Sex Specific Differences in Fetal Middle Cerebral Artery and Umbilical Venous Doppler

Background

The incidence of several adverse pregnancy outcomes including fetal growth restriction are higher in pregnancies where the fetus is male, leading to suggestions that placental insufficiency is more common in these fetuses. Placental insufficiency associated with fetal growth restriction may be identified by multi-vessel Doppler assessment, but little evidence exists regarding sex specific differences in these Doppler indices or placental function. This study aims to investigate sex specific differences in fetal and placental perfusion and to correlate these changes with intra-partum outcome.

Methods and Findings

This is a prospective cohort study. We measured Doppler indices of 388 term pregnancies immediately prior to the onset of active labour (≤3 cm dilatation). Fetal sex was unknown at the time of the ultrasound assessment. Information from the ultrasound scan was not made available to clinical staff. Case notes and electronic records were reviewed following delivery. We report significantly lower Middle Cerebral artery pulsatility index (1.34 vs. 1.43, p = 0.004), Middle Cerebral artery peak velocity (53.47 cm/s vs. 58.10 cm/s, p = <0.001), and Umbilical venous flow/kg (56 ml/min/kg vs. 61 ml/min/kg, p = 0.02) in male fetuses. These differences however, were not associated with significant differences in intra-partum outcome.

Conclusion

Sex specific differences in feto-placental perfusion indices exist. Whilst the physiological relevance of these is currently unknown, the identification of these differences adds to our knowledge of the physiology of male and female fetuses in utero. A number of disease processes have now been shown to have an association with changes in fetal haemodynamics in-utero, as well as having a sex bias, making further investigation of the sex specific differences present during fetal life important. Whilst the clinical application of these findings is currently limited, the results from this study do provide further insight into the gender specific circulatory differences present in the fetal period.     

Bariatric Surgery Improves the Cavernosal Neuronal,Vasorelaxation, and Contraction Mechanisms for Erectile Dysfunction As Result of Amelioration of Glucose Homeostasis in a Diabetic Rat Model

Background

Bariatric surgery is an effective treatment option for both obesity and obesity-related type 2 diabetes mellitus (T2DM). However, little is known regarding the effects of bariatric surgery on erectile dysfunction among patients with T2DM. Therefore, we investigated whether bariatric surgery would lead to structural and biochemical changes in the corpus cavernosum.

Material and Method

Twenty-five male Otsuka Long-Evans Tokushima Fatty rats were assigned to either a control group (sham operation, n = 10) or a bariatric surgery group (gastric bypass surgery, n = 15). Four weeks after the operation, each group of rats was evaluated with an oral glucose tolerance test (OGTT). The penile intracavernous pressure was measured for erectile functional analysis. Histologic evaluation of the tissue was performed with Masson''s trichrome staining. Endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), Rho kinase, and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels in the corpus cavernosum were assayed by using western blot and ELISA.

Results

The mean body weight of the bariatric surgery group was lower than the control group (p = 0.002). The postoperative OGTT result was lower in the bariatric surgery group than in the control group (p = 0.014), and this was lower than the preoperative value (p = 0.037). The intracavernous pressure/mean arterial pressure ratio was higher in the bariatric surgery group compared to the control group (p = 0.021), and a higher cavernosum smooth muscle/collagen ratio was observed in the bariatric surgery group compared to the control group (p = 0.025). Likewise, the expression of eNOS and nNOS was higher in bariatric surgery group than in the control group (p = 0.027 and p = 0.008, respectively). Decreased expression of Rho kinase and levels of 8-OHdG were observed in the bariatric surgery group (p = 0.032).

Conclusion

In this animal model, bariatric surgery appears to ameliorate T2DM-related metabolic dysfunction leading to structural and biochemical changes in the corpus cavernosum, and thus, results in improvement of erectile dysfunction associated with T2DM.     

Sperm Recovery and IVF after Testicular Sperm Extraction (TESE): Effect of Male Diagnosis and Use of Off-Site Surgical Centers on Sperm Recovery and IVF

Objective

Determine whether testicular sperm extractions and pregnancy outcomes are influenced by male and female infertility diagnoses, location of surgical center and time to cryopreservation.

Patients

One hundred and thirty men undergoing testicular sperm extraction and 76 couples undergoing 123 in vitro fertilization cycles with testicular sperm.

