Efficiency of Original versus Generic Intravenous Iron Formulations in Patients on Haemodialysis

Aims

The appropriate use of intravenous (IV) iron is essential to minimise the requirements for erythropoiesis-stimulating agents (ESAs). The clinical efficacy of generic IV iron compared to the original formulation is controversial. We evaluated the changes that were induced after switching from a generic IV iron to an original formulation in a stable, prevalent haemodialysis (HD) population.

Methods

A total of 342 patients were included, and the follow-up period was 56 weeks for each formulation. Anaemia parameters and doses of ESA and IV iron were prospectively recorded before and after the switch from generic to original IV iron.

Results

To maintain the same haemoglobin (Hb) levels after switching from the generic to the original formulation, the requirements for IV iron doses were reduced by 34.3% (from 52.8±33.9 to 34.7±31.8mg/week, p<0.001), and the ESA doses were also decreased by 12.5% (from 30.6±23.6 to 27±21μg/week, p<0.001). The erythropoietin resistance index declined from 8.4±7.7 to 7.4±6.7 IU/kg/week/g/dl after the switch from the generic to the original drug (p = 0.001). After the switch, the transferrin saturation ratio (TSAT) and serum ferritin levels rose by 6.8%(p<0.001) and 12.4%(p = 0.001), respectively. The mortality rate was similar for both periods.

Conclusions

The iron and ESA requirements are lower with the original IV iron compared to the generic drug. In addition, the uses of the original formulation results in higher ferritin and TSAT levels despite the lower dose of IV iron. Further studies are necessary to analyse the adverse effects of higher IV iron dosages.     

Chronic Endotoxemia in Subjects with Type-1 Diabetes Is Seen Much before the Onset of Microvascular Complications

Background

Lipopolysaccharide (LPS)/Endotoxin is hypothesized to play an important role in chronic inflammation associated with Type-1 diabetes (T1DM) and its complications. Endotoxin core antibodies (EndoCAb), LPS binding protein (LBP) and soluble CD14 (sCD14) act as modulators of LPS induced activation of innate immune system in vivo. For the present study we estimated the levels of LPS and its translocation markers in T1DM subjects with and without microvascular complications (MVC) and correlate them with clinical parameters of T1DM and serum inflammatory cytokine levels (TNF-α, IL-6, IL-1β and GM-CSF).

Methods

A total of 197 subjects (64 normal glucose tolerance (NGT) subjects, 97 T1DM subjects without MVC and 36 with MVC) were included in this study and the levels of serum LPS, its translocation markers and cytokines measured by immunoassays.

Results

Compared to NGT, T1DM subjects (both with and without MVC) had significantly higher levels of LPS, reduced levels of LBP and EndoCAb along with significant increase in the levels of IL-1β, IL-6, TNF-α and GM-CSF (p<0.05). No significant change was seen in the levels of these biomarkers between T1DM subjects with and without MVC.

Conclusions

Decreased levels of EndoCAb and LBP suggest sustained endotoxin activity in T1DM subjects even before the onset of microvascular complications.     

Comparison of Early Changes in Ocular Surface and Inflammatory Mediators between Femtosecond Lenticule Extraction and Small-Incision Lenticule Extraction

Purpose

To evaluate the short-term changes in ocular surface measures and tear inflammatory mediators after femtosecond lenticule extraction (FLEx) and small-incision lenticule extraction (SMILE) procedures.

Methods

Eighteen subjects (18 eyes) underwent FLEx and 23 subjects (23 eyes) underwent SMILE in this single-center and prospective study. Central corneal sensitivity, Schirmer I test (SIT), noninvasive tear breakup time (NI-TBUT), tear meniscus height, corneal fluorescein (FL) staining, and ocular surface disease index (OSDI) were assessed in all patients. Concentrations of interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), nerve growth factor (NGF), interferon-γ (IFN-γ), transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase-9 (MMP-9) in collected tears were measured by multiplex antibody microarray.

