Meta-Analysis of European Clinical Trials Characterizing the Healthy-Adult Serum 25-hydroxyvitamin D Response to Vitamin D Supplementation.

To obtain reliable data that allow health authorities to re-evaluate recommendations for oral vitamin D uptake, we conducted a meta-analysis to investigate the impact of supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in healthy adults in Europe. Of the publications identified (n = 4005) in our literature search (PUBMED, through 2 January 2022), 49 primary studies (7320 subjects, 73 study arms) were eligible for inclusion in our meta-analysis. The risk of bias was assessed using the Cochrane RoB tool based on seven categories, according to which each study is rated using three grades, and overall was rated as rather low. The median duration of intervention was 136.78 days (range, 1088 days); the mean weighted baseline 25(OH)D concentration and mean age were 33.01 vs. 33.84 nmol/L and 46.8 vs. 44.8 years in the vitamin D and placebo groups, respectively. Using random-effects models, 25(OH)D levels were increased by 36.28 nmol/L (95% CI 31.97-40.59) in the vitamin D group compared to the placebo, with a relative serum increment of 1.77 nmol/L per 2.5 µg of vitamin D daily. Notably, the relative serum 25(OH)D increment was affected by various factors, including the dosage and baseline serum 25(OH)D concentration, decreasing with increasing vitamin D doses and with increasing baseline serum levels. We estimate that supplementation in all healthy adults in Europe with appr. 25 µg of vitamin D (1000 IU) daily would raise serum 25(OH)D levels in 95% of the population to ≥50 nmol/L. Our work provides health authorities with reliable data that can help to re-evaluate recommendations for oral vitamin D supplementation.

Multifaceted determinants of social-emotional problems in preschool children in Sweden: An ecological systems theory approach.

Social-emotional problems occurring early in life can place children at future risk of adverse health, social and economic outcomes. Determinants of social-emotional problems are multi-layered and originate from different contexts surrounding children, though few studies consider them simultaneously. We adopted a holistic approach by using Bronfenbrenner's process-person-context-time model as a structuring device. We aimed to assess what characteristics of families and children from pregnancy, over birth, and up to 3 years of age are associated with social-emotional problems in boys and girls. This study used regional data from the Salut Programme, a universal health promotion programme implemented in Antenatal and Child Health Care, and data from national Swedish registers. The study population included 6033 3-year-olds and their parents during the period 2010-2018. Distinct logistic regression models for boys and girls were used to assess associations between the family social context, parents' lifestyle, parent's mental health, children's birth characteristics, and indicators of proximal processes (the independent variables); and children's social-emotional problems as measured by the parent-completed Ages and Stages Questionnaire: Social-Emotional between 33 and 41 months of age (the outcome). Overall, a less favourable family social context, detrimental lifestyle of the parents during pregnancy, and parents' mental illness from pregnancy onwards were associated with higher odds of social-emotional problems in 3-year-olds. Higher screentime and infrequent shared book-reading were associated with higher odds of social-emotional problems. The multifaceted determinants of children's social-emotional problems imply that many diverse targets for intervention exist. Additionally, this study suggests that Bronfenbrenner's process-person-context-time theoretical framework could be relevant for public health research and policy.

An Appraisal to Address Health Consequences of Vitamin D Deficiency With Food Fortification and Supplements: Time to Act!

A symposium entitled "Vitamin D in Prevention and Therapy" was held on May 4-5, 2022, in Homburg, Germany to discuss important new advances in the field, including identification of new vitamin D signaling pathways, of new biologic effects of vitamin D-compounds (e.g., on the microbiome), and convincing proof of the relevance of vitamin D deficiency for the risk and outcome of many chronic diseases, including cancer, cardio-vascular, auto-immune, metabolic, and infectious diseases. Concerning the COVID-19-pandemic, an inverse association between 25(OH)D serum concentrations and SARS-CoV-2-infections, morbidity, and mortality was shown. In relation to cancer, several meta-analyses recently demonstrated an association of vitamin D-supplementation with significantly decreased mortality rates, which presumably would reduce health care costs. Considering the impressive body of evidence and the high safety of oral supplementation and food fortification with vitamin D, it was concluded that there is now an urgent need to act. In many countries worldwide, health care authorities need to increase efforts to address vitamin D deficiency, e.g., via food fortification and/or supplementation with vitamin D, and/or promoting moderate UV-exposure. It was estimated that in many countries, vitamin D intakes of the order of appr. 1,000 IE (25 µg)/day would be needed to bring and/or keep the vast majority of people over a serum 25(OH)D threshold of 20 ng/ml (50 nmol/l), which would be difficult to obtain alone from food fortification. New developments in personalized medicine may represent helpful tools to identify populations at risk for vitamin D deficiency and their responsiveness to vitamin D treatment.

