Comparisons of serum vitamin d levels, status, and determinants in populations with and without chronic kidney disease not requiring renal dialysis: a 24-hour urine collection population-based study.

OBJECTIVE: Vitamin D deficiency is frequent in the general population and might be even more prevalent among populations with kidney failure. We compared serum vitamin D levels, vitamin D insufficiency/deficiency status, and vitamin D level determinants in populations without chronic kidney disease (CKD) and with CKD not requiring renal dialysis. DESIGN AND METHODS: This was a cross-sectional, multicenter, population-based study conducted from 2010 to 2011. Participants were from 10 centers that represent the geographical and cultural diversity of the Swiss adult population (≥15 years old). INTERVENTION: CKD was defined using estimated glomerular filtration rate and 24-hour albuminuria. Serum vitamin D was measured by liquid chromatography-tandem mass spectrometry. Statistical procedures adapted for survey data were used. MAIN OUTCOME MEASURE: We compared 25-hydroxy-vitamin D (25(OH)D) levels and the prevalence of vitamin D insufficiency/deficiency (serum 25(OH)D < 30 ng/mL) in participants with and without CKD. We tested the interaction of CKD status with 6 a priori defined attributes (age, sex, body mass index, walking activity, serum albumin-corrected calcium, and altitude) on serum vitamin D level or insufficiency/deficiency status taking into account potential confounders. RESULTS: Overall, 11.8% (135 of 1,145) participants had CKD. The 25(OH)D adjusted means (95% confidence interval [CI]) were 23.1 (22.6-23.7) and 23.5 (21.7-25.3) ng/mL in participants without and with CKD, respectively (P = .70). Vitamin D insufficiency or deficiency was frequent among participants without and with CKD (75.3% [95% CI 69.3-81.5] and 69.1 [95% CI 53.9-86.1], P = .054). CKD status did not interact with major determinants of vitamin D, including age, sex, BMI, walking minutes, serum albumin-corrected calcium, or altitude for its effect on vitamin D status or levels. CONCLUSION: Vitamin D concentration and insufficiency/deficiency status are similar in people with or without CKD not requiring renal dialysis.

Secretory IgA in human serum.

Secretory component (SC) was detected by the radioactive single radial diffusion technique in nearly all sera examined. The SC was shown to be associated with polymeric serum IgA. The mean level of secretory IgA (SIgA) in normal sera from India, Africa and Europe was about 0.03 to 0.04 mg/ml. The mean level was elevated in patients with a variety of disorders involving secretory surfaces (e.g., acute bacterial enterocolitis or respiratory tract carcinoma), but also in disorders with no known involvement of secretory surfaces. The highest levels were seen in lactating women, with a mean level five times higher than that in the general population. SIgA was also found at lower levels in cord serum, serum from breast-fed newborns and serum from children 3 to 10 years old.

Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout.

OBJECTIVE: Losartan has been shown to increase urinary uric acid excretion and hence to lower serum uric acid levels. The purposes of the present study were: (1) to evaluate the effects of losartan on serum uric acid in hypertensive patients with hyperuricemia and gout, (2) to compare the effects of losartan with those of irbesartan, another angiotensin II receptor antagonist and (3) to evaluate whether losartan 50 mg b.i.d. has a greater impact on serum uric acid levels than losartan 50 mg once a day. METHODS: Thirteen hypertensive patients with hyperuricaemia and gout completed this prospective, randomized, double-blind, cross-over study. Uric acid-lowering drugs were stopped 3 weeks before the beginning of the study. Patients were randomized to receive either losartan 50 mg or irbesartan 150 mg once a day, for 4 weeks. During this phase, a placebo was given in the evening. After 4 weeks, the dose was increased to losartan 50 mg b.i.d., or irbesartan 150 mg b.i.d. for another 4 week period. Subsequently, the patients were switched to the alternative treatment modality. Enalapril (20 mg o.d.) was given during the run-in period and between the two treatment phases. Serum and urinary uric acid were measured at the beginning and at the end of each treatment phase. RESULTS: Our results show that losartan 50 mg once daily decreased serum uric acid levels from 538 +/- 26 to 491 +/- 20 micromol/l (P < 0.01). Irbesartan had no effect on serum uric acid. Increasing the dose of losartan from 50 mg o.d. to 50 mg twice a day, did not further decrease serum uric acid. This may in part be due to a low compliance to the evening dose as measured with an electronic device. Indeed, whatever the prescribed drug, the mean compliance of the evening dose was always significantly lower than that of the morning dose. The uricosuric effect of losartan appears to decrease with time when a new steady state of lower serum uric acid is reached. CONCLUSIONS: In contrast to irbesartan, losartan was uricosuric and decreased serum uric acid levels. Losartan 50 mg b.i.d. did not produce a greater fall in serum uric acid than losartan once a day. Losartan might be a useful therapeutic tool to control blood pressure and reduce serum uric acid levels in hypertensive patients with hyperuricaemia and gout.

