Kinetics of cytokine and chemokine responses in patients with primary human herpesvirus 6 infection

BackgroundCytokines and chemokines induced by human herpesvirus 6 (HHV-6) infection may play an important role in the observed HHV-6-associated clinical complications. However, basic data for cytokine and chemokine synthesis in primary HHV-6 infected patient without complication is lacking.ObjectiveAim of this study was to elucidate basic kinetic data for expressions of cytokines and chemokines in patients with primary HHV-6 infection without complication.Study designTwenty-six patients suffering from fever were enrolled in this study. Fourteen biomarkers were measured in 74 serially collected sera samples from 26 patients. Additionally, serum samples obtained from 14 healthy children were used for control.ResultsTwenty of the 26 patients were diagnosed with primary HHV-6 infection based on viral isolation and serological analysis. The mean age (P = 0.1289) and proportion of males to females (P = 0.9999) between the patients with and without primary HHV-6 infection were not statistically different. At the acute phase of the disease, three cytokines (IFN-γ; P = 0.0046, IL-2; P = 0.0366, and IL-4; P = 0.0255) and one chemokine (MCP-1; P = 0.0019) were significantly higher in patients with primary HHV-6 infection compared to those without infection. Interleukin-5 levels during the convalescent period were significantly higher in patients with HHV-6 infection (P = 0.0205). By 1 month post-infection, cytokine and chemokine expression had returned to almost basal levels.ConclusionAs suggested by the previous in vitro studies, present in vivo analysis also suggests that HHV-6 has potency for induction of cytokines and chemokines.     

HHV-6 cell receptor CD46 expression on various cell subsets of six blood and graft sources: A prospective series

BackgroundCord Blood (CB) are increasingly used as an alternative stem cells source in adults for allogeneic Stem Cell Transplantation (allo-SCT). The risk of human herpesvirus (HHV-6) reactivation is significantly higher after CB transplant vs unrelated peripheral blood stem cells (PBSC) allo-SCT. Higher HHV-6 cell receptor CD46 expression on progenitor cells in CB may explain this difference.ObjectivesTo prospectively compare the HHV-6 cell receptor CD46 expression on various cell subsets of three freshly harvested blood sources on one hand and of three graft sources on the other hand.Study design52 samples were used for the purpose of this study. They were issued from peripheral blood (PB, n = 10), G-CSF mobilised PB (GCSF-PB, n = 10), cord blood (CB, n = 10), unmanipulated bone marrow (uBM, n = 5), leukapheresis product (LP, n = 10) and thawed CB graft (n = 7). CD46 expression was assessed by FACS analysis on total lymphocytes, monocytes, NK cells, T and B cells subsets, plasmacytoid (pDCs) dendritic cells and stem cells.ResultsAs all cell subsets were found CD46 positive, CD46 mean fluorescence intensity (MFI) was then considered for comparison between the three blood sources and the three graft sources. The most impressive result observed was that HHV-6 cell receptor CD46 expression was significantly reduced in almost all cell components of thawed CB graft compared to other graft sources.ConclusionsThis original study shows strong differences in term of quantitative CD46 expression between several blood and grafts samples. Our results suggest that other factors than the qualitative CD46 expression play a role in the higher HHV-6 reactivation observed after CB transplant in adults.     

Detection of human herpesvirus-6 variants in pediatric brain tumors: Association of viral antigen in low grade gliomas

BackgroundHuman herpesvirus-6 (HHV-6) has been associated with a diverse spectrum of central nervous system (CNS) diseases and reported glial tropism.ObjectiveTo determine if HHV-6 is present in a series of pediatric brain tumors.Study designPediatric gliomas from 88 untreated patients represented in a tissue microarray (TMA) were screened for HHV-6 by nested polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemistry (IHC) and compared to non-glial tumors (N = 22) and control brain (N = 32). Results were correlated with tumor grade and overall survival.ResultsHHV-6 U57 was detected by nested PCR in 68/120 (57%) tumors and 7/32 (22%) age-matched non-tumor brain (P = 0.001). HHV-6 U31 was positive in 73/120 (61%) tumors and 11/32 (34%) controls (P = 0.019). Seventy-two percent (43/60) of tumors were HHV-6 Variant A. HHV-6 U57 was confirmed by ISH in 83/150 (54%) tumors and 10/32 (31%) controls (P = 0.021), revealing a non-lymphocytic origin of HHV-6. HHV-6A/B gp116/64/54 late antigen was detected by IHC in 50/124 (40%) tumors and 6/32 (18%) controls (P = 0.013). Interestingly, 58% of low grade gliomas (N = 67) were IHC positive compared to 19% of high grade gliomas (N = 21, P = 0.002) and 25% of non-gliomas (N = 36, P = 0.001). HHV-6A/B gp116/64/54 antigen co-localized with glial fibrillary acidic protein, confirming the astrocytic origin of antigen. Overall, there was no primary association between HHV-6A/B gp116/64/54 antigen detection and survival (P = 0.861).ConclusionsWe provide the first reported series of HHV-6 detection in pediatric brain tumors. The predominance of HHV-6 in glial tumors warrants further investigation into potential neurooncologic disease mechanisms.     

