bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene–environment interactions and alcohol use and dependence: current status and future challenges
Authors: Van Der Zwaluw Carmen S. , Engels Rutger C. M. E.
Published: May 2009

Aim  To discuss the current status of gene–environment interaction research with regard to alcohol use and dependence. Further, we highlight the difficulties concerning gene–environment studies.

Methods  Overview of the current evidence for gene–environment interactions in alcohol outcomes, and of the associated challenges in gene–environment studies.

Results  Attention to the causative roles of gene–environment interactions in alcohol use and dependence is increasing. Studies with twin designs are beginning to examine gene‐shared environment effects, and animal studies have investigated gene–environment interaction effects on alcohol intake in primates. Thirteen studies incorporated gene–environment interactions in examining alcohol use or dependence in humans. These studies held a variety of candidate genes and environmental risk factors and their heterogeneity made it impossible to draw firm general conclusions.

Conclusions  Challenges for future gene–environment studies are abundant, and consist of, for example, the development of clear theoretical assumptions about neurobiological mechanisms and the recruitment of large longitudinal samples that already start in childhood. Replication is essential to prevent an overload of false‐positive results. Despite the difficulties, it is crucial to include gene–environment interactions in future studies in order to unravel the aetiological factors of human alcohol outcomes.
Drugs and violent death: comparative toxicology of homicide and non‐substance toxicity suicide victims
Authors: Darke Shane , Duflou Johan , Torok Michelle
Published: May 2009

Aims  To determine the comparative toxicology of death by homicide and suicide by means other than substance toxicity.

Design  Cross‐sectional (autopsy reports).

Setting  Sydney, Australia.

Cases  A total of 1723 cases of violent death were identified, comprising 478 homicide (HOM) cases and 1245 non‐substance toxicity suicide (SUI) cases.

Findings  Substances were detected in 65.5% of cases, and multiple substances in 25.8%, with no group differences. Illicit drugs were detected in 23.9% of cases, and multiple illicit in 5.3%. HOM cases were significantly more likely to have an illicit drug [odds ratio (OR) 2.09] and multiple illicits (OR 2.94), detected, HOM cases being more likely to have cannabis (OR 2.39), opioids (OR 1.53) and psychostimulants (OR 1.59) present. HOM cases were, however, significantly less likely to have benzodiazepines (OR 0.53), antidepressants (OR 0.22) and antipsychotics (OR 0.23) present. Alcohol was present in 39.6% of cases (median blood alcohol concentration = 0.12), with no group difference in prevalence.

Conclusions  The role drugs play in premature death extends far beyond overdose and disease, with illicit drugs associated strongly with homicide.
Urinary ethyl glucuronide (EtG) and ethyl sulphate (EtS) assessment: valuable tools to improve verification of abstention in alcohol‐dependent patients during in‐patient treatment and at follow‐ups
Authors: Junghanns Klaus , Graf Iris , Pflüger Juliane , Wetterling Gunnar , Ziems Christian , Ehrenthal Dieter , Zöllner Maike , Dibbelt Leif , Backhaus Jutta , Weinmann Wolfgang , Wurst Friedrich M.
Published: May 2009

Aims  The aims of this study were (i) to assess the effect of additional urinary ethyl glucuronide (EtG) and ethyl sulphate (EtS) assessment on diagnosed relapse rates in detoxified alcohol‐dependent patients; and (ii) to compare dropout rates between EtG‐ and EtS‐negative and ‐positive patients.

Design  Two studies on detoxified alcohol‐dependent patients. If patients had no indication of relapse they were asked for a urinary sample at discharge from in‐patient treatment 3, 6 and 12 weeks after discharge (study 1) and 1, 3 and 6 weeks after discharge (study 2), respectively.

Setting  Department of Psychiatry, University of Luebeck, Germany.

Participants  A total of 107 and 32 detoxified alcohol‐dependent patients having participated in a 3‐week in‐patient motivation enhancement programme.

Measurement  Personal interviews, breathalyzer tests, assessment of urinary EtG and EtS with liquid chromatography‐tandem mass spectrometry (LC‐MS/MS analysis).

Finding  Urinary EtG and EtS were always positive at the same time. In the first study 13.5% of the patients were already positive before being discharged from hospital. At the follow‐ups 3, 6 and 12 weeks after discharge 12.2, 19.4 and 28.0%, respectively, of the patients coming to the follow‐up and denying relapse were positive on urinary EtG and EtS. In the second study, of those patients showing up for follow‐up after 1 week and denying relapse, EtG and EtS were positive in four cases (17.4%). Only one EtG‐ and EtS‐positive relapser (3.1%) came to the next follow‐ups. In both studies the rates of detected relapses were significantly higher for early follow‐ups if urinary EtG and EtS results were considered additionally. Dropout rates until the next follow‐up were significantly higher among positive than EtG‐ and EtS‐negative patients.

Conclusion  Urinary EtG and EtS improve verification of abstinence in studies of alcohol‐dependent patients.
Lifetime alcohol use, abuse and dependence among university students in Lebanon: exploring the role of religiosity in different religious faiths
Authors: Ghandour Lilian A. , Karam Elie G. , Maalouf Wadih E.
Published: May 2009

Aims  To examine alcohol consumption and the role of religiosity in alcohol use disorders in Christian, Druze and Muslim youth in Lebanon, given their distinct religious doctrines and social norms.

Methods  Using a self‐completed anonymous questionnaire, data were collected on 1837 students, selected randomly from two large private universities in Beirut. Life‐time abuse and dependence were measured as per the Diagnostic and Statistical Manual version IV.

