Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Electropolymerization of Polydopamine at Electrode-Supported Insulating Mesoporous Films.

Bioinspired, stimuli-responsive, polymer-functionalized mesoporous films are promising platforms for precisely regulating nanopore transport toward applications in water management, iontronics, catalysis, sensing, drug delivery, or energy conversion. Nanopore technologies still require new, facile, and effective nanopore functionalization with multi- and stimuli-responsive polymers to reach these complicated application targets. In recent years, zwitterionic and multifunctional polydopamine (PDA) films deposited on planar surfaces by electropolymerization have helped surfaces respond to various external stimuli such as light, temperature, moisture, and pH. However, PDA has not been used to functionalize nanoporous films, where the PDA-coating could locally regulate the ionic nanopore transport. This study investigates the electropolymerization of homogeneous thin PDA films to functionalize nanopores of mesoporous silica films. We investigate the effect of different mesoporous film structures and the number of electropolymerization cycles on the presence of PDA at mesopores and mesoporous film surfaces. Our spectroscopic, microscopic, and electrochemical analysis reveals that the amount and location (pores and surface) of deposited PDA at mesoporous films is related to the combination of the number of electropolymerization cycles and the mesoporous film thickness and pore size. In view of the application of the proposed PDA-functionalized mesoporous films in areas requiring ion transport control, we studied the ion nanopore transport of the films by cyclic voltammetry. We realized that the amount of PDA in the nanopores helps to limit the overall ionic transport, while the pH-dependent transport mechanism of pristine silica films remains unchanged. It was found that (i) the pH-dependent deprotonation of PDA and silica walls and (ii) the insulation of the indium-tin oxide (ITO) surface by increasing the amount of PDA within the mesoporous silica film affect the ionic nanopore transport.

Impact of HIV infection on access to cancer care and survival among women with invasive cervical cancer in Côte d'Ivoire: A prospective cohort study.

OBJECTIVE: To assess the impact of HIV on access to invasive cervical cancer (ICC) care and overall survival (OS) in a time of universal access to antiretroviral therapy (ART). METHODS: A cohort of women prospectively diagnosed with ICC was consecutively recruited from 2018 to 2020 in public/private cancer centers in Côte d'Ivoire. Follow-up data were collected through facility- and phone-based approaches. Logistic and Cox regression models allowed analysis of factors associated with access to cancer care and OS, respectively. RESULTS: Overall, 294 women with ICC aged 50 years (interquartile range [IQR] 43-60) were enrolled, including 21.4% of women living with HIV (WLHIV), 87% being on ART. An advanced ICC clinical stage (III-IV) was less frequent in WLHIV (63.5% vs. 77.1% in HIV-uninfected women; P = 0.029). Cancer care was initiated in 124 (42.2%) women (54.0% in WLHIV; 39.0% in HIV-uninfected; P = 0.030). Factors independently associated with access to cancer care were International Federation of Gynecology and Obstetrics (FIGO) stage I-II (adjusted odds ratio [aOR] 3.58, 95% CI 2.01-6.38) and no treatment by traditional healers prior to ICC diagnosis (aOR 3.69, 95% CI 1.96-6.96). The 2-year OS was 37.9% (95% CI 30.0-47.9). HIV status was not predictive of mortality (adjusted hazard ratio [aHR] 0.98, 95% CI 0.60-1.69). An advanced clinical stage was the only measured predictor of death (aHR 1.59, 95% CI 1.02-2.47). CONCLUSION: In a time of universal access to ART, HIV infection was not associated with OS among women with ICC in Côte d'Ivoire. Higher access to cancer care in WLHIV might be mediated by enhanced access to ICC screening services, supporting the need to expand these services to other types of healthcare facilities.

Survey of ptosis practice patterns among surgeons in Asia Pacific Society of Ophthalmic Plastic and Reconstructive Surgery (APSOPRS).

