Mid-gut ACTH-secreting neuroendocrine tumor unmasked with (18)F-dihydroxyphenylalanine-positron emission tomography.

Ectopic ACTH Cushing's syndrome (EAS) is often caused by neuroendocrine tumors (NETs) of lungs, pancreas, thymus, and other less frequent locations. Localizing the source of ACTH can be challenging. A 64-year-old man presented with rapidly progressing fatigue, muscular weakness, and dyspnea. He was in poor condition and showed facial redness, proximal amyotrophy, and bruises. Laboratory disclosed hypokalemia, metabolic alkalosis, and markedly elevated ACTH and cortisol levels. Pituitary was normal on magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus blood sampling with corticotropin-releasing hormone stimulation showed no significant central-to-periphery gradient of ACTH. Head and neck, thoracic and abdominal computerized tomography (CT), MRI, somatostatin receptor scintigraphy (SSRS), and (18)F-deoxyglucose-positron emission tomography (FDG-PET) failed to identify the primary tumor. (18)F-dihydroxyphenylalanine (F-DOPA)-PET/CT unveiled a 20-mm nodule in the jejunum and a metastatic lymph node. Segmental jejunum resection showed two adjacent NETs, measuring 2.0 and 0.5 cm with a peritoneal metastasis. The largest tumor expressed ACTH in 30% of cells. Following surgery, after a transient adrenal insufficiency, ACTH and cortisol levels returned to normal values and remain normal over a follow-up of 26 months. Small mid-gut NETs are difficult to localize on CT or MRI, and require metabolic imaging. Owing to low mitotic activity, NETs are generally poor candidates for FDG-PET, whereas SSRS shows poor sensitivity in EAS due to intrinsically low tumor concentration of type-2 somatostatin receptors (SST2) or to receptor down regulation by excess cortisol. However, F-DOPA-PET, which is related to amine precursor uptake by NETs, has been reported to have high positive predictive value for occult EAS despite low sensitivity, and constitutes a useful alternative to more conventional methods of tumor localization. LEARNING POINTS: Uncontrolled high cortisol levels in EAS can be lethal if untreated.Surgical excision is the keystone of NETs treatment, thus tumor localization is crucial.Most cases of EAS are caused by NETs, which are located mainly in the lungs. However, small gut NETs are elusive to conventional imaging and require metabolic imaging for detection.FDG-PET, based on tumor high metabolic rate, may not detect NETs that have low mitotic activity. SSRS may also fail, due to absent or low concentration of SST2, which may be down regulated by excess cortisol.F-DOPA-PET, based on amine-precursor uptake, can be a useful method to localize the occult source of ACTH in EAS when other methods have failed.

The rare cancer network: ongoing studies and future strategy.

The Rare Cancer Network (RCN) was formed in the early 1990's to create a global network that could pool knowledge and resources in the studies of rare malignancies whose infrequency prevented both their study with prospective clinical trials. To date, the RCN has initiated 74 studies resulting in 46 peer reviewed publications. The First International Symposium of the Rare Cancer Network took place in Nice in March of 2014. Status updates and proposals for new studies were heard for fifteen topics. Ongoing studies continue for cardiac sarcomas, thyroid cancers, glomus tumors, and adult medulloblastomas. New proposals were presented at the symposium for primary hepatic lymphoma, solitary fibrous tumors, Rosai-Dorfman disease, tumors of the ampulla of Vater, salivary gland tumors, anorectal melanoma, midline nuclear protein in testes carcinoma, pulmonary lymphoepithelioma-like carcinoma, adenoid cystic carcinoma of the trachea, osteosarcomas of the mandible, and extra-cranial hemangiopericytoma. This manuscript presents the abstracts of those proposals and updates on ongoing studies, as well a brief summary of the vision and future of the RCN.

IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs.

The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22-blocking agents in B-cell-mediated autoimmune conditions.

