new AI was calculated in which CD68+ cells replaced endocapillary hypercellularity. Clinical parameters were obtained from time of biopsy, 1 year after, and 2 years after., Results: The number of glomerular CD68+ cells significantly correlated with endocapillary hypercellularity. A cutoff value of 7 for the maximum number of CD68+ cells within 1 glomerulus in a biopsy yielded a sensitivity of 88% and a specificity of 67% for the presence of endocapillary hypercellularity. Both endocapillary hypercellularity and CD68+ cells correlated with renal function during follow-up. The current and the new AI correlated equally well with the clinical outcome., Conclusion: In LN, CD68+ cells can be used as a surrogate marker for endocapillary hypercellularity., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Objective: 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., Methods: 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., Results: 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., Discussion: 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.

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ET A R) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ET A R with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ET A R antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: The podocyte is thought to be the mainly affected cell type in focal segmental glomerulosclerosis (FSGS). However, recent studies have also indicated a role for glomerular endothelial cells and podocyte-endothelial crosstalk in FSGS development. An experimental model for podocyte injury showed that increased endothelin-1 (ET-1) signaling between podocytes and endothelial cells induces endothelial oxidative stress and subsequent podocyte loss. In the current study, we investigated endothelial endothelin receptor A (ET A R) expression in patients with FSGS and its association with podocyte injury and glomerular oxidative stress., Methods: We selected 39 biopsy samples of patients with FSGS and 8 healthy control subjects, and stained them for ET A R, nephrin and 8-oxo-guanine, a DNA lesion caused by oxidative damage. Glomeruli with ET A R-positive endothelium and with nephrin loss were scored, and the 8-oxo-guanine-positive glomerular area was measured., Results: The mean percentage of glomeruli with ET A R-positive endothelial cells in patients with FSGS was higher compared to that in healthy control subjects (52% vs. 7%; P  < 0.001). The presence of glomerular ET A R-positive endothelium was strongly associated with nephrin loss both on the biopsy level (rho = 0.47; P  < 0.01), as on the level of individual glomeruli (odds ratio = 2.0; P  < 0.001). Moreover, glomeruli with ET A R-positive endothelium showed more 8-oxo-guanine-positive staining (1.9% vs. 2.4%; P  = 0.037). Finally, 8-oxo-guanine positivity in glomeruli was associated with increased levels of proteinuria., Conclusion: Taking together our findings, we show that ET A R is increased in glomerular endothelial cells of patients with FSGS and associated with podocyte damage and glomerular oxidative stress. These findings support the hypothesis that ET-1 signaling in glomerular endothelial cells contributes to disease development in patients with FSGS., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

The endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ET A R blockade, but not dual ET A/B R blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.

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 ( p < 0.001). Endoglin expression was also correlated with reduced eGFR ( p = 0.001), increased creatinine ( p < 0.01), increased systolic blood pressure ( p < 0.05), hypertension ( p < 0.05), and higher IFTA scores ( p < 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 SERPINE1 , CTGF , and ACTA2 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., Competing Interests: The authors declare no conflict of interest.

Background and Objectives: 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., Design, Setting, Participants, & Measurements: 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., Results: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes ( P <0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class ( P =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 ( P <0.001). These survival percentages are higher compared with the percentages in the original study., Conclusions: 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., (Copyright © 2020 by the American Society of Nephrology.)