Oxidative status and chymotrypsin-like activity in right and left ventricle hypertrophy in an experimental model of emphysema

Although cardiac muscle hypertrophy has been studied in association with several diseases, its mechanism in patients with emphysema, in particular in relation to oxidative stress and proteolysis, remains unknown. The role of oxidative stress and proteolysis in right and left ventricle hypertrophy was investigated in hamsters with emphysema induced by 2 different doses of papain (20 mg/mL, E20 and 40 mg/mL, E40). The thickness of the ventricles, total and cardiac weight, lipid peroxidation, carbonyl proteins, total antioxidant capacity (TAC), and proteasomal proteolytic activity were evaluated in the right ventricle (RV) and the left ventricle (LV) of control and emphysema hamsters. RV thickness was increased by 12% in the E20 group and by 29% in the E40 group. Lipid peroxidation measured by chemiluminescence was increased in the E40 group (from 3350.68 ± 392.44 URL/g tissue to 4696.63 ± 1076.70 URL/g tissue, p < 0.05). TAC also increased only in the E40 group. In the LV, chemiluminescence values increased from 4044.77 ± 503.39 to 5517.10 ± 388.27 in the E20 group and to 8169.14 ± 1748.77 URL/g tissue in the E40 group (p < 0.05, both). TAC significantly increased in the E20 and E40 groups. No differences were detected in substances reactive to thiobarbituric acid or carbonyl proteins when comparing ventricles or doses. Chymotrypsin-like proteolytic activity significantly decreased in both groups and ventricles. Emphysema can induce right and left ventricle lipid peroxidation and result in antioxidant mobilization. These data together support the idea that cardiac hypertrophy in response to emphysema is mediated in part by proteolytic pathways with involvement of reactive species.     

Association of HHV-6 and HHV-7 reactivation with the development of chronic allograft nephropathy

BackgroundThe long-term effect of HHV-6 and HHV-7 infections on chronic allograft nephropathy (CAN) development after renal transplantation is uncertain.ObjectivesTo determine HHV-6 and HHV-7 reactivation during the post-transplantation period and to evaluate its effect on CAN development in renal transplant patients.Study designEighty-one renal allograft recipients (28 with CAN, 53 with normal transplant function) were studied to determine the frequency of HHV-6 and HHV-7 reactivation during 36.4 ± 7.8 months after renal transplantation using nested PCR. HHV-6 variants were identified using restriction endonuclease analysis. Patients were monitored for the development of CAN.ResultsThe frequency of HHV-6 and/or HHV-7 plasma DNA was significantly higher in CAN patients (25/28, 89.3%) compared to control patients (15/50, 30.0%, p = 0.0001). CAN patients also had an increased incidence of dual active infections (20/25, 80% and 2/15, 13.3%, p = 0.007, respectively). In all 34 HHV-6 positive cases, the HHV-6B variant was identified. The presence of HHV-7 DNA in plasma preceded the presence of HHV-6 DNA. Early development of CAN and graft loss was detected only in patients with simultaneous HHV-6 and HHV-7 plasma DNA.ConclusionsReactivation of HHV-6 and HHV-7 in renal graft recipients is a risk factor for CAN development. The presence of concurrent HHV-6 and HHV-7 DNA in the plasma is an unfavorable prognostic factor.     