Innate and Adaptive Immunity in Orolabial Herpes Simplex

Oral mucosa is a frequent site of primary herpes simplex virus type 1 (HSV-1) infection, whereas intraoral recurrent disease is very rare. Instead, reactivation from latency predominantly results in asymptomatic HSV shedding to saliva or recurrent labial herpes (RLH) with highly individual frequency. The current study aimed to elucidate the role of human oral innate and acquired immune mechanisms in modulation of HSV infection in orolabial region. Saliva was found to neutralize HSV-1, and to protect cells from infection independently of salivary antibodies. Neutralization capacity was higher in saliva from asymptomatic HSV-seropositive individuals compared to subjects with history of RLH or seronegative controls. Neutralization was at least partially associated with salivary lactoferrin content. Further, lactoferrin and peroxidase-generated hypothiocyanite were found to either neutralize HSV-1 or interfere with HSV-1 replication, whereas lysozyme displayed no anti-HSV-1 activity. Lactoferrin was also shown to modulate HSV-1 infection by inhibiting keratinocyte proliferation. RLH susceptibility was further found to be associated with Th2 biased cytokine responses against HSV, and a higher level of anti- HSV-IgG with Th2 polarization, indicating lack of efficiency of humoral response in the control of HSV disease. In a three-dimensional cell culture, keratinocytes were found to support both lytic and nonproductive infection, suggesting HSV persistence in epithelial cells, and further emphasizing the importance of peripheral immune control of HSV. These results suggest that certain innate salivary antimicrobial compounds and Th1 type cellular responses are critically important in protecting the host against HSV disease, implying possible applications in drug, vaccine and gene therapy design.

Efecto de masticar chicle sobre la halitosis

Fundamento y objetivo: Este estudio pretende estimar la prevalencia de halitosis oral en una población joven y mostrar el efecto del chicle sobre el aliento. Pacientes y método: Estudio prospectivo de campo descriptivo correlacional, de corte transversal. Se seleccionaron a conveniencia 121 jóvenes, de los que 98 concluyeron el estudio, el cual se realizó en el Hospital Odontológico Universitario-Universidad de Barcelona. El protocolo consistió en: cuestionario, evaluación clínica oral, prueba organoléptica (PO) y medición de compuestos volátiles sulfurados (CVS) con monitor de sulfuros, antes y después de masticar chicle durante 15 min, con 2 investigadores calibrados. Resultados: Un 87,8% tenían higiene oral adecuada, el 17,3% refirieron mal aliento, y un 29,6%, xerostomía. En la PO 44 sujetos tenían un grado ≥ 2; la concordancia de examinadores fue del 75%. La determinación de CVS en 53 individuos fue ≤ 100 partes por billón (ppb) y en 45 sujetos > 100 ppb. Se obtuvo una reducción de CVS post de 17,34%, con una media de disminución de 1,8-9,0 ppb (p = 0,003). Conclusiones: La prevalencia de halitosis fue del 36,7%. El uso de chicle como adyuvante en casos de halitosis disminuye los CVS, mejorando la percepción de terceros y del propio paciente

Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects.

BACKGROUND: After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans. METHODS: In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects. RESULTS: Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed. CONCLUSIONS: In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.

