Type and intensity distribution of structured and incidental lifestyle physical activity of students and office workers: a retrospective content analysis.

BACKGROUND: Physical activity (PA) guidelines acknowledge the health benefits of regular moderate-to-vigorous physical activity (MVPA) regardless of bout duration. However, little knowledge exists concerning the type and intensity distribution of structured and incidental lifestyle PA of students and office workers. The present study aimed to i) assess the duration and distribution of intensity of MVPAs during waking hours ≥50% of heart rate reserve (HRR), ii) to identify the type of PA through diary assessment, iii) to assign these activities into structured and lifestyle incidental PA, and iv) to compare this information between students and office workers. METHODS: Twenty-three healthy participants (11 students, 12 office workers) recorded heart rate (HR) with a wrist-worn HR monitor (Polar M600) and filled out a PA diary throughout seven consecutive days (i.e. ≥ 8 waking h/day). Relative HR zones were calculated, and PA diary information was coded using the Compendium of PA. We matched HR data with the reported PA and identified PA bouts during waking time ≥ 50% HRR concerning duration, HRR zone, type of PA, and assigned each activity to incidental and structured PA. Descriptive measures for time spend in different HRR zones and differences between students and office workers were calculated. RESULTS: In total, we analyzed 276.894 s (76 h 54 min 54 s) of waking time in HRR zones ≥50% and identified 169 different types of PA. The participants spend 31.9 ± 27.1 min/day or 3.9 ± 3.2% of their waking time in zones of ≥50% HRR with no difference between students and office workers (p > 0.01). The proportion of assigned incidental lifestyle PA was 76.9 ± 22.5%. CONCLUSIONS: The present study provides initial insights regarding the type, amount, and distribution of intensity of structured and incidental lifestyle PA ≥ 50% HRR. Findings show a substantial amount of incidental lifestyle PA during waking hours and display the importance of promoting a physically active lifestyle. Future research could employ ambulatory assessments with integrated electronic diaries to detect information on the type and context of MVPA during the day.

Novel Ex Vivo Human Osteochondral Explant Model of Knee and Spine Osteoarthritis Enables Assessment of Inflammatory and Drug Treatment Responses.

Osteoarthritis of the knee and spine is highly prevalent in modern society, yet a disease-modifying pharmacological treatment remains an unmet clinical need. A major challenge for drug development includes selection of appropriate preclinical models that accurately reflect clinical phenotypes of human disease. The aim of this study was to establish an ex vivo explant model of human knee and spine osteoarthritis that enables assessment of osteochondral tissue responses to inflammation and drug treatment. Equal-sized osteochondral fragments from knee and facet joints (both n = 6) were subjected to explant culture for 7 days in the presence of a toll-like receptor 4 (TLR4) agonist and an inhibitor of transforming growth factor-beta (TGF-β) receptor type I signaling. Markers of inflammation, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), but not bone metabolism (pro-collagen-I) were significantly increased by treatment with TLR4 agonist. Targeting of TGF-β signaling resulted in a strong reduction of pro-collagen-I and significantly decreased IL-6 levels. MCP-1 secretion was increased, revealing a regulatory feedback mechanism between TGF-β and MCP-1 in joint tissues. These findings demonstrate proof-of-concept and feasibility of explant culture of human osteochondral specimens as a preclinical disease model, which might aid in definition and validation of disease-modifying drug targets.

The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function.