Results

Central corneal sensitivity was reduced in both groups, but the scores in the SMILE group were higher than those in the FLEx group at all time points postoperatively (P<0.01). Lower FL scores and longer NI-BUT were observed in the SMILE group 1 week after surgery (P<0.05). OSDI scores in both groups increased rapidly at 1 day and 1 week postoperatively, then returned to their preoperative levels within 1 month (P<0.05). There were no significant differences in SIT or tear meniscus height between the two groups. Lower and faster recovery of tear NGF, TGF-β1 and IL-1α concentration were found in the SMILE group compared to the FLEx group postoperatively. No significant difference was found in tear TNF-α, IFN-γ and MMP-9 for either group before or after surgery. Tear NGF, TGF-β1 and IL-1α show a correlation with ocular surface changes after FLEx or SMILE surgery.

Conclusion

SMILE has superiority over FLEx in early ocular surface changes and NGF, TGF-β1 and IL-1α may contribute to the process of ocular surface recovery.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02540785","term_id":"NCT02540785"}}NCT02540785     

Neuropeptide Y and α-MSH Circadian Levels in Two Populations with Low Body Weight: Anorexia Nervosa and Constitutional Thinness

Context

Anorexia nervosa (AN) presents an adaptive appetite regulating profile including high levels of ghrelin and 26RFa (orexigenic) and low levels of leptin and PYY (anorexigenic). However, this adaptive mechanism is not effective in promoting food intake. The NPY/proopiomelanocortin (POMC) system plays a crucial role in the regulation of feeding behavior as NPY is the most potent orexigenic neuropeptide identified so far and as the POMC-derived peptide α-MSH drastically reduces food intake, and this peptidergic system has not been thoroughly studied in AN.

Objective

The aim of the present study was thus to investigate whether a dysfunction of the NPY/POMC occurs in two populations with low body weight, AN and constitutional thinness (CT).

Design and Settings

This was a cross-sectional study performed in an endocrinological unit and in an academic laboratory.

Investigated Subjects

Three groups of age-matched young women were studied: 23 with AN (AN), 22 CT and 14 normal weight controls.

Main Outcome Measures

Twelve-point circadian profiles of plasma NPY and α-MSH levels were measured in the three groups of investigated subjects.

Results

No significant circadian variation of NPY was detected between the three groups. Plasma α-MSH levels were significantly lower in AN (vs controls) all over the day. The CT group, compared to controls, presented lower levels of α-MSH in the morning and the evening, and an important rise during lunchtime.

Conclusion

In AN patients, the NPY system is not up-regulated under chronic undernutrition suggesting that this may play a role in the inability of anorectic women to adapt food intake to their energy demand. In contrast, low circadian α-MSH levels integrate the adaptive profile of appetite regulation of this disease. Finally, in CT women, the important α-MSH peak detected during lunchtime could explain why these patients are rapidly food satisfied.     

A New Enzyme Immunoassay for the Quantitative Determination of Classical Autotaxins (ATXα, ATXβ, and ATXγ) and Novel Autotaxins (ATXδ and ATXε)

Background

Autotaxin (ATX) is a secreted enzyme that converts lysophosphatidylcholine to lysophosphatidic acid, a potent bioactive lipid mediator, through its lysophospholipase D activity. Although five alternative splicing isoforms of ATX have been identified as ATXα, ATXβ, ATXγ, ATXδ, and ATXε and the expression patterns of each isoform differ among several tissues, the clinical significance of each isoform remains to be elucidated.

Methods

Anti-ATXβ and anti-ATXδ monoclonal antibodies were produced by immunization with recombinant human ATXβ and ATXδ expressed using a baculovirus system, respectively. We then developed enzyme immunoassays to measure the serum concentrations of “classical ATX” (ATXα, ATXβ, and ATXγ) and “novel ATX” (ATXδ and ATXε) antigens and evaluated the usefulness of these assays using human serum samples.