Outcome Measures

Successful sperm recovery defined as 1–2 sperm/0.5 mL by diagnosis including obstructive azoospermia (n = 60), non-obstructive azoospermia (n = 39), cancer (n = 14), paralysis (n = 7) and other (n = 10). Obstructive azoospermia was analyzed as congenital absence of the vas deferens (n = 22), vasectomy or failed vasectomy reversal (n = 37) and “other”(n = 1). Sperm recovery was also evaluated by surgical site including infertility clinic (n = 54), hospital operating room (n = 67) and physician’s office (n = 11). Treatment cycles were evaluated for number of oocytes, fertilization, embryo quality, implantation rate and clinical/ongoing pregnancies as related to male diagnosis, female diagnosis, and use of fresh or cryopreserved testicular sperm.

Results

Testicular sperm recovery from azoospermic males with all diagnoses was high (70 to 100%) except non-obstructive azoospermia (31%) and was not influenced by distance from surgical center to laboratory. Following in vitro fertilization, rate of fertilization was significantly lower with non-obstructive azoospermia (43%, p = <0.0001) compared to other male diagnoses (66%, p = <0.0001, 59% p = 0.015). No differences were noted in clinical pregnancy rate by male diagnosis; however, the delivery rate per cycle was significantly higher with obstructive azoospermia (38% p = 0.0371) compared to diagnoses of cancer, paralysis or other (16.7%). Women diagnosed with diminished ovarian reserve had a reduced clinical pregnancy rate (7.4% p = 0.007) compared to those with other diagnoses (44%).

Conclusion

Testicular sperm extraction is a safe and effective option regardless of the etiology of the azoospermia. The type of surgical center and/or its distance from the laboratory was not related to success. Men with non-obstructive azoospermia have a lower chance of successful sperm retrieval and fertilization.     

Innate Immune Responses and Antioxidant/Oxidant Imbalance Are Major Determinants of Human Chagas Disease

Background

We investigated the pathological and diagnostic role of selected markers of inflammation, oxidant/antioxidant status, and cellular injury in human Chagas disease.

Methods

Seropositive/chagasic subjects characterized as clinically-symptomatic or clinically-asymptomatic (n = 116), seronegative/cardiac subjects (n = 102), and seronegative/healthy subjects (n = 45) were analyzed for peripheral blood biomarkers.

Results

Seropositive/chagasic subjects exhibited an increase in sera or plasma levels of myeloperoxidase (MPO, 2.8-fold), advanced oxidation protein products (AOPP, 56%), nitrite (5.7-fold), lipid peroxides (LPO, 12–17-fold) and malondialdehyde (MDA, 4–6-fold); and a decline in superoxide dismutase (SOD, 52%) and glutathione (GSH, 75%) contents. Correlation analysis identified a significant (p<0.001) linear relationship between inflammatory markers (AOPP/nitrite: r = 0.877), inflammation and antioxidant/oxidant status (AOPP/glutathione peroxidase (GPX): r = 0.902, AOPP/GSH: r = 0.806, Nitrite/GPX: 0.773, Nitrite/LPO: 0.805, MDA/MPO: 0.718), and antioxidant/oxidant levels (GPX/MDA: r = 0.768) in chagasic subjects. Of these, MPO, LPO and nitrite biomarkers were highly specific and sensitive for distinguishing seropositive/chagasic subjects from seronegative/healthy controls (p<0.001, training and fitting AUC/ROC >0.95). The MPO (r = 0.664) and LPO (r = 0.841) levels were also correlated with clinical disease state in chagasic subjects (p<0.001). Seronegative/cardiac subjects exhibited up to 77% decline in SOD, 3–5-fold increase in LPO and glutamate pyruvate transaminase (GPT) levels, and statistically insignificant change in MPO, AOPP, MDA, GPX, GSH, and creatine kinase (CK) levels.

Conclusions

The interlinked effects of innate immune responses and antioxidant/oxidant imbalance are major determinants of human Chagas disease. The MPO, LPO and nitrite are excellent biomarkers for diagnosing seropositive/chagasic subjects, and MPO and LPO levels have potential utility in identifying clinical severity of Chagas disease.     