HHV-8 DNA replication correlates with the clinical status in AIDS-related Kaposi’s sarcoma

BackgroundThe value of plasma levels of human herpesvirus 8 (HHV-8) DNA as a marker of clinical status in acquired immunodeficiency syndrome-related Kaposi’s sarcoma (AIDS-KS) remains to be elucidated.ObjectivesTo investigate the relationship between the plasma HHV-8 DNA viral load and the clinical status of AIDS-KS.Study DesignA total of 378 blood samples were obtained from 62 patients with AIDS-KS followed longitudinally. All patients received antiretroviral therapy (ART) or anti-neoplastic therapy. The patients were divided into four groups according to their clinical status: onset disease (OD), progressive disease (PD), stable or partial remission (S/PR) and complete remission (CR).ResultsPlasma HHV-8 DNAaemia was detected in all samples obtained from patients with OD or PD (100%); in contrast, HHV-8 DNAaemia was found only in a minority of patients with CR (8%) and was invariably undetectable in patients with stable CR. HHV-8 DNA detection in plasma was strongly associated with an unfavourable outcome (odds ratio = 231.9; p < 0.0001). Conversely, neither the HIV-1 viral load nor peripheral CD4⁺ T-cell counts were associated with the KS clinical status, though both parameters did affect HHV-8 DNAaemia levels (p < 0.0001). Multivariate analysis confirmed that HHV-8 DNAaemia was strongly and independently correlated with both clinical status (p < 0.05) and HIV-1 plasma viraemia (p = 0.027).ConclusionsThe strong association of plasma HHV-8 DNAaemia with onset or progressive disease is compatible with an active role of replicating virus in clinically active AIDS-KS. An accurate evaluation of the plasma HHV-8 load might be useful for monitoring AIDS-KS under antiretroviral or antineoplastic therapy.     

Consumers report lower confidence in their genetics knowledge following direct-to-consumer personal genomic testing

PurposeThe aim of this study was to measure changes to genetics knowledge and self-efficacy following personal genomic testing (PGT).MethodsNew customers of 23andMe and Pathway Genomics completed a series of online surveys. We measured genetics knowledge (nine true/false items) and genetics self-efficacy (five Likert-scale items) before receipt of results and 6 months after results and used paired methods to evaluate change over time. Correlates of change (e.g., decision regret) were identified using linear regression.Results998 PGT customers (59.9% female; 85.8% White; mean age 46.9 ± 15.5 years) were included in our analyses. Mean genetics knowledge score was 8.15 ± 0.95 (out of 9) at baseline and 8.25 ± 0.92 at 6 months (P = 0.0024). Mean self-efficacy score was 29.06 ± 5.59 (out of 35) at baseline and 27.7 ± 5.46 at 6 months (P < 0.0001); on each item, 30–45% of participants reported lower self-efficacy following PGT. Change in self-efficacy was positively associated with health-care provider consultation (P = 0.0042), impact of PGT on perceived control over one’s health (P < 0.0001), and perceived value of PGT (P < 0.0001) and was negatively associated with decision regret (P < 0.0001).ConclusionLowered genetics self-efficacy following PGT may reflect an appropriate reevaluation by consumers in response to receiving complex genetic information.     

Cardiac and renal distribution of ACE and ACE-2 in rats with heart failure

Congestive heart failure is often associated with impaired kidney function. Over-activation of the renin–angiotensin–aldosterone system (RAAS) contributes to avid salt and water retention in heart failure. While the expression of angiotensin converting enzyme (ACE), a key enzyme in the synthesis of angiotensin II (Ang II), is well established, the expression of angiotensin converting enzyme-2 (ACE-2), an enzyme responsible for angiotensin 1–7 generation, is largely unknown. This issue is of a special interest since angiotensin 1–7 counteracts many of the proliferative and hypertensive effects of angiotensin II. Therefore, the present study was designed to investigate the expression of both enzymes in the kidney and heart of rats with heart failure. Heart failure (CHF) was induced in male Sprague Dawley rats (n = 9) by the creation of a surgical aorto-caval fistula. Sham-operated rats served as controls (n = 8). Two weeks after surgery, the animals were sacrificed and their hearts and kidneys were harvested for assessment of cardiac remodeling and ACE and ACE-2 immunoreactivity by immunohistochemical staining. ACE immunostaining was significantly increased in the kidneys (4.34 ± 0.39% vs. 2.96 ± 0.40%, P < 0.05) and hearts (4.57 ± 0.54% vs. 2.19 ± 0.37%, P < 0.01) of CHF rats as compared with their sham controls. In a similar manner, ACE-2 immunoreactivity was also elevated in the kidneys (4.65 ± 1.17% vs. 1.75 ± 0.29%, P < 0.05) and hearts (5.48 ± 1.11% vs. 1.13 ± 0.26%, P < 0.01) of CHF rats as compared with their healthy controls. This study showed that both ACE and ACE-2 are overexpressed in the cardiac and renal tissues of animals with heart failure as compared with their sham controls. The increased expression of the beneficial ACE-2 in heart failure may serve as a compensatory response to the over-activity of the deleterious isoform, namely, angiotensin converting enzyme 1(ACE-1).     