Identification and characterization of piperine synthase from black pepper, Piper nigrum L.

Black pepper (Piper nigrum L.) is the world's most popular spice and is also used as an ingredient in traditional medicine. Its pungent perception is due to the interaction of its major compound, piperine (1-piperoyl-piperidine) with the human TRPV-1 or vanilloid receptor. We now identify the hitherto concealed enzymatic formation of piperine from piperoyl coenzyme A and piperidine based on a differential RNA-Seq approach from developing black pepper fruits. This enzyme is described as piperine synthase (piperoyl-CoA:piperidine piperoyl transferase) and is a member of the BAHD-type of acyltransferases encoded by a gene that is preferentially expressed in immature fruits. A second BAHD-type enzyme, also highly expressed in immature black pepper fruits, has a rather promiscuous substrate specificity, combining diverse CoA-esters with aliphatic and aromatic amines with similar efficiencies, and was termed piperamide synthase. Recombinant piperine and piperamide synthases are members of a small gene family in black pepper. They can be used to facilitate the microbial production of a broad range of medicinally relevant aliphatic and aromatic piperamides based on a wide array of CoA-donors and amine-derived acceptors, offering widespread applications.

Update: Solar UV Radiation, Vitamin D, and Skin Cancer Surveillance in Organ Transplant Recipients (OTRs).

Although great progress has been achieved during the last decades, the clinical management of organ transplant recipients (OTRs) remains a challenge. OTRs need in general lifelong immunosuppressive therapy that is associated with an increased risk to develop skin cancer and with an unfavorable clinical outcome of these malignancies. Skin cancer prevention measures, including regular full-body examinations, are therefore necessary in OTRs to detect and treat suspicious lesions at an early stage. The frequency of aftercare depends on the individual risk factors of the patient. Patients should apply consistent sun protection with sunscreens and clothing, as well as a monthly self-examination. On the other hand, the need of UVR avoidance increases the risk of vitamin D deficiency, which itself is associated with an increased risk for many diseases, including malignancies. OTRs should therefore be monitored for 25(OH)D status and/or should take vitamin D supplements. It has to be emphasized that an interdisciplinary approach, coordinated by the transplant center, that includes regular skin examinations by a dermatologist, is needed to ensure the best care for the OTRs.

The Tapetal Major Facilitator NPF2.8 Is Required for Accumulation of Flavonol Glycosides on the Pollen Surface in Arabidopsis thaliana.

The exine of angiosperm pollen grains is usually covered by a complex mix of metabolites including pollen-specific hydroxycinnamic acid amides (HCAAs) and flavonoid glycosides. Although the biosynthetic pathways resulting in the formation of HCAAs and flavonol glycosides have been characterized, it is unclear how these compounds are transported to the pollen surface. In this report we provide several lines of evidence that a member of the nitrate/peptide transporter family is required for the accumulation and transport of pollen-specific flavonol 3-o-sophorosides, characterized by a glycosidic ß-1,2-linkage, to the pollen surface of Arabidopsis (Arabidopsis thaliana). Ectopic, transient expression in Nicotiana benthamiana epidermal leaf cells demonstrated localization of this flavonol sophoroside transporter (FST1) at the plasmalemma when fused to green fluorescent protein (GFP). We also confirmed the tapetum-specific expression of FST1 by GFP reporter lines driven by the FST1 promoter. In vitro characterization of FST1 activity was achieved by microbial uptake assays based on 14C-labeled flavonol glycosides. Finally, rescue of an fst1 insertion mutant by complementation with an FST1 genomic fragment restored the accumulation of flavonol glycosides in pollen grains to wild-type levels, corroborating the requirement of FST1 for transport of flavonol-3-o-sophorosides from the tapetum to the pollen surface.