Background: Liver transplantation remains the only effective evidence based treatment for advanced primary sclerosing cholangitis. However, recurrence of disease occurs in approximately 18%., Aims: This study aimed to assess risk factors of recurrence of primary sclerosing cholangitis., Methods: A retrospective cohort study was performed on patients undergoing transplantation for recurrence of primary sclerosing cholangitis in two academic centers (Leuven, Belgium and Leiden, The Netherlands). Besides other risk factors, the degree of mucosal inflammation was assessed as a potential risk factor using histological Geboes scores., Results: 81 patients were included, of which 62 (76.5%) were diagnosed with ulcerative colitis. Seventeen patients (21.0%) developed rPSC during a median follow-up time of 5.2 years. In a subset of 42 patients no association was found between the degree of mucosal inflammation and recurrence, using both original Geboes scores and multiple cut-off points. In the total cohort, cytomegaloviremia post-transplantation (HR: 4.576, 95%CI 1.688-12.403) and younger receiver age at time of liver transplantation (HR: 0.934, 95%CI 0.881-0.990) were independently associated with an increased risk of recurrence of disease., Conclusion: This study found no association between the degree of mucosal inflammation and recurrence of primary sclerosing cholangitis. An association with recurrence was found for cytomegaloviremia post-liver transplantation and younger age at time of liver transplantation., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Obstetric brachial plexus injuries result from traction injuries during delivery, and 30% of these children have persisting functional limitations related to an external rotation deficit of the shoulder. Little is known about the long-term effect of soft-tissue procedures of the shoulder in patients with obstetric brachial plexus injuries., Questions/purposes: (1) After soft-tissue release for patients with passive external rotation less than 20° and age younger than 2 years and for patients older than 2 years with good external rotation strength, what are the improvements in passive external rotation and abduction arcs at 1 and 5 years? (2) For patients who underwent staged tendon transfer after soft-tissue release, what are the improvements in active external rotation and abduction arcs at 1 and 5 years? (3) For patients with passive external rotation less than 20° and no active external rotation, what are the improvements in active external rotation and abduction arcs at 1 and 5 years?, Methods: This was a retrospective analysis of a longitudinally maintained institutional database. Between 1996 and 2009, 149 children underwent a soft-tissue procedure of the shoulder for an internal rotation contracture. The inclusion criteria were treatment with an internal contracture release and/or tendon transfer, a maximum age of 18 years at the time of surgery, and a minimum follow-up period of 2 years. Six patients were older than 18 years at the time of surgery and 31 children were seen at our clinic until 1 year postoperatively, but because they had good clinical results and lived far away from our center, these children were discharged to physical therapists in their hometown for annual follow-up. Thus, 112 children (59 boys) were available for analysis. Patients with passive external rotation less than 20° and age younger than 2 years and patients older than 2 years with good external rotation strength received soft-tissue release only (n = 37). Of these patients, 17 children did not have adequate active external rotation, and second-stage tendon transfer surgery was performed. For patients with passive external rotation less than 20° with no active external rotation, single-stage contracture release with tendon transfer was performed (n = 68). When no contracture was present (greater than 20° of external rotation) but the patient had an active deficit (n = 7), tendon transfer alone was performed; this group was not analyzed. A functional assessment of the shoulder was performed preoperatively and postoperatively at 6 weeks, 3 months, and annually thereafter and included abduction, external rotation in adduction and abduction, and the Mallet scale., Results: Internal contracture release resulted in an improvement in passive external rotation in adduction and abduction of 29° (95% confidence interval, 21 to 38; p < 0.001) and 17° (95% CI, 10 to 24; p < 0.001) at 1 year of follow-up and 25° (95% CI, 15-35; p < 0.001) and 15° (95% CI, 7 to 24; p = 0.001) at 5 years. Because of insufficient strength of the external rotators after release, 46% of the children (17 of 37) underwent an additional tendon transfer for active external rotation, resulting in an improvement in active external rotation in adduction and abduction at each successive follow-up visit. Patients with staged transfers had improved active function; improvements in active external rotation in adduction and abduction were 49° (95% CI, 28 to 69; p < 0.05) and 45° (95% CI, 11 to 79; p < 0.001) at 1 year of follow-up and 38° (95% CI, 19 to 58; p < 0.05) and 23° (95% CI, -8 to 55; p < 0.001) at 5 years. In patients starting with less than 20° of passive external rotation and no active external rotation, after single-stage contracture release and tendon transfer, active ROM was improved. Active external rotation in adduction and abduction were 75° (95% CI, 66 to 84; p < 0.001) and 50° (95% CI, 43 to 57; p < 0.001) at 1 year of follow-up and 65° (95% CI, 50 to 79; p < 0.001) and 40° (95% CI, 28 to 52; p < 0.001) at 5 years., Conclusion: Young children with obstetric brachial plexus injuries who have internal rotation contractures may benefit from soft-tissue release. When active external rotation is lacking, soft-tissue release combined with tendon transfer improved active external rotation in this small series. Future studies on the degree of glenohumeral deformities and functional outcome might give more insight into the level of increase in external rotation., Level of Evidence: Level III, therapeutic study.

