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Hintergrund: Die Bedeutung des Vitamin D-Stoffwechsels bei Infektionen ist bereits bekannt. Dennoch ist dessen Signifikanz bei periprothetischen Infektionen (PPIs) nach totaler Hüft- oder Knie-Endoprothese weitestgehend unerforscht. Das Ziel dieser Studie ist die präzise Analyse der Vitamin D-Balance von Patienten mit PPIs nach totalem endoprothetischem Ersatz am Hüft- und Kniegelenk. Dabei dienen Fälle von primären Endoprothesen und Revisionen aufgrund aseptischer Lockerungen als Kontrollgruppen. Material und Methode: In dieser prospektiven matched-pair-Analyse wurden die Patienten mit PPI am Hüft- oder Kniegelenk in die Studiengruppe (SG) (n=80) eingeschlossen. Die Kontrollgruppen (CG) setzten sich aus Patienten mit primärer Endoprothese (CG 1) (n=80) und Patienten, welche sich einer Revisionsoperation aufgrund einer aseptischen Lockerung unterziehen mussten (CG 2) (n=80) zusammen. Zusätzlich zu 25-Hydroxyvitamin-D3 und Calcium wurden Parameter des Knochenstoffwechsels und des Proteinhaushaltes bestimmt. Alle Patienten erhielten zudem einen Osteoporose-spezifischen Fragebogen. Ergebnisse: Es konnten keine signifikanten Unterschiede in den Blutspiegeln von 25-Hydroxyvitamin-D3 zwischen der SG (17,9±8,9) und den beiden Kontrollgruppen (CG 1: 16,8±6,9; CG 2: 19,7±7,9) festgestellt werden. Die Patienten der Studiengruppe wiesen, im Vergleich zu denen der Kontrollgruppen, signifikant niedrigere Blutspiegel an Calcium und alkalischer Phosphatase auf. Auffällig waren die signifikant niedrigeren Werte von Parametern der Proteinbalance bei Patienten mit PPI. Akute PPIs zeigten einen signifikant niedrigeren 25-Hydroxyvitamin-D3-Spiegel im Vergleich zu chronischen Infektionen (8.3±5.98 versus 21.6±8.40, p=0.002). Calcium und die Parameter der Proteinbalance waren ebenfalls bei akuter PPI vermindert. Zusammenfassung: Akute PPIs am Hüft- oder Kniegelenk zeigen signifikant niedrigere Blutspiegel für 25-Hydroxyvitamin-D3 und verminderte Parameter der Proteinbalance (Albumin und Gesamtprotein) im Vergleich zu chronischen Infektionen sowie zu primären Endoprothesen und Revisionen aufgrund aseptischer Lockerung. Eine Substitution von Vitamin D3 in Verbindung mit Calcium, bei gleichzeitiger Adaptation der Proteinbalance, ist für alle PPIs, speziell akute PPIs, empfohlen.:Inhaltsverzeichnis ........................................................................................................ I Bibliographische Beschreibung .................................................................................. II Abkürzungsverzeichnis .............................................................................................. III 1 Einleitung ............................................................................................................. 1 1.1 Einführung in die Thematik ............................................................................ 1 1.2 Vitamin D – Zentraler Wirkstoff im menschlichen Organismus ...................... 2 1.2.1 Bildung und natürliche Quellen ............................................................... 2 1.2.2 Signalweg und Wirkungsweise ............................................................... 3 1.2.3 Bedeutung in der inflammatorischen Reaktion........................................ 4 1.2.4 Vitamin D-Defizienz ................................................................................ 5 1.2.5 Nutzen und Sinnhaftigkeit einer Vitamin D-Supplementation .................. 7 1.3 Periprothetische Infektionen am Hüft- und Kniegelenk .................................. 9 1.3.1 Bedeutung............................................................................................... 9 1.3.2 Ätiologie .................................................................................................. 9 1.3.3 Klassifikation und Einteilung ................................................................. 12 1.3.4 Behandlungsstrategien ......................................................................... 13 1.4 Rationale der Publikation und Zielsetzung der Arbeit .................................. 