Findings  Alcohol use was more common in Christians, who started drinking younger and were twice as likely to be diagnosed with abuse and dependence. However, among ever drinkers, the odds of alcohol use disorders were comparable across religious groups. Believing in God and practising one's faith were related inversely to alcohol abuse and dependence in all religious groups, even among ever drinkers (belief in God only). The associations were sometimes stronger for Muslims, suggesting that religiosity may play a larger role in a more proscriptive religion, as postulated by‘reference group theory’.

Conclusions  Students belonging to conservative religious groups may be shielded from the opportunity to try alcohol. Once an ever drinker, however, religion is not related to the odds of an alcohol use disorder. Religiosity (i.e. belief in God and religious practice) is, nevertheless, related inversely to alcohol‐related problems, even among drinkers. Findings from this culturally and religiously diverse Arab country corroborate the international literature on religion, religiosity and alcohol use, highlighting potential differences between Christians and Muslims.
A cohort study to examine whether time and risk preference is related to smoking cessation success
Authors: Goto Rei , Takahashi Yuko , Nishimura Shuzo , Ida Takanori
Published: May 2009

Aim  To identify whether time and risk preference predicts relapse among smokers trying to quit.

Design  A cohort study of smokers who had recently started to quit. Time and risk preference parameters were estimated using a discrete choice experiment (DCE).

Participants  A total of 689 smokers who began quitting smoking within the previous month.

Measurements  Time discount rate, coefficient of risk‐aversion measured at study entry and duration of smoking cessation measured for 6 months.

Findings  In the unadjusted model, Cox's proportional hazard regression showed that those with a high time discount rate were more likely to relapse [hazard ratio: 1.18, 95% confidence interval (CI): 1.11–1.25]. A high coefficient of risk‐aversion reduced the hazard of relapse (0.96, 0.96–0.97). When adjusted for other predictors of relapse (age, gender, self‐efficacy of quitting, health status, mood variation, past quitting experience, the use of nicotine replacement therapy, nicotine dependence), the hazard ratios of time discount rate and the coefficient of risk‐aversion is 1.17 (95% CI: 1.10–1.24) and 0.98 (95% CI: 0.97–0.99), respectively.

Conclusions  Those who emphasize future rewards (time–patient preference) and those who give more importance to rewards that are certain (higher risk‐aversion) were significantly more likely to continue to abstain from smoking.
Recognition of Phytophthora infestans Avr4 by potato R4 is triggered by C‐terminal domains comprising W motifs
Authors: VAN POPPEL PIETER M. J. A. , JIANG RAYS H. Y. , ŚLIWKA JADWIGA , GOVERS FRANCINE
Published: May 2009

Oomycete RXLR‐dEER effector proteins are rapidly evolving proteins with the selective pressure targeted predominantly at their C‐terminal ends. The majority of RXLR‐dEER proteins have recognizable motifs of 21–30 amino acids in the C‐terminal domain that are named after conserved amino acid residues at fixed positions within the respective motifs. In this article, it is reported that the Phytophthora infestans RXLR‐dEER protein Avr4 contains three W motifs and one Y motif in its C‐terminal domain. Agroinfection assays using constructs encoding modified forms of PiAvr4 have shown that the region containing the W2 motif, in combination with either the W1 or W3 motif, triggers a necrotic response in potato plants carrying the resistance gene R4. By mining the superfamily of avirulence homologues (Avh) deduced from three sequenced Phytophthora genomes, several Avh proteins were identified as homologues of PiAvr4: six in P. infestans, one in P. ramorum and seven in P. sojae. One very close homologue of PiAvr4 was cloned from the sibling species, P. mirabilis. This species is not pathogenic on potato but, similar to PiAvr4, PmirAvh4 triggered a necrotic response on potato clones carrying R4, but not on clones lacking R4. Genes encoding RXLR‐dEER effectors are often located in regions showing genome rearrangements. Alignment of the genomic region harbouring PiAvr4 with syntenic regions in P. sojae and P. ramorum revealed that PiAvr4 is located on a 100‐kb indel block and is surrounded by transposable elements.
Specialty care and education associated with greater disease‐specific knowledge but not satisfaction with care for chronic hepatitis C
Authors: BESTE L. A. , STRAITS‐TROSTER K. , ZICKMUND S. , LARSON M. , CHAPKO M. , DOMINITZ J. A.
Published: May 2009

Background  Little is known about differences among hepatitis C virus (HCV) patients managed by generalists vs. specialists with respect to patient‐centred outcomes, such as disease‐specific knowledge, health‐related quality of life (HRQoL) and satisfaction with care.

Aim  To examine selected patient‐centred outcomes of HCV‐related care provided in primary care, specialty care or both.

Methods  A total of 629 chronic HCV patients completed a survey including an HCV knowledge assessment and validated instruments for satisfaction and HRQoL. Multivariable linear regression was used to compare outcomes between groups.

Results  Adjusted total HCV knowledge score was lower among patients who did not attend specialty care (P < 0.01). Primary care and specialty patients did not differ in adjusted general HRQoL or satisfaction. Sixty percent of specialty patients underwent formal HCV education, which was associated with 5% higher knowledge score (P = 0.01). General HRQoL and patient satisfaction did not differ between primary care and specialty groups. Disease‐specific knowledge and care satisfaction were independent of mental illness, substance abuse, socio‐economic variables, history of antiviral treatment, formal HCV education and duration of time between last visit and survey completion.

Conclusions  Primary care patients with chronic HCV have lower adjusted disease‐specific knowledge than specialty patients, but no difference in general HRQoL or patient satisfaction.
Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections
Authors: SCHNEEWEISS S. , KORZENIK J. , SOLOMON D. H. , CANNING C. , LEE J. , BRESSLER B.
Published: May 2009

Background There remain concerns about the safety of infliximab therapy in patients with inflammatory bowel disease (IBD).