Low Frequency Magnetic Fields Enhance Antitumor Immune Response against Mouse H22 Hepatocellular Carcinoma

Objective

Many studies have shown that magnetic fields (MF) inhibit tumor growth and influence the function of immune system. However, the effect of MF on mechanism of immunological function in tumor-bearing mice is still unclear.

Methods

In this study, tumor-bearing mice were prepared by subcutaneously inoculating Balb/c mice with hepatocarcinoma cell line H22. The mice were then exposed to a low frequency MF (0.4 T, 7.5 Hz) for 30 days. Survival rate, tumor growth and the innate and adaptive immune parameters were measured.

Results

MF treatment could prolong survival time (n = 28, p<0.05) and inhibit tumor growth (n = 9, p<0.01) in tumor-bearing mice. Moreover, this MF suppressed tumor-induced production of cytokines including interleukin-6 (IL-6), granulocyte colony- stimulating factor (G-CSF) and keratinocyte-derived chemokine (KC) (n = 9–10, p<0.05 or 0.01). Furthermore, MF exposure was associated with activation of macrophages and dendritic cells, enhanced profiles of CD4⁺ T and CD8⁺ T lymphocytes, the balance of Th17/Treg and reduced inhibitory function of Treg cells (n = 9–10, p<0.05 or 0.01) in the mice model.

Conclusion

The inhibitory effect of MF on tumor growth was related to the improvement of immune function in the tumor-bearing mice.     

Multidisciplinary Team-Based Approach for Comprehensive Preoperative Pulmonary Rehabilitation Including Intensive Nutritional Support for Lung Cancer Patients

Background

To decrease the risk of postoperative complication, improving general and pulmonary conditioning preoperatively should be considered essential for patients scheduled to undergo lung surgery.

Objective

The aim of this study is to develop a short-term beneficial program of preoperative pulmonary rehabilitation for lung cancer patients.

Methods

From June 2009, comprehensive preoperative pulmonary rehabilitation (CHPR) including intensive nutritional support was performed prospectively using a multidisciplinary team-based approach. Postoperative complication rate and the transitions of pulmonary function in CHPR were compared with historical data of conventional preoperative pulmonary rehabilitation (CVPR) conducted since June 2006. The study population was limited to patients who underwent standard lobectomy.

Results

Postoperative complication rate in the CVPR (n = 29) and CHPR (n = 21) were 48.3% and 28.6% (p = 0.2428), respectively. Those in patients with Charlson Comorbidity Index scores ≥2 were 68.8% (n = 16) and 27.3% (n = 11), respectively (p = 0.0341) and those in patients with preoperative risk score in Estimation of Physiologic Ability and Surgical Stress scores >0.3 were 57.9% (n = 19) and 21.4% (n = 14), respectively (p = 0.0362). Vital capacities of pre- and post intervention before surgery in the CHPR group were 2.63±0.65 L and 2.75±0.63 L (p = 0.0043), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6815). Forced expiratory volumes in one second of pre- and post intervention before surgery in the CHPR group were 1.73±0.46 L and 1.87±0.46 L (p = 0.0012), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6424).

Conclusions

CHPR appeared to be a beneficial and effective short-term preoperative rehabilitation protocol, especially in patients with poor preoperative conditions.     

Association of Eosinophilic Inflammation with FKBP51 Expression in Sputum Cells in Asthma

Background

Airway eosinophilia is a predictor of steroid responsiveness in steroid-naïve asthma. However, the relationship between airway eosinophilia and the expression of FK506-binding protein 51 (FKBP51), a glucocorticoid receptor co-chaperone that plays a role in steroid insensitivity in asthma, remains unknown.

Objective

To evaluate the relationship between eosinophilic inflammation and FKBP51 expression in sputum cells in asthma.

Methods

The FKBP51 mRNA levels in sputum cells from steroid-naïve patients with asthma (n = 31) and stable asthmatic patients on inhaled corticosteroid (ICS) (n = 28) were cross-sectionally examined using real-time PCR. Associations between FKBP51 levels and clinical indices were analyzed.