Results

The with-run and between-run precision, interference, detection limit, and linearity studies for the present assay were well validated. In healthy subjects, the serum concentrations of classical ATX and novel ATX were significantly (P < 0.01) higher in women than in men, while the ratios of classical ATX or novel ATX to total ATX were not different between women and men. The concentrations of both classical ATX and novel ATX in normal pregnant subjects and patients with chronic liver diseases or follicular lymphoma were significantly higher than those in healthy subjects, while the ratio of both ATX isoforms to total ATX did not vary among these groups.

Conclusions

We have developed a new enzyme immunoassay to determine the concentrations of classical ATX and novel ATX in human serum. These assays may be helpful for elucidating the distinct functional roles of each ATX isoform, which are largely unknown at present.     

Adjunctive Medical Therapy with α-Blocker after Extracorporeal Shock Wave Lithotripsy of Renal and Ureteral Stones: A Meta-Analysis

Background

Although some trials assessed the efficacy and safety of the α-blocker in facilitating renal and ureteral stones expulsion after extracorporeal shock wave lithotripsy (ESWL), the role of the α-blocker in facilitating upper urinary calculi expulsion after ESWL remain controversial.

Aims

To determine the efficacy and safety of the α-blocker in facilitating renal and ureteral stones expulsion after ESWL.

Methods

A literature search was carried out using the PubMed database, EMBASE and the Cochrane Library database to identify relevant studies. Two reviewers independently extracted data and assessed methodological quality. Pooled effect estimates were obtained using a fixed- and random-effects meta-analysis.

Results

The meta-analysis included 23 RCTs, α-blocker significantly enhanced expulsion rate of upper urinary tract calculi after ESWL (P<0.00001; RR 1.21; 95% CI 1.12–1.31), significantly promoted steinstrasse expulsion (P=0.03; RR 1.25; 95% CI 1.03–1.53), significantly shortened the discharge time of upper urinary tract calculi (P=0.0001; MD -2.12; 95% CI -3.20–-1.04), significantly reduced the patient''s pain VAS score (P=0.001; RR -1.0; 95% CI -1.61–-0.39). Compared with the control group, dizziness (P=0.002; RR 5.48; 95% CI 1.91–15.77), anejaculation (P=0.02; RR 12.17; 95% CI 1.61–91.99) and headache (P=0.04; RR 4.03; 95% CI 1.04–15.72) in the α-blocker group was associated with a higher incidence.

Conclusions

Treatment with α-blocker after ESWL appears to be effective in enhancing expulsion rate of upper urinary tract calculi, shortening the discharge time of upper urinary tract calculi, reducing the patient''s pain. The side effects of α-blocker were light and few.     

RGD-Targeted Ultrasound Contrast Agent for Longitudinal Assessment of Hep-2 Tumor Angiogenesis In Vivo

Objective

To prepare arginine-glycine-aspartate (RGD)-targeted ultrasound contrast microbubbles (MBs) and explore the feasibility of their use in assessing dynamic changes in αvβ3 integrin expression in a murine model of tumor angiogenesis.

Methods

RGD peptides were conjugated to the surfaces of microbubbles via biotin-avidin linkage. Microbubbles bearing RADfK peptides were prepared as controls. The RGD-MBs were characterized using an Accusizer 780 and optical microscopy. The binding specificity of the RGD-MBs for ανβ3-expressing endothelial cells (bEnd.3) was demonstrated in vitro by a competitive inhibition experiment. In an in vivo study, mice bearing tumors of three different stages were intravenously injected with RGD-MBs and subjected to targeted, contrast-enhanced, high-frequency ultrasound. Subsequently, tumors were harvested and sectioned for immunofluorescence analysis of ανβ3 expression.

Results

The mean size of the RGD-MBs was 2.36 ± 1.7 μm. The RGD-MBs showed significantly higher adhesion levels to bEnd.3 cells compared to control MBs (P < 0.01). There was rarely binding of RGD-MBs to αvβ3-negative MCF-7 cells. Adhesion of the RGD-MBs to the bEnd.3 cells was significantly inhibited following treatment with anti-alpha(v) antibodies. The quantitative acoustic video intensity for high-frequency, contrast-enhanced ultrasound imaging of subcutaneous human laryngeal carcinoma (Hep-2) tumor xenografts was significantly higher in small tumors (19.89 ± 2.49) than in medium tumors (11.25 ± 2.23) and large tumors (3.38 ± 0.67) (P < 0.01).