Aortic elastic properties and cognitive function in elderly individuals: The Ikaria Study

BackgroundThe aim of this work was to evaluate the association between aortic elastic properties and cognitive function in elderly individuals, permanent inhabitants of Ikaria Island.MethodsIn 535 individuals (75 ± 6 years, 53% males) aortic distensibility (AoD) was non-invasively calculated from the aortic diameters measured with echocardiography and brachial artery pressure using the formula by Stefanadis et al.; cognitive status was evaluated using the Mini Mental State Examination (MMSE).Results88% of the elders had normal values of MMSE score (i.e., ≥24). Elders who achieved MMSE score ≥24 had higher values of AoD (1.90 ± 2.06 vs. 1.08 ± 1.42, p < 0.001), as well as were more physically active (85% vs. 69%, p = 0.05), had higher educational status (8.5 ± 2.8 years vs. 6 ± 2 years, p = 0.001), higher creatinine clearance levels (70 ± 21 vs. 63 ± 23, p = 0.05) and lower pulse pressure (PP) values (63 ± 16 vs. 68 ± 18, p = 0.06), as compared with those individuals with MMSE < 24. Logistic regression analysis showed that for every unit increase in AoD there was a 25% higher likelihood of having MMSE ≥ 24 (OR per 1000 × mmHg^?1 = 1.25, 95%CI 0.99–1.58), after adjustments for age, gender, current smoking, cardiovascular disease, creatinine clearance, hypertension, diabetes mellitus, obesity, physical activity status and education status. Furthermore having PP levels in the upper tertile (>70 mmHg), increases by 55% the likelihood of having MMSE < 24 (OR for above 70 mmHg = 0.45, 95%CI 0.22, 0.92), after the same adjustments were made.ConclusionArterial aging seems to affect cognitive function; a finding that states a novel research hypothesis about the pathophysiological mechanisms of mental functioning.     

Analysis of the shedding of three β-herpesviruses DNA in Polish patients subjected to allogeneic hematopoietic stem cell transplantation: Six-year follow up

BackgroundInfections with human β-herpesviruses are common worldwide and are still frequent in patients after hematopoietic stem cell transplantation. Some data suggest that HHV-6 and HHV-7 could take part in CMV reactivation from latency and/or progression of CMV disease in immunosupressed patients.ObjectivesThe aims of this study were: (1) to summarise retrospectively the results of β-herpesviruses DNA detection in a large group of adult allogeneic haematopoietic stem cell transplant recipients; and (2) to find a potential correlation between viruses belonging to this subfamily.Study designAlloHSCT recipients (N = 142) were examined in the early post-transplant period (median = 89 days). The presence of CMV, HHV-6 and HHV-7 was confirmed through detection and quantification of viral DNA, isolated from 1679 sera samples.ResultsCMV DNA alone was detected in 23.9% of patients, while single HHV-6 and HHV-7 were detected in 14.8% and 9.9% of individuals, respectively. The reactivation of more than one virus was identified in 31% of analysed patients. In cases of concurrent infection, HHV-7 was detected at the same time as HHV-6, and both of them were usually reactivated before CMV. The kinetics of virus reactivation and measured viral load may suggest a potential role of HHV-6 and HHV-7 as co-factors in CMV reactivation.ConclusionsThe observed kinetics of virus reactivation may strongly suggest a potential role of HHV-6 and/or HHV-7 as co-factors of CMV reactivation. The co-infection with these β-herpesviruses could predispose patients after hematopoietic stem cell transplantation to a longer and more severe CMV infection.     

Role of left atrial speckle tracking echocardiography in predicting persistent atrial fibrillation electrical cardioversion success and sinus rhythm maintenance at 6 months