Recent studies suggest that complement plays a role in the pathogenesis of focal segmental glomerulosclerosis (FSGS). Moreover, co-localization of IgM and C3 deposits with FSGS lesions has frequently been reported. Here, we investigated whether glomerular complement deposition precedes the development of FSGS and whether it represents local complement activation. Renal biopsies from 40 patients with primary FSGS, 84 patients with minimal change disease, and 10 healthy individuals were stained for C4d, C1q, and mannose-binding lectin. C4d deposits were also measured in renal allograft biopsies from 34 patients with native primary FSGS, 18 of whom subsequently developed recurrent FSGS. Lastly, we measured C4d deposits in the Munich Wistar Frömter rat model of FSGS. The prevalence of C4d-positive glomeruli was significantly higher among patients with FSGS (73%) compared to patients with minimal change disease (21%) and healthy individuals (10%). Moreover, segmental sclerosis was absent in 42% of C4d-positive glomeruli. Glomerular C1q was significantly more prevalent in FSGS compared to minimal change disease or healthy individuals, while mannose-binding lectin was infrequently observed. C4d deposition was significantly more prevalent in recurrent FSGS (72%) before the development of sclerotic lesions compared to control transplant samples (27%). Finally, at the onset of albuminuria but before the development of FSGS lesions, Munich Wistar Frömter rats had a significantly higher percentage of C4d-positive glomeruli (31%) compared to control rats (4%). Thus, glomerular C4d deposition can precede the development of FSGS, suggesting that complement activation may play a pathogenic role in the development of FSGS., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Complement factor C4d was recently observed in renal biopsies from patients who had IgA nephropathy and a poor prognosis. We previously reported that C4d is a common denominator in microangiopathies. In this retrospective cohort study, we investigated whether C4d is a marker of microangiopathy in both IgA nephropathy and IgA vasculitis with nephritis, and whether patients with C4d and microangiopathy have poor renal outcome. We examined 128 renal biopsies from adult and pediatric patients, including normotensive and hypertensive patients, who presented with IgA nephropathy or IgA vasculitis with nephritis. Biopsies were re-evaluated in accordance with the Oxford classification, scored for additional lesions, and stained for complement proteins using immunohistochemistry, including C4d and C5b-9. Clinical data were collected with a mean (±SD) follow-up period of 51 ± 39 months. Changes in estimated glomerular filtration rate over time were compared using linear mixed-effects models. Renal survival was analyzed using multivariable Cox regression. Microangiopathic lesions were present in 20% of all biopsies (23% and 9% of patients with IgA nephropathy and IgA vasculitis with nephritis, respectively). Microangiopathy was associated with C4d and C5b-9 deposits, a higher number of chronic lesions, and hypertension (all p < 0.05). Patients with C4d and microangiopathic lesions had significantly poorer renal survival than patients without these findings, corrected for hypertension (p < 0.01). In conclusion, patients with IgA nephropathy or IgA vasculitis with nephritis with a combination of C4d positivity and microangiopathy comprise a clinical subgroup with an increased number of chronic lesions, lower estimated glomerular filtration rate, and poorer renal survival, even when corrected for hypertension. These data suggest that complement activation is involved in the development of microangiopathy in patients with IgA nephropathy and IgA vasculitis with nephritis, and that complement-mediated microangiopathy contributes to disease progression.

Introduction: Hypercholesterolemia is a well-known risk factor for developing atherosclerosis and subsequently for the risk of a myocardial infarction (MI). Moreover, it might also be related to the extent of damaged myocardium in the event of a MI. The aim of this study was to evaluate the association of baseline low density lipoprotein-cholesterol (LDL-c) level with infarct size in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneously coronary intervention (pPCI)., Methods: Baseline blood samples were obtained from all patients admitted between 2004 and 2014 with STEMI who underwent pPCI. Patients were excluded in case of out of hospital cardiac arrest, treatment delay of at least 10 h or no complete reperfusion after pPCI in the culprit vessel. Peak creatine kinase (CK) level was used for infarct size estimation, defined as the maximal value during admission., Results: A total of 2248 patients were included in this study (mean age 61.8 ± 12.2 years; 25.0% female). Mean LDL-c level was 3.6 ± 1.1 mmol/L and median peak CK level was 1275 U/L (IQR 564-2590 U/L). Baseline LDL-c level [β = 0.041; (95% CI 0.019-0.062); p < 0.001] was independently associated with peak CK level. Furthermore, left anterior descending artery as culprit vessel, initial TIMI 0-1 flow in the culprit vessel, male gender, and treatment delay were also correlated with high peak CK level (p < 0.05). Prior aspirin therapy was associated with lower peak CK level [β = - 0.073 (95% CI - 0.146 to 0.000), p = 0.050]., Conclusion: This study demonstrates that besides the more established predictors of infarct size, elevated LDL-c is associated with augmented infarct size in patients with STEMI treated with pPCI.