RATIONALE: Endothelial dysfunction is an early event in cardiovascular disease and characterized by reduced production of nitric oxide (NO). The F-BAR protein NO synthase traffic inducer (NOSTRIN) is an interaction partner of endothelial NO synthase and modulates its subcellular localization, but the role of NOSTRIN in pathophysiology in vivo is unclear. OBJECTIVE: We analyzed the consequences of deleting the NOSTRIN gene in endothelial cells on NO production and cardiovascular function in vivo using NOSTRIN knockout mice. METHODS AND RESULTS: The levels of NO and cGMP were significantly reduced in mice with endothelial cell-specific deletion of the NOSTRIN gene resulting in diastolic heart dysfunction. In addition, systemic blood pressure was increased, and myograph measurements indicated an impaired acetylcholine-induced relaxation of isolated aortic rings and resistance arteries. We found that the muscarinic acetylcholine receptor subtype M3 (M3R) interacted directly with NOSTRIN, and the latter was necessary for correct localization of the M3R at the plasma membrane in murine aorta. In the absence of NOSTRIN, the acetylcholine-induced increase in intracellular Ca(2+) in primary endothelial cells was abolished. Moreover, the activating phosphorylation and Golgi translocation of endothelial NO synthase in response to the M3R agonist carbachol were diminished. CONCLUSIONS: NOSTRIN is crucial for the localization and function of the M3R and NO production. The loss of NOSTRIN in mice leads to endothelial dysfunction, increased blood pressure, and diastolic heart failure.

Direct aqueous measurement of 25-hydroxyvitamin D levels in a cellular environment by LC-MS/MS using the novel chemical derivatization reagent MDBP.

Vitamin D measurements in biological fluids by mass spectrometry are challenging at very low concentration levels. As a result, chemical derivatization is often employed to enhance the ionization properties of low abundant vitamin D compounds. Cookson-type reagents such as 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) or similar derivatives work well but require careful, water-free experimental conditions, as traces of water inactivate the reagent and inhibit or stop the derivatization reactions, thus making quantitative measurements in aqueous samples impossible. We describe a novel electrospray liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for determining 25-hydroxyvitamin D3 (25(OH)D3) directly in aqueous cellular systems using a new derivatization reagent, the ionic liquid 12-(maleimidyl)dodecyl-tri-n-butylphosphonium bromide (MDBP). The proof-of-concept for the MDBP assay was demonstrated by measuring the levels of 25(OH)D3 in four different human cell types, namely T cells, helper T cells, B cells, and macrophages. In addition to the ability to determine the levels of 25(OH)D3 directly in aqueous samples, the cellular integrity was maintained in our application. We show the time-dependent uptake of 25(OH)D3 into the investigated cells to demonstrate the applicability of the new label. Furthermore, the MDBP derivatization technique may be equally useful in imaging mass spectrometry, where it could be used for response enhancements of spatially localized vitamin D metabolites on wet tissue surfaces, without destroying the integrity of the tissue surface. Graphical Abstract MDBP labelling of 25-hydroxyvitamin D in the extracellular space.

Mass spectrometric profiling of vitamin D metabolites beyond 25-hydroxyvitamin D.

BACKGROUND: The frequency of measurements of vitamin D in the human population has significantly increased over the last decade because vitamin D has now been linked to many diseases, in addition to its established role in bone health. Usually, serum 25-hydroxyvitamin D concentrations are measured to assess the vitamin D status of individuals. Unfortunately, many studies investigating links between vitamin D and disease also use only this single metabolite. Intricate correlations with other vitamin D metabolites or dynamic effects of downstream metabolites may therefore be overlooked. Fortunately, powerful LC-MS/MS approaches have recently become available that can simultaneously quantify the concentrations of multiple vitamin D metabolites. These approaches are challenging, however, because of inherent instrumental problems with detection of vitamin D compounds and the low concentrations of the metabolites in biological fluids. CONTENT: This review summarizes recent mass spectrometry assays for the quantitative measurement of multiple vitamin D metabolites and their application in clinical research, with a particular focus on the low-abundance downstream metabolic species generated after the initial hydroxylation to 25-hydroxyvitamin D. SUMMARY: To study the pathobiological effects and function of vitamin D metabolites in disease, in particular in low-abundance species beyond 25-hydroxyvitamin D, we need to know their concentrations. Although detection of these vitamin D species is challenging, a number of recent mass spectrometry assays have successfully demonstrated that LC-MS/MS methods can quantify multiple vitamin D compounds over a wide dynamic range individually or as part of multimetabolite assays.

The transcription factor ZNF469 regulates collagen production in liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the world's population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development.

Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

Reduced vowel space in video conferences via Zoom: Evidence from read speecha).

This exploratory study compared vowel space area (VSA) in face-to-face situations and video conference situations using the software Zoom. Twenty native German participants read word lists recorded before and after spontaneous conversation. The overall VSA in Zoom was reduced significantly by 11.9%, with a more reduced VSA before and less reduction after the spontaneous conversation. Of nine peripheral vowels in German, /aː iː yː/ showed a significantly reduced Euclidean distance to the centroid of the vowel space. The observed hypoarticulation is discussed in light of the experimental setup, situational differences, and less involvement in Zoom than in face-to-face situations.

Fracture healing research: Recent insights.

Bone has the rare capability of scarless regeneration that enables the complete restoration of the injured bone area. In recent decades, promising new technologies have emerged from basic, translational and clinical research for fracture treatment; however, 5-10 % of all bone fractures still fail to heal successfully or heal in a delayed manner. Several comorbidities and risk factors have been identified which impair bone healing and might lead to delayed bone union or non-union. Therefore, a considerable amount of research has been conducted to elucidate molecular mechanisms of successful and delayed fracture healing to gain further insights into this complex process. One focus of recent research is to investigate the complex interactions of different cell types and the action of progenitor cells during the healing process. Of particular interest is also the identification of patient-specific comorbidities and how these affect fracture healing. In this review, we discuss the recent knowledge about progenitor cells for long bone repair and the influence of comorbidities such as diabetes, postmenopausal osteoporosis, and chronic stress on the healing process. The topic selection for this review was made based on the presented studies at the 2022 annual meeting of the European Calcified Tissue Society (ECTS) in Helsinki.

Activation function 2 (AF2) domain of estrogen receptor-α regulates mechanotransduction during bone fracture healing in estrogen-competent mice.

External mechanostimulation applied by whole-body low-magnitude high-frequency vibration (LMHFV) was demonstrated to cause no or negative effects on fracture healing in estrogen-competent rodents, while in ovariectomized (OVX), estrogen-deficient rodents bone formation after fracture was improved. Using mice with an osteoblast-specific deletion of the estrogen receptor α (ERα), we demonstrated that ERα signaling in osteoblasts is required for both the anabolic and catabolic effects of LMHFV during bone fracture healing in OVX and non-OVX mice, respectively. Because the vibration effects mediated by ERα were strictly dependent on the estrogen status, we hypothesized different roles of ligand-dependent and -independent ERα signaling. To investigate this assumption in the present study, we used mice with a deletion of the C-terminal activation function (AF) domain-2 of the ERα receptor, which mediated ligand-dependent ERα signaling (ERαAF-20). OVX and non-OVX ERαAF-20 animals were subjected to femur osteotomy followed by vibration treatment. We revealed that estrogen-competent mice lacking the AF-2 domain were protected from LMHFV-induced impaired bone regeneration, while the anabolic effects of vibration in OVX mice were not affected by the AF-2 knockout. RNA sequencing further showed that genes involved in Hippo/Yap1-Taz and Wnt signaling were significantly downregulated upon LMHFV in the presence of estrogen in vitro. In conclusion, we demonstrated that the AF-2 domain is crucial for the negative effects of vibration during bone fracture healing in estrogen-competent mice suggesting that the osteoanabolic effects of vibration are rather mediated by ligand-independent ERα signaling.

Neutrophil-derived catecholamines mediate negative stress effects on bone.

Mental traumatization is associated with long-bone growth retardation, osteoporosis and increased fracture risk. We revealed earlier that mental trauma disturbs cartilage-to-bone transition during bone growth and repair in mice. Trauma increased tyrosine hydroxylase-expressing neutrophils in bone marrow and fracture callus. Here we show that tyrosine hydroxylase expression in the fracture hematoma of patients correlates positively with acknowledged stress, depression, and pain scores as well as individual ratings of healing-impairment and pain-perception post-fracture. Moreover, mice lacking tyrosine hydroxylase in myeloid cells are protected from chronic psychosocial stress-induced disturbance of bone growth and healing. Chondrocyte-specific ß2-adrenoceptor-deficient mice are also protected from stress-induced bone growth retardation. In summary, our preclinical data identify locally secreted catecholamines in concert with ß2-adrenoceptor signalling in chondrocytes as mediators of negative stress effects on bone growth and repair. Given our clinical data, these mechanistic insights seem to be of strong translational relevance.