PurposeWe assessed the value of left atrium speckle tracking imaging (STI) indices, and clinical and other echocardiographic parameters in persistent atrial fibrillation (AF) patients to predict the efficacy of electrical cardioversion (EC) and sinus rhythm (SR) maintenance at 6 months.Material/methodsEighty persistent AF patients planned to receive EC, underwent echocardiography including STI. After 24 h, patients with successful EC were examined to predict SR maintenance. After 6 months patients with no AF recurrence in electrocardiogram (ECG) underwent 7-day ECG to exclude silent AF. Every AF > 1 min was a recurrence.ResultsSR restored in 61 patients, 19 unsuccessful. Prior use of statins (68.8% vs. 42.1%, p = 0.03) was the only factor, determined later by univariate analysis to be a significant EC success predictor (OR = 1.09, CL ± 95% 1.001–1.019, p < 0.03). Both groups received similar antiarrhythmics and had similar echocardiographic parameters. After 6 months, SR was maintained in 19 patients (31.1%, Group I); AF recurrences were registered in 42 patients (68.8%, Group II). In Group I, only the mitral valve deceleration time (MVDT) 224.18 ± 88.13 vs. 181.6 ± 60.6 in Group II, p = 0.04) and the dispersion of time to peak longitudinal strain (dTPLS) (86.0 ± 68.3 vs. 151.8 ± 89.6, p = 0.03) differed significantly. The univariate analysis revealed dTPLS as a significant predictor of SR maintenance.ConclusionHigh EC efficacy and frequent AF recurrences were observed. The dispersion of time to the maximal longitudinal strain (LS) of left atrial segments facilitated prediction of SR maintenance. The value of 7-day ECG monitoring for detection of arrhythmia after 6 months was limited.     

Relationship between perilipin gene polymorphisms and body weight and body composition during weight loss and weight maintenance

BackgroundGenetic variation in the perilipin (PLIN) gene may play a role in the etiology and treatment of obesity.ObjectiveTo examine different polymorphisms in the PLIN gene in relation to body-weight regulation.Methods118 subjects followed a 6 wk VLCD, followed by 1 year weight maintenance. Body-weight (BW), body-composition, leptin concentration, and polymorphisms of the PLIN gene: PLIN1:rs2289487, PLIN4:rs894160, PLIN6:rs1052700, PLIN5:rs2304795 and PLIN7:rs 2304796 were determined.ResultsBW loss during VLCD was 7.0 ± 3.1 kg (p < 0.05), and BW regain was 3.7 ± 1.4 kg (p < 0.05), including changes in body mass index (BMI), waist-circumference, body-composition and leptin concentrations (p < 0.05).Linkage disequilibria were observed between PLIN1 and PLIN4: D' > 0.9, r² = 0.72; PLIN5 and PLIN7: D' > 0.9, r² = 0.85.In men, body weight, BMI, waist circumference, body fat, leptin concentrations were significantly lower for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). In women weight loss and loss of fat mass were larger for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). For PLIN6 genotypes body weight and body fat were lower for homozygotes of the minor allele (T/T) in the men; in the women leptin concentrations were lower.The haplotype of PLIN5 and PLIN7 consisting of A/G and G/G of PLIN5 and A/A of PLIN7 showed a reduction in FM: 5.9 ± 0.6 kg vs 3.1 ± 0.4 kg, % body fat: 5.5 ± 0.6% vs 2.2 ± 0.2%, and leptin: 20.5 ± 10.8 ng/ml vs 12.9 ± 6.7 ng/ml over time in the women (p < 0.05).ConclusionSince the haplotype of the minor alleles PLIN1–4, PLIN5–7 and PLIN6, was related to body-weight regulation at a lower level of body-weight in the men as well in the women we conclude that the PLIN1–4, 6, and 5–7 locus appears as a genetic influencer of obesity risk in humans.     

Impact of stem cell graft on early viral infections and immune reconstitution after allogeneic transplantation in adults

BackgroundViral infections are well-known complications after allogeneic stem cell transplant (allo-SCT).ObjectivesWe compared prospectively incidences of DNAemia and active infections (AI) for five opportunistic viruses (Human Herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), BK polyomavirus (BKPyV), Cytomegalovirus (CMV) and Adenovirus (ADV)) and kinetics of immune reconstitution (IR) in adults receiving either double umbilical cord blood (dUCB group) or unrelated peripheral blood stem cell (uPBSC group) allo-SCT after a reduced-intensity conditioning (RIC) regimen.Study designWhole blood samples were collected at transplant, every 15 days during the first 3 months and at 4, 5 and 6 months post-transplant.ResultsSixty-five patients were enrolled (uPBSC n = 34; dUCB n = 31). Incidences of HHV-6 and BKPyV DNAemia were significantly higher for dUCB (97% vs 23.5% and 58% vs 32%, respectively) while EBV DNAemia was more frequently detected in uPBSC (71% vs 26%). The incidence of CMV DNAemia was similar between both groups. ADV AI developed only in dUCB. HHV-6 AI were also higher in dUCB (84% vs 21%). In multivariate analysis, dUCB graft was the only independent factor associated with HHV-6 DNAemia (OR: 19.0; 95%CI: 5.2–69.1; p < 0.0001) while EBV DNAemia were significantly associated with uPBSC (OR: 29.9; 95%CI: 5.68–158; p < 0.0001). dUCB graft was also the only factor associated with HHV-6 AI. Finally, higher counts and faster recoveries of B lymphocytes (p<0.0001) and monocytes (p = 0.0007) were observed in the dUCB group.ConclusionWe demonstrate a strong correlation between sources of graft and patterns of viral DNAemia and AI and IR after RIC allo-SCT.     