Pronóstico y tratamiento de la boca seca. Revisión sistemática

No existen protocolos claramente establecidos para el tratamiento de la boca seca. El objetivo de este trabajo es realizar una revisión sistemática de la literatura médica de los últimos 10 años. Hemos utilizado las palabras: «dry mouth», «prognosis», «treatment» y «dentistry». En una primera búsqueda hemos encontrado 1.450 entradas. Con la restricción «clinical trials OR randomized controlled trial OR systemic reviews» se han reducido a 522, de las que 145 eran metaanálisis y revisiones sistemáticas. Se han eliminado las que no eran pertinentes al tema y han quedado reducidas a 53. Posteriormente se descartaron 24 (8 no pertinentes, 7 revisiones y 9 opiniones personales). De los 29 artículos analizados, 15 son ensayos clínicos controlados, 2 ensayos no controlados, 4 estudios observacionales, 2 revisiones sistemáticas y 5 revisiones. Los enfermos mejor estudiados son los pacientes con síndrome de Sjögren y los pacientes irradiados. El tratamiento se centra en el etiológico, preventivo, sintomático, de estimulación salival local y sistémicos. Podemos concluir que el tratamiento debe ser individualizado, pudiéndose aplicar sustitutos salivales y diferentes técnicas de estimulación mecánica. There are no clearly established protocols for the treatment of dry mouth. The aim of this paper is a systematic review of the literature of the past 10 years using the words «dry mouth», «prognosis», «treatment» and «dentistry». The initial search found 1,450 entries and within the restriction «clinical trials OR randomized controlled trial OR systemic reviews» it has been reduced to 522, which 145 were meta-analysis and systematic reviews. Papers not relevant to the issue were removed reducing the entries to 53. Twenty-four were dismissed (8 irrelevant, 7 reviews without adequate information and 9 personal opinions). Of the 29 items tested, 15 were controlled trials, 2 uncontrolled trials, 4 observational studies, 2 systematic reviews and 5 non systematic reviews. The most studied patients were Sjögren's syndrome and the irradiated patients. Treatments are focused on the etiology, prevention, symptomatic, local salivary stimulation and systemic treatments. It can be concluded that treatment must be individualized, salivary substitutes and mechanical stimulation techniques can be applied.

Life-course socioeconomic status and DNA methylation of genes regulating inflammation

BACKGROUND: In humans, low socioeconomic status (SES) across the life course is associated with greater diurnal cortisol production, increased inflammatory activity and higher circulating antibodies for several pathogens, all suggesting a dampened immune response. Recent evidence suggests that DNA methylation of pro-inflammatory genes may be implicated in the biological embedding of the social environment. METHODS: The present study examines the association between life-course SES and DNA methylation of candidate genes, selected on the basis of their involvement in SES-related inflammation, in the context of a genome-wide methylation study. Participants were 857 healthy individuals sampled from the EPIC Italy prospective cohort study. RESULTS: Indicators of SES were associated with DNA methylation of genes involved in inflammation. NFATC1, in particular, was consistently found to be less methylated in individuals with low vs high SES, in a dose-dependent manner. IL1A, GPR132 and genes belonging to the MAPK family were also less methylated among individuals with low SES. In addition, associations were found between SES and CXCL2 and PTGS2, but these genes were consistently more methylated among low SES individuals. CONCLUSIONS: Our findings support the hypothesis that the social environment leaves an epigenetic signature in cells. Although the functional significance of SES-related DNA methylation is still unclear, we hypothesize that it may link SES to chronic disease risk.

Inverted ductal papilloma of the oral cavity secondary to lower lip trauma. A case report and literature review

Inverted ductal papilloma of the oral cavity is an infrequent benign neoplasm of papillary appearance that originates in the secretory duct of a salivary gland. The etiology is unknown, though some authors have related it to human papillomavirus (HPV) infection. We present the case of a 40-year-old woman with a tumor of the lower lip mucosa. Histopathological study of the lesion diagnosed inverted ductal papilloma of the oral cavity. Human papillomavirus DNA detection and typing based on tumor lesion DNA amplification and posterior hybridization, revealed no presence of viral DNA. The antecedents of trauma reported by the patient could have played an important role in the development of this tumor

Maladie de Whipple: quand y penser [Whipple's disease, when to think about it?].