A Critical Appraisal of Strategies to Optimize Vitamin D Status in Germany, a Population with a Western Diet.

During the last decade, our scientific knowledge of the pleiotropic biological effects of vitamin D metabolites and their relevance to human health has expanded widely. Beyond the well-known key role of vitamin D in calcium homeostasis and bone health, it has been shown that vitamin D deficiency is associated with a broad variety of independent diseases, including several types of cancer, and with increased overall mortality. Moreover, recent findings have demonstrated biological effects of the vitamin D endocrine system that are not mediated via activation of the classical nuclear vitamin D receptor (VDR) by binding with high affinity to its corresponding ligand, the biologically active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D). In contrast, many of these new biological effects of vitamin D compounds, including regulation of the circadian clock and many metabolic functions, are mediated by other vitamin D metabolites, including 20-hydroxyvitamin D and 20,23-dihydroxyvitamin D, and involve their binding to the aryl hydrocarbon receptor (AhR) and retinoid-orphan receptor (ROR). In most populations, including the German population, UVB-induced cutaneous vitamin D production is the main source for fulfilling the human body's requirements of vitamin D. However, this causes a dilemma because solar or artificial UVR exposure is associated with skin cancer risk. In addition to UVB-induced vitamin D production in skin, in humans, there are two other possible sources of vitamin D: from diet and supplements. However, only a few natural foods contain substantial amounts of vitamin D, and in most populations, the dietary source of vitamin D cannot fulfill the body´s requirements. Because an increasing body of evidence has convincingly demonstrated that vitamin D deficiency is very common worldwide, it is the aim of this paper to (i) give an update of the vitamin D status in a population with a western diet, namely, the German population, and to (ii) develop strategies to optimize the vitamin D supply that consider both the advantages as well as the disadvantages/risks of different approaches, including increasing vitamin D status by dietary intake, by supplements, or by UVB-induced cutaneous synthesis of vitamin D.

Pre- and perioperative aspects of dermatosurgery.

Dermatosurgery occupies an exceptional position among all surgical disciplines. Above all, this includes the fact that, with very few exceptions, the vast majority of surgical interventions can be performed under local or regional anesthesia, usually in smaller procedure rooms that are spatially separated from larger operating suites. Thus, peri- and postinterventional patient monitoring is the responsibility of the dermatosurgeon and his team. Though inherently smaller, this team still has to observe numerous perioperative requirements that - in larger surgical specialties - would be attended to by a host of various specialists working in concert. Said requirements include hygienic aspects, knowledge concerning pre- and intraoperative patient monitoring, managing surgical site infections, adequate postsurgical pain management, as well as detailed pharmacological knowledge with respect to common local anesthetics and the toxic and allergic reactions associated therewith. Not only does this require interdisciplinary collaboration and shared responsibility for the patient. It also necessitates the development and implementation of quality-oriented and evidence-based guidelines that, in the dermatosurgical setting, usually extend far beyond the scope of the specialty per se. The objective of the present CME article is the condensed presentation of interdisciplinary aspects relating to the most important perioperative issues.

Report on immediate irradiation of a rapidly growing sarcoma of the scalp prior to wound closure.

Cutaneous sarcomas are primarily treated with extensive surgery, and occasionally require adjuvant radiation therapy following complete wound healing. Thus, sarcoma surgery leads to large and deep wounds, and the initiation of adjuvant radiation therapy depends on the time required for defect closure. We present the case of a male patient with pleomorphic sarcoma of the temporal skin, which was treated with multiple wide and deep excisions, instant application of an Integra(®) bilayer, and immediate radiation therapy prior to wound closure. The objective was to investigate the usefulness of a dermal substitute (Integra(®) ) in accelerating the effect of adjuvant radiation therapy on scalp defects after tumor surgery. A ring-shaped skin area - at risk for recurrence - around the Integra(®) bilayer was irradiated with a total of 59.4 Gy. No necrosis, infection, or major radiotoxicity was observed, and a subsequent split skin graft following radiation therapy remained fully vital until complete healing. In conclusion, a combined procedure consisting of sequential tumor surgery and subsequent application of a dermal substitute in conjunction with immediate initiation of adjuvant radiation therapy is, in principle, possible, and may permit innovative therapeutic options in dermatooncology and dermatosurgery.