OBJECTIVE: To characterize the preferred ptosis practice patterns and variations among oculoplastic surgeons in the Asia-Pacific region. METHODS: A web-based questionnaire was sent to both members and non-members registered under the Asia Pacific Society of Ophthalmic Plastic and Reconstructive Surgery (APSOPRS)'s email database. The survey included preoperative testing practices, surgical preferences for adult aponeurotic and congenital ptosis, various surgical techniques (anterior and posterior approach ptosis procedures, and frontalis sling procedures) and postoperative practices. RESULTS: A total of 386 survey invitations were sent. There was a response rate of 68.7% from respondents from 20 countries in the Asia-Pacific region. There was variation in the preoperative evaluation and management of ptosis. Anterior approach ptosis surgery (96.6%) and frontalis sling procedures (86.8%) were performed by more surgeons than posterior approach ptosis surgery (47.2%). There was a deviation from the traditional frontalis sling procedures for patients with poor levator function. CONCLUSIONS: Our survey results provide insight into the variation in the assessment and management of ptosis amongst oculoplastic surgeons in the Asia-Pacific region. It also demonstrates some differences between practice patterns in Asia-Pacific and America.

Acute kidney injury requiring kidney replacement therapy in childhood lupus nephritis: a cohort study of the Pediatric Nephrology Research Consortium and Childhood Arthritis and Rheumatology Research Alliance.

BACKGROUND: Acute kidney injury (AKI) is common in lupus nephritis (LN) and a risk factor for development of chronic kidney disease. In adults with LN, AKI severity correlates with the incidence of kidney failure and patient survival. Data on AKI outcomes in children with LN, particularly those requiring kidney replacement therapy (KRT), are limited. METHODS: A multicenter, retrospective cohort study was performed in children diagnosed between 2010 and 2019 with LN and AKI stage 3 treated with dialysis (AKI stage 3D). Descriptive statistics were used to characterize demographics, clinical data, and kidney biopsy findings; treatment data for LN were not included. Logistic regression was used to examine the association of these variables with kidney failure. RESULTS: Fifty-nine patients (mean age 14.3 years, 84.7% female) were identified. The most common KRT indications were fluid overload (86.4%) and elevated blood urea nitrogen/creatinine (74.6%). Mean follow-up duration was 3.9 ± 2.9 years. AKI recovery without progression to kidney failure occurred in 37.3% of patients. AKI recovery with later progression to kidney failure occurred in 25.4% of patients, and there was no kidney recovery from AKI in 35.6% of patients. Older age, severe (> 50%) tubular atrophy and interstitial fibrosis, and National Institutes of Health (NIH) chronicity index score > 4 on kidney biopsy were associated with kidney failure. CONCLUSIONS: Children with LN and AKI stage 3D have a high long-term risk of kidney failure. Severe tubular atrophy and interstitial fibrosis at the time of AKI, but not AKI duration, are predictive of kidney disease progression. A higher resolution version of the Graphical abstract is available as Supplementary information.

Mental and psychosocial health and health related quality of life before and after cardiac rehabilitation: a prospective cohort study with comparison to specific population norms.

BACKGROUND: Data on mental health improvement after cardiac rehabilitation (CR) are contradictory. The aim was to examine the mental and psycho-social health of patients admitted to our rehabilitation center following hospital treatment for acute coronary syndrome, before and after multidisciplinary CR. METHODS: Outcome was measured at admission and discharge by the 36-Item Short Form Survey (SF-36), the Symptom Checklist-90 Revised (SCL-90R), the Coping Strategy Questionnaire (CSQ) and the 6-min-walking distance test. The patients' health status was compared with norms of sex-, age- and comorbidity-matched data from the German general population. Score differences from norms were measured by standardized mean differences (SMDs); health changes were quantified by standardized effect sizes (ESs). Their importance for comprehensive assessment was quantified by explorative factor analysis. RESULTS: Of n = 70 patients followed-up (male: 79%; mean age: 66.6 years), 79% had ≥ 3 comorbidities. At baseline, SF-36 Physical functioning (SMD = - 0.75), Role physical (- 0.90), Social functioning (SMD = - 0.44), and Role emotional (SMD = - 0.45) were significantly worse than the norm. After CR, almost all scores significantly improved by ES = 0.23 (SCL-90R Interpersonal sensitivity) to 1.04 (SF-36 Physical functioning). The strongest factor (up to 41.1% explained variance) for health state and change was the mental health domain, followed by function & pain (up to 26.3%). CONCLUSIONS: Normative deficits in physical and psycho-social health were reported at baseline. After CR, at follow-up, all scores, except phobia, showed significant improvement. The comprehensive measurement of bio-psycho-social health should not be limited to depression and anxiety but include, especially, the somatization and social participation dimensions.