Whipple's disease is a chronic, systemic, bacterial infection caused by Tropheryma whipplei. Its cardinal symptoms include intermittent and recurrent arthralgia or arthritis together with chronic diarrhoea, abdominal pain and weight loss. It may mimick many chronic inflammatory diseases, and the diagnosis remains a challenge. Salivary and faecal quantitative PCR for T. whipplei should be ensued, if positive, by an upper endoscopy for duodenal biopsies. The treatment consists of a combination of oral doxycycline and hydroxychloroquine for 12 months followed by life-long doxycycline. Whipple's disease, although rare, is an entity that should be considered regularly, as its progression may be fatal if left untreated.

Conséquences du stress en période périnatale sur la réponse émotionnelle chez l'enfant prématuré

Problématique: Les naissances prématurées sont des situations cliniques à risque pour l'enfant. Celui-ci arrive au monde avec une capacité amoindrie à être autonome, que ce soit, par exemple, au niveau respiratoire ou de la régulation thermique. Lors de leur séjour aux soins intensifs, les enfants prématurés subissent des interventions qui peuvent être douloureuses, ils sont souvent manipulés et exposés à des bruits et des lumières intenses; ceci peut induire un stress important pour l'enfant qui est déjà vulnérable du fait de sa prématurité. Lorsque confronté à une situation stressante, l'organisme humain réagit par l'activation de l'axe hypothalamo-hypophysio-surrénalien (HHS). Une des hormones principales sécrétées par l'axe HHS est le cortisol. Plusieurs études suggèrent que le cortisol, lorsque sécrété en quantités importantes, risque d'altérer la matière grise, en induisant une diminution de volume, notamment celui de l'hippocampe (Plotsky & Meaney, 1993; Sapolsky, 2000; McEwen, 1994; 2000; Sandman et al., 1994; Meaney et al., 1991;1996). Ces altérations auraient comme effet un dérèglement de l'axe HHS (Heim & Nemeroff, 1999) avec comme conséquence une variation de la réponse au stress mais aussi de la mémoire et de la régulation émotionnelle (Stam et al., 2000 et Siegel, 1998). Objectifs: Nous allons nous intéresser aux grands prématurés nés à moins de 32 semaines de gestations selon leur exposition à des interventions stressantes et douloureuses ou des complications postnatales. Nous allons étudier l'impact qu'un stress modéré ou sévère sur un prématuré a sur la réponse de l'axe HHS et sur sa régulation émotionnelle lorsque celui-ci est confronté à des situations de stress modéré ultérieurement, plus précisément à six mois d'age corrigé. Méthodologie: Dans le cadre de l'étude «Stress néonatal et réactivité au stress ultérieur: effets préventifs d'une intervention précoce» (SNF 3200 BO-104230) menée au SUPEA en collaboration avec le service de néonatologie du DMCP, le Lab-TAB (Laboratory Temperament Assessment Battery, prelocomotor version 3.1, Goldsmith & Rothbart, 1999) a été utilisé comme outil pour analyser le tempérament d'un enfant par l'analyse de ses réactions émotionnelles à certaines situations. L'enfant, qui était filmé, a été confronté à des mises en scène conçues pour susciter diverses émotions comme la peur, la colère, la frustration, la curiosité ou le plaisir. Un système de codage dérivé de celui du Lab-TAB sera utilisé par deux codeurs différents pour analyser les réactions émotionnelles des enfants. Les taux de cortisol sécrétés ont été mesurés dans la salive de l'enfant. La mesure du cortisol libre dans la salive montre une bonne corrélation avec le cortisol plasmatique ; plusieurs prélèvements de salive ont été faits avant, pendant et après la situation de stress. Les situations filmées n'ont pas encore été codés, ni les taux analysés par l'équipe de la SUPEA. Nous allons observer 40 vidéos, 20 d'enfants nés prématurément et 20 d'enfants nés à terme comme groupe contrôle, et examiner la réponse endocrinienne au stress ainsi que leur régulation émotionnelle au niveau de leur comportement comme l'excitation, les pleurs, l'évitement... Hypothèse : L'intensité de l'exposition au stress postnatal chez l'enfant prématuré induirait des variations de la réponse de l'axe HHS mais aussi de la régulation émotionnelle. Il n'est pas clair selon la littérature actuelle si les variations des réponses de l'axe HHS dues à l'exposition à un stress précoce vont dans les sens de l'hypo- ou l'hyperréactivité, et si cette réponse corrèle avec la régulation émotionnelle au niveau des comportements. C'est ce que l'analyse des données nous permettra de déterminer.