Prospective Investigation of 25(OH)D3 Serum Concentration Following UVB Narrow Band Phototherapy in Patients with Psoriasis and Atopic Dermatitis.

Vitamin D deficiency represents a major health issue. It is a worldwide endemic and is associated with a broad variety of severe diseases. The skin is a key tissue for the human body's vitamin D endocrine system. It represents a target tissue for biologically active vitamin D metabolites. Approximately 90% of the human body's requirements of vitamin D have to be synthesised in the skin by the action of UVB-radiation. However, individual factors that influence a person's cutaneous synthesis of vitamin D are still not well understood. In our present prospective study we investigated the effect of UVB narrow band (UVBnb, 311 nm) and PUVA phototherapy on 25(OH)D3 serum concentration, in patients with psoriasis, atopic dermatitis and a few cases with other dermatoses (n=41). We found that two weeks of UVBnb treatment resulted in an increase of 25(OH)D3 serum concentration from 11.4 to 20.5 ng/ml (p<0.001), while in contrast PUVA-treatment did not significantly alter vitamin D status. These findings question the hypothesis of a relevant vitamin D metabolizing effect of UVA. Psoriasis patients showed a trend for a stronger increase in 25(OH)D3 serum levels following UVBnb compared to patients with atopic dermatitis. Patients with relatively low baseline serum 25(OH)D3 concentrations had a stronger increase in 25(OH)D3 concentrations compared to patients with relatively high 25(OH)D serum concentrations. In general patients with skin types (Fitzpatrick) I and II (median=14.3 ng/ml) had a higher baseline of 25(OH)D3 serum concentration compared to patients with skin types III (median=11.2 ng/ml) or IV-V (median=12.3 ng/ml), although these differences were not statistically significant (p=0.106). Baseline 25(OH)D3 serum concentrations were correlated with presence of genetic variants (SNPs of VDR, CYP2R1, VDBP/GC) that influence vitamin D status, and with other individual factors such as body mass index, age and gender. We also investigated the effect of phototherapy on blood pressure and a variety of laboratory parameters such as CRP, HbA1c, LDL, HDL, triglycerides and cholesterol. In conclusion, our pilot study shows that UVBnb phototherapy efficiently increases 25(OH)D3 serum concentration and reports interesting preliminary findings that have to be re-evaluated in larger follow-up studies.

Vestibular thalamus: Two distinct graviceptive pathways.

OBJECTIVE: To determine whether there are distinct thalamic regions statistically associated with either contraversive or ipsiversive disturbance of verticality perception measured by subjective visual vertical (SVV). METHODS: We used modern statistical lesion behavior mapping on a sample of 37 stroke patients with isolated thalamic lesions to clarify which thalamic regions are involved in graviceptive otolith processing and whether there are distinct regions associated with contraversive or ipsiversive SVV deviation. RESULTS: We found 2 distinct systems of graviceptive processing within the thalamus. Contraversive tilt of SVV was associated with lesions to the nuclei dorsomedialis, intralamellaris, centrales thalami, posterior thalami, ventrooralis internus, ventrointermedii, ventrocaudales and superior parts of the nuclei parafascicularis thalami. The regions associated with ipsiversive tilt of SVV were located in more inferior regions, involving structures such as the nuclei endymalis thalami, inferior parts of the nuclei parafascicularis thalami, and also small parts of the junction zone of the nuclei ruber tegmenti and brachium conjunctivum. CONCLUSIONS: Our data indicate that there are 2 anatomically distinct graviceptive signal processing mechanisms within the vestibular network in humans that lead, when damaged, to a vestibular tone imbalance either to the contraversive or to the ipsiversive side.

Evolutionarily conserved phenylpropanoid pattern on angiosperm pollen.

