Placental iron transport and maternal absorption

The iron need in pregnancy is significantly higher in comparison to that in the nonpregnant state. The iron absorbed during pregnancy is used for expansion of the maternal erythrocyte mass, to fulfill the fetus's iron needs, to create placenta, and to cope with blood loss at delivery. Term neonates have a total body store of about 1 g of iron, all derived from the mother. Despite the overall increase in nutritional requirements, biochemical, metabolic, and physiological adjustments of the maternal organism happen in order to meet the extra demands and to support the homeostasis of iron. In all healthy pregnant women with sufficient iron stores, the increased iron absorption is coupled with the mobilization of iron stores. Unfortunately, iron deficiency during pregnancy is alarmingly common. The function of placental transport determines the composition of umbilical cord blood providing nutrients and oxygen to the fetus to ensure appropriate fetal growth. Iron in the developing fetus is accumulated against a concentration gradient and, in the case of maternal iron deficiency, the placenta can protect the fetus significantly through the increased expression of placental transferrin receptor together with a rise in divalent metal transporter 1 (DMT1). Despite the resistance of the fetus to maternal deficiency, any stress that alters placental development or function may have consequences for the developing fetus. Despite its central importance in fetal development, little is known about the mechanism of iron transfer across the placenta. Consequently, it is crucial to understand the molecular basis of placental iron transport in order to optimize the iron intake recommendation, reducing adverse pregnancy outcomes for both the mother and her child.     

Safety and efficacy of endoscopic retrograde cholangiopancreatography in patients with post-liver transplant biliary complications: results of a cohort study with long-term follow-up

Background/Aims

Endoscopic retrograde cholangiopancreatography (ERCP) is the standard approach for the management of biliary complications in liver transplant patients; however, its safety and efficacy have not been established in this setting. This study was performed to evaluate the safety and long-term efficacy of ERCP in transplant patients.

Methods

The case reports of 1,500 liver transplant patients were reviewed. Orthotopic liver transplantation (OLT) patients were matched 1:2 with non-OLT patients and followed-up for long-term outcome (median, 7.4 years).

Results

Of the 1,500 liver transplant patients, 94 (6.3%) underwent 150 ERCPs after OLT. Anastomotic strictures were present in 45 patients, biliary stones in 24, biliary leaks in 7, papillary stenosis in 2, and primary sclerosing cholangitis in 1. An ERCP success rate of 90.7% was achieved; biliary stenting led to resolution of the bile leak in 7/7 (100%) patients, and biliary stones were removed in 21/24 (87.5%) patients. In addition, 34 of 45 patients with anastomotic stricture underwent endoscopic dilation. We obtained complete resolution in 22/34 (64.7%) patients. OLT patients did not show a higher probability of complications (odds ratio [OR], 1.04), of pancreatitis (OR, 0.80) or of bleeding (OR, 1.34).

Conclusions

ERCP is safe and effective for the treatment of post-OLT biliary complications, has a low rate of pancreatitis and results in a durable effect.     

Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150

Ontogenesis of T cells in the thymus is a complex process whose molecular control is poorly understood. The present study investigated microRNAs involved in human thymocyte differentiation by comparing the microRNA expression profiles of thymocytes at the double-positive, single-positive CD4(+) and single-positive CD8(+) maturation stages. Microarray analysis showed that each thymocyte population displays a distinct microRNA expression profile that reflects their developmental relationships. Moreover, analysis of small-RNA libraries generated from human unsorted and double-positive thymocytes and from mature peripheral CD4(+) and CD8(+) T lymphocytes, together with the microarray data, indicated a trend toward up-regulation of microRNA expression during T-cell maturation after the double-positive stage and revealed a group of microRNAs regulated during normal T-cell development, including miR-150, which is strongly up-regulated as maturation progresses. We showed that miR-150 targets NOTCH3, a member of the Notch receptor family that plays important roles both in T-cell differentiation and leukemogenesis. Forced expression of miR-150 reduces NOTCH3 levels in T-cell lines and has adverse effects on their proliferation and survival. Overall, these findings suggest that control of the Notch pathway through miR-150 may have an important impact on T-cell development and physiology.     

Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party

To specify the incidence and risk factors for secondary autoimmune diseases (ADs) after HSCT for a primary AD, we retrospectively analyzed AD patients treated by HSCT reported to EBMT from 1995 to 2009 with at least 1 secondary AD (cases) and those without (controls). After autologous HSCT, 29 of 347 patients developed at least 1 secondary AD within 21.9 (0.6-49) months and after allogeneic HSCT, 3 of 16 patients. The observed secondary ADs included: autoimmune hemolytic anemia (n = 3), acquired hemophilia (n = 3), autoimmune thrombocytopenia (n = 3), antiphospholipid syndrome (n = 2), thyroiditis (n = 12), blocking thyroid-stimulating hormone receptor antibody (n = 1), Graves disease (n = 2), myasthenia gravis (n = 1), rheumatoid arthritis (n = 2), sarcoidosis (n = 2), vasculitis (n = 1), psoriasis (n = 1), and psoriatic arthritis (n = 1). After autologous HSCT for primary AD, the cumulative incidence of secondary AD was 9.8% ± 2% at 5 years. Lupus erythematosus as primary AD, and antithymocyte globulin use plus CD34(+) graft selection were important risk factors for secondary AD by multivariate analysis. With a median follow-up of 6.2 (0.54-11) years after autologous HSCT, 26 of 29 patients with secondary AD were alive, 2 died during their secondary AD (antiphospholipid syndrome, hemophilia), and 1 death was HSCT-related. This European multicenter study underlines the need for careful management and follow-up for secondary AD after HSCT.     

Occurrence of organ-specific and systemic autoimmune diseases among the first- and second-degree relatives of Caucasian patients with connective tissue diseases: report of data obtained through direct patient interviews

Studies have demonstrated a familial aggregation of systemic and organ-specific autoimmune diseases. The aim of the present survey was to obtain, by patient interviews, a preliminary estimate of the prevalence of systemic and organ-specific autoimmune diseases among the first- and second-degree relatives of Caucasian patients with connective tissue diseases (CTD) or inflammatory arthritis followed at our unit. Between June 2007 and January 2008, 626 patients and 85 controls (patients with osteoarthritis, osteoporosis, or fibromyalgia) were interviewed. Three hundred ten patients (50%) versus 21 controls (25%) were found to have at least one relative affected with an autoimmune condition (p < 0.0001). The most common conditions were organ-specific autoimmune diseases: 160 (34%) autoimmune thyroid (AT) disease, 112 (24%) psoriasis, 21 vitiligo, and 19 insulin-dependent diabetes mellitus. Systemic autoimmune diseases were reported in 126 relatives: rheumatoid arthritis (66 cases, 14%), 16 sacroileitis, and CTD (43 cases). A significant difference was observed in the prevalence of AT disease between the relatives of the patients and controls (3% versus 0.5%). In conclusion, these data confirm the high prevalence of autoimmune conditions, particularly of AT disease, among the relatives of patients.     

Simvastatin treatment in subjects at high cardiovascular risk modulates AT1R expression on circulating monocytes and T lymphocytes

OBJECTIVE: Angiotensin II, through the activation of angiotensin II type 1 receptors, plays a crucial role in atherosclerosis. Statins may interfere with the effects of angiotensin II. METHODS: We have investigated the expression of angiotensin II type 1 receptor, angiotensin II type 2 receptor and angiotensinogen on circulating monocytes and T-lymphocytes from subjects at high risk for vascular events before and during simvastatin treatment, and healthy controls. In-vitro experiments were also performed to assess the ability of simvastatin to interfere with angiotensin II signalling. RESULTS: In comparison with controls, high-risk subjects had similar angiotensin II type 1 receptor expression on the cell membranes but significantly higher angiotensin II type 1 receptor mRNA levels at least in monocyte subsets whereas their expression on T cells was similar. Angiotensin II type 2 receptor mRNA expression was higher than controls in both monocytes and T lymphocytes. No differences were observed in angiotensinogen expression on monocytes while T lymphocytes of high-risk subjects show higher expression. One-month treatment of high-risk subjects with simvastatin resulted in a reduction of angiotensin II type 1 receptor mRNA without affecting angiotensin II type 2 receptor whereas angiotensinogen mRNA expression was reduced at least in monocytes. Incubation in vitro with simvastatin reduces the expression of angiotensin II type 1 receptor mRNA levels on monocytes from untreated subjects. CONCLUSION: Simvastatin induces down-regulation of the angiotensin II type 1 receptor, interferes with angiotensin II activity in immune cells and contributes to the anti-inflammatory profile of statins that can explain the therapeutic effects of these drugs.     

