Co-administration of S enterica serovar Typhimurium expressing s

Co-administration of S. enterica serovar Typhimurium expressing swIL-18 and swIFN-α produced enhanced Th1-biased humoral and cellular immune responses against Fulvestrant the inactivated PrV vaccine, when compared to single

administration of S. enterica serovar Typhimurium expressing either swIL-18 or swIFN-α. Also, enhanced immune responses in co-administered piglets occurred rapidly after virulent PrV challenge, and piglets that received co-administration of S. enterica serovar Typhimurium expressing swIL-18 and swIFN-α displayed a greater alleviation of clinical severity following the virulent PrV challenge, as determined by clinical scores and cumulative daily weight gain. Furthermore, this enhancement was confirmed by reduced nasal shedding of PrV following viral challenge. Therefore, these results suggest see more that oral co-administration of S. enterica serovar Typhimurium expressing swIL-18 and swIFN-α provide enhanced Th1-biased immunity against inactivated PrV vaccine to alleviate clinical signs caused by PrV challenge. The

combined administration of two or more cytokines may produce effects that are antagonistic, additive, or synergistic (1). The potential effectiveness of cytokine combinations has been addressed empirically, based upon mechanisms to determine the nature of innate and acquired immunity (2–4). Among such effects, additive and synergistic effects may be useful when immunizing hosts. The enhanced Anidulafungin (LY303366) effects of cytokine

combinations for immunomodulation or antiviral activity have been evaluated in several infectious diseases of livestock animals such as FMD (5,6), PRRS (7), and PrV (8). The outstanding feature of interferon-alpha (IFN-α), which is a type I IFN, is its ability to nonspecifically inhibit viral growth by inducing the expression of numerous cellular genes through interaction with specific type I receptor complexes and triggering of the Janus-activated kinases (JAKs)-signal transducer and activators of transcription (STAT) 1/2 pathways (9). Interleukin 18 (IL-18), originally known as IGIF, can act on T helper 1 (Th1) cells, non-polarized T cells, NK cells, B cells, and DCs to produce IFN-γ in the presence of IL-12, through specific IL-18R complexes and triggering of MyD88-IRAK-TRAF (10). In addition, virus-infected macrophage-derived IL-18 and type I IFN (IFN-α/β) produced by the same cells synergistically induce rapid IFN-γ production, leading to the induction of Th1 immune responses (11). Therefore, type II IFN-γ induced by IL-18 may act synergistically with type I IFN to produce enhanced modulation of immune responses against specific antigens (5). Pseudorabies virus (PrV) is an alpha-herpes virus that causes a fatal illness in swine known as Aujeszky’s disease.

The definition of early sexual debut varied across studies and is

The definition of early sexual debut varied across studies and is displayed

for each study in Table 1. Studies that explored the impact of early age at first sexual debut on only high-risk behaviours, perceived risks or determinants of HIV/AIDS risk, such as condom use, multiple partners, other STIs or circumcision, were excluded. The abstracts of all 1572 relevant studies were screened by a single reviewer (NK) after 100% agreement was reached on applying the inclusion criteria to a sample of 250 abstracts between the two reviewers (NK and HS). Following this, the full texts of all studies learn more that could potentially be included in the review were obtained. After removing 13 duplicates, 128 full texts were retrieved and double-screened independently by two reviewers (NK and HS). Any differences in decisions were resolved through discussions. It had been decided that a third reviewer (CW) would be approached if there were differences in decision that could not be resolved; however,

this was not necessary as an agreement was reached on all studies. A total of 26 articles met the inclusion criteria and were included in the review. Two articles this website reported on the same data, and their information was therefore combined in the analysis, and they were treated Epothilone B (EPO906, Patupilone) as one study.[12, 13] Information about sample characteristics, setting,

study design, variables adjusted for and statistical results were extracted from the study by one reviewer (NK), and a confirmatory data extraction and quality appraisal were carried out by a second reviewer (HS). The quality appraisal was conducted using seven appraisal questions adapted from the graphical appraisal tool for epidemiological studies (GATE).[30] Each study could obtain a maximum score of 14, indicating the highest level of evidence. For each of the following components, a maximum score of two was given per study: focus of the study, generalisability of the findings, study design, use of adequate control variables, reliable and sensible outcome measures, sensitive reporting of biases and outcomes and ethics. It was agreed that a total score of 0–4 would imply very low quality, 5–8 low quality, 9–11 medium and 12–14 high. Any differences in scoring were resolved through discussions between the two reviewers. The findings of the systematic search first report the unadjusted bivariate associations that emerged in this review. Due to their equivocal outcomes, the multivariate findings of the review were summarised according to the conceptual framework (Fig. 2). Only studies that found a significant association in the unadjusted analysis are examined in the multivariate analysis.