Aim To assess the association between the initiation of infliximab and other immunomodulating drugs and the risk of serious bacterial infection in the treatment of IBD.

Methods We assembled a cohort study of patients with IBD, including Crohn’s disease (CD) and ulcerative colitis (UC). All patients initiating an immunomodulating drug between January 2001 and April 2006 were identified in British Columbia from linked health care utilization databases. Exposure of interest was initiation of infliximab or corticosteroids compared with initiation of other immunosuppressive agents, including azathioprine, mercaptopurine (MP) and methotrexate (MTX). Outcome of interest was serious bacterial infections requiring hospitalization, includingClostridium difficile.

Results Among 10 662 IBD patients, the incidence rate of bacteriaemia ranged from 3.8 per 1000 person‐years (95% confidence interval 2.1–6.2) for other immunosuppressive agents to 7.4 (3.3–19.3) for infliximab with slightly higher rate for serious bacterial infections resulting in an adjusted relative risk 1.4 (0.47–4.24).Clostridium difficileinfections occurred in 0/1000 (0–5.4) among 521 infliximab initiations and 14/1000 (10.6–18.2) for corticosteroids. Corticosteroid initiation tripled the risk ofC. difficileinfections (RR = 3.4; 1.9–6.1) compared with other immunosuppressant agents. This corticosteroid effect was neither dose‐dependent nor duration‐dependent. Bacteriaemia and other serious bacterial infections were not increased by corticosteroids or infliximab (5 events).

Conclusions In a population‐based cohort of patients with IBD, we found no meaningful association between infliximab and serious bacterial infections, although some subgroups had few events. Corticosteroid initiation increased the risk forC. difficileinfections in these patients.
Gastric mucosal injury in systemic lupus erythematosus patients receiving pulse methylprednisolone therapy
Authors: Luo Jiing‐Chyuan , Chang Full‐Young , Chen Tseng‐Shing , Ng Yee‐Yung , Lin Han‐Chieh , Lu Ching‐Liang , Chen Chih‐Yen , Lin Hsiao‐Yi , Lee Shou‐Dong
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Whether glucocorticoids induce gastric mucosal injury remains uncertain, and Helicobacter pylori infection in steroid users has not been well evaluated in the past.

• Pulse methylprednisolone therapy with the very high dose of steroid that is 100 times larger than the physiological dose will be a special model to evaluate whether glucocorticoids induce gastric mucosal injury.

WHAT THIS STUDY ADDS

• Use of nonsteroidal anti‐inflammatory drugs/aspirin, but not H. pylori infection, increases gastric mucosal injury in systemic lupus erythematosus patients receiving pulse methylprednisolone therapy.

• Very high‐dose steroids de novo seem not to induce gastric mucosal injury in these patients.

• However, a larger, case‐controlled study enrolling a heterogeneous population is needed to clarify the role of glucocorticoids in gastric mucosal injury.

AIMS

Whether glucocorticoids induce gastric mucosal injury remains uncertain. We investigated whether very high‐dose steroids caused gastric mucosal injury in systemic lupus erythematous (SLE) patients and evaluated the possible risk factors for mucosal injury.

METHODS

In this prospective paired study, 67 SLE patients who had received pulse methylprednisolone therapy were enrolled. Each patient underwent endoscopic examination and tissue and blood sampling before and after pulse steroid therapy. Mucosal injury was diagnosed if the follow‐up injury scale was higher than the initial scale. Examined parameters included Helicobacter pylori infection, cyclooxygenase (COX)‐1 and COX‐2 activity, and current nonsteroidal anti‐inflammatory drug (NSAID) usage including aspirin.

RESULTS

Eleven (16.4%) of 67 cases who developed gastric mucosal injury after pulse therapy had significantly higher rates of peptic ulcer history, NSAID/aspirin use, lower gastric thromboxane B2 and prostaglandin E2 levels when compared with cases without gastric mucosal injury (P < 0.05). Infection by H. pylori was not a risk factor for gastric mucosal injury. Multivariate logistic regression analysis showed that NSAID/aspirin use was the only risk factor for gastric mucosal injury in these patients (odds ratio 26.99, 95% confidence interval 4.91, 148.57, P < 0.0001). Pulse steroid therapy alone did not induce gastric mucosal injury in fifty SLE patients without taking any NSAID/aspirin.

CONCLUSIONS

Use of NSAIDs/aspirin, but not H. pylori infection, increases gastric mucosal injury in SLE patients receiving pulse methylprednisolone therapy. Very high‐dose steroids de novo seem not to induce gastric mucosal injury in these patients. A larger case‐controlled study enrolling a heterogeneous population is needed to clarify the role of glucocorticoids in gastric mucosal injury.
The use of antipsychotic and anticholinergic antiparkinson drugs in Norway after the withdrawal of orphenadrine
Authors: Gjerden Pål , Slørdal Lars , Bramness Jørgen G.
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Extrapyramidal side‐effects induced by antipsychotic agents are treated with dose reduction, switching of antipsychotic medication or the addition of anticholinergic antiparkinson drugs.

WHAT THIS STUDY ADDS

• The use of anticholinergic antiparkinson drugs appears to be superfluous in a large number of patients.

AIMS

Extrapyramidal side‐effects induced by antipsychotic drugs are treated with dose reduction or substitution with another antipsychotic drug or by the addition of anticholinergic antiparkinson agents. The withdrawal of orphenadrine from the Norwegian market provided a possibility to investigate to what degree these alternative measures were taken in clinical practice.