Background: It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia., Methods and Results: This multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P = 0.47 and P = 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P = 0.54 at 3‑month and P = 0.15 at 12-month follow-up)., Conclusion: Intramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia., Clinical Trial Registration: NTR2516.

Low serum 25-hydroxyvitamin D (25OHD) concentrations have been associated with increased cancer risk, but the relative importance of seasonality, i.e. high summer concentrations versus low winter concentrations, is unclear. We investigated this issue in a high risk group: kidney transplant recipients with known increased risk of cancer and low vitamin D statuses. We examined the relationship between registered concentrations of 25OHD binned by quarter and subsequent risk of internal malignancy or cutaneous squamous cell carcinoma in 1112 kidney transplant recipients. Hazard ratios for internal malignancies were significantly increased with lower pre-diagnostic 25OHD concentrations in the first quarter of the year (January-March); a 1.4 fold increase (95%CI 1.1;1.7) per 10 nmol L-1 decrease in 25OHD. Except for women in April-June (1.3 (1.01;1.7) per 10 nmol L-1 decrease) pre-diagnostic 25OHD concentrations in the other quarters were not statistically significantly associated with internal malignancies. Higher 25OHD concentrations tended to be associated with the development of cutaneous squamous cell carcinomas, independent of the time of the year. Our study indicates that low wintertime 25OHD concentrations are associated with an increased risk of internal malignancies and that transplant recipients may benefit from wintertime vitamin D supplementation. Our findings need further corroboration, but suggest that the lowest concentrations of vitamin D, which occur in winter, are important for the risk of internal malignancies.

In diabetic nephropathy, differential expression of growth factors leads to vascular changes, including endothelial cell activation, monocyte infiltration, and inflammation. Endoglin plays an important role in endothelial function and is also associated with inflammation. In the kidney, vascular endoglin expression is increased in animal models of renal injury, where it contributes to disease severity, possibly by promoting endothelial cell activation and inflammation. Herein, we investigated whether endoglin expression is associated with diabetic nephropathy. In addition, we examined whether reducing endothelial endoglin expression in vitro affects endothelial cell activation and monocyte adhesion and, if so, which intracellular pathways are involved. Finally, we analyzed whether glomerular endoglin expression is correlated with endothelial cell activation in patients with diabetic nephropathy. Endoglin levels were significantly increased in mice with type 1 diabetes compared with control mice. Reducing endoglin expression in cultured endothelial cells significantly impaired the vascular endothelial growth factor-A-induced up-regulation of activation markers and monocyte adhesion. This was mediated by increased phosphorylation of Akt, thereby inhibiting activating transcription factor 2 phosphorylation, which regulates vascular cell adhesion molecule-1 (VCAM1) gene transcription in these cells. Last, endoglin colocalized with VCAM-1 in the glomeruli of diabetic patients, glomerular VCAM-1 expression was significantly increased in these patients, and this increase in VCAM-1 expression was correlated with increased glomerular endoglin expression. Thus, targeting endoglin function may have therapeutic value in patients at risk for diabetic nephropathy., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Hand osteoarthritis is a prevalent disease with limited treatment options. Since joint inflammation is often present, we investigated tumour necrosis factor (TNF) as treatment target in patients with proven joint inflammation in a proof-of-concept study., Methods: This 1-year, double-blind, randomised, multicentre trial (NTR1192) enrolled patients with symptomatic erosive inflammatory hand osteoarthritis. Patients flaring after non-steroidal anti-inflammatory drug washout were randomised to etanercept (24 weeks 50 mg/week, thereafter 25  mg/week) or placebo. The primary outcome was Visual Analogue Scale (VAS) pain at 24 weeks. Secondary outcomes included clinical and imaging outcomes (radiographs scored using Ghent University Scoring System (GUSS, n=54) and MRIs (n=20))., Results: Of 90 patients randomised to etanercept (n=45) or placebo (n=45), respectively, 12 and 10 discontinued prematurely. More patients on placebo discontinued due to inefficacy (6 vs 3), but fewer due to adverse effects (1 vs 6). The mean between-group difference (MD) in VAS pain was not statistically significantly different (-5.7 (95% CI -15.9 to 4.5), p=0.27 at 24 weeks; - 8.5 (95% CI -18.6 to 1.6), p=0.10 at 1  year; favouring etanercept). In prespecified per-protocol analyses of completers with pain and inflammation at baseline (n=61), MD was -11.8 (95% CI -23.0 to -0.5) (p=0.04) at 1  year. Etanercept-treated joints showed more radiographic remodelling (delta GUSS: MD 2.9 (95% CI 0.5 to 5.4), p=0.02) and less MRI bone marrow lesions (MD -0.22 (95% CI -0.35 to -0.09), p = 0.001); this was more pronounced in joints with baseline inflammation., Conclusion: Anti-TNF did not relieve pain effectively after 24 weeks in erosive osteoarthritis. Small subgroup analyses showed a signal for effects on subchondral bone in actively inflamed joints, but future studies to confirm this are warranted., Competing Interests: Competing interests: MK reports an unrestricted grant paid to the institution and study medication free of charge from Pfizer (Wyeth) during the conduct of the study, outside the submitted work. MK reports advisory board fees from Levicept, GlaxoSmithKline, AbbVie, Merck and Pfizer, grants from IMI-EFPIA APPROACH, grants from Pfizer, and other from AbbVie. W-YK reports an unrestricted grant from Pfizer (Wyeth) during the conduct of the study. TWJH/Department of Rheumatology LUMC has received grants/lecture fees/consultancy fees from Merck, UCB, Bristol-Myers Squibb, Pfizer, Roche, Sanofi-Aventis, Crescendo Bioscience and Eli Lilly. JSS reports grants from AbbVie, Lilly, Pfizer and Roche, personal fees from AbbVie, Amgen, AstraZeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi and UCB, outside the submitted work. RWi reports having a patent GUSS issued., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Metal on Metal total hip arthroplasty is associated with elevated serum cobalt levels. In this study we investigate if there is a relation between the inclination and anteversion angle of the cup and the anatomical reconstruction of the hip on the serum cobalt level. Postoperative cobalt serum levels were measured in 250 patients with the M2a-38 cup and Taperloc stem combination. On standardized radiographs inclination and anteversion angle, lower limb length, lateral offset and center of rotation distance were evaluated. A difference of more than 5 millimeter compared to the preoperative situation was considered as a non-anatomical reconstruction. For every 10 degrees increase in inclination the cobalt level increased 14% (p = 0.036). Women with the same cup inclination angle showed 34% higher cobalt levels than men (p = 0.013). No relation was found between the anteversion angle, anatomical reconstruction and the serum cobalt levels. A higher inclination of the cup leads to higher serum cobalt levels, but a non-anatomical reconstruction has no influence on serum cobalt levels.