Hidden dependence of spreading vulnerability on topological complexity.

Many dynamical phenomena in complex systems concern spreading that plays out on top of networks with changing architecture over time-commonly known as temporal networks. A complex system's proneness to facilitate spreading phenomena, which we abbreviate as its "spreading vulnerability," is often surmised to be related to the topology of the temporal network featured by the system. Yet, cleanly extracting spreading vulnerability of a complex system directly from the topological information of the temporal network remains a challenge. Here, using data from a diverse set of real-world complex systems, we develop the "entropy of temporal entanglement" as a quantity to measure topological complexities of temporal networks. We show that this parameter-free quantity naturally allows for topological comparisons across vastly different complex systems. Importantly, by simulating three different types of stochastic dynamical processes playing out on top of temporal networks, we demonstrate that the entropy of temporal entanglement serves as a quantitative embodiment of the systems' spreading vulnerability, irrespective of the details of the processes. In being able to do so, i.e., in being able to quantitatively extract a complex system's proneness to facilitate spreading phenomena from topology, this entropic measure opens itself for applications in a wide variety of natural, social, biological, and engineered systems.

Amine-Functionalized Nanoporous Silica Monoliths for Heterogeneous Catalysis of the Knoevenagel Condensation in Flow.

Porous carrier materials functionalized with organocatalysts offer substantial advantages compared to homogeneous catalysts, e.g., easy separation of the catalyst, scalability, and an improved implementation in continuous operations. Here, we report the immobilization of (3-aminopropyl)trimethoxysilane (APTMS) onto self-prepared silica monoliths and its application as a heterogeneous catalyst in the Knoevenagel condensation between cyano ethylacetate and various aromatic aldehydes under continuous-flow conditions. The meso-macroporous silica monoliths (6-7 cm in length) were optimized to be used in flow taking advantage of their hierarchical meso- and macroporosity. The monoliths were cladded with a poly(ether ether ketone) (PEEK) tube by a refined procedure to guarantee tight connection between the carrier material and PEEK. Functionalization of the bare silica monoliths consisting of APTMS can be efficiently performed in flow in ethanol and toluene. While a large grafting gradient is obtained for toluene, the grafting in ethanol proceeds homogenously throughout the monolith, as evidenced by elemental analysis and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The silica monoliths exhibit high conversion up to 95% with concurrent low back pressures, which is of importance in flow catalysis. By connecting two monoliths, high conversions can be maintained for several flow rates. Two types of monoliths were synthesized, possessing different mesopore sizes. The monolith bearing the larger mesopore size showed an enhanced turnover frequency (TOF), while the monolith with the smaller mesopores allowed for larger quantities of the product to be synthesized, due to the higher surface area. A long-term stability test showed that the functionalized monoliths were still active after 66 h of continuous usage, while the overall yield decreased over time.

Publisher Correction: Whole Transcriptome Analysis of Renal Intercalated Cells Predicts Lipopolysaccharide Mediated Inhibition of Retinoid X Receptor alpha Function.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Human Papillomavirus Vaccination in Male and Female Adolescents Before and After Kidney Transplantation: A Pediatric Nephrology Research Consortium Study.

Background: Kidney transplant (KT) recipients have higher incidence of malignancies, including Human Papillomavirus (HPV)-associated cancers. Thus, HPV vaccines may have an important role in preventing HPV-related disease in this population; however, immunogenicity and safety data are lacking. Objective: To examine the immunological response and tolerability to HPV vaccination in pediatric KT recipients compared to future KT candidates. Methods: The quadrivalent HPV vaccine was administered to girls and boys age 9-18 recruited from seven centers part of the Pediatric Nephrology Research Consortium. Subjects were recruited for three groups: (1) CKD: chronic kidney disease stages 3, 4, and 5 not on dialysis; (2) Dialysis; (3) KT recipients. The outcome consisted of antibody concentrations against HPV 6, 11, 16, and 18. Geometric mean titers (GMTs) and seroconversion rates were compared. Vaccine tolerability was assessed. Results: Sixty-five participants were recruited: 18 in the CKD, 18 in the dialysis, and 29 into the KT groups. KT patients had significantly lower GMTs after vaccination for all serotypes. The percentages of subjects who reached seroconversion were overall lower for the KT group, reaching statistical significance for HPV 6, 11, and 18. Comparing immunosuppressed subjects (anyone taking immunosuppression medications, whether KT recipient or not) with the non-immunosuppressed participants, the former had significantly lower GMTs for all the HPV serotypes and lower seroconversion rates for HPV 6, 11, and 18. KT females had higher GMTs and seroconversion rates for certain serotypes. There were no adverse events in either group. Conclusions: HPV vaccine was well-tolerated in this population. Pediatric KT recipients had in general lower GMTs and seroconversion rates compared to their peers with CKD or on dialysis. Immunosuppression played a role in the lack of seroconversion. Our results emphasize the importance of advocating for HPV vaccination prior to KT and acknowledge its safety post transplantation. Future studies are needed to investigate the effect of a supplemental dose of HPV vaccine in KT recipients who do not seroconvert and to evaluate the long-term persistence of antibodies post-KT.