METHODS

Data were drawn from the Norwegian Prescription Database on the sales of antipsychotics and one of the two anticholinergic antiparkinson agents marketed in 2004, orphenadrine and biperiden, to a total of 39 758 outpatients. The patients were reinvestigated in 2007. The consequences of the withdrawal of orphenadrine from the Norwegian market in 2005 regarding dosing, switching and cessation of antipsychotics and use of anticholinergics were assessed for orphenadrine users compared with biperiden users.

RESULTS

Of the patients originally using orphenadrine, 28.4% stopped using the drug without reducing the antipsychotic dose or replacing orphenadrine with another anticholinergic agent. The corresponding number for biperiden users was 19.3%. Only 11.8% of patients switched to another antipsychotic drug, but they used significantly lower antipsychotic doses than those who stayed on the same drug.

CONCLUSION

The use of anticholinergic antiparkinson agents could be seen as superfluous for at least one‐third of patients.
Prospective observational study of adverse drug reactions to diclofenac in children
Authors: Standing Joseph F. , Ooi Kuan , Keady Simon , Howard Richard F. , Savage Imogen , Wong Ian C. K.
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac is frequently used off‐label in children for acute pain, but little information is available on diclofenac adverse drug reactions in this population.

WHAT THIS STUDY ADDS

• The common adverse drug reactions of diclofenac for acute pain in children are of a similar type to those seen in adults.

• Serious adverse reactions occur in <0.8% of children and the incidence of diclofenac‐induced bronchospasm in asthmatic children is <2.7%.

AIM

The aim of this study was to investigate the type of common (occurring in >1% of patients) adverse reactions caused by diclofenac when given to children for acute pain.

METHODS

A prospective observational study was undertaken on paediatric surgical patents aged ≤12 years at Great Ormond Street and University College London Hospitals. All adverse events were recorded, and causality assessment used to judge the likelihood of them being due to diclofenac. Prospective recruitment meant not all patients were prescribed diclofenac, allowing an analysis of utilization. Causality of all serious adverse events was reviewed by an expert panel.

RESULTS

Children prescribed diclofenac were significantly older, and stayed in hospital for shorter periods than those who were not. Diclofenac was not avoided in asthmatic patients. Data on 380 children showed they suffer similar types of nonserious adverse reactions to adults. The incidence (95% confidence interval) of rash was 0.8% (0.016, 2.3); minor central nervous system disturbance 0.5% (0.06, 1.9); rectal irritation with suppositories 0.3% (0.009, 1.9); and diarrhoea 0.3% (0.007, 1.5). No serious adverse event was judged to be caused by diclofenac, meaning the incidence of serious adverse reactions to diclofenac in children is <0.8%.

CONCLUSION

Children given diclofenac for acute pain appeared to suffer similar types of adverse reactions to adults; the incidence of serious adverse reaction is <0.8%.
Tolerability and safety of GS‐101 eye drops, an antisense oligonucleotide to insulin receptor substrate‐1: a ‘first in man’ Phase I investigation
Authors: Kain Hermann , Goldblum David , Geudelin Bernard , Thorin Eric , Beglinger Christoph
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Corneal proliferative angiogenesis is an orphan disease leading to cornea loss.

• Today's therapeutic approach is not clearly established, although essentially based on topical corticosteroids.

• There is therefore a need for new therapeutic alternatives specifically targeting angiogenesis.

WHAT THIS PAPER ADDS

• Preclinical data demonstrated the efficacy of GS‐101, an antisense oligonucleotide inhibiting insulin receptor substrate‐1 expression, at inhibiting experimental corneal angiogenesis.

• This study demonstrates the excellent safety and tolerability profile of GS‐101 applied as eye drops three times daily in this ‘first‐in‐man’ study.

• Upon validation in human of its immediate benefit, GS‐101 would offer an alternative to antivascular endothelial growth factor therapies in the treatment of corneal angiogenesis.

AIMS

GS‐101 (GeneSignal, Epalinges, Switzerland) is an antisense oligonucleotide that inhibits the expression of the scaffold protein insulin receptor substrate‐1 (IRS‐1). Inhibition of IRS‐1 results in the prevention of neovascular growth and was shown to prevent the angiogenic process in preclinical in vitro and in vivo experiments. There is therefore a strong therapeutic rational for targeting angiogenesis in pathological neovascularization. We aimed to investigate the safety, tolerability and bioavailability of GS‐101 eye drops.

METHODS

This was a Phase I open‐label study. The investigation was performed in two steps. Local ocular tolerability was first assessed with the application of one single low dose in one eye. After no signs of intolerance were observed in the subjects, the dose escalation phase of the study was initiated, and the remaining subjects received three times daily escalating doses of GS‐101 in one eye for 14 days.

RESULTS

The 14 healthy volunteers tolerated well 14 days' continued use of escalating doses of GS‐101 from 43 to 430 µg per day. Other than itching, experienced also in the control eye by one subject and determined to be unrelated to the study treatment, no signs of intolerance were observed.