The two-sided two-sample t-test was used to compare the mean chan

The two-sided two-sample t-test was used to compare the mean change in TGF-β between the treatment group and the control group. The significance level was 0·05. For secondary outcomes, the change from baseline (day 0) to values at days 3, 14, 28 and 63 was compared by group. Secondary measurements included expression of CD26 on lymphocyte subsets in PBMCs, percentages of lymphocyte subsets within PBMCs, cytokine and chemokine concentrations in plasma, cytokine

and chemokine Transferase inhibitor concentrations in LPS-stimulated PBMCs, clinical complete blood count (CBC) values, gene expression in whole blood, proliferation and production of cytokines and chemokines (including TGF-β) in supernatants from anti-CD3-stimulated PBMCs. Comparison of the two groups at specific time-points was performed with t-test or Mann–Whitney

U-test for quantitative variables and χ2 or Fisher’s exact test for categorical variables. The primary analysis of these secondary variables included day 28 only, and did not adjust for baseline. Subsequent analyses used generalized linear models to investigate changes over time and a Bonferroni’s correction was applied to account for the multiple time-points. A P-value of 0·0125 was used. These analyses included an adjustment for baseline and log transformation Selleck EPZ6438 as needed. The analysis of correlations between the change in activity level of DPP-4 and changes

in immune parameters was performed using Pearson’s correlations using GraphPad Prism. Each individual’s percentage change in DPP-4 activity level mafosfamide was calculated from their individual day 0 value and each subsequent on-drug time-point (days 3, 14, 28); Pearson’s correlations were then calculated between this percentage baseline DPP4 activity and immune parameters (calculated as change from baseline at each time-point, as indicated above). A significant increase in active GLP-1 levels was observed in the sitagliptin group but not the placebo group, indicating that this group was taking active drug (Fig. 2a). As expected, because participants were fasting at the time of the blood draws, GLP-1 levels were low, with an average of 4·9 pg/ml at baseline (day 0). In addition, DPP-4 enzyme activity levels were measured, and a significant drop (P < 0·0001) in the percentage activity compared to day 0 was observed in the sitagliptin group, but not the placebo group (Fig. 2b). On average, while taking sitagliptin, this group showed 50–60% inhibition of activity. The primary outcome for this study was the change in total plasma TGF-β levels from baseline (day 0) to day 28, comparing the group that received sitagliptin and the placebo group.

Two relatively recent studies have used a more systematic approac

Two relatively recent studies have used a more systematic approach to RNAi to evaluate its use as a functional genomic profiling tool. Mourao et al. (76) selected 32 genes including antioxidants, transcription factors, cell signalling molecules and metabolic enzymes to determine whether gene knock-down by RNAi was associated with morphologically definable phenotypic changes in early larval development (miracidia/sporocyst). A ‘size-reducing’ phenotype was observed in 33% of the treated parasites. Interestingly, only six of the 11 phenotype-associated

genes showed a consistent knock-down of the corresponding transcript. In similar experiments using schistosomula, Stefanic and colleagues (77) Selleckchem Caspase inhibitor evaluated genes that are expressed in different tissues of the parasite.

Parameters that were investigated included transfection strategy, time and dose-dependency of RNAi, and dosing limits. The authors concluded that RNAi was best achieved by soaking parasites in dsRNA and that electroporation provided no added benefit, in contrast to an earlier report (75). Similar to the results reported by Mourão et al., the efficiency of RNAi was transcript dependent and varied from 40% to 75%. Together, these reports showed that gene-specific testing of RNAi might be necessary to achieve discernable phenotypic effects, which might limit the use of RNAi as a screening method. Liver flukes are responsible for substantial disease in humans and livestock in most countries around the world