Results

In steroid-naïve patients, the FKBP51 levels were negatively correlated with eosinophil proportions in blood (r = −0.52) and sputum (r = −0.57), and exhaled nitric oxide levels (r = −0.42) (all p<0.05). No such associations were observed in patients on ICS. In steroid-naïve patients, improvement in forced expiratory volume in one second after ICS initiation was correlated with baseline eosinophil proportions in blood (r = 0.74) and sputum (r = 0.76) and negatively correlated with FKBP51 levels (r = −0.73) (all p<0.0001) (n = 20). Lastly, the FKBP51 levels were the lowest in steroid-naïve asthmatic patients, followed by mild to moderate persistent asthmatic patients on ICS, and the highest in severe persistent asthmatic patients on ICS (p<0.0001).

Conclusions

Lower FKBP51 expression in sputum cells may reflect eosinophilic inflammation and glucocorticoid responsiveness in steroid-naïve asthmatic patients.     

Platelet Content of Nitric Oxide Synthase 3 Phosphorylated At Serine1177 Is Associated with the Functional Response of Platelets to Aspirin

Objective

To analyse if platelet responsiveness to aspirin (ASA) may be associated with a different ability of platelets to generate nitric oxide (NO).

Patients/Methods

Platelets were obtained from 50 patients with stable coronary ischemia and were divided into ASA-sensitive (n = 26) and ASA-resistant (n = 24) using a platelet functionality test (PFA-100).

Results

ASA-sensitive platelets tended to release more NO (determined as nitrite + nitrate) than ASA-resistant platelets but it did not reach statistical significance. Protein expression of nitric oxide synthase 3 (NOS3) was higher in ASA-sensitive than in ASA-resistant platelets but there were no differences in the platelet expression of nitric oxide synthase 2 (NOS2) isoform. The highest NOS3 expression in ASA-sensitive platelets was independent of the presence of T-to-C mutation at nucleotide position −786 (T⁻⁷⁸⁶→C) in the NOS3-coding gene. However, platelet content of phosphorylated NOS3 at Serine (Ser)¹¹⁷⁷, an active form of NOS3, was higher in ASA-sensitive than in ASA-resistant platelets. The level of platelet NOS3 Ser¹¹⁷⁷ phosphorylation was positively associated with the closure time in the PFA-100 test. In vitro, collagen failed to stimulate the aggregation of ASA-sensitive platelets, determined by lumiaggregometry, and it was associated with a significant increase (p = 0.018) of NOS3 phosphorylation at Ser¹¹⁷⁷. On the contrary, collagen stimulated the aggregation of ASA-resistant platelets but did not significantly modify the platelet content of phosphorylated NOS3 Ser¹¹⁷⁷. During collagen stimulation the release of NO from ASA-sensitive platelets was significantly enhanced but it was not modified in ASA-resistant platelets.

Conclusions

Functional platelet responsiveness to ASA was associated with the platelet content of phosphorylated NOS3 at Ser¹¹⁷⁷.     

High Levels of Asymmetric Dimethylarginine Are Strongly Associated with Low HDL in Patients with Acute Myocardial Infarction

Objectives

Low levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of acute myocardial infarction possibly through impaired endothelial atheroprotection and decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) mediates endothelial function by inhibiting nitric oxide synthase activity. In patients with acute myocardial infarction, we investigated the relationship between serum levels of HDL and ADMA.

Approach and Results

Blood samples from 612 consecutive patients hospitalized for acute MI <24 hours after symptom onset were taken on admission. Serum levels of ADMA, its stereoisomer, symmetric dimethylarginine (SDMA) and L-arginine were determined using high-performance liquid chromatography. Patients with low HDL (<40 mg/dL for men and <50 mg/dL for women) were compared with patients with higher HDL. Most patients (59%) had low HDL levels. Median ADMA levels were markedly higher in the low HDL group (0.69 vs. 0.50 µmole/L, p<0.001). In contrast, SDMA and L-arginine levels were similar for the two groups (p = 0.120 and p = 0.064). Notably, ADMA, but not SDMA or L-arginine, was inversely correlated with HDL (r = −0.311, p<0.001). In stratified analysis, this relationship was only found for low HDL levels (r = −0.265, p<0.001), but not when HDL levels were higher (r = −0.077, p = 0.225). By multivariate logistic regression analysis, ADMA level was strongly associated with low HDL levels (OR(95%CI):6.06(3.48–10.53), p<0.001), beyond traditional confounding factors.

Conclusions

Our large population-based study showed for the first time a strong inverse relationship between HDL and ADMA in myocardial infarction patients, suggesting a functional interaction between HDL and endothelium, beyond metabolic conditions associated with low HDL levels.     