CONCLUSIONS

The tolerability profile obtained from this study suggests that GS‐101 is safe for human use. Further clinical evaluations in diseases related to abnormal angiogenesis are being targeted. In particular, the neovascularization‐related orphan indications of corneal graft rejection, retinopathy of pre‐maturity and neovascular glaucoma are currently under Phase II clinical investigation and are showing promising results.
Plasminogen activator inhibitor‐1 and asthma: role in the pathogenesis and molecular regulation
Authors: Ma Z. , Paek D. , Oh C. K.
Published: May 2009

Plasminogen activator inhibitor (PAI)‐1 is a major inhibitor of the fibrinolytic system. PAI‐1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI‐1 production. Recent studies suggest that PAI‐1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at −675 bp of the PAI‐1 gene is the major genetic determinant of PAI‐1 expression. Plasma PAI‐1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI‐1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI‐1 promoter with the 4G allele renders higher transcription activity than the PAI‐1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele‐mediated higher PAI‐1 expression is associated with greater binding of upstream stimulatory factor‐1 to the E‐box adjacent to the 4G site (E‐4G) than to the E‐5G. In summary, PAI‐1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI‐1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI‐1‐associated diseases.
Vaccination with collagen-pulsed dendritic cells prevents the onset and reduces the disease severity in the mouse model of spontaneous polychondritis
Authors: Sidhu M , Griffiths M M , Bradley D S
Published: May 2009

Immature dendritic cells (iDCs) have a tolerogenic potential due to low expression of important co-stimulatory cell surface molecules required for antigen presentation and induction of an effective immune response. We report here that injection of iDCs pulsed with chick type II collagen (CII) delayed the onset significantly and suppressed the severity of spontaneous polychondritis (SP) in the human leucocyte antigen (HLA)-DQ6αβ8αβ transgenic mouse model. Bone marrow-derived iDCs were pulsed in vitro with CII and transferred into 6-week-old HLA-DQ6αβ8αβ transgenic mice. Mice receiving CII-pulsed iDCs did not display any clinical signs of disease until 5·5 months of age, indicating the ability of the DC vaccine to delay significantly the onset of SP. Control groups receiving unpulsed iDCs or phosphate-buffered saline (PBS) developed polyarthritis at 3·5 months, as we have reported previously. The severity and incidence of disease was reduced in mice injected with CII-pulsed iDCs. Proinflammatory cytokines were in low to undetectable levels in the serum and tissue in the CII-pulsed iDC mice, correlating with the protection. This is the first evidence of iDC therapy controlling SP and suggests that iDC vaccination may provide a tool to reducing clinical manifestations in human inflammatory autoimmune disease such as relapsing polychondritis and rheumatoid arthritis.
The skin homing receptor cutaneous leucocyte-associated antigen (CLA) is up-regulated byLeishmaniaantigens in T lymphocytes during active cutaneous leishmaniasis
Authors: Mendes-Aguiar C de O , Gomes-Silva A , Nunes Jr E , Pereira-Carvalho R , Nogueira R S , Oliveira-Neto M de P , Bertho A L , Da-Cruz A M
Published: May 2009

The cutaneous leucocyte-associated antigen receptor (CLA) can direct Leishmania-specific T lymphocytes towards inflamed skin lesions. Homing receptors [CLA, lymphocyte-associated antigen 1 (LFA-1) or CD62L] were analysed in lymphocytes from blood and cutaneous leishmaniasis (CL) lesions. CL patients with active lesions (A-CL) presented lower levels of T lymphocytes expressing the CLA+ phenotype (T CD4+ = 10·4% ± 7·5% and T CD8+ = 5·8% ± 3·4%) than did healthy subjects (HS) (T CD4+ = 19·3% ±  13·1% and T CD8+ = 21·6% ± 8·8%), notably in T CD8+ (P < 0·001). In clinically cured patients these percentages returned to levels observed in HS. Leishmanial antigens up-regulated CLA in T cells (CLA+ in T CD4+ =  33·3% ± 14·1%; CLA+ in T CD8+ = 22·4% ± 9·4%) from A-CL but not from HS. An enrichment of CLA+ cells was observed in lesions (CLA+ in T CD4+ = 45·9% ± 22·5%; CLA+ in T CD8+ = 46·4% ± 16·1%) in comparison with blood (CLA+ in T CD4+ = 10·4% ± 7·5%; CLA+ in T CD8+ = 5·8% ±  3·4%). Conversely, LFA-1 was highly expressed in CD8+ T cells and augmented in CD4+ T from peripheral blood of A-CL patients. In contrast, CD62L was not affected. These results suggest that Leishmania antigens can modulate molecules responsible for migration to skin lesions, potentially influencing the cell composition of inflammatory infiltrate of leishmaniasis or even the severity of the disease.
β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis
Authors: Zhang W , Moritoki Y , Tsuneyama K , Yang G-X , Ilan Y , Lian Z-X , Gershwin M E
Published: May 2009

We have demonstrated spontaneous development of autoimmune cholangitis, similar to human primary biliary cirrhosis, in mice expressing a dominant negative form of the transforming growth factor-β receptor (dnTGF-βRII) restricted to T cells. The autoimmune cholangitis appears to be mediated by autoreactive CD8+ T lymphocytes that home to the portal tracts and biliary system. Because the liver pathology is primarily secondary to CD8+ T cells, we have determined herein whether administration of β-glucosylceramide (GC), a naturally occurring plant glycosphingolipid, alters the natural history of disease in this model. We chose GC because previous work has demonstrated its ability to alter CD8+ T cell responses and to down-regulate tissue inflammation. Accordingly, dnTGF-βRII mice were treated with either GC or control for a period of 18 weeks beginning at 6 weeks of age. Importantly, in mice that received GC, there was a significant decrease in the frequency and absolute number of autoreactive liver-infiltrating CD8+ T cells, accompanied by a significant decrease in activated CD44high CD8+ T cell populations. Further, there was a significant reduction in portal inflammation in GC-treated mice. Interestingly, there were no changes in anti-mitochondrial antibodies, CD4+ T cells, CD19+ B cells or natural killer (NK) T cell populations, indicating further that the beneficial effects of GC on liver inflammation were targeted specifically to liver-infiltrating CD8+ T cells. These data suggest that further work on GC in models of CD8+ T-mediated inflammation are needed and point to a new therapeutic venue for potentially treating and/or modulating autoimmune disease.
Relative seroprevalence of human herpes viruses in patients with chronic lymphocytic leukaemia
Authors: Steininger C. , Rassenti L. Z. , Vanura K. , Eigenberger K. , Jäger U. , Kipps T. J. , Mannhalter C. , Stilgenbauer S. , Popow‐Kraupp T.
Published: May 2009

Background  Herpes virus infections may have a significant role in chronic lymphocytic leukaemia (CLL) due to their ability to modulate the host’s immune system.