Bone mineral density in pediatric survivors of Hodgkin and non-Hodgkin lymphomas

PurposeTo assess skeletal mass in survivors of childhood Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) 1–5 years after treatment, and to identify potential risk factors influencing bone mineral density (BMD).Patients/methodsThis cross-sectional study was conducted in a cohort of 43 survivors (HD = 31; NHL = 12); mean age: 16.21 ± 4.4. Total body bone mineral content (TBMC) and density (TBBMD), and lumbar spine density (LSBMD) were determined using dual-energy X-ray absorptiometry.ResultsThree of all 43 patients developed low BMD. No significant differences in height, weight, and/or BMD Z-scores were found between HD and NHL survivors, children who received and did not receive radiotherapy, and the groups with different chemotherapeutic blocks. No differences were noted between the Z-scores of BMC (mean ± SD: 0.31 ± 1.29 vs. −0.089 ± 0.61, p = 0.165), TBBMD (mean ± SD: −0.32 ± 1.21 vs. −0.27 ± 0.91, p = 0.76), or the LSBMD (mean ± SD: −0.183 ± 1.54 vs. −0.17 ± 0.87, p = 0.637) in subgroups, in accordance with time after therapy (subgroup I < 2 years and subgroup II > 2 years after treatment). In HD survivors, age at diagnosis only affected the TBBMD Z-score (a decrease of 0.127 in total BMD Z-score per each year, R² = 0.999, p < 0.001).ConclusionsChildhood lymphoma survivors demonstrate no significant deficits in bone mass and tend to maintain their BMD within the normal range when presenting during one to five years’ follow-up. However, this specific group requires longitudinal investigation to assess the pattern of peak bone mass achievement and the risk of future bone loss.     

Macrophage migration inhibitory factor contributes to anti-neutrophil cytoplasmic antibody-induced neutrophils activation

BackgroundMacrophage migration inhibitory factor (MIF) is an inflammatory mediator released by macrophages that is central to the innate immune system, with an upstream role in the inflammatory cascade. MIF is one of the most important pathogenic factors in the development of the autoimmune diseases. In the current study, we investigated the role of MIF in anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation.MethodsPlasma levels of MIF from 31 patients with active ANCA-associated vasculitis (AAV) were analyzed by ELISA. The various effects of MIF in ANCA-induced neutrophil respiratory burst and degranulation were measured.ResultsPlasma levels of circulating MIF were significantly higher in AAV patients with active disease compared with those in remission and healthy controls. Compared with MIF-primed neutrophils, the MFI value increased significantly in MIF-primed neutrophils further activated with MPO-ANCA-positive IgG or PR3-ANCA-positive IgG (270.8 ± 9.7 vs. 421.5 ± 9.7, P < 0.001; 270.8 ± 9.7 vs. 414.1 ± 15.6, P < 0.001, respectively). Compared with MIF-primed neutrophils, the lactoferrin concentration increased significantly in the supernatant of MIF-primed neutrophils further activated by MPO-ANCA-positive IgG (567.8 ± 61.2 ng/ml vs. 1677.0 ± 42.5 ng/ml, P < 0.001) or PR3-ANCA-positive IgG (567.8 ± 61.2 ng/ml vs. 1546.0 ± 116.2 ng/ml, P < 0.001), respectively. Interleukin-8 (IL-8), IL-6 and IL-23 were involved in ANCA-induced activation of MIF-primed neutrophils.ConclusionsMIF primes neutrophils by increasing ANCA antigen translocation. The primed neutrophils can be further induced by ANCA, resulting in respiratory burst and degranulation.     