Generation of reconstituted human plasma-derived secretory-like IgA and IgM and their protective effect on intestinal epithelium

Les muqueuses sont les membranes tapissant les cavités du corps, tel que le tube digestif, et sont en contact direct avec l'environnement extérieur. Ces surfaces subissent de nombreuses agressions pouvant être provoquées par des agents pathogènes (bactéries, toxines ou virus). Cela étant, les muqueuses sont munies de divers mécanismes de protection dont notamment deux protéines-clés permettant de neutraliser les agents pathogènes : les anticorps ou immunoglobulines sécrétoires A (SIgA) et M (SIgM). Ces anticorps sont, d'une part, fabriqués au niveau de la muqueuse sous forme d'IgA et IgM. Lorsqu'ils sont sécrétés dans l'intestin, ils se lient à une protéine appelée pièce sécrétoire et deviennent ainsi SIgA et SïgM. La présence de la pièce sécrétoire est essentielle pour que les anticorps puissent fonctionner au niveau de la muqueuse. D'autre part, ces anticorps sont également fabriqués dans d'autres parties du corps en général et se retrouvent dans le sang sous forme d'IgA et IgM Chez l'homme, des thérapies basées sur l'injection d'anticorps donnent de bons résultats depuis de nombreuses années notamment dans le traitement des infections. Bien qu'un certain nombre d'études ont montré le rôle protecteur des anticorps de type IgA et IgM, ceux-ci ne sont que rarement utilisés dans les thérapies actuelles. La principale raison de cette faible utilisation réside dans la production ou la purification des IgA/IgM ou SIgA/SIgM (la forme active au niveau des muqueuses) qui est difficile à réaliser à large échelle. Ainsi, le but de la thèse était (1) d'étudier la possibilité d'employer des IgA et des IgM provenant du sang humain pour générer des SIgA et SIgM et (2) de voir si ces anticorps reconstitués pouvaient neutraliser certains agents pathogènes au niveau des muqueuses. Tout d'abord, une analyse biochimique des IgA et des IgM issues du sang a été effectuée. Nous avons observé que ces anticorps avaient des caractéristiques similaires aux anticorps naturellement présents au niveau des muqueuses. De plus, nous avons confirmé que ces anticorps pouvaient être associés à une pièce sécrétoire produite en laboratoire pour ainsi donner des SIgA et SIgM reconstituées. Ensuite, la fonctionnalité des anticorps reconstitués a été testée grâce à un modèle de couche unique de cellules intestinales différenciées (monocouches) en laboratoire imitant la paroi de l'intestin. Ces monocouches ont été infectées par une bactérie pathogène, Shigella flexneri, responsable de la shigellose, une maladie qui provoque des diarrhées sanglantes chez l'homme. L'infection des monocouches par les bactéries seules ou combinées aux SIgA et SIgM reconstituées a été analysée. Nous avons observé que les dommages des cellules étaient moins importants lorsque les SIgA étaient présentes. Il apparaît que les SIgA neutralisent les bactéries en se fixant dessus, ce qui provoque leur agrégation, et diminuent l'inflammation des cellules. La protection s'est montrée encore plus efficace avec les SIgM. De plus, nous avons vu que les SIgA et SIgM pouvaient diminuer la sécrétion de facteurs nocifs produits par les bactéries. Utilisant le même modèle des monocouches, la fonctionnalité des IgA issues du sang humain a aussi été testée contre une toxine sécrétée par une bactérie appelée Clostridium diffìcile. Cette bactérie peut être présente naturellement dans l'intestin de personnes saines, cependant elle peut devenir pathogène dans certaines conditions et être à l'origine de diarrhées et d'inflammations de l'intestin via la sécrétion de toxines. Des préparations d'anticorps contenant une certaine proportion de SIgA reconstituées ont amené à une diminution des dommages et de l'inflammation des monocouches causés par la toxine. L'ensemble