Conclusions

RGD-MBs enable noninvasive in vivo visualization of changes in tumor angiogenesis during tumor growth in subcutaneous cancer xenografts.     

Determining an Optimal Cutoff of Serum β-Human Chorionic Gonadotropin for Assisting the Diagnosis of Intracranial Germinomas

Background

Beta (β)-human chorionic gonadotropin (β-HCG) is used to confirm the diagnosis and plan treatment of intracranial germinomas. However, the cutoff values of serum β-HCG in diagnosis of intracranial germinomas reported in the literature are inconsistent. To establish an appropriate cutoff value of serum β-HCG for diagnosis of intracranial germinomas, we retrospectively reviewed the records of intracranial tumor patients who received serum β-HCG and α-fetoprotein (AFP) tests for diagnostic purposes at our hospital from 2005 to 2014.

Methods

A total of 93 intracranial germinomas and 289 intracranial non-germ cell tumors were included in this study. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of 3 cutoffs (0.1, 0.4, and 0.5 mIU/mL) for diagnosing intracranial germinomas. The serum β-HCG level of intracranial germinoma patients was further analyzed to investigate the effect of metastasis status and tumor location on serum β-HCG level.

Results

The area under the ROC curve was 0.81 (P < .001), suggesting β-HCG is an effective marker. Of the 3 cutoff values, 0.1 mIU/mL possessed a highest sensitivity (66.67%) and good specificity (91%). Although there was no β-HCG level difference between metastatic and non-metastatic intracranial germinoma patients, the diagnostic rate of metastatic neurohypophyseal germinomas was significantly higher than that of its non-metastatic counterpart (P < .05), implying that the location of the germinoma might need to be considered when β-HCG is used as a marker to predict metastasis.

Conclusions

Determining an optimal cutoff of serum β-HCG is helpful for assisting the diagnosis of intracranial germinoma.     

Galactomannan and Zymosan Block the Epinephrine-Induced Particle Transport in Tracheal Epithelium

Background

Ciliary beating by respiratory epithelial cells continuously purges pathogens from the lower airways. Here we investigated the effect of the fungal cell wall polysaccharides Galactomannan (GM) and Zymosan (Zym) on the adrenergic activated particle transport velocity (PTV) of tracheal epithelium.

Methods

Experiments were performed using tracheae isolated from male C57BL/6J mice. Transport velocity of the cilia bearing epithelial cells was measured by analysing recorded image sequences. Generation of reactive oxygen species (ROS) were determined using Amplex Red reagents. PCR experiments were performed on isolated tracheal epithelium to identify adrenergic receptor mRNA.

Results

The adrenergic receptors α1D, α2A, β1 and β2 have been identified in isolated tracheal epithelium. We found epinephrine responsible for an increase in PTV, which could only be reduced by selective β-receptor-inhibition. In addition, either GM or Zym prevented the epinephrine induced PTV increase. Furthermore, we observed a strong ROS generation evoked by GM or Zym. However, epinephrine induced increase in PTV recovered in the presence of GM and Zym after application of ROS scavengers.

Conclusion

Both GM or Zym trigger reversible ROS generation in tracheal tissue leading to inhibition of the β-adrenergic increase in PTV.     

Association between Poor Glycemic Control,Impaired Sleep Quality,and Increased Arterial Thickening in Type 2 Diabetic Patients

Objective

Poor sleep quality is an independent predictor of cardiovascular events. However, little is known about the association between glycemic control and objective sleep architecture and its influence on arteriosclerosis in patients with type-2 diabetes mellitus (DM). The present study examined the association of objective sleep architecture with both glycemic control and arteriosclerosis in type-2 DM patients.

Design

Cross-sectional study in vascular laboratory.