Effects of a continuous-combined regimen of low-dose hormone therapy (oestradiol and norethindrone acetate) and tibolone on the quality of life in symptomatic postmenopausal women: A double-blind,randomised study

ObjectiveThis study compared the effects of a continuous-combined regimen of low-dose hormone therapy (LD-HT) versus tibolone and supplemental calcium/vitamin D3 (control) on quality of life (QoL) in symptomatic postmenopausal women.DesignThis study was a prospective, randomised, double-blind, comparative trial with a control group.SettingThe study was conducted in a climacteric outpatient clinic in the University Hospital of Federal University of Juiz de Fora, Brazil.PopulationA total of 174 postmenopausal women under 60 years of age who attended the climacteric outpatient clinic between June 2009 and June 2011 were recruited. These women complained of moderate or intense vasomotor symptoms and exhibited no contraindications for the use of hormone therapy.InterventionsThe patients were randomised into three groups: (1) daily treatment with 2.5 mg tibolone (n = 64), (2) 50 mg calcium carbonate + 200 IU vitamin D3 (Ca/Vit D3, n = 54) or (3) 1 mg oestradiol + 0.5 mg norethindrone acetate (E2/NETA, n = 56) for 12 weeks.Primary outcome measuresThe primary outcome was the evaluation of QoL using the Women's Health Questionnaire (WHQ) in all subjects at baseline and after 4, 8 and 12 weeks of treatment.ResultsA total of 130 women in the following groups completed the study: tibolone (n = 42), Ca/Vit D3 (n = 44) and E2/NETA (n = 44). An improved QoL based on the WHQ was observed at T0 (80.12 ± 14.04, 77.73 ± 15.3, 77.45 ± 15.4) and T12 (57.0 ± 15.5, 55.7 ± 16.7, 58.4 ± 12.6) for the tibolone, E2 + NETA and Ca/Vit D3 groups, respectively (p values <0.05). The three groups exhibited significantly different scores at T12 for sexual behaviour and vasomotor symptoms. The tibolone group exhibited better sexual function compared with the E2/NETA and Ca/Vit D3 groups (4.2 ± 26, 5.6 ± 2.8, 5.4 ± 2.8, respectively, p values <0.05). LD-HT was superior to tibolone and Ca/Vit D3 treatment for improvements in vasomotor symptoms (3.2 ± 1.5, 4.0 ± 1.8, 4.3 ± 2.0, respectively, p values <0.05). Adverse effects were few and mild.ConclusionsAn improved QoL was observed in the three study groups. Tibolone primarily improved sexual function, and E2/NETA exhibited a superior response for vasomotor symptoms.     

Sensitivity of human herpesvirus 6 and other human herpesviruses to the broad-spectrum antiinfective drug artesunate

BackgroundAntiviral therapy for HHV-6 infection with conventional anti-herpesviral drugs is problematic so novel drugs are required. Artesunate is a well-tolerated drug approved for malaria therapy which possesses antiviral activity.ObjectiveThe artesunate sensitivity of HHV-6 was analyzed and compared to that of several other human herpesviruses.Study designCultured human cells were productively infected with strains of HHV-6 or other human herpesviruses to measure artesunate inhibition of viral protein synthesis (Western blot analysis) or viral genome replication (qPCR), and to determine IC₅₀ values by immunofluorescence or plaque reduction assays.ResultsSensitivity of HHV-6 to artesunate was demonstrated with an IC₅₀ of 3.80 ± 1.06 μM. This is in a range similar to IC₅₀ values for HCMV and EBV. Artesunate treatment of HHV-6-infected cells significantly reduced viral early and late protein synthesis that occurred in the absence of drug-induced apoptosis or necrotic cytotoxicity. HHV-6A genome replication was markedly reduced by artesunate.ConclusionsArtesunate possesses anti-HHV-6 activity in vitro and may be useful for treatment of HHV-6 infections.     

Sonographic evaluation of endothelial function in letrozole and tamoxifen users

ObjectivesStudies have shown that women previously treated for breast cancer present fewer cardiovascular events, indicating a possible protective effect of tamoxifen treatment. The effects of these aromatase inhibitors on cardiovascular protection remain controversial. The aim of this study was to compare some cardiovascular risk markers among breast cancer survivors following treatment with tamoxifen group (TMXg), letrozole group (LTZg) or no endocrine treatment group (NETg).MethodsA total of 103 breast cancer survivors: 35 using TMXg, 34 using letrozole group (LTZg) and 34 using no endocrine treatment group (NETg) were evaluated. Ultrasonographic evaluation of brachial artery flow-mediated dilation (FMD), carotid intima–media thickness (IMT) and stiffness index (β); blood total cholesterol, HDL and triglycerides were assessed.ResultsAll three groups presented similar values of HDL and IMT. TMXg showed the lowest total cholesterol (219.29 ± 36.31 mg/dL vs. 250.59 ± 38.37 mg/dL vs. 245.09 ± 35.35 mg/dL; TMXg vs. LTZg vs. NETg, respectively; p < 0.01—ANOVA), the highest triglycerides (139.34 ± 41.82 mg/dL vs. 111.35 ± 28.22 mg/dL vs. 122.09 ± 33.42 mg/dL; p < 0.01), the highest FMD (6.32 ± 2.33% vs. 4.10 ± 2.06% vs. 4.66 ± 2.52%; p < 0.01) and the lowest stiffness index (β) (5.08 ± 1.68 vs. 6.28 ± 1.75 vs. 5.99 ± 1.86; p = 0.01). LTZg did not differ significantly from NETg on any evaluated parameter.ConclusionsWe did not observe any effect of LTZg on the evaluated cardiovascular risk parameters compared to NETg. As such, the observed difference on lipid values, stiffness index (β) and FMD between women receiving tamoxifen and letrozole might be best attributed to the beneficial effect of tamoxifen than to a detrimental effect of letrozole.     