Dengue Fever Surveillance in Mato Grosso do Sul: Insights from Genomic Analysis and Implications for Public Health Strategies.

Since its discovery in early 1916, dengue fever, a common vector-borne illness in Brazil, has resulted in extensive urban outbreaks and poses a serious threat to the public's health. Understanding the dynamics of Dengue Virus (DENV) serotypes circulating in different regions of Brazil is essential for implementing effective disease control and prevention measures. In response to this urgent need, we conducted an on-site training program in genomic surveillance in collaboration with the Central Laboratory of Health and the Secretary of Health of the Mato Grosso do Sul state. This initiative resulted in the generation of 177 DENV genome sequences collected between May 2021 and May 2022, a period during which over 11,391 dengue fever cases were reported in the state. Through this approach, we were able to identify the co-circulation of two different dengue serotypes (DENV1 and DENV2) as well as the existence of diverse viral lineages within each genotype, suggesting that multiple introduction events of different viral strains occurred in the region. By integrating epidemiological data, our findings unveiled temporal fluctuations in the relative abundance of different serotypes throughout various epidemic seasons, highlighting the complex and changing dynamics of DENV transmission throughout time. These findings demonstrate the value of ongoing surveillance activities in tracking viral transmission patterns, monitoring viral evolution, and informing public health actions.

Myeloid cell-derived catecholamines influence bone turnover and regeneration in mice.

Catecholamine signaling is known to influence bone tissue as reuptake of norepinephrine released from sympathetic nerves into bone cells declines with age leading to osteoporosis. Further, ß-adrenoceptor-blockers like propranolol provoke osteoprotective effects in osteoporotic patients. However, besides systemic adrenal and sympathetic catecholamine production, it is also known that myeloid cells can synthesize catecholamines, especially under inflammatory conditions. To investigate the effects of catecholamines produced by CD11b+ myeloid cells on bone turnover and regeneration, a mouse line with specific knockout of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, in CD11b+ myeloid cells (THflox/flox/CD11b-Cre+, referred to as THCD11b-Cre) was generated. For bone phenotyping, male mice were sacrificed at eight and twelve weeks of age and harvested bones were subjected to bone length measurement, micro-computed tomography, fluorescence-activated cell sorting of the bone marrow, gene expression analysis, histology and immunohistochemistry. Support for an age-dependent influence of myeloid cell-derived catecholamines on bone homeostasis is provided by the fact that twelve-week-old, but not eight-week-old THCD11b-Cre mice, developed an osteopenic phenotype and showed increased numbers of neutrophils and T lymphocytes in the bone marrow, while CCL2, IL-6, IL-4 and IL-10 mRNA expression was reduced in sorted myeloid bone marrow cells. To investigate the influence of myeloid cell-derived catecholamines on fracture healing, mice received a diaphyseal femur osteotomy. Three days post-fracture, immunohistochemistry revealed an increased number of macrophages, neutrophils and cytotoxic T lymphocytes in the fracture hematoma of THCD11b-Cre mice. Micro-computed tomography on day 21 showed a decreased tissue mineral density, a reduced bone volume and less trabeculae in the fracture callus indicating delayed fracture healing, probably due to the increased presence of inflammatory cells in THCD11b-Cre mice. This indicates a crucial role of myeloid cell-derived catecholamines in immune cell-bone cell crosstalk and during fracture healing.

Effect of new alleles of the histidine kinase gene ciaH on the activity of the response regulator CiaR in Streptococcus pneumoniae R6.