Methods

The subjects were 63 type-2 DM inpatients (M/F, 32/31; age, 57.5±13.1) without taking any sleeping promoting drug and chronic kidney disease. We examined objective sleep architecture by single-channel electroencephalography and arteriosclerosis by carotid-artery intima-media thickness (CA-IMT).

Results

HbA1c was associated significantly in a negative manner with REM sleep latency (interval between sleep-onset and the first REM period) (β=-0.280, p=0.033), but not with other measurements of sleep quality. REM sleep latency associated significantly in a positive manner with log delta power (the marker of deep sleep) during that period (β=0.544, p=0.001). In the model including variables univariately correlated with CA-IMT (REM sleep latency, age, DM duration, systolic blood pressure, and HbA1c) as independent variables, REM sleep latency (β=-0.232, p=0.038), but not HbA1c were significantly associated with CA-IMT. When log delta power was included in place of REM sleep latency, log delta power (β=-0.257, p=0.023) emerged as a significant factor associated with CA-IMT.

Conclusions

In type-2 DM patients, poor glycemic control was independently associated with poor quality of sleep as represented by decrease of REM sleep latency which might be responsible for increased CA-IMT, a relevant marker for arterial wall thickening.     

Histological Characterization of the Tumorigenic “Peri-Necrotic Niche” Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma

Background

Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically.

Methods

Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α⁺) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II–IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay.

Results

A small subpopulation of HIF-1α⁺ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α⁺ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α⁺ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity.

Conclusions

These data suggest that the “peri-necrotic niche” harboring HIF-1α⁺ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.     

Cancer Associated Fibroblasts in Stage I-IIIA NSCLC: Prognostic Impact and Their Correlations with Tumor Molecular Markers

Background

Cancer Associated Fibroblasts (CAFs) are thought to regulate tumor growth and metastasis. Fibroblast Activating Protein 1 (FAP-1) is a marker for fibroblast activation and by many recognized as the main marker of CAFs. Alpha Smooth Muscle Actin (α-SMA) is a general myofibroblast marker, and can be used to identify CAFs. This study investigates the prognostic impact of FAP-1 and α-SMA in non-small cell lung cancer (NSCLC) patients and correlates their expression to 105 proteins investigated in the same cohort.

Methods

Tumor specimens from 536 NSCLC patients were obtained and tissue micro-arrays were constructed. Immunohistochemistry was used to evaluate the expression of FAP-1 and α-SMA and explore their impact on survival and association with other tumor molecular markers in NSCLC patients.

Results

High expression of FAP-1, but not α-SMA, in squamous cell carcinoma (SCC, P = 0.043, HR = 0.63 95% CI 0.40–0.99) was significantly associated with increased disease-specific survival. FAP-1 and α-SMA were not significantly correlated to each other. Analyses of FAP-1 and α-SMA associated with other tumor-related proteins revealed histotype-specific correlation patterns.

Conclusion

The presence of FAP-1 expressing CAFs is an indicator of positive outcome for NSCLC-SCC patients. In addition, correlation analyses suggest FAP-1 and α-SMA to label different subsets of fibroblasts and their associations with other tumor-related proteins diverge according to histological subtype.     

Oocyte Scoring Enhances Embryo-Scoring in Predicting Pregnancy Chances with IVF Where It Counts Most

Context

Our center’s quality improvement optimization process on many occasions anecdotally suggested that oocyte assessments might enhance embryo assessment in predicting pregnancy chances with in vitro fertilization (IVF).

Objective

To prospectively compare a morphologic oocyte grading system to standard day-3 morphologic embryo assessment.

Design, Setting, Patients

We prospectively investigated in a private academically-affiliated infertility center 94 consecutive IVF cycles based on 6 criteria for oocyte quality: morphology, cytoplasm, perivitelline space (PVS), zona pellucida (ZP), polar body (PB) and oocyte size, each assigned a value of -1 (worst), 0 (average) or +1 (best), so establishing an average total oocyte score (TOS). Embryo assessment utilized grade and cell numbers of each embryo on day-3 after oocyte retrieval. Clinical pregnancy was defined by presence of at least one intrauterine gestational sac.

Interventions

Standard IVF cycles in infertile women.