(78). Although traditionally regarded as a disease of livestock, fascioliasis is now recognized as a serious, and neglected, emerging zoonotic disease. In spite of the major socioeconomic impact of fascioliasis, there are presently no nuclear genomic sequence datasets for Fasciola or related species. Until recently, <7000 ESTs representing adult Fasciola hepatica from two different hosts and two different countries have been generated ( and but these data have yet to Phospholipase D1 be annotated or analysed in detail. To date, two reports have been published (Tables 1 and 2) to evaluate the utility of RNAi in these parasites. Rinaldi et al. transformed newly excysted juveniles (NEJs) by electroporation with luciferase mRNA and were subsequently able to detect luciferase enzyme activity. The presence of an active RNAi pathway in F. hepatica was then shown by knocking down the exogenous luciferase activity by additional introduction of dsRNA specific to luciferase. The authors also tested the RNAi pathway by targeting LAP. They observed a significant reduction in specific mRNA levels (79). A few months later, McGonigle et al. reported successful silencing of the cysteine proteases cathepsin B and L in NEJs.

The action of PTH on the kidneys remains until GFR decreases to a

The action of PTH on the kidneys remains until GFR decreases to as low as 3 mL/min. Residual renal function plays a significant role in phosphate elimination, and it is possible that FGF-23 no longer acts effectively to excrete phosphate in the urine in these patients. “
“Background:  We tested the hypothesis that patterns of serum creatinine concentrations (S-cr) prior to percutaneous renal biopsy (PRB) predict the utility of PRB in safely making renal diagnoses, revealing treatable disease, and altering therapy

in chronic kidney EX 527 cost disease patients. Methods:  PRB specimens (170 patients) were assigned to 1 of 5 groups: S-cr never greater than 0.11 mM for at least 6 months prior to PRB (Group 1); S-cr greater than 0.11 mM but less than 0.18 mM during the 6 months prior to PRB (Groups 2); S-cr less than 0.18 mM during the 6 months prior to PRB but greater than 0.18 mM prior to these 6 months (Group 3); S-cr greater than 0.18 mM for

less than 6 months prior to PRB (Group 4); S-cr greater than 0.18 mM for more than 6 months prior to PRB (Group 5). Results:  Histopathology chronicity score (0–9) increased with increasing group number: 2.1 (Group 1); 4.4 (Group 2); 4.5 (Group 3); 5.4 (Group 4); 7.0 (Group 5). Post-PRB bleeding was more common with increasing group number. New therapy was instituted after PRB most frequently in Group 4 (62%) and least frequently in Group 5 (24%). Conclusion:  After more prolonged elevations of S-cr, PRB may be less safe and less likely to reveal treatable disease and opportunities for therapy. “
“Aim:  Blind peritoneal dialysis (PD) catheter instrumentation with a Tenckhoff trocar is performed Interleukin-3 receptor without direct visualization of the peritoneum. This method requires the least equipment, it is safe and it can be performed mainly by nephrologists. We report here on our long-term experience with this method as performed by nephrologists. Methods: 

We reviewed the medical records at Yeungnam University Hospital in Korea and identified all the patients who had undergone blind PD catheter instrumentation with a Tenckhoff trocar by nephrologists. Four hundred and three patients were enrolled. Results:  Early complications occurred in 7.7% (four patients with pericatheter bleeding, one patient with pleural leakage, two patients with migration, two patients with omental wrapping, three patients with exit site/tunnel infection and 19 patients with peritonitis). The late mechanical complications included eight cases of hernia, three cases of catheter extrusion, five cases of leakage, four cases of migration and five cases of omental wrapping. Exit site/tunnel infection and peritonitis occurred at a rate of 0.067 and 0.40 episodes/year, respectively. The intervention free survival rate was 84.5% at one year and 63.3% at 5 years. The catheter survival rate was 96.5% at one year and 83.6% at 5 years.