de ces résultats prometteurs, montrant que des SIgA et SIgM reconstituées peuvent protéger la paroi de l'intestin des infections bactériennes, nous conduisent à approfondir la recherche sur ces anticorps dans des modèles animaux. L'aboutissement de ce type de recherche permettrait de tester, par la suite, l'efficacité sur l'homme de traitements des infections des muqueuses par injection d'anticorps de type SIgA et SIgM reconstituées. Les muqueuses, telle que la muqueuse gastrointestinale, sont des surfaces constamment exposées à l'environnement et leur protection est garantie par une combinaison de barrières mécaniques, physicochimiques et immunologiques. Parmi les divers mécanismes de protection immunologiques, la réponse humorale spécifique joue un rôle prépondérant et est assurée par les immunoglobulines sécrétoires de type A (SIgA) et M (SIgM). Les thérapies basées sur l'administration d'IgG apportent d'importants bénéfices dans le domaine de la santé. Bien que des études sur les animaux aient montré que l'administration par voie muqueuse d'IgA polymérique (plgA) ou SIgA pouvaient protéger des infections, des IgA/SIgA n'ont été utilisées qu'occasionnellement dans les thérapies. De plus, des études précliniques et cliniques ont démontré que l'administration par voie systémique de préparations enrichies en IgM pouvait aussi protéger des infections. Cependant, l'administration par voie muqueuse d'IgM/SIgM purifiées n'a pas été examinée jusqu'à présent. La principale raison est que la purification ou là production des IgA/SIgA et IgM/SIgM est difficile à réaliser à large échelle. Le but de ce travail de thèse était d'examiner la possibilité d'associer des IgA et IgM polyclonals purifiées à partir du plasma humain avec une pièce sécrétoire recombinante humaine afin de générer des SIgA et SIgM reconstituées fonctionnelles. Tout d'abord, une analyse biochimique des IgA et IgM issues du plasma humain a été effectuée par buvardage de western et Chromatographie. Ces molécules avaient des caractéristiques biochimiques similaires à celles des immunoglobulines issues de la muqueuse. L'association entre plgA ou IgM issues du plasma humain et la pièce sécrétoire recombinante humaine a été confirmée, ainsi que la stoechiométrie 1:1 de l'association. Comme dans les conditions physiologiques, cette association permettait de retarder la dégradation des SIgA et SIgM reconstituées exposées à des protéases intestinales. Ensuite, la fonctionnalité et le mode d'action des IgA et IgM issues du plasma humain, ainsi que des SIgA et SIgM reconstituées, ont été explorés grâce à un modèle in vitro de monocouches de cellules intestinales épithéliales polarisées de type Caco-2, qui imite l'épithélium intestinal. Les monocouches ont été infectées par un pathogène entérique, Shigella flexneri, seul ou combiné aux immunoglobulines issues du plasma humain ou aux immunoglobulines sécrétoires reconstituées. Bien que les dommages des monocouches aient été retardés par les plgA et SIgA reconstituées, les IgM et SIgM reconstituées se sont montrées supérieures dans le maintien de l'intégrité des cellules. Une agrégation bactérienne et une diminution de l'inflammation des monocouches ont été observées avec les plgA et SIgA reconstituées. Ces effets étaient augmentés avec les IgM et SIgM reconstituées. De plus, il s'est révélé que les deux types d'immunoglobulines de type sécrétoire reconstituées agissaient directement sur la virulence des bactéries en réduisant leur sécrétion de facteurs de virulence. La fonctionnalité des IgA issues du plasma humain a aussi été testée contre la toxine A de Clostridium difficile grâce au même modèle de monocouches de cellules épithéliales. Nous avons démontré que des préparations enrichies en IgA provenant du plasma humain pouvaient diminuer les dommages et l'inflammation des monocouches induits par la toxine. L'ensemble