The two-component regulatory system CiaRH of Streptococcus pneumoniae affects ß-lactam susceptibility, autolysis, bacteriocin production, competence development, host colonization and virulence. The system was discovered in a screen for S. pneumoniae R6 mutants resistant to the ß-lactam antibiotic cefotaxime. A mutation in the histidine kinase gene ciaH led to this phenotype by enhancing CiaR-mediated gene expression. Additional mutations in ciaH have been described in other spontaneous ß-lactam-resistant mutants of S. pneumoniae R6, but their influence on CiaR-mediated gene regulation has not been determined. Likewise, altered ciaH alleles are present in clinical S. pneumoniae isolates, none of which had been characterized. These novel ciaH variants were introduced into S. pneumoniae R6 to measure their ability to activate CiaR-dependent regulation. The ciaH alleles from spontaneous mutants obtained in the laboratory increased the activity of CiaR-dependent promoters between four- and 26-fold, while variants from clinical strains were less effective, with a threefold activation at most. Accordingly, phenotypes associated with a hyperactive CiaRH system, ß-lactam resistance, and prevention of competence development, were far more pronounced in the laboratory mutants. Amino acid changes affecting CiaH function were positioned throughout the protein. Five of the most activating changes are located close to the conserved histidine and one in the extracytoplasmic sensor domain. The characterization of new alleles of ciaH expands the spectrum of CiaH variants, which may help to elucidate signal transduction of this important regulatory system. Our study also demonstrates that ciaH alleles overstimulating CiaR regulon expression are present in clinical isolates of S. pneumoniae.

Haplotype-assisted characterization of germline mutations at short tandem repeat loci.

In this study, 98 families with 101 mutations were analyzed in depth in which a mutation had been observed at one of the four loci D3S1358, FGA, ACTBP2, and VWA. To determine the origin (male/female) of the mutation, five to seven polymorphic flanking markers were selected for each locus concerned and used to construct family-specific haplotypes. Additionally, all alleles of the STR system concerned were sequenced. With this duplicate approach, it was possible to identify the mutated structure and/or mutation event in the vast majority of cases. The ratio of one-step to two-step mutations was 100:1. The ratio of paternal to maternal mutations was 76:8. The ratio of gains to losses was 47:50. Also, the mutation rates in two systems, ACTBP2 and VWA, were clearly higher than those given in the literature.

A new bone-ligament-bone autograft from the plantar plates of the toes and its potential use in scapholunate reconstruction: an anatomical study.

The study was performed to investigate a new bone-ligament-bone autograft from the plantar plate of the toes. The anatomic properties of the plantar ligaments and the technical feasibility to harvest a bone-ligament-bone graft were examined to evaluate the potential use of this graft for a suitable reconstruction of the scapholunate (SL) interosseous ligament. The plantar plate of the metatarsophalangeal joints of the second to fifth toe and the proximal interphalangeal joints of the second to fourth toe were examined in 20 cadaver feet (15 fresh and 5 embalmed cadavers) and measurements such as length, thickness, and width were taken. The average length of the plantar ligaments of the proximal interphalangeal joint was 0.63 cm (D3) and 0.62 cm (D4). The length of the plantar plates of the proximal interphalangeal joint of the third and fourth toe was found to be similar to that of the SL ligament. In addition to the measurements, a bone-ligament-bone autograft of the plantar plates of the metatarsophalangeal joint was designed as an SL-ligament substitute and successfully transplanted into cadaveric wrists. This new autograft is intercalated between the scaphoid and lunate and, contrary to all previous methods, not simply superimposed upon them. Length of the plantar plates was considered by the authors as the main criteria for selection of the new bone-ligament-bone graft. The plantar plate of the proximal interphalangeal joint of the third and fourth toe showed a similar length compared with the SL ligament. Therefore, it can be concluded from the data that this bone-ligament-bone graft can be a suitable replacement for the SL ligament.

Minimal invasive screw fixation and early mobilization of acute scaphoid fractures in the middle third: operative technique and early functional outcome.