The Cost of Prostate Biopsies and their Complications: A Summary of Data on All Medicare Fee-for-Service Patients over 2 Years.

INTRODUCTION: We define the cost of a contemporary prostate biopsy and the rate and incremental impact of complications on costs. METHODS: A retrospective analysis of all Medicare fee-for-service claims for prostate biopsies in the United States from January 31, 2014 to December 1, 2015 was performed. Costs of each biopsy episode (including 30 days after each biopsy) were calculated. The effects of complications, biopsy setting and subsequent inpatient hospitalization were explored. RESULTS: The average cost of the 234,819 biopsies reviewed was $2,020 and 46% of biopsy costs occurred in the 30 days following each biopsy. Biopsies performed in the office setting comprised 66% of the total and were least costly ($1,750) compared to biopsies performed in ambulatory surgical centers ($2,260) and outpatient hospital settings ($2,730, both p <0.001). Biopsies performed in the office setting were associated with fewer complications (10%) compared to the outpatient hospital (19%) or ambulatory surgical center settings (12%, both p <0.001). An uncomplicated biopsy episode cost an average of $1,740, which increased to $4,060 when at least 1 complication occurred (difference +$2,320, p <0.001). The largest charges incurred were related to inpatient admissions, which added $13,840 to the cost of a prostate biopsy (p <0.001) but were rare, constituting only 2.8% of biopsies. CONCLUSIONS: Nearly half of costs during prostate biopsy episodes occur due to complications that occur in the days following a biopsy. These data should be used as benchmarks to incentivize interventions to reduce complications and subsequent admissions following biopsies.

Local loop opening in untangled ring polymer melts: a detailed "Feynman test" of models for the large scale structure.

The conformational statistics of ring polymers in melts or dense solutions is strongly affected by their quenched microscopic topological state. The effect is particularly strong for untangled (i.e. non-concatenated and unknotted) rings, which are known to crumple and segregate. Here we study these systems using a computationally efficient multi-scale approach, where we combine massive simulations on the fiber level with the explicit construction of untangled ring melt configurations based on theoretical ideas for their large scale structure. We find (i) that topological constraints may be neglected on scales below the standard entanglement length, Le, (ii) that rings with a size 1 ≤ Lr/Le ≤ 30 exhibit nearly ideal lattice tree behavior characterized by primitive paths which are randomly branched on the entanglement scale, and (iii) that larger rings are compact with gyration radii Rg2(Lr) ∝ Lr2/3. The detailed comparison between equilibrated and constructed ensembles allows us to perform a "Feynman test" of our understanding of untangled rings: can we convert ideas for the large scale ring structure into algorithms for constructing (nearly) equilibrated ring melt samples? We show that most structural observables are quantitatively reproduced by two different construction schemes: hierarchical crumpling and ring melts derived from the analogy to interacting branched polymers. However, the latter fail the "Feynman test" with respect to the magnetic radius, Rm, which we have defined based on an analogy to magnetostatics. While Rm is expected to vanish for double-folded structures, the observed values of Rm2(Lr) ∝ Rg2(Lr) provide a simple and computationally convenient measure of the presence of a non-negligible amount of local loop opening in crumpled rings.

Whole Transcriptome Analysis of Renal Intercalated Cells Predicts Lipopolysaccharide Mediated Inhibition of Retinoid X Receptor alpha Function.