de ces résultats démontrent que des IgA et IgM de type sécrétoire peuvent être générées à partir d'IgA et IgM issues du plasma humain en les associant à la pièce sécrétoire et que ces molécules protègent l'épithélium intestinal contre des bactéries pathogènes. Ces molécules pourraient dès lors être testées dans des modèles in vivo. Le but final serait de les utiliser chez l'homme à des fins d'immunisation passive dans le traitement de pathologies associées à la muqueuse telles que les infections. - Mucosal surfaces, such as gastrointestinal mucosa, are constantly exposed to the external environment and their protection is ensured by a combination of mechanical, physicochemical and immunological barriers. Among the various immunological defense mechanisms, specific humoral mucosal response plays a crucial role and is mediated by secretory immunoglobulins A (SIgA) and M (SIgM). Immunoglobulin therapy based on the administration of IgG molecules leads important health benefits. Even though animal studies have shown that mucosal application of polymeric IgA (plgA) or SIgA provided protection against infections, IgA/SIgA have been only used occasionally for therapeutic application. Moreover, preclinical and clinical studies have demonstrated that systemic administration of IgM-enriched preparations could also afford protection against infections. Nevertheless, mucosal application of purified IgM/SIgM has not been examined. The main reason is that the purification or production of IgA/SIgA and IgM/SIgM at large scale is difficult to achieve. The aim of this PhD project was to examine the possibility to associate polyclonal human plasma-derived IgA and IgM with recombinant human secretory component (SC) to generate functional secretoiy-like IgA and IgM. First, biochemical analysis of human plasma IgA and IgM was performed by western blotting and chromatography. These molecules exhibited the same biochemical features as mucosa-derived antibodies (Abs). The association between human plasma plgA or IgM and recombinant human SC was confirmed, as well as the 1:1 stoichiometry of association. Similarly to physiological conditions, this association delayed the degradation of secretory-like IgA or IgM by intestinal proteases. Secondly, the function activity and the mode of action of human plasma IgA and IgM, as well as secretory-like IgA and IgM were explored using an in vitro model of polarized intestinal epithelial Caco-2 cell monolayers mimicking intestinal epithelium. Cell monolayers were infected with an enteropathogen, Shigella flexneri, alone or in combination to plasma Abs or secretory-like Abs. Even though plasma plgA and secretoiy-like IgA resulted in a delay of bacteria-induced damages of cell monolayers, plasma IgM and secretory-like IgM were shown to be superior in maintenance of cell integrity. Polymeric IgA and secretory-like IgA induced bacterial aggregation and decreased cell monolayer inflammation, effects further amplified with IgM and secretory-like IgM. In addition, both secretory-like Abs directly impacted on bacterial virulence leading to a reduction in secretion of virulence factors by bacteria. The functionality of human plasma IgA was also tested against Clostridium difficile toxin A using Caco-2 cell monolayers. Human plasma IgA- enriched preparations led to a diminution of cell monolayer damages and a decrease of cellular inflammation induced by the toxin. The sum of these results demonstrates that secretory-like IgA and IgM can be generated from purified human plasma IgA and IgM associated to SC and that these molecules are functional to protect intestinal epithelium from bacterial infections. These molecules could be now tested using in vivo models. The final goal would be to use them by passive immunization in the treatment of mucosa-associated pathologies like infections in humans.

Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection.

BACKGROUND & AIMS: In the last decade, pegylated interferon-α (PegIFN-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed at studying genetic determinants of RBV kinetics, efficacy and treatment-associated anemia. METHODS: We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726, and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101, and followed for treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients, RBV serum levels were additionally measured during treatment. RESULTS: Patients with SLC28A2 rs11854484 genotype TT had higher dosage- and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop ≥3 g/dl during treatment, in genotype (relative risk (RR)=2.1, 95% CI 1.3-3.5) as well as allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as allelic analyses (RR=2.0, 95% CI 1.1-3.4). CONCLUSIONS: The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype, as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV-induced anemia and treatment response, may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.

HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer.

The transmembrane protein HER2 is over-expressed in approximately 15% of invasive breast cancers as a result of HER2 gene amplification. HER2 proteolytic cleavage (HER2 shedding) generates soluble truncated HER2 molecules that include only the extracellular domain and the concentration of which can be measured in the serum fraction of blood. HER2 shedding also generates a constitutively active truncated intracellular receptor of 95kDa (p95(HER2)). Another soluble truncated HER2 protein (Herstatin), which can also be found in serum, is the product of an alternatively spliced HER2 transcript. Recent preclinical findings may provide crucial insights into the biological and clinical relevance of increased sHER2 concentrations for the outcome of HER2-positive breast cancer and sensitivity to trastuzumab and lapatinib treatment. We present here the most recent findings about the role and biology of sHER2 based on data obtained using a standardized test, which has been cleared by FDA in 2000, for measuring sHER2. This test includes quality control assessments and has been already widely used to evaluate the clinical utility of sHER2 as a biomarker in breast cancer. We will describe in detail data concerning the assessment of sHER2 as a surrogate maker to optimize the evaluation of the HER2 status of a primary tumor and as a prognosis and predictive marker of response to therapies, both in early and metastatic breast cancer.

Significance of serum adiponectin levels in patients with chronic liver disease.

Adiponectin, which plays a pivotal role in metabolic liver diseases, is reduced in concentration in patients with NASH (non-alcoholic steatohepatitis). The aim of the present study was to determine adiponectin concentrations in patients with different forms and stages of chronic liver diseases. Serum adiponectin concentrations were measured in 232 fasting patients with chronic liver disease: 64 with NAFLD (non-alcoholic fatty liver disease), 123 with other chronic liver disease (e.g. viral hepatitis, n=71; autoimmune disease, n=18; alcohol-induced liver disease, n=3; or elevated liver enzymes of unknown origin, n=31) and 45 with cirrhosis. Circulating adiponectin levels were significantly lower in patients with NAFLD in comparison with patients with other chronic liver disease (4.8+/-3.5 compared with 10.4+/-6.3 microg/ml respectively; P<0.0001). Circulating adiponectin levels were significantly higher in patients with cirrhosis in comparison with patients without cirrhosis (18.6+/-14.5 compared with 8.4+/-6.1 microg/ml respectively; P<0.0001). Adiponectin concentrations correlated negatively with body weight (P<0.001), serum triacylglycerols (triglycerides) (P<0.001) and, in women, with BMI (body mass index) (P<0.001). Adiponectin concentrations correlated positively with serum bile acids (P<0.001), serum hyaluronic acid (P<0.001) and elastography values (P<0.001). Adiponectin levels were decreased in patients with NAFLD. In conclusion, adiponectin levels correlate positively with surrogate markers of hepatic fibrosis (transient elastography, fasting serum bile acids and hyaluronate) and are significantly elevated in cases of cirrhosis.

Facilitation by serum albumin of renal tubular secretion of organic anions.

The role of albumin in tubular secretion of the organic anions p-aminohippurate (PAH, 21% albumin-bound at 1 microM) and methotrexate (MTX, 55% bound at 1 microM), and of the organic cation N1-methylnicotinamide (NMN, not bound), was investigated in isolated rabbit S2 proximal tubules. PAH or MTX secretory rates were low in the absence of colloids or in the presence of 1 g/dl dextran 40, and were reversibly two- to sevenfold stimulated by either 1 g/dl bovine (BSA, either regular, defatted, and/or dialyzed) or rabbit serum albumin, or by dialyzed native rabbit plasma. NMN secretion was not stimulated by either dextran or albumin. Luminal BSA had no effect, but stimulation of PAH secretion was observed when albumin was present in both lumen and bath. This secretion was BSA concentration-dependent up to a 1 g/dl BSA. Saturation experiments suggested that 1 g/dl BSA may increase PAH apparent affinity for secretion, with no change in its maximum velocity. Albumin appears therefore to facilitate organic anion proximal secretion by an effect unrelated to oncotic pressure or to the extent of organic anion binding.

The value of serum procalcitonin level for differentiation of infectious from noninfectious causes of fever after orthopaedic surgery.