15 2 Publikation ......................................................................................................... 17 3 Zusammenfassung ............................................................................................. 25 4 Abbildungsverzeichnis ....................................................................................... 30 5 Literaturverzeichnis ............................................................................................ 31 6 Darstellung des eigenen Beitrags ...................................................................... 37 7 Erklärung über die eigenständige Abfassung der Arbeit .................................... 38 8 Lebenslauf ......................................................................................................... 39 9 Danksagung ....................................................................................................... 41

La VD (VD) est impliquée dans de nombreux processus physiologiques, dont le contrôle de certains paramètres de la biologie du tissu adipeux, son site principal de stockage. Ainsi elle y exerce des effets anti-inflammatoires et métaboliques forts, mais de nombreux aspects de ces régulations n’ont jamais été étudiés. Le but de cette thèse est d’avancer dans la connaissance de l’interrelation entre la VD, le tissu adipeux et l’obésité.Dans un premier temps, nous avons donc mis en évidence que la VD limitait l’expression de 3 miRs (miR-146a, miR-150 et miR-155) en inhibant la voie de signalisation NF-κB, in vitro et in vivo, au niveau du tissu adipeux et de l’adipocyte, lors d’un stress inflammatoire. Ensuite, nous avons mis en évidence que la VD modulait l’expression génique de certaines enzymes impliquées dans son propre métabolisme au niveau du tissu adipeux et de l’adipocyte et que la cubiline était impliquée dans l’absorption de la 25(OH)D au niveau des adipocytes. De plus, nous avons montré qu’un régime riche en graisse pendant 4 jours, 7 et 11 semaines engendrait une modulation de la concentration plasmatique de certains métabolites de la VD ainsi que des ARNm de certains acteurs impliqués dans le métabolisme de la VD, suggérant un stockage de la VD sous forme de 25(OH)D dans le tissu adipeux. Enfin, un retour à l’état basal des niveaux d’expressions géniques au niveau du tissu adipeux des différents acteurs mis en jeu dans le métabolisme de la VD ainsi que les dosages plasmatiques et adipocytaires dee métabolites de la VD a été mis en évidence chez les souris ayant subi une prise puis une perte de poids, démontrant ainsi la réversibilité des résultats. / Vitamin D (VD) is involved in many physiological processes, including the control of parameters of adipose tissue biology, its main storage site. Thus, it exerts strong anti-inflammatory and metabolic effects, but many other aspects of this regulation have never been studied. The aim of this thesis is to advance in the knowledge of the interrelation between VD, adipose tissue and obesity.Firstly, we have therefore demonstrated that VD limits the expression of 3 miRs (miR-146a, miR-150 and miR-155) by inhibition of NF-κB signaling pathway, in vitro and in vivo, in adipose tissue and adipocyte, during inflammatory stress. We showed that VD modulated gene expression of enzymes involved in its own metabolism in adipose tissue and adipocyte, during a treatment of VD, in vivo and in vitro, known only in the liver and kidney. Moreover, the involvement of cubiline in 25(OH)D uptake in adipocytes has been demonstrated. Then, we showed that a high fat diet for 4 days, 7 and 11 weeks leads to a modulation of plasma concentration of VD metabolites as well as mRNAs of some actors involved in VD metabolism, suggested a possible storage of VD under 25(OH)D form in adipose tissue. Finally, the effect of weight gain induced by a high-fat diet followed by a return to a control diet was studied in mice. The levels of gene expression in the adipose tissue of the actors involved in VD metabolism as well as the plasma and adipocyte dosages of VD and its metabolites show a return to the basal state in mice having undergone weight loss. These results demonstrate the reversibility of changes induced by an obesogenic diet on VD metabolism.