The renal collecting duct consists of intercalated cells (ICs) and principal cells (PCs). We have previously demonstrated that collecting ducts have a role in the innate immune defense of the kidney. Transcriptomics is an important tool used to enhance systems-level understanding of cell biology. However, transcriptomics performed on whole kidneys provides limited insight of collecting duct cell gene expression, because these cells comprise a small fraction of total kidney cells. Recently we generated reporter mouse models to enrich collecting duct specific PC and ICs and reported targeted gene expression of anti-microbial peptide genes. Here we report transcriptomics on enriched ICs and PCs and performed a pilot study sequencing four single ICs. We identified 3,645 genes with increased relative expression in ICs compared to non-ICs. In comparison to non-PCs, 2,088 genes had higher relative expression in PCs. IC associated genes included the innate interleukin 1 receptor, type 1 and the antimicrobial peptide(AMP) adrenomedullin. The top predicted canonical pathway for enriched ICs was lipopolysaccharide/Interleukin 1 mediated inhibition of Retinoid X Receptor alpha function and decreased Retinoid X Receptor expression was confirmed to occur 1-hour post experimental murine UTI in ICs but not in non-ICs.

Cell-specific qRT-PCR of renal epithelial cells reveals a novel innate immune signature in murine collecting duct.

The urinary tract is usually culture negative despite its close proximity to microbial flora. The precise mechanism by which the kidneys and urinary tract defends against infection is not well understood. The initial kidney cells to encounter ascending pathogens are the collecting tubule cells that consist of principal cells (PCs) that express aquaporin 2 (AQP2) and intercalated cells (ICs) that express vacuolar H+-ATPase (V-ATPase, B1 subunit). We have previously shown that ICs are involved with the human renal innate immune defense. Here we generated two reporter mice, VATPase B1-cre+tdT+ mice to fluorescently label ICs and AQP2-cre+tdT+ mice to fluorescently label PCs, and then performed flow sorting to enrich PCs and ICs for analysis. Isolated ICs and PCs along with proximal tubular cells were used to measure antimicrobial peptide (AMP) mRNA expression. ICs and PCs were significantly enriched for AMPs. Isolated ICs responded to uropathogenic Escherichia coli (UPEC) challenge in vitro and had higher RNase4 gene expression than control while both ICs and PCs responded to UPEC challenge in vivo by upregulating Defb1 mRNA expression. To our knowledge, this is the first report of isolating murine collecting tubule cells and performing targeted analysis for multiple classes of AMPs.

Multiplexing Genetic and Nucleosome Positioning Codes: A Computational Approach.

Eukaryotic DNA is strongly bent inside fundamental packaging units: the nucleosomes. It is known that their positions are strongly influenced by the mechanical properties of the underlying DNA sequence. Here we discuss the possibility that these mechanical properties and the concomitant nucleosome positions are not just a side product of the given DNA sequence, e.g. that of the genes, but that a mechanical evolution of DNA molecules might have taken place. We first demonstrate the possibility of multiplexing classical and mechanical genetic information using a computational nucleosome model. In a second step we give evidence for genome-wide multiplexing in Saccharomyces cerevisiae and Schizosacharomyces pombe. This suggests that the exact positions of nucleosomes play crucial roles in chromatin function.

Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND: Cross-sectional studies of children with prevalent nephrotic syndrome (NS) have shown 25-vitamin D (25(OH)D) deficiency rates of 20-100 %. Information on 25(OH)D status in incident patients or following remission is limited. This study aimed to assess 25(OH)D status of incident idiopathic NS children at presentation and longitudinally with short-term observation. METHODS: Multicenter longitudinal study of children (2-18 years old) from 14 centers across the Midwest Pediatric Nephrology Consortium with incident idiopathic NS. 25(OH)D levels were assessed at diagnosis and 3 months later. RESULTS: Sixty-one children, median age 5 (3, 11) years, completed baseline visit and 51 completed second visit labs. All 61 (100 %) had 25(OH)D < 20 ng/ml at diagnosis. Twenty-seven (53 %) had 25(OH)D < 20 ng/ml at follow-up. Fourteen (28 %) children were steroid resistant. Univariate analysis showed that children prescribed vitamin D supplements were less likely to have 25(OH)D deficiency at follow-up (OR 0.2, 95 % CI 0.04, 0.6). Steroid response, age, and season did not predict 25(OH)D deficiency. Multivariable linear regression modeling showed higher 25(OH)D levels at follow-up by 13.2 ng/ml (SE 4.6, p < 0.01) in children supplemented with vitamin D. CONCLUSIONS: In this incident idiopathic NS cohort, all children at diagnosis had 25(OH)D deficiency and the majority continued to have a deficiency at 2-4 months. Supplemental vitamin D decreased the odds of 25(OH)D deficiency at follow-up, supporting a role for supplementation in incident NS.