BACKGROUND: Early diagnosis of postoperative orthopaedic infections is important in order to rapidly initiate adequate antimicrobial therapy. There are currently no reliable diagnostic markers to differentiate infectious from noninfectious causes of postoperative fever. We investigated the value of the serum procalcitonin level in febrile patients after orthopaedic surgery. METHODS: We prospectively evaluated 103 consecutive patients with new onset of fever within ten days after orthopaedic surgery. Fever episodes were classified by two independent investigators who were blinded to procalcitonin results as infectious or noninfectious origin. White blood-cell count, C-reactive protein level, and procalcitonin level were assessed on days 0, 1, and 3 of the postoperative fever. RESULTS: Infection was diagnosed in forty-five (44%) of 103 patients and involved the respiratory tract (eighteen patients), urinary tract (eighteen), joints (four), surgical site (two), bloodstream (two), and soft tissues (one). Unlike C-reactive protein levels and white blood-cell counts, procalcitonin values were significantly higher in patients with infection compared with patients without infection on the day of fever onset (p = 0.04), day 1 (p = 0.07), and day 3 (p = 0.003). Receiver-operating characteristics demonstrated that procalcitonin had the highest diagnostic accuracy, with a value of 0.62, 0.62, and 0.71 on days 0, 1, and 3, respectively. In a multivariate logistic regression analysis, procalcitonin was a significant predictor for postoperative infection on days 0, 1, and 3 of fever with an odds ratio of 2.3 (95% confidence interval, 1.1 to 4.4), 2.3 (95% confidence interval, 1.1 to 5.2), and 3.3 (95% confidence interval, 1.2 to 9.0), respectively. CONCLUSIONS: Serum procalcitonin is a helpful diagnostic marker supporting clinical and microbiological findings for more reliable differentiation of infectious from noninfectious causes of fever after orthopaedic surgery.

Tartrate-Resistant Acid Phosphatase 5b: a Serum Marker of Bone Resorption

Bone is a physiologically dynamic tissue being constantly regenerated throughout life as a consequence of bone turnover by bone-resorbing osteoclasts and bone-forming osteoblasts. In certain bone diseases, such as osteoporosis, the imbalance in bone turnover leads to bone loss and increased fracture risk. Measurement of bone mineral density (BMD) predicts the risk of fracture, but also biochemical markers of bone metabolism have been suggested to be suitable for prediction of fractures and monitoring the efficacy of antiresorptive treatment. Tartrate-resistant acid phosphatase 5b (TRACP 5b) is an enzyme released from osteoclasts into the circulation, from where it can be detected kinetically or immunologically. Conventional assays for serum total TRACP were spectrophotometric and suffered from interference by other acid phosphatases and non-osteoclastic TRACP 5a isoform. Our aim was to develop novel immunoassays for osteoclastic TRACP 5b. Serum TRACP 5b levels were elevated in individuals with high bone turnover, such as children, postmenopausal women, patients with osteoporosis, Paget’s disease and breast cancer patients with bone metastases. As expected, hormone replacement therapy (HRT) in postmenopausal women decreased the levels of serum TRACP 5b. Surprisingly, the highest TRACP 5b levels were observed in individuals with rare autosomal dominant osteopetrosis type II (ADO2), which is characterized by high BMD and fracture risk with simultaneously elevated levels of deficient osteoclasts. In ADO2 patients, elevated levels of serum TRACP 5b were associated with high fracture frequency. It is likely that serum TRACP 5b reflects the number of inactive osteoclasts in ADO2. Similar results supporting the hypothesis that TRACP 5b would reflect the number of osteoclasts instead of their activity were observed with cultured osteoclasts and in animal models. Novel TRACP 5b immunoassays may prove to be of value either as independent or combinatory tools with other bone metabolic markers and BMD measurements in clinical practice and bone research.

Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy.

Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels. Conclusion: In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.

Undetectable serum anti-Müllerian hormone levels and occurrence of ongoing pregnancy.

OBJECTIVE: To discuss, on the basis of the experience of two clinical cases and extensive literature review, the significance of extremely low levels of anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting substance, in infertile women. DESIGN: Case report. SETTING: University-based infertility clinic at a medical center in Switzerland. PATIENT(S): Two women, 29 and 41 years of age and with a 2- and 4-year history of secondary infertility, respectively. INTERVENTION(S): Clinical, radiological, and biological investigation of infertility, including repeated measurements of the serum AMH with serial ELISA assays. MAIN OUTCOME MEASURE(S): Levels of AMH and development of ongoing pregnancy. RESULT(S): Both women had a spontaneous ongoing pregnancy despite undetectable AMH levels. CONCLUSION(S): Although it is helpful for day-to-day management of infertile patients, the predictive value of AMH for the occurrence of a spontaneous ongoing pregnancy has limits.