Influence of corevalve revalving system implantation on mitral valve function

Objectives : The purpose of this study is to verify whether transcatheter aortic valve implantation (TAVI) determined changes in mitral valve (MV) function, in terms of mitral regurgitation (MR) and stenosis. Background : Little data is available regarding the effects of TAVI on global MV function, often derived from analysis primarily focused on clinical and aortic related outcomes. Methods : From May 2008 to March 2010, 73 patients with severe symptomatic aortic stenosis underwent TAVI with the CoreValve ReValving System. The study population consisted of 58 patients (27 males, mean age 82 ± 7 years) who underwent transthoracic echocardiography at least ≥1 month after implantation (mean follow‐up 7.8 ± 5.4 months). Results : In patients with a left ventricular dysfunction (ejection fraction, EF, <45%) at the baseline, EF significantly increased from 37 ± 6% to 48 ± 7% after TAVI (P = 0.003). Before TAVI, 42 patients had no or mild MR, 13 mild‐to‐moderate, and 3 moderate or moderate‐to‐severe. During follow‐up, the MR degree was unchanged in the majority of patients (55%), 12% reduced, and 33% worsened. Variables associated with worsening in MR were depth of aortic prosthesis (P = 0.02 for the distance between the ventricular end and the right coronary cusp; P = 0.04 for mean distance right‐left coronary cusps) and left atrium area at the baseline (P = 0.02). After TAVI, six patients (10%) developed mild or moderate mitral stenosis, often in a native valve with anterior calcifications. Conclusions : In the majority of patients no significant changes occurred in the degree of MR in native valve, but we found that if the aortic valve was deeply implanted in the left ventricle outflow tract, a worsening in MR can be observed. A mitral stenosis development must be sought in patients with heavy calcifications of the anterior leaflet. © 2011 Wiley‐Liss, Inc.     

Prognostic value of troponins in patients with non-ST-segment elevation acute coronary syndromes and chronic kidney disease

BACKGROUND: The prognostic value of cardiac troponins (cTn) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and chronic kidney disease (CKD) is debated. HYPOTHESIS: We tested the performance of cTnI and cTnT for risk stratification in patients with CKD and evaluated the prognostic significance of cTnI and cTnT elevations by their magnitude across the range of CKD severity. METHODS: We examined correlations among cTn elevation, CKD, and in-hospital mortality in 31,586 high-risk patients with NSTE ACS included in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines initiative (CRUSADE). Cardiac tropinins I and T levels were categorized as ratios of each site's upper limit of normal (ULN) for myocardial necrosis: normal (cTn ratio < or =1 x ULN), mild (cTn ratio > 1-3 x ULN), and major (cTn ratio > 3 x ULN) elevation. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Stages of CKD were categorized as normal to mild (eGFR > 60 mL/min), moderate (eGFR 30-60 mL/min), or severe (eGFR < 30 mL/min). RESULTS: Mortality increased more steeply across CKD stages (2.0%-12.9%) than across cTn ratio categories (2.7%-5.4%). In normal or mild CKD, mortality was low regardless of cTn elevations. In moderate CKD, mortality increased incrementally with cTnI (3.3% versus 5.4% versus 7.4%) and cTnT (3.7% versus 5.3% versus 7.3%) elevation. Among severe CKD patients, only major cTn elevations further distinguished risk (cTnI: 10.1% versus 9.7% versus 14.6%; cTnT: 7.0% versus 5.7% versus 14.0%). CONCLUSIONS: In patients with CKD, cTnI and cTnT perform equally in differentiating short-term prognosis following NSTE ACS; however, the prognostic impact of cTn is dependent upon the degree of CKD severity.     