Readout of a neo-epitope on the TCC, which is dependent of hydrop

Readout of a neo-epitope on the TCC, which is dependent of hydrophobic interactions with the target, could thus be influenced by other factors than the upstream complement components. The complement activity levels were analysed

in patients with defined complement deficiencies. Serum samples deficient in C2 showed normal AP activity but undetectable CP DAPT in vitro and LP activity. This is due to a lack of formation of a functional CP and LP C3-convertase. Factor I and factor H deficiency leads to sustained consumption of complement, which explains the reduced complement activity in all the pathways. Sera from patients diagnosed with HAE, due to lack of the inhibitor of C1r/s (C1INH) were also tested. Lack of C1INH leads to consumption of components of the classical pathway [24], and consistent with this, a decreased functional activity of the classical pathway was demonstrated

in nine of 10 of these sera. These results demonstrate that by analysing and comparing the functional capacity of each complement p38 MAPK signaling pathway, it is possible to obtain reliable clues to which component(s) of the complement system that are functionally defect or present in insufficient amount to activate complement. In summary, we have developed and analysed ELISA-based assays for the measurement of the functional activation capacity of the three complement pathways. These methods are applicable at high serum concentrations, which minimize false negative and represent – especially for the assessment of the MBL activity – an improvement on the existing assays. This work was supported by the University of Southern Denmark and the John and Birthe Meyer Foundation. A PCT application (PCT/DK2008/050221) has been submitted

for the use of SPS in complement assays. “
“Infections that occur early in life may have a beneficial effect Flavopiridol (Alvocidib) on the immune system and thereby reduce the risk of allergen sensitization and/or allergic disease. It is not yet clear to what extent specific virus and/or bacteria can mediate this effect. The purpose of this study was to assess the role of virus and bacteria in CD4+ T cell-derived cytokine production in newborns. We compared the effects of five bacteria (Staphlococcus aureus, Escherichia coli, Clostridium difficile, Lactobacillus rhamnosus and Bifidobacterium bifidus) and seven virus (adenovirus, coronavirus, cytomegalovirus, herpes simplex virus, influenza virus, morbillivirus and poliovirus) on the Th1/Th2 cytokine production in mixed lymphocyte reactions using CD4+ T cells from cord blood cocultured with allogenic myeloid or plasmacytoid dendritic cells. When comparing the baseline cytokine production prior to microbial stimulation, we observed that cord plasmacytoid DC were stronger inducers of Th2 cytokines (IL-5 and IL-13) compared with cord myeloid DC and to adult DC.

Indocyanine green (ICG) lymphography using near-infrared camera s

Indocyanine green (ICG) lymphography using near-infrared camera system visualizes superficial lymph flows, and greatly helps lymphatic supermicrosurgeons to decide skin incision sites for LVA surgery.[5-9] However, finding lymphatic vessels is not easy even PARP inhibitor with preoperative ICG lymphography guidance, because translucent lymphatic vessels exist in the yellow fat tissue and are difficult to be illuminated by ICG lymphography during microscopic dissection. Recently, a microscope

equipped with an integrated near-infrared illumination system has been used for intraoperative evaluation of blood flow in neurosurgery.[10, 11] The microscope illuminates ICG-enhanced blood vessels during microscopic procedures, and is useful for precise blood flow evaluation after neurosurgical vascular reconstruction. The microscope is considered ideal tool for lymphatic visualization during microscopic dissection of lymphatic vessels, and we adopted the microscope for LVA surgery as intraoperative microscopic ICG lymphography. This study aimed to evaluate usefulness of the microscope for lymphatic supermicrosurgery. From August 2010 to March 2011 under the University of Tokyo Hospital ethical committee-approved protocol, we performed ICG lymphography and LVAs on 12 patients with secondary lower extremity lymphedema (LEL)

refractory to compression therapy using elastic stockings. All PD0332991 solubility dmso patients included in this study had undergone radical hysterectomy and pelvic lymphadenectomy for the treatment of uterine carcinoma, and suffered from progressive lymphedema due to obstruction of lymph flow at the pelvic region. Patients’ age ranged from 36 to 71 years (average, 52.0 years), body mass index (BMI) ranged from 19 to 29 (average, 22.9), and leg dermal backflow (LDB) stage determined by ICG lymphography ranged from

stages II to V (Fig. 1).[6] All patients gave written consent to this study. As we reported previously, 0.2 ml of 0.25% ICG was subcutaneously injected at the first web space of the foot the day before surgery for preoperative severity evaluation and intraoperative guidance.[5, 6] An operating microscope equipped with an integrated near-infrared illumination system (OME-9000; Olympus, Tokyo, Japan) was adopted for LVA surgery OSBPL9 in 7 cases; an operating microscope without the illumination system was used in other 5 cases. Incision sites were decided based on preoperative ICG lymphography using a hand-held near infrared illumination camera system (Photodynamic Eye, Hamamatsu Photonics K.K., Hamamatsu, Japan), and were usually made along the greater saphenous vein. After infiltration anesthesia with 1% lidocaine with 1:100,000 epinephrine, ∼2 cm-long skin incision was made. Adipose layer was dissected seeking for lymphatic vessels with or without guidance of intraoperative microscopic ICG lymphography using the microscope.