Main Outcome Measures

Predictability of pregnancy based on oocyte and embryo-grading systems.

Results

Average age for all patients was 36.5 ± 7.3 years; mean oocyte yield was 7.97± 5.76; Patient specific total oocyte score (PTOS) was -1.05 ± 2.24. PTOS, adjusted for patient age, was directly related to odds of increased embryo cell numbers (OR 1.12, P = 0.025), embryo grade (OR 1.19, P < 0.001) and clinical pregnancy [OR 1.58 (95%CI 1.23 to 2.02), P < 0.001]. Restricting the analysis to day three embryos of high quality (8-cell/ good grades), TOS was still predictive of clinical pregnancy (OR 2.08 (95%CI 1.26 to 3.44, P = 0.004). Among the 69 patients with embryos of Grade 4 or better available for transfer 23 achieved Clinical Pregnancy. When the analysis was restricted to the 69 transfers with good quality embryos (≥ Grade 4) the Oocyte Scoring System (TOS) (AUC±SE 0.863±0.044, oocyte score) provided significantly greater predictive value for clinical pregnancy compared to the embryo grade alone (AUC 0.646 ± 0.072, embryo grade) p = 0.015.

Conclusions

Oocyte-scoring, thus, provides useful clinical information especially in good prognosis patients with large numbers of high quality embryos. This finding appears of particular importance at a time when many IVF centers are committing sizable investments to closed incubation systems with time-lapse photography, which are exclusively meant to define embryo morphology.     

The Effects of Hyperbaric Oxygen Therapy on Post-Training Recovery in Jiu-Jitsu Athletes

Objectives

The present study aimed to evaluate the effects of using hyperbaric oxygen therapy during post-training recovery in jiu-jitsu athletes.

Methods

Eleven experienced Brazilian jiu-jitsu athletes were investigated during and following two training sessions of 1h30min. Using a cross-over design, the athletes were randomly assigned to passive recovery for 2 hours or to hyperbaric oxygen therapy (OHB) for the same duration. After a 7-day period, the interventions were reversed. Before, immediately after, post 2 hours and post 24 hours, blood samples were collected to examine hormone concentrations (cortisol and total testosterone) and cellular damage markers [creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH)]. Moreover, the rating of perceived exertion (RPE) and recovery (RPR) scales were applied.

Results

Final lactate [La] values (control: 11.9 ± 1.4 mmol/L, OHB: 10.2 ± 1.4 mmol/L) and RPE [control: 14 (13–17 a.u.), OHB: 18 (17–20 a.u.)] were not significantly different following the training sessions. Furthermore, there was no difference between any time points for blood lactate and RPE in the two experimental conditions (P>0.05). There was no effect of experimental conditions on cortisol (F_1,20 = 0.1, P = 0.793, η² = 0.00, small), total testosterone (F_1,20 = 0.03, P = 0.877, η² = 0.00, small), CK (F_1,20 = 0.1, P = 0.759, η² = 0.01, small), AST (F_1,20 = 0.1, P = 0.761, η² = 0.01, small), ALT (F_1,20 = 0.0, P = 0.845, η² = 0.00, small) or LDH (F_1,20 = 0.7, P = 0.413, η² = 0.03, small). However, there was a difference between the two experimental conditions in RPR with higher values at post 2 h and 24 h in OHB when compared to the control condition (P<0.05).

Conclusions

Thus, it can be concluded that OHB exerts no influence on the recovery of hormonal status or cellular damage markers. Nonetheless, greater perceived recovery, potentially due to the placebo effect, was evident following the OHB condition.     

Elevated Plasma CXCL12α Is Associated with a Poorer Prognosis in Pulmonary Arterial Hypertension

Rationale

Recent work in preclinical models suggests that signalling via the pro-angiogenic and pro-inflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12α were elevated in patients with PAH and related to mortality.

Methods

Plasma samples were collected from patients with idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with connective tissue diseases (CTD-PAH) attending two pulmonary hypertension referral centres (n = 95) and from age and gender matched healthy controls (n = 44). Patients were subsequently monitored throughout a period of five years.