Quadriceps/hamstrings co-activation increases early after total knee arthroplasty

Quadriceps and hamstrings weakness and co-activation are present following total knee arthroplasty (TKA) and may impair functional performance. How surgery and post-operative rehabilitation influence muscle activation during walking early after surgery is unclear.PurposeExamine muscle strength and activation during walking before and one and 6-months post-TKA.MethodsTen patients (n = 6 female; age: 64.7 ± 7.9 years; body mass index[BMI]:29.2 ± 2.5 kg/m²) and 10 healthy adults (n = 6 female; age: 60.6 ± 7.4 years; BMI: 25.5 ± 4.0 kg/m²) participated. The patients underwent bilateral quadriceps and hamstrings strength testing and assessment of quadriceps/hamstrings co-activation and on/off timing using surface electromyography during a six-minute walk test (6MW). Groups, limbs, and changes with TKA surgery were compared.ResultsPatients reported greater 6MW knee pain pre- versus post-TKA and compared to controls (P < 0.05). Patients had weaker surgical limb hamstrings (P < 0.05) and bilateral quadriceps (P < 0.05) strength than controls pre- and post-TKA. Before and 1-month post-TKA, patients had side-to-side differences in quadriceps and hamstrings strength (P < 0.05). Controls walked farther than patients (P < 0.01). Patients demonstrated greater surgical limb co-activation pre-operatively than controls (P < 0.05). Co-activation was higher bilaterally one-month post-TKA compared to controls (P < 0.05). Patients turned off their quadriceps later during stance than controls before and 1-month post-TKA (P < 0.05).ConclusionsMuscle strength, co-activation, and timing differed between patients and controls before and early after surgery. Rehabilitation to improve strength and muscle activation seems imperative to restore proper muscle firing patterns early after surgery.     

Anterior cruciate ligament fixation: Is radial force a predictor of the pullout strength of soft-tissue interference devices?

BackgroundIn anterior cruciate ligament (ACL) reconstruction, an interference device achieves soft-tissue graft fixation by radially compressing the graft against the bone.PurposeThe objective of this study was to measure the radial force generated by different interference devices and evaluate the effect of this radial force on the pullout strength of graft-device constructs.Study DesignControlled laboratory study.MethodsA resultant force (F_R) was used as a representative measure of the total radial force generated. Bovine tendons were fixated in either synthetic bone or porcine tibia using one of following devices: (1) RCI titanium screw, (2) PEEK screw, (3) IntraFix sheath-and-screw device, and (4) ExoShape sheath-and-insert device. F_R was measured while each device was inserted into synthetic bone mounted on a test machine (n = 5 for each device). In a subsequent test series, graft-device constructs were loaded to failure at 50 mm/min. The pullout strength was measured as the ultimate load before failure (n = 10 for each device).ResultsThe F_R values generated during insertion into synthetic bone were 777 ± 86 N, 865 ± 140 N, 1313 ±198 N, and 1780 ± 255 N for the RCI screw, PEEK screw, IntraFix, and ExoShape, respectively. The pullout strengths in synthetic bone for the RCI screw, PEEK screw, IntraFix and ExoShape were 883 ± 125 N, 716 ± 249 N, 1147 ± 142 N, and 1233 ± 190 N, respectively.ConclusionsThese results suggest that the F_R generated during interference fixation affects the pullout strength with sheath-based devices providing superior F_R compared with interference screws. The use of synthetic bone was validated by comparing the pullout strengths to those when tested in porcine tibia.Clinical relevanceThese results could be valuable to a surgeon when determining the best fixation device to use in the clinical setting.