Raised Plasma Robo4 and Cardiac Surgery-Associated Acute Kidney Injury

Objective

Endothelial dysfunction associated with systemic inflammation can contribute to organ injury/failure following cardiac surgery requiring cardiopulmonary bypass (CPB). Roundabout protein 4 (Robo4), an endothelial-expressed transmembrane receptor and regulator of cell activation, is an important inhibitor of endothelial hyper-permeability. We investigated the hypothesis that plasma levels of Robo4 are indicative of organ injury, in particular acute kidney injury (AKI), after cardiac surgery.

Methods

Patients (n = 32) undergoing elective cardiac surgery with CPB were enrolled, prospectively. Plasma Robo4 concentrations were measured pre-, 2 and 24 h post-operatively, using a commercially available ELISA. Plasma and endothelial markers of inflammation [interleukin (IL) -6, -8, -10: von Willibrand factor (vWF) and angiopoeitin-2 (Ang-2)] and the AKI marker, neutrophil gelatinase-associated lipocalin (NGAL), were also measured by ELISA.

Results

Plasma Robo4 increased significantly (p<0.001) from pre-operative levels of 2515±904 pg/ml to 4473±1915 pg/ml, 2 h after surgery; and returned to basal levels (2682±979 pg/ml) by 24 h. Plasma cytokines, vWF and NGAL also increased 2 h post-operatively and remained elevated at 24 h. Ang-2 increased 24 h post-operatively, only. There was a positive, significant correlation (r = 0.385, p = 0.0298) between Robo-4 and IL-10, but not other cytokines, 2 h post-operatively. Whilst raised Robo4 did not correlate with indices of lung dysfunction or other biomarkers of endothelial activation; there was a positive, significant correlation between raised (2 h) plasma NGAL and Robo4 (r = 0.4322, p = 0.0135). When patients were classed as AKI or non-AKI either using NGAL cut-off of 150 ng/ml, or the AKI Network (AKIN) clinical classification; plasma Robo4 was significantly higher (p = 0.0073 and 0.003, respectively) in AKI vs. non-AKI patients (NGAL cut-off: 5350±2191 ng/ml, n = 16 vs. 3595±1068 pg/ml, n = 16; AKIN: 6546 pg/ml, IQR 5025–8079, n = 6; vs. 3727 pg/ml, IQR 1962–3727, n = 26) subjects.

Conclusion

Plasma Robo4 levels are increased, transiently, following cardiac surgery requiring CPB; and higher levels in patients with AKI suggest a link between endothelial dysregulation and onset of AKI.     

GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus

Background

The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.

Methods

Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).

Results

Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.

Conclusions

Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.     

Replicated Evidence of Absence of Association between Serum S100B and (Risk of) Psychotic Disorder

Background

S100B is a potential marker of neurological and psychiatric illness. In schizophrenia, increased S100B levels, as well as associations with acute positive and persisting negative symptoms, have been reported. It remains unclear whether S100B elevation, which possibly reflects glial dysfunction, is the consequence of disease or compensatory processes, or whether it is an indicator of familial risk.

Methods

Serum samples were acquired from two large independent family samples (n = 348 and n = 254) in the Netherlands comprising patients with psychotic disorder (n = 140 and n = 82), non-psychotic siblings of patients with psychotic disorder (n = 125 and n = 94) and controls (n = 83 and n = 78). S100B was analyzed with a Liaison automated chemiluminescence system. Associations between familial risk of psychotic disorder and S100B were examined.

Results

Results showed that S100B levels in patients (P) and siblings (S) were not significantly different from controls (C) (dataset 1: P vs. C: B = 0.004, 95% CI −0.005 to 0.013, p = 0.351; S vs. C: B = 0.000, 95% CI −0.009 to 0.008, p = 0.926; and dataset 2: P vs. C: B = 0.008, 95% CI −0.011 to 0.028, p = 0.410; S vs. C: B = 0.002, 95% CI −0.016 to 0.021, p = 0.797). In patients, negative symptoms were positively associated with S100B (B = 0.001, 95% CI 0.000 to 0.002, p = 0.005) in one of the datasets, however with failure of replication in the other. There was no significant association between S100B and positive symptoms or present use or type of antipsychotic medication.