Orientador: Anderson Marliere Navarro / Banca: Rodrigo Carvalho Santana / Banca: Thais Borges César / Resumo: Introdução: A vitamina D é um nutriente essencial para a mineralização do esqueleto e manutenção de massa óssea. Evidências recentes têm demonstrado uma alta prevalência de deficiência de vitamina D em infectados pelo HIV, principalmente em uso de tenofovir (TDF), por afetar as células tubulares renais, causando a perda de eletrólito e a redução da massa óssea. Objetivo: avaliar os efeitos do tenofovir nos níveis séricos de vitamina D e seu impacto sobre a densidade mineral óssea em pacientes sob regime de tenofovir ou não. Metodologia: Estudo transversal com 127 indivíduos, de ambos os sexos, com idades entre 18 e 60 anos. Os participantes foram subdivididos em 3 grupos, sendo: grupo em uso do tenofovir (GTDF+): n= 48 participantes, grupo sem uso de tenofovir (GTDF-): n= 49 participantes e grupo controle (GC): n= 30 participantes soronegativos para HIV. Realizou-se dual energy x-ray absorptiometry (DXA) para avaliação da densidade mineral óssea (DMO) e composição corporal. Amostras de sangue periférico foram coletadas para determinações da 25 hidroxivitamina D (25(OH)D), hormônio da paratireoide (PTH), hormônio luteinizante (LH), hormônio folículo estimulante (FSH), testosterona, estradiol, creatinina, uréia, albumina, cálcio, magnésio e fósforo. Calculou-se a taxa de filtração glomerular e avaliação do consumo alimentar. Resultados: A vitamina D sérica apresentou valores insuficientes na maioria dos participantes e o consumo alimentar de vitamina D, cálcio e magnésio mostraram abaixo da recomendação dietética em todos os grupos do estudo. O GTDF+ apresentou valores séricos menores de vitamina D quando observado com os valores do grupo GTDF-. A deficiência de vitamina D foi observada em 31% dos pacientes em uso de TDF e em 20% dos pacientes sem uso de tenofovir. Observou-se que até 25% dos participantes em uso de tenofovir... / Abstract: Introduction: Vitamin D is an essential nutrient for the mineralization of the skeleton and maintenance of bone mass. Recent evidence has shown a high prevalence of vitamin D deficiency in HIV-infected, mainly in use of tenofovir (TDF), to affect the renal tubular cells, causing the loss of electrolyte and reduced bone mass. Objective: To evaluate the effects of tenofovir in serum levels of vitamin D and its impact on bone mineral density by comparing patients on tenofovir system versus non tenofovir. Methods: Cross-sectional study with 127 individuals of both genders, aged between 18 and 60 years. Participants were divided into the following 3 groups: group using tenofovir (GTDF+): n = 48 participants, group not using tenofovir (GTDF-): n = 49 participants and control group (CG): n = 30 participants seronegative for HIV. Dual energy x-ray absorptiometry (DXA) was performed to evaluate bone mineral density (BMD) and body composition. Peripheral blood samples were collected for the determination of 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, estradiol, creatinine, urea, albumin, calcium, magnesium and phosphorus. The glomerular filtration rate was calculated and the dietary intake evaluated. Results: Vitamin D had insufficient serum levels in all study groups as shown inadequate dietary intake. The GTDF + group showed lower serum levels of vitamin D when viewed with the values of GTDF- group, and 31% of patients using TDF showed serum deficiency. It was observed that up to 25% of the participants use of tenofovir showed osteopenia, especially in the lumbar spine bone site, whereas the group without tenofovir was higher percentage for osteoporosis. Conclusion: Most of the participants infected with HIV under control or not of tenofovir had insufficient vitamin D deficient levels ... / Mestre

Intro: Hypovitaminosis D (vitamin D deficiency) has been observed in ageing patients with brain calcification and loss of the vitamin D receptor leads to abnormal calcification of the basal ganglia and thalamus. We have found that vitamin D can reverse calcification of human osteosarcoma SaOs-2 cells in vitro, in apparent contrast to its known effects of increasing bone strength in patients with Rickets and Osteomalacia. Vitamin-D functions through binding to two Vitamin-D responsive proteins; the vitamin D receptor (VDR) and Protein Disulfide isomerase A3 (PDIA3). The aim of this project was to establish VDR and PDIA3 knockout SaOs-2 cells using CRISPR-Cas9 technology. Methods: We designed guide RNA (gRNA) sequences against PDIA3 and VDR using ChopChop, selecting only gRNAs with low predicting non-specific binding probabilities. These gRNA sequences were ordered as oligonucleotides and dimerised before directional cloning into a Cas-9 plasmid. Plasmids were amplified in DH5 E. coli and purified before transfection into SaOs-2 cells together with a plasmid containing the puromycin resistance gene. Cells were treated with puromycin (1 ug/ml) for 4 days to eliminate non-transfected cells. SaOs-2 cells were maintained for 7 days before being passaged and plated for colony selection. Results: Real Time quantitative PCR showed 1 SaOs-2 clone had non-detectable levels of PDIA3 while 4 out of 6 clones had no detectable VDR mRNA relative to wild type cells. Two clones were selected for further analysis. Western blotting of these two clones probing for VDR and PDIA3 confirmed there were no detectable levels of these two proteins. Conclusion: We successfully knocked out expression of the Vitamin-D receptors VDR and PDIA3 in SaOS2 cells. These cells will be used for further study of Vitamin-D related signaling.