Results

CXCL12α concentrations were elevated in PAH groups compared to controls (P<0.05) and receiver-operating-characteristic analysis showed that plasma CXCL12α concentrations discriminated patients from healthy controls (AUC 0.80, 95% confidence interval 0.73-0.88). Kaplan Meier analysis indicated that elevated plasma CXCL12α concentration was associated with reduced survival (P<0.01). Multivariate Cox proportional hazards model showed that elevated CXCL12α independently predicted (P<0.05) earlier death in PAH with a hazard ratio (95% confidence interval) of 2.25 (1.01-5.00). In the largest subset by WHO functional class (Class 3, 65% of patients) elevated CXCL12α independently predicted (P<0.05) earlier death, hazard ratio 2.27 (1.05-4.89).

Conclusions

Our data show that elevated concentrations of circulating CXCL12α in PAH predicted poorer survival. Furthermore, elevated circulating CXCL12α was an independent risk factor for death that could potentially be included in a prognostic model and guide therapy.     

Obstructive Sleep Apnoea Syndrome,Endothelial Function and Markers of Endothelialization. Changes after CPAP

Study objectives

This study tries to assess the endothelial function in vivo using flow-mediated dilatation (FMD) and several biomarkers of endothelium formation/restoration and damage in patients with obstructive sleep apnoea (OSA) syndrome at baseline and after three months with CPAP therapy.

Design

Observational study, before and after CPAP therapy.

Setting and Patients

We studied 30 patients with apnoea/hypopnoea index (AHI) >15/h that were compared with themselves after three months of CPAP therapy. FMD was assessed non-invasively in vivo using the Laser-Doppler flowmetry. Circulating cell-free DNA (cf-DNA) and microparticles (MPs) were measured as markers of endothelial damage and the vascular endothelial growth factor (VEGF) was determined as a marker of endothelial restoration process.

Measurements and results

After three month with CPAP, FMD significantly increased (1072.26 ± 483.21 vs. 1604.38 ± 915.69 PU, p< 0.005) cf-DNA and MPs significantly decreased (187.93 ± 115.81 vs. 121.28 ± 78.98 pg/ml, p<0.01, and 69.60 ± 62.60 vs. 39.82 ± 22.14 U/μL, p<0.05, respectively) and VEGF levels increased (585.02 ± 246.06 vs. 641.11 ± 212.69 pg/ml, p<0.05). These changes were higher in patients with more severe disease. There was a relationship between markers of damage (r = -0.53, p<0.005) but not between markers of damage and restoration, thus suggesting that both types of markers should be measured together.

Conclusions

CPAP therapy improves FMD. This improvement may be related to an increase of endothelial restoration process and a decrease of endothelial damage.     

Nevirapine,Sodium Concentration and HIV-1 RNA in Breast Milk and Plasma among HIV-Infected Women Receiving Short-Course Antiretroviral Prophylaxis

Introduction

Risk factors for breast milk transmission of HIV-1 from mother to child include high plasma and breast milk viral load, low maternal CD4 count and breast pathology such as mastitis.

Objective

To determine the impact of nevirapine and subclinical mastitis on HIV-1 RNA in maternal plasma and breast milk after intrapartum single-dose nevirapine combined with either 1-week tail of Combivir (zidovudine/lamivudine) or single-dose Truvada (tenofovir/emtricitabine).

Methods

Maternal plasma and bilateral breast milk samples were collected between April 2008 and April 2011 at 1, 4 and 6 weeks postpartum from HIV-infected Tanzanian women. Moreover, plasma samples were collected at delivery from mother and infant.