Materials and methods  We examined the seroprevalence of four herpes viruses [Cytomegalovirus (CMV), Epstein–Barr Virus (EBV), human herpes virus (HHV)‐6 and ‐7] in a cohort of European CLL patients (cohort 1, n = 100) in relation to the immunoglobulin variable heavy (IGHV) chain gene use and compared serological results with those obtained from age‐ and gender‐matched healthy adults (n = 100).

Results  CMV‐seroprevalence was significantly higher in CLL cohort 1 (79%) than in the control cohort (57%, P = 0·001); the seroprevalence of EBV (89% vs. 94%), HHV‐6 (73% vs. 60%), or HHV‐7 (35% vs. 35%) was not. In CLL cohort 1, use of IGHV3‐30 was more prevalent among CMV‐seropositive and of IGHV3‐21 among HHV‐7‐seronegative cases. To investigate the generalizability of these findings, we investigated the herpes virus seroprevalence in a second cohort of age‐matched CLL patients from a different geographical area (USA, n = 100, cohort 2). In cohort 2, CMV‐seroprevalence was comparable with that of the control cohort (53%). Seroprevalence of EBV, HHV‐6 and HHV‐7 were 85%, 88% and 73% respectively. In CLL cohort 2, use of IGHV3‐30 or IGHV3‐21 was not associated with any of the herpes viruses investigated.

Conclusions  CMV‐seropositivity is associated with CLL in selected patient cohorts. However, the considerable variation in herpes virus‐specific seropositivity between geographically distinct CLL cohorts indicates that seropositivity for any of the four human herpes viruses investigated is not generally associated with CLL.
Early atherosclerosis and IgG2 to bacteria are associated with FcγRIIa genotype in non‐smokers
Authors: Sämpi M. , Ukkola O. , Päivänsalo M. , Kesäniemi Y. A. , Hörkkö S.
Published: May 2009

Background  Involvement of low density lipoprotein (LDL) immune complexes (ICs) in atherogenesis has been proposed. Human FcγRIIa receptor (CD32) plays a crucial role in the phagocytosis of IgG2 ICs and a functional point mutation 131His/Arg diminishes IgG2 binding to the receptor.

Study design  We examined FcγRIIa‐131His/Arg polymorphism, IgG2 antibody titres to oxidized low‐density lipoprotein (OxLDL) and Streptococcus pneumoniae cell wall polysaccharide (CWPS) and subclinical atherosclerosis in a large cohort of Finnish subjects (n = 1041).

Results  Non‐smoking subjects with homozygous 131His/His genotype had more premature atherosclerosis (P = 0·004) and higher IgG2 to bacterial CWPS (P = 0·002) compared with other genotypes. Smoking subjects had significantly higher intima‐media thickness (IMT) than that of non‐smokers (P < 0·001) and genotype‐dependent associations were indistinct. There was no association between FcγRIIa genotype and antibody titres to OxLDL.

Conclusions  Our data demonstrate that FcγRIIa 131His/Arg polymorphism is associated with subclinical atherosclerosis in non‐smoking subjects. Furthermore, FcγRIIa genotype is associated with IgG2 titres to bacterial CWPS, but not to OxLDL. These data propose possible involvement of FcγRIIa receptor in atherogenesis.
Effect of polymerized‐type I collagen in knee osteoarthritis. I. In vitro study
Authors: Furuzawa‐Carballeda J. , Muñoz‐Chablé O. A. , Barrios‐Payán J. , Hernández‐Pando R.
Published: May 2009

Background  Polymerized‐type I collagen (polymerized‐collagen) is a down‐regulator of inflammation and a tissue regenerator biodrug. The aim of this study was to evaluate its effect in co‐cultures of cartilage and synovial tissue from patients with knee osteoarthritis (OA).

Materials and methods  Cartilage and synovial tissue from five patients with OA were co‐cultured for 7 days in the presence or absence of 1% polymerized‐collagen. To determine proteoglycans content, tissues were stained with alcian blue technique. Pro‐ and anti‐inflammatory cytokines [interleukin (IL)‐1β, IL‐8, IL‐10, IL‐12, tumour necrosis factor (TNF)‐α, and interferon (IFN)‐γ] and tissue inhibitor of metalloproteinase (TIMP)‐1 were measured in supernatants by ELISA and results were normalized by total protein concentration. Cartilage oligomeric matrix protein (COMP), type II collagen, TNF‐α, IL‐10 and Ki‐67 expression were determined by immunohistochemistry.

Results  Polymerized‐type I collagen induced an increase of 3‐ to 6fold cell proliferation (Ki‐67), proteoglycans content, and COMP and type II collagen expression, whereas it inhibited IL‐1β and TNF‐α production. IL‐10 levels were up‐regulated in treated vs. untreated cultures. No differences were found on IL‐8 or TIMP‐1 levels in supernatants from polymerized‐collagen‐treated co‐cultures when compared with untreated cultures. IL‐12 and IFN‐γ were undetectable.