Clostridium difficile and staphylococcal infections are associated with increased morbidity, mortality and healthcare costs. Vitamin D deficiency may also contribute to increased healthcare costs. There is increasing evidence that vitamin D may have an antimicrobial role. We examined the relationship of serum 25(OH)D levels to staphylococcal and C. difficile infections to determine if vitamin D deficiency was associated with adverse outcomes. In the outpatient setting, vitamin D deficiency in patients with C. difficile and staphylococcal infections were associated with significantly increased total outpatients costs and fee-based consultation. Laboratory expenses had a trend towards higher costs in the vitamin D-deficient group but did not reach statistical significance. The differences were most clearly seen in the in-patient group with enhanced laboratory, pharmacy and radiology costs. These differences resulted in vitamin D-deficient patients with C. difficile or staphylococcal infections having costs more than five times higher than the non-deficient patients. The total length of hospital stay was four times greater in the vitamin D-deficient group. In addition, the total number of hospitalizations was also significantly greater in the vitamin D-deficient group. Surgery costs demonstrated a tendency to be higher in the vitamin D-deficient group but failed to reach statistical significance. Vitamin D deficiency is intimately linked to adverse health outcomes and costs in Veterans with staphylococcal and C. difficile infections in North East Tennessee. We recommend that vitamin D status be checked in patients with these infections and appropriate therapy be instituted to restore vitamin D level to normal in an expeditious manner.

Advanced Glycation Endproducts (AGEs) akkumulieren bei zunehmendem Alter. Die Haut ist das einzige Organ der durch ultraviolettes Licht ausgelösten Vitamin D Synthese. Die Akkumulation von AGEs in der Haut könnte die Synthese von Vitamin D stören, während Mikroinflammation und oxidativer Stress (beides mit Vitamin D-Mangel assoziiert), sowohl die toxischen Effekte der AGEs, als auch deren Bildung selbst verstärken könnten. Wir untersuchten zunächst potentielle Zusammenhänge zwischen zirkulierendem Vitamin D3, AGEs im Blut und AGEs in der Haut mit Markern für Inflammation und oxidativem Stress bei Nichtdiabetikern. In der vorliegenden Studie untersuchten wir 146 Probanden (119 gesunde Probanden und 27 Patienten mit arterieller Hypertonie; 73 Männer und 73 Frauen; durchschnittliches Alter 57.0 ± 15.5 Jahre). Mit Hilfe des AGE-Readers wurden die Advanced Glycation Endproducts in der Haut (SAF) gemessen. Außerdem wurde Vitamin D3, AGE-assoziierte Fluoreszenz (AGE-Fl) im Plasma, hoch-sensitives C-reaktives Protein (hs-CRP), Advanced Oxidation Protein Products (AOPPs) und die Nierenfunktion bestimmt. Außerdem wurden in einer Untergruppe von 61 Probanden N-Carboxymethyllysin (CML), der lösliche Rezeptor für AGEs (soluble RAGE) und das lösliche Vascular Adhesion Protein-1 (sVAP-1) bestimmt. Der durchschnittlich gemessene Vitamin D-Spiegel betrug 22.5 ± 8.9 ng/ml. Eine Vitamin D-Insuffizienz (20 – 29 ng/ml) lag bei 43% und ein manifester Vitamin D-Mangel bei 37% vor. Der altersabhängige Anstieg der Haut-AGEs war bei Rauchern und Patienten mit arterieller Hypertonie stärker ausgeprägt. Einen Zusammenhang zwischen der Hautfluoreszenz (SAF) und Vitamin D-Mangel fand sich nicht. Bei Rauchern konnte eine inverse Beziehung zwischen Vitamin D3 und Plasma AGE assoziierter Fluoreszenz sowie dem Soluble Vascular Adhesion Protein-1 nachgewiesen werden. Unsere Ergebnisse lassen vermuten, dass bei Probanden mit nichtdiabetischer Stoffwechsellage ein Vitamin D-Mangel nicht zu einer vermehrten Toxizität und Akkumulation der Advanced Glycation Endproducts führt. Nur bei Rauchern wäre solch eine Wechselwirkung denkbar. Weil bei Diabetes mellitus die Akkumulation von Advanced Glycation Endproducts mit vermehrter kardiovaskulärer Morbidität und Mortalität in Zusammenhang steht, fragten wir uns außerdem ob ein Vitamin D-Mangel mit vermehrter AGE-Bildung und Toxizität bei Diabetikern einhergeht. Hierzu untersuchten wir 276 