Clinical and ultrasonographic monitoring of response to adalimumab treatment in rheumatoid arthritis

OBJECTIVE: To evaluate by clinical, laboratory, and sonographic assessment the effects of adalimumab therapy in patients with rheumatoid arthritis (RA) over 24 months of treatment. METHODS: Twenty-five patients with RA were commenced on adalimumab therapy. Before the beginning of the therapy (Time 0) and after 3 (T1), 12 (T2), and 24 (T3) months we evaluated erythrocyte sedimentation rate, C-reactive protein, physician and patient visual analog scale for disease activity, number of tender and swollen joints, Health Assessment Questionnaire, and Disease Activity Score in 28 joints. In addition, musculoskeletal ultrasound (US) was performed bilaterally in the 2nd and 5th metacarpophalangeal, 3rd interphalangeal, wrist, and knee joints and in the tendon sheaths and bursae of those areas. A semiquantitative score (0 3) was used to indicate the presence of a localized inflammatory process and/or structural damage. The summed total was used as an indicator of global change in each joint (single joint score). The sum of the single joint scores was used as an indicator of overall polyarticular involvement in each patient (total score). RESULTS: Patients who did not submit to the planned examinations strictly on time were excluded from the study. Then 25 patients were examined at T0 and T1, 20 at T2, and 9 at T3. All clinical and laboratory measures as well as the US scores were significantly reduced during the followup. CONCLUSION: A positive response to treatment with adalimumab was demonstrated by clinical, laboratory, and US evaluation by both short- and longterm followup.     

Ghrelin inhibits steroid biosynthesis by cultured granulosa-lutein cells

CONTEXT: Growing evidence indicates that ghrelin may participate in the regulation of different aspects of reproductive function. The genes encoding for this peptide and its receptor are expressed in the human ovary, but their functional role is still unknown. OBJECTIVE: The aim of our study was to assess whether ghrelin has any effect on steroid synthesis by human granulosa-lutein cells and to identify the receptor isoform through which this potential effect is exerted. DESIGN, PATIENTS, AND METHODS: Thirty-five women with spontaneous ovulatory cycles undergoing in vitro fertilization for infertility due to uni- or bilateral tubal impatency or male factor were studied. Granulosa-lutein cells obtained from follicular fluid were incubated with increasing amounts of human acylated ghrelin (10(-11) to 10(-7) mol/liter) either alone or together with a 1:500 concentration of a specific anti-ghrelin receptor antibody [GH secretagogue receptor 1a (GHS-R1a)]. Culture media were tested for estradiol (E(2)) and progesterone (P(4)). The expression of GHS-R1a and GHS-R1b in human granulosa-lutein cells was also studied by real-time quantitative PCR. RESULTS: E(2) and P(4) concentrations in the culture media were significantly reduced by ghrelin in a dose-dependent fashion. The maximal decrease in E(2) (25%) and P(4) (20%) media concentrations was obtained with the 10(-7) and 10(-8) mol/liter ghrelin concentrations, respectively. The inhibitory effect of all ghrelin concentrations used was antagonized by the specific anti-ghrelin receptor-1a antibody added to the culture media and not by the specific anti-ghrelin receptor-1b antibody. Both 1a and 1b isoforms of the GHS-R were expressed in human granulosa-lutein cells, with the latter exceeding the former's expression (GHS-R1b/GHS-R1a ratio, 143.23 +/- 28.15). CONCLUSIONS: Ghrelin exerts an inhibitory effect on granulosa-lutein cells steroidogenesis by acting through its functional GHS-R1a. This suggests that ghrelin may serve an autocrine-paracrine role in the control of gonadal function and be part of a network of molecular signals responsible for the coordinated control of energy homeostasis and reproduction.