The role of the renal mineralocorticoid versus the glucocorticoid receptor in renal sodium and potassium transport

Dans le néphron distal sensible à l'aldostérone, le récepteur aux minéralocorticoïdes (RM) et le récepteur aux glucocorticoids (RG) sont exprimés et peuvent être liés et activés par l'aldostérone et le Cortisol, respectivement. La réabsorption rénale de sodium est principalement contrôlée par le RM. Cependant, des modèles expérimentaux in vitro et in vivo suggèrent que le RG pourrait également jouer un rôle dans le transport rénal du sodium. Afin d'étudier l'implication du RG et/ou du RM exprimés dans les cellules épithéliales adultes dans le transport rénal du sodium, nous avons généré deux modèles de souris, dans lesquelles l'expression du RG (Nr3c1Pax8/LC1) ou du RM (Nr3c2Pax8/LC1) peut être abolie de manière inductible et cela spécifiquement dans les tubules rénaux. Les souris déficientes pour le gène du RM survivent mais développent un phénotype sévère de PHA-1, caractérisé par un retard de croissance, une augmentation des niveaux urinaires de Na+, une diminution de la concentration du Na+ dans le plasma, une hyperkaliémie et une augmentation des niveaux d'aldostérone plasmatique. Ce phénotype empire et devient létal lorsque les souris sont nourries avec une diète déficiente en sodium. Les niveaux d'expression en protéine de NCC, de la forme phosphorylée de NCC et de aENaC sont diminués, alors que l'expression en ARN messager et en protéine du RG est augmentée. Une diète riche en Na+ et pauvre en K+ ne corrige pas la concentration élevée d'aldostérone dans le plasma pour la ramener à des niveaux conformes, mais est suffisante pour corriger la perte de poids et les niveaux anormaux des électrolytes dans le plasma et l'urine. -- In the aldosterone-sensitive distal nephron, both the mineralocorticoid (MR) and the glucocorticoid (GR) receptor are expressed. They can be bound and activated by aldosterone and Cortisol, respectively. Renal Na+ reabsorption is mainly controlled by MR. However, in vitro and in vivo experimental models suggest that GR may play a role in renal Na+ transport. Therefore, to investigate the implication of MR and/or GR in adult epithelial cells in renal sodium transport, we generated inducible renal tubule- specific MR (Nr3c2Pax8/LC1) and GR (Nr3c1Pax8/LC1) knockout mice. MR-deficient mice survived but developed a severe PHA-1 phenotype with failure to thrive, higher urinary Na+, decreased plasma Na+ levels, hyperkalemia and higher levels of plasma aldosterone. This phenotype further worsened and became lethal under a sodium-deficient diet. NCC protein expression and its phosphorylated form, as well as aENaC protein level were downregulated, whereas the mRNA and protein expression of GR was increased. A diet rich in Na+and low in K+ did not normalize plasma aldosterone to control levels, but was sufficient to restore body weight, plasma and urinary electrolytes. Upon switch to a Na+-deficient diet, GR-mutant mice exhibited transient increased urinary Na+ and decreased K+ levels, with transitory higher plasma K+ concentration preceded by a significant increase in plasma aldosterone levels within the 12 hours following diet switch. We found no difference in urinary aldosterone levels, plasma Na+ concentration and plasma corticosterone levels. Moreover, NHE3, NKCC2, NCC

SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis.

Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases.

The risk factors for fractures and trabecular bone-score value in patients with endogenous Cushing's syndrome.