Background: The aim of this study was to assess the sensibility of the hand in children with a neonatal brachial plexus palsy (NBPP) involving the C5 and C6, and to correlate results with dexterity., Methods: Fifty children with NBPP (30 after nerve surgery, mean age 9.8 years) and 25 healthy controls (mean age 9.6 years) were investigated. Sensibility was assessed with two-point discrimination and Semmes-Weinstein monofilaments. Dexterity was evaluated with a single item from the Movement Assessment Battery for Children-2. We compared the affected side with the nondominant hand of the control group., Results: The sensibility in the first and second fingers was significantly diminished in the NBPP for both two-point discrimination (P = 0.005 and P = 0.014, respectively) and monofilament test (P < 0.001). Dexterity was significantly lower in the NBPP group than in control group, corrected for age (P = 0.023). There was a significant difference toward decreasing hand function with decreasing sensibility according to the Semmes-Weinstein test for the thumb (Jonckheere-Terpstra nonparametric trend test, P = 0.036)., Conclusions: The sensibility of the thumb and index finger in children with an upper plexus lesion (either surgically or conservatively treated) is diminished. The decreased sensibility has a negative impact on hand function. Appreciation of diminished hand function in patients with NBPP involving C5 and C6 is important to optimize treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The aims of the study were (1) to assess hand sensibility in healthy young children using instruments validated for adults; (2) to identify which test tools are suitable; and (3) to compare the dominant and nondominant sides., Methods: Twenty-five healthy children aged seven to 11 years (mean = 9.5 years) were investigated. Sensibility was assessed with the Semmes-Weinstein monofilament test, two-point discrimination, localization test, and stereognosis object recognition., Results: The thinnest Semmes-Weinstein filament (D = 2.83 mm) was felt at 94% of examined points. A two-point discrimination at the smallest distance of 2 mm was found in the thumb in 84% of children and in the index finger in 94%. Only 60% felt this distance in the fifth digit. The difference between little finger and index finger was statistically significant. Near-maximum value on the localization test was scored in both hands. All children had a 100% score for both hands in the stereognosis object recognition., Conclusions: Most children can detect touch in the digits at low pressure. The majority are able to discern two points 2 mm apart in the first and second digits, but significantly less so in the fifth digit. Children are well able to localize on which side of a fingertip pressure is applied. Objects are recognized well. There appear to be no differences between the dominant and nondominant hands in either test. Adjustment of sensory test protocols routinely used in adults is necessary to optimize hand sensation testing in children, in view of the detection limits., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Pseudotumors, a well-known complication of metal-on-metal total hip arthroplasty (MoM THA), are well identified on metal artifact-reducing sequences magnetic resonance imaging (MARS-MRI). Several MRI grading systems are described in the orthopedic literature, but their validity is unknown in large clinical studies. Our study was undertaken to describe the classification of pseudotumors in a preselected cohort divided into high- and low-risk patients, using three pseudotumor grading systems applied on MARS-MRI, and to determine the interobserver reliability of the grading systems., Patients and Methods: A retrospective study was performed on 377 consecutive patients (240 MRI scans) treated with an M2a-38 and Taperloc stem combination (Biomet, Warsaw, IN, USA). Patients were divided into a high-risk and a low-risk group based on previous published risk factors. Two observers determined the presence of pseudotumors using three different pseudotumor grading systems for classifying MARS-MRI results., Results: The prevalence of pseudotumors as determined with MARS-MRI was 59% in our high-risk group, 0% in the low-risk group and 43% in the control group. Serum cobalt values were increased in the high-risk group. The kappa values of the Anderson, Hauptfleisch and Matthies grading system scores were 0.43, 0.44, and 0.49 respectively., Conclusions: High-risk patients are at a high risk for pseudotumor development. No pseudotumor development was found in low-risk patients. Interobserver reliability scored best with the Matthies system, but all three grading systems showed only a moderate agreement.