Conclusion  The addition of polymerized‐type I collagen to cartilage and synovial tissue co‐cultures induced up‐regulation of chondrocytes proliferation and cartilage extracellular matrix proteins production (COMP, type II collagen and proteoglycans) as well as an anti‐inflammatory cytokine (IL‐10) and the down‐modulation of pro‐inflammatory cytokines (IL‐1β and TNF‐α). It is possible that this mechanism might contribute to induce tissue regeneration and down‐regulation of inflammation in OA.
DRAGON, a GPI‐anchored membrane protein, inhibits BMP signaling in C2C12 myoblasts
Authors: Kanomata Kazuhiro , Kokabu Shoichiro , Nojima Junya , Fukuda Toru , Katagiri Takenobu
Published: May 2009

Bone morphogenetic proteins (BMPs) induce osteoblastic differentiation of myoblasts via binding to cell surface receptors. Repulsive guidance molecules (RGMs) have been identified as BMP co‐receptors. We report here that DRAGON/RGMb, a member of the RGM family, suppressed BMP signaling in C2C12 myoblasts via a novel mechanism. All RGMs were expressed in C2C12 cells that were differentiated into myocytes and osteoblastic cells, but RGMc was not detected in immature cells. In C2C12 cells, only DRAGON suppressed ALP and Id1 promoter activities induced by BMP‐4 or by constitutively activated BMP type I receptors. This inhibition by DRAGON was dependent on the secretory form of the von Willbrand factor type D domain. DRAGON even suppressed BMP signaling induced by constitutively activated Smad1. Over‐expression of neogenin did not alter the inhibitory capacity of DRAGON. Taken together, these findings indicate that DRAGON may be an inhibitor of BMP signaling in C2C12 myoblasts. We also suggest that a novel molecule(s) expressed on the cell membrane may mediate the signal transduction of DRAGON in order to suppress BMP signaling in C2C12 myoblasts.
Trends and uncertainties in Siberian indicators of 20th century warming
Authors: ESPER JAN , FRANK DAVID , BÜNTGEN ULF , VERSTEGE ANNE , HANTEMIROV RASHIT M. , KIRDYANOV ALEXANDER V.
Published: May 2009

Estimates of past climate and future forest biomass dynamics are constrained by uncertainties in the relationships between growth and climatic variability and uncertainties in the instrumental data themselves. Of particular interest in this regard is the boreal‐forest zone, where radial growth has historically been closely connected with temperature variability, but various lines of evidence have indicated a decoupling since about the 1960s. We here address this growth‐vs.‐temperature divergence by analyzing tree‐ring width and density data from across Siberia, and comparing 20th century proxy trends with those derived from instrumental stations. We test the influence of approaches considered in the recent literature on the divergence phenomenon (DP), including effects of tree‐ring standardization and calibration period, and explore instrumental uncertainties by employing both adjusted and nonadjusted temperature data to assess growth‐climate agreement. Results indicate that common methodological and data usage decisions alter 20th century growth and temperature trends in a way that can easily explain the post‐1960 DP. We show that (i) Siberian station temperature adjustments were up to 1.3 °C for decadal means before 1940, (ii) tree‐ring detrending effects in the order of 0.6–0.8 °C, and (iii) calibration uncertainties up to about 0.4 °C over the past 110 years. Despite these large uncertainties, instrumental and tree growth estimates for the entire 20th century warming interval match each other, to a degree previously not recognized, when care is taken to preserve long‐term trends in the tree‐ring data. We further show that careful examination of early temperature data and calibration of proxy timeseries over the full period of overlap with instrumental data are both necessary to properly estimate 20th century long‐term changes and to avoid erroneous detection of post‐1960 divergence.
Improved quality and shelf life of farmed trout (Oncorhynchus mykiss) by whole processing in a combined ozonised flow ice refrigeration system
Authors: Aubourg Santiago P. , Testi Silvia , Sanxuás Minia , Gil Carolina , Barros‐Velázquez Jorge
Published: May 2009

A combined refrigeration system consisting of ozone and flow ice was evaluated for the sacrifice, cooling and chilled storage of continental trout. The batch processed in ozonised flow ice exhibited significant (P < 0.05) reductions (0.97 and 1.51 log CFU cm−2) in skin aerobes and psychrotrophs on days 6 and 9, respectively, and significant (P < 0.05) reductions (0.94 log CFU g−1 and 0.96 log CFU g−1) in aerobes, and proteolytic bacteria in muscle on day 13. A significant (P < 0.05) inhibition of TMA‐N formation after 9 days was also observed, with an average reduction of 28.4% along the storage period, Slight reductions in autolytic breakdown mechanisms were also observed in the ozonised batch, a maximum reduction of 14.82% being reached on day 13. The microbial and biochemical changes were well correlated with the sensory evaluation, which revealed relevant differences between the batches on day 13 and a shelf life extension of the ozonised batch up to day 16.
The application of Taguchi method to determine the optimum blend of unifloral honeys to most closely match thyme honey quality
Authors: Dimou Maria , Marnasidis Simos , Antoniadou Ioanna , Pliatsika Maria , Besseris George J.
Published: May 2009