Conclusions

S100B is neither an intermediate phenotype, nor a trait marker for psychotic illness.     

Tumor Necrosis Factor Alpha Blocking Agents as Treatment for Ulcerative Colitis Intolerant or Refractory to Conventional Medical Therapy: A Meta-Analysis

Background

Efficacy of tumor necrosis factor alpha (TNF-α) blockers for treatment of ulcerative colitis that is unresponsive to conventional therapy is unclear due to recent studies yielding conflicting results.

Aim

To assess the efficacy and safety of anti-TNF-α agents for treatment of ulcerative colitis patients who were intolerant or refractory to conventional medical therapy.

Methods

Pubmed, Embase, and the Cochrane database were searched. Analysis was performed on randomized controlled trials that assessed anti-TNF-α therapy on ulcerative colitis patients that had previously failed therapy with corticosteroids and/or immunosuppressants. The primary outcome focused on was the frequency of patients that achieved clinical remission. Further trial outcomes of interest included rates of remission without patient use of corticosteroids during the trial, extent of mucosal healing, and the number of cases that resulted in colectomy and serious side effects.

Results

Eight trials from seven studies (n = 2122) met the inclusion criteria and were thus included during analysis. TNF-α blockers demonstrated clinical benefit as compared to placebo control as evidenced by an increased frequency of clinical remission (p<0.00001), steroid-free remission (p = 0.01), endoscopic remission (p<0.00001) and a decrease in frequency of colectomy (p = 0.03). No difference was found concerning serious side effects (p = 0.05). Three small trials (n = 57) comparing infliximab to corticosteroid treatment, showed no difference in frequency of clinical remission (p = 0.93), mucosal healing (p = 0.80), and requirement for a colectomy (p = 0.49). One trial compared infliximab to cyclosporine (n = 115), wherein no difference was found in terms of mucosal healing (p = 0.85), colectomy frequency (p = 0.60) and serious side effects (p = 0.23).

Conclusion

TNF-α blockers are effective and safe therapies for the induction and maintenance of long-term remission and prevention of treatment by colectomy for patients with refractory ulcerative colitis where conventional treatment was previously ineffective. Furthermore, infliximab and cyclosporine were found to be comparable for treating acute severe steroid-refractory ulcerative colitis.     

NT-proBNP,C-Reactive Protein and Soluble uPAR in a Bi-Ethnic Male Population: The SAfrEIC Study

Objective and design

This cross-sectional study aimed to investigate associations between a marker of cardiac strain, the N-terminal prohormone B-type natriuretic peptide (NT-proBNP), and inflammation as reflected by either a conventional or novel inflammatory marker in a bi-ethnic South African cohort.

Methods and subjects

We measured NT-proBNP, C-reactive protein (CRP) and plasma-soluble urokinase plasminogen activator receptor (suPAR) levels along with conventional biomarkers in black (n = 117) and white (n = 116) men.

Results

NT-proBNP, CRP and suPAR levels were higher in black compared to white men. NT-proBNP was significantly associated with both CRP (r = 0.38; p = 0.001) and suPAR (r = 0.42; p<0.001) in black men only. After full adjustment in multiple regression analyses, the above associations of NT-proBNP with CRP (β = 0.199; p = 0.018) and suPAR (β = 0.257; p<0.01) were confirmed in black men.

Conclusion

These results suggest that a low-grade inflammatory state as reflected by both a conventional and novel marker of inflammation may contribute to higher cardiovascular risk as reflected by the associations obtained with a marker of cardiac strain in black South African men.     

Organ Dysfunction among Piglets Treated with Inhaled Nitric Oxide and Intravenous Hydrocortisone during Prolonged Endotoxin Infusion

Objective

It has previously been shown that a combination of inhaled nitric oxide (iNO) and intravenous (IV) steroid attenuates endotoxin-induced organ damage in a 6-hour porcine endotoxemia model. We aimed to further explore these effects in a 30-hour model with attention to clinically important variables.

Design

Randomized controlled trial.

Setting

University animal laboratory.

Subjects

Domestic piglets (n = 30).

Interventions

Animals were randomized into 5 groups (n = 6 each): 1) Controls, 2) LPS-only (endotoxin/lipopolysaccharide (LPS) infusion), 3) LPS + iNO, 4) LPS + IV steroid, 5) LPS + iNO + IV steroid.