In a cohort study of 182 consecutive patients with active endogenous Cushing's syndrome, the only predictor of fracture occurrence after adjustment for age, gender bone mineral density (BMD) and trabecular bone score (TBS) was 24-h urinary free cortisol (24hUFC) levels with a threshold of 1472 nmol/24 h (odds ratio, 3.00 (95 % confidence interval (CI), 1.52-5.92); p = 0.002). INTRODUCTION: The aim was to estimate the risk factors for fracture in subjects with endogenous Cushing's syndrome (CS) and to evaluate the value of the TBS in these patients. METHODS: All enrolled patients with CS (n = 182) were interviewed in relation to low-traumatic fractures and underwent lateral X-ray imaging from T4 to L5. BMD measurements were performed using a DXA Prodigy device (GEHC Lunar, Madison, Wisconsin, USA). The TBS was derived retrospectively from existing BMD scans, blinded to clinical outcome, using TBS iNsight software v2.1 (Medimaps, Merignac, France). Urinary free cortisol (24hUFC) was measured by immunochemiluminescence assay (reference range, 60-413 nmol/24 h). RESULTS: Among enrolled patients with CS (149 females; 33 males; mean age, 37.8 years (95 % confidence interval, 34.2-39.1); 24hUFC, 2370 nmol/24 h (2087-2632), fractures were confirmed in 81 (44.5 %) patients, with 70 suffering from vertebral fractures, which were multiple in 53 cases; 24 patients reported non-vertebral fractures. The mean spine TBS was 1.207 (1.187-1.228), and TBS Z-score was -1.86 (-2.07 to -1.65); area under the curve (AUC) was used to predict fracture (mean spine TBS) = 0.548 (95 % CI, 0.454-0.641)). In the final regression model, the only predictor of fracture occurrence was 24hUFC levels (p = 0.001), with an increase of 1.041 (95 % CI, 1.019-1.063), calculated for every 100 nmol/24-h cortisol elevation (AUC (24hUFC) = 0.705 (95 % CI, 0.629-0.782)). CONCLUSIONS: Young patients with CS have a low TBS. However, the only predictor of low traumatic fracture is the severity of the disease itself, indicated by high 24hUFC levels.

Reference intervals for 24 laboratory parameters determined in 24-hour urine collections.

BACKGROUND: Reference intervals for many laboratory parameters determined in 24-h urine collections are either not publicly available or based on small numbers, not sex specific or not from a representative sample. METHODS: Osmolality and concentrations or enzymatic activities of sodium, potassium, chloride, glucose, creatinine, citrate, cortisol, pancreatic α-amylase, total protein, albumin, transferrin, immunoglobulin G, α1-microglobulin, α2-macroglobulin, as well as porphyrins and their precursors (δ-aminolevulinic acid and porphobilinogen) were determined in 241 24-h urine samples of a population-based cohort of asymptomatic adults (121 men and 120 women). For 16 of these 24 parameters creatinine-normalized ratios were calculated based on 24-h urine creatinine. The reference intervals for these parameters were calculated according to the CLSI C28-A3 statistical guidelines. RESULTS: By contrast to most published reference intervals, which do not stratify for sex, reference intervals of 12 of 24 laboratory parameters in 24-h urine collections and of eight of 16 parameters as creatinine-normalized ratios differed significantly between men and women. For six parameters calculated as 24-h urine excretion and four parameters calculated as creatinine-normalized ratios no reference intervals had been published before. For some parameters we found significant and relevant deviations from previously reported reference intervals, most notably for 24-h urine cortisol in women. Ten 24-h urine parameters showed weak or moderate sex-specific correlations with age. CONCLUSIONS: By applying up-to-date analytical methods and clinical chemistry analyzers to 24-h urine collections from a large population-based cohort we provide as yet the most comprehensive set of sex-specific reference intervals calculated according to CLSI guidelines for parameters determined in 24-h urine collections.