Hooibrink, T van Capel, F van Alphen, and E Mul for help with

Hooibrink, T. van Capel, F. van Alphen, and E. Mul for help with FACS sorting, E.Mul and T. Poplonski for help with ImageStream analysis, and the volunteers for donating blood. We also thank Dr. M. Nolte for critical reading of the manuscript. This work has been supported by the Dutch Science Foundation (VENI 916.76.127, M.C.W.). J.J.K. is supported through a personal VIDI grant (917.66.310; Dutch Science Foundation) to B.B. The authors declare no financial or commercial conflict of interest. Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Supporting Information Figure 1. (A) NAB2 is induced in human pDCs upon CpG, but not upon type I IFN stimulation.

Primary human pDCs were activated for 4h with 12.5 μg/ml CpG A or 200 ng/ml IFNα, and NAB2 protein levels were assessed. (B-F) CpG activated CAL-1 cells express CD40, IFNβ and MXA, and kill target cells in a TRAIL-dependent manner. CAL-1 HIF pathway C646 price cells were left untreated (-) or activated with Control CpG (Ctrl), CpG or IFNβ for 4h, and CD40 protein levels were measured by flow cytometry and compared with isotype control staining of CpG treated CAL-1 cells (B). mRNA levels of CD40 (C), IFNβ (D) and MXA (E) were assessed by RT-PCR. (F) CAL-1-EV cells were left untreated or CpG-activated for 6h prior to co-culture with DDAO-labeled Jurkat cells for 20h in a ratio 25:1. TRAIL-dependent killing was assessed

by adding 10 μg/ml anti-TRAIL antibody to CAL-1 cells 30 min prior to the co-culture (CpG+αTRAIL). Apoptosis induction of DDAO+ Jurkat cells was assessed by AnnexinV or Active Methocarbamol Caspase-3 stainings. Numbers represent the percentage of AnnexinV or Active Caspase-3 positive cells. Data are representative of at least 8 (B-D) or 2 (E-F) independent experiments (**p<0.005, ***p<0.001). Supporting Information Figure 2. Activation of CAL1 cell variants with CpG results

in comparable induction of CD40, TNF-α and IRF-7. CAL-1 cell variants were left untreated (Ctrl) or activated for 6h with CpG. (A) CD40 levels were assessed by flow cytometry. Left panel: one representative analysis of CD40 expression of one of 3 independently performed experiments combined in the right panel. (B) TNF-α and IL-6 cytokine expression were measured in the supernatant of 6h untreated or CpG-stimulated CAL-1 cell variants. (C) IRF-7 expression was measured by intracellular flow cytometry staining in CAL-1-EV, – NAB2, -NAB2E51K untreated or stimulated for o/n with CpG. The mean of GeoMFI of IRF-7 minus isotype control are shown. Data are representative of 3 independent experiments (*p<0.05, ***p<0.001). ND: not detectable. Supporting Information Figure 2. IRF-7 nuclear translocation in CAL-1 cells is not affected by exogenous expression of NAB2 or NAB2E51K. (D-F) CAL-2-EV, -NAB2, or -NAB2E51K were left untreated (Ctrl) or stimulated with CpG for 6h, and IRF-7 translocation was measured with ImageStream technology.