Fractures of the scaphoid are relatively common injuries. Differentiation between stable and unstable fractures (Herbert classification) cannot always be made with conventional radiographs and should be additionally evaluated by computed tomographic scan. Under most circumstances, minimal invasive surgery with cannulated screws is currently the treatment of choice. Cast immobilization is not necessary. This article describes the technique of fracture fixation in the middle third of the scaphoid from a palmar approach and early functional outcomes. The outcome assessment included measurement of active range of motion as well as grip strength and the Disability of the Arm, Shoulder and Hand questionnaire as a measurement of activities of daily living. Fifty-four patients with acute scaphoid fractures were treated with minimal invasive screw fixation between April 2001 and January 2005. All patients in this retrospective study received a preoperative computed tomographic scan before surgery. Bony consolidation was found in 52 cases after 6 weeks; 2 patients required reosteosyntheses. The results demonstrate that minimal invasive screw fixation leads to satisfying functional outcomes within a few weeks.

Rapid Quantification of 25-Hydroxyvitamin D3 in Human Serum by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry.

LC-MS/MS is widely utilized today for quantification of vitamin D in biological fluids. Mass spectrometric assays for vitamin D require very careful method optimization for precise and interference-free, accurate analyses however. Here, we explore chemical derivatization and matrix-assisted laser desorption/ionization (MALDI) as a rapid alternative for quantitative measurement of 25-hydroxyvitamin D3 in human serum, and compare it to results from LC-MS/MS. The method implemented an automated imaging step of each MALDI spot, to locate areas of high intensity, avoid sweet spot phenomena, and thus improve precision. There was no statistically significant difference in vitamin D quantification between the MALDI-MS/MS and LC-MS/MS: mean ± standard deviation for MALDI-MS-29.4 ± 10.3 ng/mL-versus LC-MS/MS-30.3 ± 11.2 ng/mL (P = 0.128)-for the sum of the 25-hydroxyvitamin D epimers. The MALDI-based assay avoided time-consuming chromatographic separation steps and was thus much faster than the LC-MS/MS assay. It also consumed less sample, required no organic solvents, and was readily automated. In this proof-of-concept study, MALDI-MS readily demonstrated its potential for mass spectrometric quantification of vitamin D compounds in biological fluids. Graphical Abstract ᅟ.

Association of maternal uric acid and cystatin C serum concentrations with maternal and neonatal cardiovascular risk markers and neonatal body composition: The Ulm SPATZ Health Study.

PURPOSE: In utero exposure to cardiometabolic risk factors may determine health related outcomes at birth and in later life. The aim of this analysis was to describe the relationship of maternal serum uric acid (SUA) and cystatin C with maternal and neonatal cardiometabolic risk markers and with birth weight and risk of small-for-gestational age (SGA) as well as large-for gestational age (LGA). MATERIAL AND METHODS: In the Ulm SPATZ Health Study, 934 singleton newborns and their mothers were recruited during their hospital stay in the University Medical Center Ulm between 04/2012 and 05/2013 (overall response 49%). The association between SUA and cystatin C (both in quartiles and as continuous measures) with risk for SGA as well as with LGA was quantified by means of multivariable logistic regression. RESULTS: Overall, n = 885 mother-newborn pairs were included in the final analysis. Most of the mothers were of German nationality (85%) and were between 26 and 35 years of age at delivery (69%). Maternal SUA was associated with maternal age, body mass index, alcohol consumption and history of hypertension as well as with many other maternal and neonate cardiovascular risk markers. Cystatin C was associated with parity. No clear association of SUA with SGA and LGA was observed in fully adjusted models. However, cystatin C was negatively associated with SGA with an odds ratio (OR) of 0.35 (95% CI: 0.16-0.77; p for trend 0.04) comparing the top quartile vs. the bottom quartile and was positively associated with LGA with an OR of 5.92 (95% CI: 2.27-15.44; p for trend <0.0001) after adjustment for covariates. CONCLUSIONS: We found a positive association of cystatin C with birth weight and a clearly increased risk for LGA with maternal increased cystatin C values in a population with fairly normal renal function.

Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway.

Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.