Diabetiker (160 Männer und 116 Frauen; Alter 65 ± 13.4 Jahre; 43 Typ 1-Diabetiker, 233 Typ 2-Diabetiker) und 121 Nichtdiabetiker (60 Männer und 61 Frauen; Alter 58.6 ± 15.5 Jahre). Die gleichen Parameter wie zuvor wurden bestimmt. Diabetiker zeigten höhere Werte an SAF und AGE-Fl als die Kontrollen. SAF und AGE-Fl korrelierte mit Alter, Diabetesdauer und Einschränkung der Nierenfunktion. Bei den Typ 2-Diabetikern korrelierte der altersabhängige AGE-Anstieg direkt mit hs-CRP und sVAP-1. Die Vitamin D-Spiegel der Diabetiker und Nichtdiabetiker waren beide gleich erniedrigt und lagen im Durchschnitt bei 22.5 ng/ml. Eine Beziehung zwischen Vitamin D und den erhobenen Parametern fand sich außer mit sVAP-1 (bei den Diabetikern) nicht. Zusammenfassend scheint ein Vitamin D-Mangel bei Diabetikern nicht mit vermehrter AGE-Akkumulation und einem Anstieg der Marker für Mikroinflammation und oxidativem Stress, mit Ausnahme von sVAP-1, einherzugehen. / Advanced glycation endproducts (AGEs) accumulate during aging. Skin is the single organ of vitamin D synthesis, induced by ultraviolet B light. Accumulation of AGEs in the skin could interfere with synthesis of the vitamin, whereas the microinflammation and oxidative stress (associated with hypovitaminosis D) could amplify both the toxic effects of AGEs and their production. Clinical data on potential interactions between vitamin D3 deficiency and AGE accumulation are rare. Here we investigated potential associations between levels of circulating vitamin D3 and those of AGEs in blood and skin with regard to markers of inflammation and oxidative stress in nondiabetic subjects. In a cross-sectional study, 146 subjects (119 healthy persons and 27 hypertensive patients; 73 male and 73 female; mean age 57.0 ± 15.5 years) were included. Skin autofluorescence (SAF) and plasma levels of vitamin D3, AGE-associated fluorescence, high-sensitivity C-reactive protein level, and advanced oxidation protein products as well as renal function (estimated glomerular filtration rate) were determined. In a subgroup of 61 patients, N-carboxymethyllysine, soluble receptor of AGEs, and soluble vascular adhesion protein-1 were additionally analyzed. Vitamin D3 level averaged 22.5 ± 8.9 ng/mL. Prevalence of vitamin D insufficiency (20-29 ng/mL) was 43%, and that of deficiency (<20 ng/mL) 37%. The age-dependent rise in SAF was steeper in smokers and in subjects presenting arterial hypertension. No association between SAF and hypovitaminosis D was revealed. Among smokers, an inverse relationship manifested between vitamin D3 and plasma AGE-associated fluorescence as well as soluble vascular adhesion protein-1. Our data suggest that in nondiabetic adults, hypovitaminosis D does not enhance toxicity and accumulation of AGEs. Only in smokers interactions are conceivable. Because in diabetes accumulated advanced glycation end products (AGEs) are involved in the striking cardiovascular morbidity/mortality we also asked whether a hypovitaminosis D associates with an increased formation and toxicity of AGEs in diabetes. Methods. In 276 diabetics (160 M/116 F, mean age 65.0 ± 13.4; 43 type 1-DM and 233 type 2-DM) and 121 nondiabetic controls (60 M/61 F; mean age 58.6 ± 15.5 years) routine biochemistry, levels of 25-hydroxyvitamin D3 (25-(OH)D), skin autofluorescence (SAF), plasma AGE-associated fluorescence (AGE-FL), N-carboxymethyl)lysine (CML), soluble receptor for AGEs (sRAGE), soluble vascular adhesion protein-1 (sVAP-1), high sensitive C-reactive protein (hs-CRP), and renal function (eGFR) were determined. Results. In the diabetics SAF and AGE-Fl were higher than those of the controls and correlated with age, duration of diabetes, and degree of renal impairment. In T2DM patients but not in T1DM the age-dependent rise of SAF directly correlated with hs-CRP and sVAP-1. 25-(OH)D levels in diabetics and nondiabetics were lowered to a similar degree averaging 22.5 ng/mL. No relationship between 25-(OH)D and studied markers except for sVAP-1 was observed in the diabetics. Conclusion. In diabetics hypovitaminosis D does not augment accumulation of AGEs and studied markers of microinflammation and oxidative stress except for sVAP-1.