The male gametophyte of higher plants appears as a solid box containing the essentials to transmit genetic material to the next generation. These consist of haploid generative cells that are required for reproduction, and an invasive vegetative cell producing the pollen tube, both mechanically protected by a rigid polymer, the pollen wall, and surrounded by a hydrophobic pollen coat. This coat mediates the direct contact to the biotic and abiotic environments. It contains a mixture of compounds required not only for fertilization but also for protection against biotic and abiotic stressors. Among its metabolites, the structural characteristics of two types of phenylpropanoids, hydroxycinnamic acid amides and flavonol glycosides, are highly conserved in Angiosperm pollen. Structural and functional aspects of these compounds will be discussed.

The role of CCoAOMT1 and COMT1 in Arabidopsis anthers.

Arabidopsis caffeoyl coenzyme A dependent O-methyltransferase 1 (CCoAOMT1) and caffeic acid O-methyltransferase 1 (COMT1) display a similar substrate profile although with distinct substrate preferences and are considered the key methyltransferases (OMTs) in the biosynthesis of lignin monomers, coniferyl and sinapoylalcohol. Whereas CCoAOMT1 displays a strong preference for caffeoyl coenzyme A, COMT1 preferentially methylates 5-hydroxyferuloyl CoA derivatives and also performs methylation of flavonols with vicinal aromatic dihydroxy groups, such as quercetin. Based on different knockout lines, phenolic profiling, and immunohistochemistry, we present evidence that both enzymes fulfil distinct, yet different tasks in Arabidopsis anthers. CCoAOMT1 besides its role in vascular tissues can be localized to the tapetum of young stamens, contributing to the biosynthesis of spermidine phenylpropanoid conjugates. COMT1, although present in the same organ, is not localized in the tapetum, but in two directly adjacent cells layers, the endothecium and the epidermal layer of stamens. In vivo localization and phenolic profiling of comt1 plants provide evidence that COMT1 neither contributes to the accumulation of spermidine phenylpropanoid conjugates nor to the flavonol glycoside pattern of pollen grains.

Radiofrequency induced thermotherapy (RFITT) of varicose veins compared to endovenous laser treatment (EVLT): a non-randomized prospective study concentrating on occlusion rates, side-effects and clinical outcome.

BACKGROUND: Radiofrequency obliteration (RFO) and endovenous laser treatment (EVLT) are established techniques in varicose therapy. A novel bipolar RFO technique - Radiofrequency Induced Thermotherapy (RFITT) - was introduced in 2007. Comparative studies of RFITT and EVLT with one year follow-up are missing. OBJECTIVE: Comparison of RFITT with EVLT concentrating on occlusion, side-effects, and patients' satisfaction in a prospective non-randomized study. METHODS: 133 patients with incompetent GSV or SSV were treated by RFITT (n=66) or EVLT (n=67). Follow-up at days 1, 7, and months 3, 12 included duplex, digital photoplethysmography (DPPG), assessment of VCSS and patients' satisfaction. RESULTS: Both groups were balanced concerning clinical parameters. Occlusion rates were in trend in favour of EVLT (96.9%) vs RFITT (88.9%), p=0.093, at 12 months follow-up. Functional outcome by DPPG (refilling time: 30.8 vs 31.9 sec.), and side-effects were comparable apart from pain in the first postoperative week, which was more frequent in the EVLT group (0 vs 16.4%, p=0.001). Change in VCSS from baseline was advantageous for EVLT (89.9% vs 79.3%, p=0.005). Major complications did not occur. Both techniques provided excellent satisfaction results. CONCLUSION: After one year RFITT is similarly as effective and safe as EVLT treatment of varicose insufficiency, but needs improvement in treatment parameters.

Profiling of hydroxycinnamic acid amides in Arabidopsis thaliana pollen by tandem mass spectrometry.