This study was conducted to investigate the effect of four blossom honey types (orange, chestnut, heather and cotton) on a group of quality characteristics of thyme‐type based mixture preparations. Mixture ratios were prepared at 0%, 50% and 100% per blossom honey‐type and then were blended with thyme honey in parts 1:1. The melissopalynological, sensory and physicochemical quality characteristics for each blend were monitored. A three‐level, four‐factor orthogonal array according to the Taguchi method was utilised to plan the experiments maintaining the thyme component as a ‘slack‐variable’ to contain the number of performed trials. Subsequent anova treatment revealed that only a pure orange‐type blend favours the simultaneous maximisation of aroma (P < 0.05) and the minimisation of electrical conductivity (P < 0.05). Finally, there was a significant effect of chestnut‐type blend content on microscopical and physicochemical characteristics (P < 0.05), nevertheless, their corresponding signal‐to‐noise ratios are maximised only at a concentration of zero value.
Physicochemical properties of twenty‐one Caribbean sweet potato cultivars
Authors: Aina Adebisola J. , Falade Kolawole O. , Akingbala John O. , Titus Pathelene
Published: May 2009

The physical, chemical and physicochemical properties of twenty‐one Caribbean sweet potato cultivars were investigated. Hunter L a b colour parameters were measured, chroma, colour intensity and hue angle were calculated. Proximate composition, vitamin C, amylose, reducing and non‐reducing sugars contents were determined using standard methods. Pasting properties were determined using Rapid Visco Analyser. Tuber size (length, r = 0.72, n = 21, P < 0.0015; width, r = 0.85, n = 21, P < 0.0002) was highly correlated with weight of the tubers. External colours of the tubers (L = 28.7–63.1, a = +5.9 to +18.0, b = +3 to +19.3) were lower than the flesh colours (L = 60.8–84.0, a = −2.4 to +27.8, b = +9.9 to +28.5). Proximate composition is typical of sweet potato cultivars but significant differences exist among cultivars. Total sugar, amylose and amylopectin contents ranged from 1.8 to 4.7%, 15.3–31.2% and 68.8–84.7%, respectively. Cooking profiles of the sweet potato flours showed similar trend. Pasting temperature, peak time, swelling power and solubility ranged from 78.3 to 93.0 °C, 3.3–4.8 min, 5.6–23.5 and 11.7–45.7%, respectively.
Effects of killing conditions of vanilla (Vanilla planifolia, Andrews) pods during the curing process on aroma composition of pod ethanol extract
Authors: Pardio Violeta T. , Mariezcurrena Maria D. , Waliszewski Krzysztof N. , Sánchez Victor , Janczur Mariusz K.
Published: May 2009

The effects on the aroma compositions of ethanol extracts obtained by traditional and enzyme‐assisted methods from seven killing conditions used in vanilla pod curing were studied. Two procedures of vanilla pod killing consisted of either freezing pods at −10 °C for 24 h or immersing pods in 80 °C water for 10 s each of three times with 30 s intervals resulted in the highest vanillin values in terms percentage of dry weight of the bean (2.84 and 2.96), 4‐hydroxybenzaldehyde (0.18 and 0.20), vanillyl alcohol (0.56 and 0.57) and vanillic acid (0.18 and 0.19 respectively) when traditional vanilla ethanol extraction was used. When this extract was aged for 3 months it showed improvement in flavour compounds. Enzyme‐assisted vanilla ethanol extraction showed a higher content of flavour compounds than traditional extract, for example vanillin 4.38% and 2.96% respectively. Only vanillic acid levels were improved after ageing of the enzyme‐assisted extracts.
Tethyan vicariance, relictualism and speciation: evidence from a global molecular phylogeny of the opisthobranch genus Bulla
Authors: Malaquias Manuel António E. , Reid David G.
Published: May 2009

Aim  Our aims were: (1) to reconstruct a molecular phylogeny of the cephalaspidean opisthobranch genus Bulla, an inhabitant of shallow sedimentary environments; (2) to test if divergence times are consistent with Miocene and later vicariance among the four tropical marine biogeographical provinces; (3) to examine the phylogenetic status of possible Tethyan relict species; and (4) to infer the timing and causes of speciation events.

Location  Tropical and warm‐temperate regions of the Atlantic, Indo‐West Pacific, Australasia and eastern Pacific.

Methods  Ten of the 12 nominal species of Bulla were sampled, in a total sample of 65 individuals, together with cephalaspidean outgroups. Phylogenetic relationships were inferred by Bayesian analysis of partial sequences of the mitochondrial cytochrome c oxidase I (COI) and 16S rRNA and nuclear 28S rRNA genes. Divergence times and rates of evolution were estimated using uncorrelated relaxed‐clock Bayesian methods with fossil calibrations (based on literature review and examination of fossil specimens), implemented in beast. The geographical pattern of speciation was assessed by estimating the degree of overlap between sister lineages.

Results  Four clades were supported: Indo‐West Pacific (four species), Australasia (one species), Atlantic plus eastern Pacific (three species) and Atlantic (two species), with estimated mean ages of 35–46 Ma. Nominal species were monophyletic, but deep divergences were found within one Indo‐West Pacific and one West Atlantic species. Species‐level divergences occurred in the Miocene or earlier. The age of a sister relationship across the Isthmus of Panama was estimated at 7.9–32.1 Ma, and the divergence of a pair of sister species on either side of the Atlantic Ocean occurred 20.4–27.2 Ma.

Main conclusions  Fossils suggest that Bulla originated in the Tethys realm during the Middle Eocene. Average ages of the four main clades fall in the Eocene, and far pre‐date the 18–19 Ma closure of the Tethys Seaway. This discrepancy could indicate earlier vicariant events, selective extinction or errors of calibration. Similarly, the transisthmian divergence estimate far pre‐dates the uplift of the Panamanian Isthmus at about 3 Ma. Speciation events occurred in the Miocene, consistent with tectonic events in the central Indo‐West Pacific, isolation of the Arabian Sea by upwelling and westward trans‐Atlantic dispersal. Differences in habitat between sister species suggest that ecological speciation may also have played a role. The basal position of the Australasian species supports its interpretation as a Tethyan relict.