Brain calcification is a common occurrence in the aging process, with >20% of individuals over the age of 65 showing hardened plaques in the basal ganglia. Loss of the vitamin D receptor (VDR) in transgenic mice leads to formation of calcified plaques in the basal ganglia and thalamus within the mice. Vitamin D signals through two known vitamin D responsive proteins, protein disulfide isomerase A3 (PDIA3) and VDR. In vitro, vitamin D has been demonstrated to suppress calcification in osteoblast-like cells. Here, we aim to elucidate which of either PDIA3 or VDR transduce vitamin D mediated suppression of calcification in vitro. PDIA3 or VDR were selectively knocked out in human osteosarcoma (SaOs) cells using CRISPR-Cas9 technology to generate PDIA3 KO or VDR KO cells. Knockout for PDIA3 or VDR was confirmed by RT-qPCR assay or western blot analysis. The calcification of SaOs-2 cells was induced with treatment of β-glycerophosphate along with ascorbic acid allowing for determination of whether loss of PDIA3 or VDR would lead to altered calcium deposition. Cells null for PDIA3 but not VDR grew at a significantly slower rate than wild-type (WT) cells. Intriguingly, PDIA3 and VDR KO cells displayed significantly more calcification relative to WT control cells. Calcitriol or the synthetic analogue EB1089 suppressed calcification in vitro in WT and PDIA3 KO but not VDR KO cells as measured by alizarin red staining. These data suggest VDR is critical for mediating vitamin D’s inhibition of calcification in vitro, and that PDIA3 has a role in suppressing calcification. This study provides novel insights into vitamin D signaling and provides a foundation for further study and understanding of vitamin D related pathologies.

An increasing number of women are serving in the military. We initiated a retrospective study to evaluate vitamin D status and monitoring in female veterans, and to examine the potential link between vitamin D status, age, race, post-traumatic stress disorder (PTSD), health care costs, and utilization. Approximately 44 percent of the 3,608 female veterans evaluated between 2001 and 2010 were vitamin D deficient (25(OH)D < 20 ng/ml), a rate substantially higher than that of the general population. While younger (<55 years) and older (55+ years) women did not differ significantly in initial vitamin D status, older women had significantly more vitamin D monitoring and follow-up testing than younger women. Approximately 44 percent of vitamin D deficient women did not receive follow-up vitamin D testing. Minority female veterans were most likely to be vitamin D deficient. Female veterans with PTSD did not differ from others regarding their initial vitamin D status; those that were initially deficient were significantly more likely to receive follow-up testing and were more likely to achieve a replete state. Vitamin D deficiency in female veterans was also associated with increased health-care costs. Appropriate monitoring and replacement of vitamin D should be offered to all female veterans.

Elevation in serum parathyroid hormone (PTH) often accompanies vitamin D deficiency and renal impairment. PTH elevation in renal failure is viewed as an unfavorable development. Evidence is increasing that PTH elevation may be associated with increased morbidity and mortality. In many instances these PTH effects appear to be independent of vitamin D status. PTH mediates its effects through the ubiquitous type 1 PTH/PTH-related peptide receptor, which is notably present in the cardiovascular system. Increased PTH may promote cardiovascular disease through diminished cardiac contractility, enhanced coronary risk, and cardiac valvular and vascular calcification. High PTH levels appear to be linked to the metabolic syndrome and are aligned with hyperlipidemia, decreased insulin sensitivity, and, perhaps, decreased insulin secretion. Increased PTH also is associated with neuroendocrine activation, increased sympathetic activity, and endothelial stress. The relation between PTH and vitamin D is complex and may show significant threshold variations, especially when calcium intake, age, and race are considered. Moreover, evidence is increasing that fragments of PTH may not only be hormonally active but also may have opposing effects to PTH. Despite these caveats, PTH values provide useful clinical diagnostic and prognostic information in monitoring many chronic ailments such as heart and renal failure and multiple sclerosis.