Measurements and Main Results

Exposure to LPS temporarily increased pulmonary artery mean pressure and impeded renal function with elevated serum creatinine and acidosis compared to a control group over the 30-hour study period. Double treatment with both iNO and IV steroid tended to blunt the deterioration in renal function, although the only significant effect was on Base Excess (p = 0.045). None of the LPS + iNO + IV steroid treated animals died during the study period, whereas one animal died in each of the other LPS-infused groups.

Conclusions

This study suggests that combined early therapy with iNO and IV steroid is associated with partial protection of kidney function after 30 hours of experimental LPS infusion.     

Cerebrospinal Fluid Immunoglobulin Kappa Light Chain in Clinically Isolated Syndrome and Multiple Sclerosis

Background

Oligoclonal bands (OCB) are the most widely used CSF test to support the diagnosis of MS and to predict conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS). Since OCB tests are based on non-quantitative and difficult to standardise techniques, measurement of immunoglobulin kappa free light chains (KFLC) may represent an easier to use quantitative test.

Methods

KFLC were measured in CSF and serum of 211 patients using ELISA. These include patients without any inflammatory central nervous system reaction (NIND, n = 77), MS (n = 20), viral CNS infections (V-CNS-I, n = 10), neuroborreliosis (NB, n = 17) and other bacterial CNS infections (B-CNS-I, n = 10). Furthermore a cohort of 77 patients with CIS, including 39 patients that remained CIS over follow-up of two years (CIS-CIS) and 38 patients that developed MS over the same follow-up time (CIS-MS).

Results

CSF-serum ratio of KFLC (Q KFLC) was elevated in all patients with MS, 86.8% of patients with CIS-MS and 61.5% of patients with CIS-CIS. It was significantly elevated in CIS with presence of OCB (p<0.001). Q KFLC significantly correlated with other CSF variables such as CSF leukocyte count (p<0.001, R = 0.46), CSF CXCL13 levels (p<0.001, R = 0.64) and also intrathecal IgG synthesis (p<0.001, R = 0.74) as determined by nephelometry and quotient diagram. OCB were detected in 66.7% of CIS-CIS and in 92.1% of CIS-MS.

Conclusions

Although the measurement of CSF KFLC is a rapid and quantitative easy to standardize tool, it is almost equal but not superior to OCB with regard to diagnostic sensitivity and specificity in patients with early MS.     

Association between Common Allergic Symptoms and Cancer in the NHANES III Female Cohort

Background

Previous epidemiological studies have investigated the association between allergic symptoms and cancer occurrence. However, the role of allergy in cancer has been elusive, especially for the female population.

Methods

We examined the relationship between cancer prevalence and common allergic symptoms of rhinoconjunctivitis (RC) and wheezing (WZ) among NHANES III female participants.

Results

Among 4600 people, 36.3% (n = 1669) did not have any allergic symptoms (NO), while 47.6% (n = 2188) reported RC, and 16.2% (n = 743), WZ. The proportion of cancer among NO groups was 5.43% (91/1669), among RC group, 7.63% (167/2188), and among WZ group, 11.23% (83/743) (RC group- OR 1.44 with 95% CI 1.00–2.08; p = 0.05 while for WZ group- OR 2.20 with 95%CI 1.27–3.80; p = 0.01). After adjusting for all the possible confounding variables including age, smoking, or COPD, having symptoms of RC (AOR 1.49 with 95%CI 1.12–2.36; p = 0.01) or WC (AOR 2.08 with 95%CI 1.11–3.89; p = 0.02) demonstrated consistent strong association with cancer. Among nonsmokers (n = 2505, 54.5%) only symptoms of RC showed association with cancer (AOR 1.51 with 95%CI 1.00–2.28; p = 0.05). Among former or current smokers (n = 2094, 45.5%), only symptoms of WZ demonstrated association with cancer (AOR 2.38 with 95%CI 1.16–4.87; p = 0.02). Among different types of cancers, odds of having breast cancer among participants with symptoms of RC or WZ were approximately twice the odds of having breast cancer among participants without any of these symptoms. AOR for RC group was 1.89 with 95%CI 1.04–3.42 and p = 0.04 while AOR for WC group was 2.08 with 95%CI 0.90–4.78 and p = 0.08.