Results

HIV-1 RNA was quantified in 1,212 breast milk samples from 273 women. At delivery, 96% of the women and 99% of the infants had detectable nevirapine in plasma with a median (interquartile range, IQR) of 1.5 μg/mL (0.75–2.20 μg/mL) and 1.04 μg/mL (0.39–1.71 μg/mL), respectively (P < 0.001). At 1 week postpartum, 93% and 98% of the women had detectable nevirapine in plasma and breast milk, with a median (IQR) of 0.13 μg/mL (0.13–0.39 μg/mL) and 0.22 μg/mL (0.13–0.34 μg/mL), respectively. Maternal plasma and breast milk HIV-1 RNA correlated at all visits (R = 0.48, R = 0.7, R = 0.59; all P = 0.01). Subclinical mastitis was detected in 67% of the women at some time during 6 weeks, and in 38% of the breast milk samples. Breast milk samples with subclinical mastitis had significantly higher HIV-1 RNA at 1, 4 and 6 weeks (all P < 0.05).

Conclusion

After short-course antiretroviral prophylaxis, nevirapine was detectable in most infant cord blood samples and the concentration in maternal plasma and breast milk was high through week 1 accompanied by suppressed HIV-1 RNA in plasma and breast milk.     

Intraocular Pressure Changes during Accommodation in Progressing Myopes,Stable Myopes and Emmetropes

Purpose

To investigate the changes of intraocular pressure (IOP) induced by 3-diopter (3 D) accommodation in progressing myopes, stable myopes and emmetropes.

Design

Cross-sectional study.

Participants

318 subjects including 270 myopes and 48 emmetropes.

Methods

195 progressing myopes, 75 stable myopes and 48 emmetropes participated in this study. All subjects had their IOP measured using iCare rebound tonometer while accommodative stimuli of 0 D and 3 D were presented.

Main Outcome Measures

IOP values without accommodation and with 3 D accommodation were measured in all subjects. Baseline IOPs and IOP changes were compared within and between groups.

Results

There was no significant difference in IOPs between progressing myopes, stable myopes and emmetropes when no accommodation was induced (17.47±3.46, 16.62±2.98 and 16.80±3.62 respectively, p>0.05). IOP experienced an insignificantly slight decrease after 3 D accommodation in three groups (mean change -0.19±2.16, -0.03±1.68 and -0.39±2.65 respectively, p>0.05). Subgroup analysis showed in progressing myopic group, IOP of children (<18 years old) declined with accommodation while IOP of adults (≥18 years) increased, and the difference was statistically significant (p = 0.008). However, after excluding the age factor, accommodation induced IOP changes of high progressing myopes (≤-6 D), low, moderate and non-myopes (>-6 D) was not significantly different after Bonferroni correction (p = 0.838).

Conclusions

Although no difference was detected between the baseline IOPs and accommodation induced IOP changes in progressing myopes, stable myopes and emmetropes, this study found accommodation could cause transient IOP elevation in adult progressing myopes.     

The Placental Protein Syncytin-1 Impairs Antiviral Responses and Exaggerates Inflammatory Responses to Influenza

Background

Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1. We hypothesised that exposure of peripheral monocytes (PBMCs) to syncytin-1 would impair responses to H1N1pdm09 influenza.

Methods and Findings

Recombinant syncytin-1 was produced. PBMCs from non-pregnant women (n=10) were exposed to H1N1pdm09 in the presence and absence of syncytin-1 and compared to responses of PBMCs from pregnant women (n=12). PBMCs were characterised using flow cytometry, release of interferon (IFN)-α, IFN-λ, IFN-γ, IL-10, IL-2, IL-6 and IL-1β were measured by cytometric bead array or ELISA. Exposure of PBMCs to H1N1pdm09 resulted in the release of IFN-α, (14,787 pg/mL, 95% CI 7311-22,264 pg/mL) IFN-λ (1486 pg/mL, 95% CI 756-2216 pg/mL) and IFN-γ (852 pg/mL, 95% CI 193-1511 pg/mL) after 48 hours. This was significantly impaired in pregnant women (IFN-α; p<0.0001 and IFN-λ; p<0.001). Furthermore, in the presence of syncytin-1, PBMCs demonstrated marked reductions in IFN-α and IFN-λ, while enhanced release of IL-10 as well as IL-6 and IL-1β.

Conclusions

Our data indicates that a placental derived protein, syncytin-1 may be responsible for the heightened vulnerability of pregnant women to influenza.