Phenylpropanoid polyamine conjugates are widespread in plant species. Their presence has been established in seeds, flower buds, and pollen grains. A biosynthetic pathway proposed for hydroxycinnamoyl spermidine conjugates has been suggested for the model plant Arabidopsis thaliana with a central acyl transfer reaction performed by a BAHD-like hydroxycinnamoyl transferase. A detailed liquid chromatography (LC)-electrospray ionization-mass spectrometry- and tandem-mass-spectrometry (MS/MS)-based survey of wild-type and spermidine hydroxycinnamoyl transferase (SHT) mutants identified more than 30 different bis- and tris-substituted spermidine conjugates, five of which were glycosylated, in the methanol-soluble fraction of the pollen exine. On the basis of characterized fragmentation patterns, a high-throughput LC-MS/MS method for highly sensitive HCAA relative quantification (targeted profiling) was developed. Only minor qualitative and quantitative differences in the pattern of bis-acyl spermidine conjugates in the SHT mutant compared to wild-type plants provide strong evidence for the presence of multiple BAHD-like acyl transferases and suggest a much more complex array of enzymatic steps in the biosynthesis of these conjugates than previously anticipated.

Granulomatous jellyfish dermatitis.

The induction of a granulomatous inflammation by jellyfish toxins is rare. More typically, acute toxic and urticarial reactions are seen. An 11-year-old boy developed a striated urticarial erythema on the left cheek after contact with a gelatinous mass while swimming in the sea in Croatia. After initial erosion, a striated induration developed in the area of contact. Histological examination revealed a granulomatous inflammation with some eosinophils. While topical steroid-based antiinflammatory and antibacterial therapy over several weeks was not effective, topical therapy with tacrolimus 0.1% for two two-week treatment periods led to healing of the skin changes with a slight scar. There was no clinical recurrence after 5 month of follow-up.

Cloning and functional characterisation of two regioselective flavonoid glucosyltransferases from Beta vulgaris.

Two full-length cDNAs encoding flavonoid-specific glucosyltransferases, UGT73A4 and UGT71F1, were isolated from a cDNA library of Beta vulgaris (Amaranthaceae) cell suspension cultures. They displayed high identity to position-specific betanidin and flavonoid glucosyltransferases from Dorotheanthus bellidiformis (Aizoaceae) and to enzymes with similar substrate specificities from various plant families. The open reading frame of the sequences encode proteins of 476 (UGT73A4) and 492 (UGT71F1) amino acids with calculated molecular masses of 54.07kDa and 54.39kDa, and isoelectric points of 5.8 and 5.6, respectively. Both enzymes were functionally expressed in Escherichia coli as His- and GST-tagged proteins, respectively. They exhibited a broad substrate specificity, but a distinct regioselectivity, glucosylating a variety of flavonols, flavones, flavanones, and coumarins. UGT73A4 showed a preference for the 4'- and 7-OH position in the flavonoids, whereas UGT71F1 preferentially glucosylated the 3- or the 7-OH position. Glucosylation of betanidin, the aglycone of the major betacyanin, betanin, in B. vulgaris was also observed to a low extent by both enzymes. Several O-glycosylated vitexin derivatives isolated from leaves of young B. vulgaris plants and rutin obtained from B. vulgaris tissue culture are discussed as potential endogenous products of UGT73A4 and UGT71F1. The results are analyzed with regard to evolution and specificity of plant natural product glucosyltransferases.

Building a research consortium of large health systems: the Cancer Research Network.

Critical questions about cancer prevention, care, and outcomes increasingly require research involving large patient populations and their care delivery organizations. The Cancer Research Network (CRN) includes 11 integrated health systems funded by the National Cancer Institute (NCI) to conduct collaborative cancer research. This article describes the challenges of constructing a productive consortium of large health systems, and explores the CRN's responses. The CRN was initially funded through an NCI cooperative agreement in 1999 and has since received a second 4-year grant. Leadership and policy development are provided through a steering committee, subcommittees, and an external advisory committee. The CRN includes integral and affiliated research projects supported by a Scientific and Data Resources Core. Three characteristics of the CRN intensified the general challenges of consortium research: 1) its members are large health systems with legitimate concerns about confidentiality of data about enrollees, providers, and the organization; 2) CRN research projects often generate highly sensitive data about quality of care; and therefore 3) each participating organization wants a strong voice in CRN direction. CRN experience to date confirms that a consortium of health systems with internal research capacity can address a range of important cancer research questions that would be difficult to study in other venues. The advantages and challenges of consortium research are explored, with suggestions for the development, execution, and management of multisystem population laboratories.