Conclusions

In summary, we found associations between common allergic symptoms like rhinitis/conjunctivitis and wheezing and prevalence of cancer, specifically between rhinitis/conjunctivitis and breast cancer that were not found in previous studies. Larger prospective studies are required to validate our findings.     

Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

Objective

Low grade systemic inflammation (LGSI) as well as androgen deficiency has in older men been associated with several pathologies, including cardiovascular disease (CVD). We wanted to investigate whether low testosterone levels are linked to biomarkers of LGSI already in young age, before any concurrent manifestations of CVD or other systemic diseases.

Design

Nested cross-sectional study.

Methods

Forty subfertile biochemically hypogonadal (n = 20) or eugonadal (n = 20) men (mean age 37 years, SD = 4.3) and 20 age-matched controls were randomly selected from an ongoing study on male subfertility. Subjects comprised male partners in infertile couples in whom also subnormal sperm concentration was present. Blood sampling, interviews, and anthropometric measures were undertaken. Serum levels of testosterone, LH, estradiol, SHBG, and 21 LGSI-markers were assessed.

Results

Among 21 inflammatory markers, macrophage inflammatory protein 1-alpha (MIP1a) (ß = −0.025; p = 0.028), 1-beta (MIP1B) (ß = −0.015; p = 0.049) and tumor necrosis factor alpha (TNFa) (ß = −0.015; p = 0.040) showed negative association to total testosterone (TT) levels. MIP1a (ß = −1.95; p = 0.001) and TNFa (ß = −0.95; p = 0.014) showed negative association to calculated free testosterone (cFT) levels. Compared to men with normal TT and cFT levels, TNFa levels were higher in men with subnormal levels of TT (mean ratio 1.61; p = 0.006) and cFT (mean ratio 1.58; p = 0.007). Also, MIP1a levels were higher in men with subnormal levels of TT (mean ratio 1.84; p = 0.030).

Conclusions

Subnormal testosterone may already in young age associate to LGSI, which might be a part of the mechanism underlying adverse health outcomes of male hypogonadism.     

Endothelial Nitric Oxide Synthase and Superoxide Mediate Hemodynamic Initiation of Intracranial Aneurysms

Background

Hemodynamic insults at arterial bifurcations are believed to play a critical role in initiating intracranial aneurysms. Recent studies in a rabbit model indicate that aneurysmal damage initiates under specific wall shear stress conditions when smooth muscle cells (SMCs) become pro-inflammatory and produce matrix metalloproteinases (MMPs). The mechanisms leading to SMC activation and MMP production during hemodynamic aneurysm initiation are unknown. The goal is to determine if nitric oxide and/or superoxide induce SMC changes, MMP production and aneurysmal remodeling following hemodynamic insult.

Methods

Bilateral common carotid artery ligation was performed on rabbits (n = 19, plus 5 sham operations) to induce aneurysmal damage at the basilar terminus. Ligated animals were treated with the nitric oxide synthase (NOS) inhibitor LNAME (n = 7) or the superoxide scavenger TEMPOL (n = 5) and compared to untreated animals (n = 7). Aneurysm development was assessed histologically 5 days after ligation. Changes in NOS isoforms, peroxynitrite, reactive oxygen species (ROS), MMP-2, MMP-9, and smooth muscle α-actin were analyzed by immunohistochemistry.

Results

LNAME attenuated ligation-induced IEL loss, media thinning and bulge formation. In untreated animals, immunofluorescence showed increased endothelial NOS (eNOS) after ligation, but no change in inducible or neuronal NOS. Furthermore, during aneurysm initiation ROS increased in the media, but not the intima, and there was no change in peroxynitrite. In LNAME-treated animals, ROS production did not change. Together, this suggests that eNOS is important for aneurysm initiation but not by producing superoxide. TEMPOL treatment reduced aneurysm development, indicating that the increased medial superoxide is also necessary for aneurysm initiation. LNAME and TEMPOL treatment in ligated animals restored α-actin and decreased MMPs, suggesting that eNOS and superoxide both lead to SMC de-differentiation and MMP production.

Conclusion

Aneurysm-inducing hemodynamics lead to increased eNOS and superoxide, which both affect SMC phenotype, increasing MMP production and aneurysmal damage.