Objective: The aim of the study was to ascertain the prevalence of depressive mood and its determinants in the chronic phase after stroke., Design: Five hundred seventy-six consecutive patients were invited to participate 2 to 5 yrs after hospitalization for a first-ever stroke. Stroke characteristics at hospitalization were collected retrospectively from medical records. Patients and their caregivers completed questionnaires on depression (Hospital Anxiety and Depression Scale [HADS]), sociodemographic characteristics, healthcare usage, daily activities, quality of life, and caregiver strain. Patients with HADS depression scores of less than 8 were compared with patients with HADS depression scores of 8 or higher by means of univariate logistic regression analyses, adjusted for age, sex, and Barthel Index at discharge., Results: Two hundred seven patients (36%) returned the questionnaires. After a mean follow-up of 36.3 mos, 67 patients (34%) had a HADS depression score of 8 or higher. Male sex and being born abroad was statistically significantly associated with a high HADS depression score, adjusted for age, sex and stroke severity (where appropriate). Depressed patients had higher anxiety levels, a more avoidant coping style, less daily activities, and a lower quality of life; their caregivers experienced a higher burden., Conclusions: In the chronic phase after stroke, a considerable proportion of patients has depressive symptoms. This seems to be related to sex, country of origin, anxiety, coping style, daily activities, quality of life, and caregivers' strain. Future research should focus on causal relationships and opportunities for treatment.

Introduction Smartphone-compatible blood pressure devices may be a good alternative to enable self-measurement of blood pressure by patients. Furthermore, automatic transferral of data to the hospital allows for remote monitoring. To our knowledge, no study has compared four of these smartphone-compatible blood pressure devices. Methods Patients who were followed up for acute myocardial infarction were asked to participate during their outpatient clinic visit. After five minutes of rest, six blood pressure devices were applied. The order was randomised. Four devices were smartphone-compatible. One device was an automated oscillometric device. One device was a handheld aneroid sphygmomanometer (reference device). All measurements were compared using a linear mixed model. Results A total of 43 patients (62.7 ± 11.3 years, 79% male) were included. Compared to the reference device, four blood pressure monitors yielded a significant higher mean systolic blood pressure and four monitors yielded a significant higher diastolic BP. One device yielded a non-significant lower mean systolic blood pressure and one device yielded a non-significant higher mean diastolic blood pressure. Except for one blood pressure device, all mean differences were smaller than 5 mmHg. Conclusion In this study, average inter-device variability was shown to be statistically significant, however four devices remained within the predefined range of 5 mmHg for both systolic and diastolic blood pressures.