These results suggest that the immune system exploits the differe

These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity. CTLA-4

is an important regulator of T-cell responses [1-4]. Its critical role is highlighted by CTLA-4 knockout mice, which develop a fatal lymphoproliferative disorder soon after birth, arising from a profound failure of T-cell homeostasis [5, 6]. Despite these potent effects, the activities of CTLA-4 are only partially understood. CTLA-4 shares sequence homology and B7 ligands (CD80/CD86) with the costimulatory molecule, CD28, but differs by delivering inhibitory, rather than activating, signals to the T cells on which it is expressed as a receptor [7, 8]. Upregulation of CTLA-4 on activated T cells provides a mechanism for negative feedback MK-2206 in vitro to control their responses. However, not all its regulatory effects are explained by inhibitory costimulation, since CTLA-4 can also suppress activated effector T-cell populations without the need for them to express it [9, 10]. This latter, cell-extrinsic mechanism has

been largely attributed to CD4+ regulatory T (Treg)-cell subsets, which constitutively express high levels of CTLA-4, Small molecule library and require it for their regulatory function [11-16]. How Treg cells might use CTLA-4 to regulate effector T-cell responses remains controversial. It has been suggested that CTLA-4 on Treg cells binds B7 and thus blocks CD28-mediated effector T-cell costimulation, or that it induces inhibitory mechanisms BCKDHB in the APC such as the IDO tryptophan catabolic enzyme cascade [17], or the FoxO3 transcription factor that controls inflammatory cytokine production [18]. Recently, a direct role for CTLA-4 in mediating cell-extrinsic activity has been supported by the observation that CTLA-4 is a component of a transendocytosis process to remove CD80/CD86 from APCs, an inhibitory mechanism that suppresses costimulation of activated effector T-cell populations

[19]. However, it remains unclear whether any of these mechanisms fully explains the regulatory properties of CTLA-4. A paradox arising from the competing models of CTLA-4 activity is that the same T-cell surface molecule can apparently mediate not only cell-intrinsic negative costimulation, but also extrinsic regulation of other cells. This might be resolved if CTLA-4 had functions other than as a receptor. It has been widely assumed that all the activities of CTLA-4 are exclusive to the full-length membrane-bound receptor isoform (mCTLA-4), encoded in humans by exons 1–4 on chromosome 2, but other alternatively spliced mRNA transcripts have been detected, including one that generates a secretable soluble form, sCTLA-4 [20, 21].

We also need to better understand the relationship between altere

We also need to better understand the relationship between altered maternal angiogenic status and the remodeling of existing vessels, and to identify the linkage between changes in blood pressure, such as those that occur in preeclamptic women, and other factors that lead to the induction RG7420 nmr of endothelial dysfunction. While the term “endothelial dysfunction” is widely used, it primarily connotes altered vasodilation to acute changes in flow in vivo (such as brachial artery dilation following occlusion) or to endothelium-specific chemical stimuli such as acetylcholine in isolated vessels. For a versatile cell that carries out a number of important physiological functions

and responds to hemodynamic, humoral, and immune factors by altering its secretory and metabolic activities, we would do well to expand our understanding of normal vs. abnormal endothelial function, and of how it is affected by gestational disease. Clearly, additional research is needed to better understand the process of uterine vascular remodeling during pregnancy, and why it may be impaired in disease states such as preeclampsia and intrauterine growth restriction (IUGR). Such diseases, while simple to diagnose, remain difficult to predict and

impossible to cure. The integration of physiological with molecular, genomic, and genetic technologies can help to improve our understanding of how the processes learn more of vascular remodeling, determinants of endothelial dysfunction, and novel mechanisms such as venoarterial exchange interact at the level of the vascular wall so as to identify new treatments for these still all-too-common gestational diseases. Supported by NIH R21-HL112216 (GO) and RO1-HL079647

(LGM). George Osol is a Professor in the Division of Reproductive Investigation, Department of Obstetrics and Gynecology at the University of Vermont College Megestrol Acetate of Medicine, with secondary appointments in the Departments of Molecular Physiology and Pharmacology. His research is focused on understanding the patterns, pathways, and molecular mechanisms that underlie uterine vascular adaptation in normal vs. hypertensive/preeclamptic pregnancy. Dr. Osol is an Established Investigator of the American Heart Association and a Fellow of the American Physiological Society. He is also the Program Director of the NIH Center for Excellence in Women’s Reproductive Health Research (WRHR) at the University of Vermont College of Medicine. Lorna G. Moore is a Professor in the Department of Obstetrics and Gynecology with joint appointments in the Departments of Medicine, Emergency Medicine, and the Colorado School of Public Health. Her research uses high altitude as a natural laboratory for studying the physiological as well as genetic mechanisms that underlie the pregnancy complications of fetal growth restriction and preeclampsia, both of which are more common at high than at low altitude.