Reducing αENaC expression in the kidney connecting tubule induces pseudohypoaldosteronism type 1 symptoms during K+ loading.

Genetic inactivation of the epithelial Na(+) channel α-subunit (αENaC) in the renal collecting duct (CD) does not interfere with Na(+) and K(+) homeostasis in mice. However, inactivation in the CD and a part of the connecting tubule (CNT) induces autosomal recessive pseudohypoaldosteronism type 1 (PHA-1) symptoms in subjects already on a standard diet. In the present study, we further examined the importance of αENaC in the CNT. Knockout mice with αENaC deleted primarily in a part of the CNT (CNT-KO) were generated using Scnn1a(lox/lox) mice and Atp6v1b1::Cre mice. With a standard diet, plasma Na(+) concentration ([Na(+)]) and [K(+)], and urine Na(+) and K(+) output were unaffected. Seven days of Na(+) restriction (0.01% Na(+)) led to a higher urine Na(+) output only on days 3-5, and after 7 days plasma [Na(+)] and [K(+)] were unaffected. In contrast, the CNT-KO mice were highly susceptible to a 2-day 5% K(+) diet and showed lower food intake and relative body weight, lower plasma [Na(+)], higher fractional excretion (FE) of Na(+), higher plasma [K(+)], and lower FE of K(+). The higher FE of Na(+) coincided with lower abundance and phosphorylation of the Na(+)-Cl(-) cotransporter. In conclusion, reducing ENaC expression in the CNT induces clear PHA-1 symptoms during high dietary K(+) loading.

Computational study of remodeling in a nucleosomal array.

Chromatin remodeling complexes utilize the energy of ATP hydrolysis to change the packing state of chromatin, e.g. by catalysing the sliding of nucleosomes along DNA. Here we present simple models to describe experimental data of changes in DNA accessibility along a synthetic, repetitive array of nucleosomes during remodeling by the ACF enzyme or its isolated ATPase subunit, ISWI. We find substantial qualitative differences between the remodeling activities of ISWI and ACF. To understand better the observed behavior for the ACF remodeler, we study more microscopic models of nucleosomal arrays.

[Metformin, renal function and lactate: the MetClear Study]. / Metformine, nierfunctie en lactaat: het MetClear-onderzoek.

OBJECTIVE: To map the relation between metformin prescription and renal function in an outpatient setting. To investigate whether there is an association between renal function, metformin concentration and lactate concentration. DESIGN: Pilot for a prospective observational cohort study. METHOD: We included outpatients with diabetes mellitus type 2 who were treated with metformin. At inclusion, we determined the HbA1c, lactate, metformin and creatinine concentrations and the estimated glomerular filtration rate (eGFR). Information on the prescribed dosage of metformin was acquired from patient files. Our primary outcome measure was the number of patients in whom the dose was not adjusted to the renal function. Our secondary outcome measure was the difference in median lactate concentration between patients with a normal (≤ 2.5 mg/l) and an increased (> 2.5 mg/l) metformin concentration. RESULTS: Eighty-eight patients were included, 12 (14%) of whom had an eGFR ≤ 30, 31 (36%) an eGFR of 30-50 and 44 (50%) an eGFR > 51 ml/min/1.73 m2. In 27 (31%) of all patients, the daily dose of metformin exceeded the dose recommended in the practice guidelines. The 28 patients with an increased metformin concentration had a significantly higher median lactate concentration: 2.3 mmol/l compared to 1.5 mmol/l for the 60 patients with a normal metformin concentration (p < 0.0001). CONCLUSION: Our study shows that in outpatient practice, the metformin dose is not sufficiently adjusted to a reduced renal function in 31% of the patients. The accumulation of metformin appears to be associated with an increased lactate concentration and a reduced renal function. Extra attention to the dose of metformin in reduced renal clearance is therefore recommended.