Individual differences in inflammatory and oxidative mechanisms of stress-related mood disorders.

Emotional stress leads to the development of peripheral disorders and is recognized as a modifiable risk factor for psychiatric disorders, particularly depression and anxiety. However, not all individuals develop the negative consequences of emotional stress due to different stress coping strategies and resilience to stressful stimuli. In this review, we discuss individual differences in coping styles and the potential mechanisms that contribute to individual vulnerability to stress, such as parameters of the immune system and oxidative state. Initial differences in inflammatory and oxidative processes determine resistance to stress and stress-related disorders via the alteration of neurotransmitter content in the brain and biological fluids. Differences in coping styles may serve as possible predictors of resistance to stress and stress-related disorders, even before stressful conditions. The investigation of natural variabilities in stress resilience may allow the development of new methods for preventive medicine and the personalized treatment of stress-related conditions.

EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction.

In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with ß-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.

Prenatal and adult androgen activities in alcohol dependence.

OBJECTIVE: Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. METHOD: We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). RESULTS: The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P < 0.001) and alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P < 0.005). Moreover, stress levels (P = 0.002), alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). CONCLUSION: Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence.

Resurgence of measles in Serbia 2010-2011 highlights the need for supplementary immunization activities.

Between December 2010 and August 2011 an outbreak of measles occurred in Serbia with 363 reported cases. Sera and/or nose/throat swabs were collected from 193 patients and tested for measles-specific IgM antibodies by ELISA and viral RNA by RT-PCR, respectively. Epidemiological data were obtained from the surveillance database of the Institute of Public Health of Serbia. Of the 363 cases involved in the outbreak, 113 were laboratory confirmed. More than one third of the patients were hospitalized (n = 130, 35·8%) and for 15 (4·1% of the reported outbreak cases) the infection was complicated by pneumonia. Mostly pre-school children aged ⩽4 years (37·8%) and adults aged ⩾30 years (27·3%) were affected. The majority of patients belonged to the Roma population with a preponderance of female cases (57·0%). Nearly 94% of the patients were either unvaccinated or of unknown vaccination status. The main outbreak virus was the D4-Hamburg strain. The outbreak in Serbia occurred after several years of very low measles incidence despite a high routine immunization coverage in the general population, suggesting that special efforts to identify and vaccinate susceptible population groups are required even in countries with apparently good disease control.

Long-term transmission of measles virus in Central and continental Western Europe.

The World Health Organization (WHO) has adopted an elimination goal for measles and rubella, which is supposed to be met in the WHO European Region (EUR) by 2015. For verification of elimination, it is required that the genotyping data of detected measles viruses provide evidence for the interruption of endemic transmission. In order to record and assess the extent of endemic measles virus (MV) circulation in a part of the EUR, we analyzed transmission chains of the epidemiologically most relevant MV variants identified in Central and continental Western Europe (CCWE) from 2006 to 2013. Based on MV sequence data deposited in the WHO global database for molecular surveillance of measles (MeaNS), the circulation period was calculated for each MV variant at the country-level and for the entire region of CCWE. The MV variants "D5-Okinawa," "D4-Hamburg," "D4-Manchester," and "D8-Frankfurt-Main" spread widely in CCWE; they caused large and long-lasting outbreaks with secondary spread that resulted in additional outbreaks. Nation-wide outbreaks (epidemics) with thousands of measles cases occurred in four countries (Switzerland, France, Bulgaria, and Romania) and were characterized by continuous detection of the same MV variant for more than 12 months suggesting endemic transmission. In the entire region of CCWE, the circulation period of the four predominant MV variants ranged from 18 to 44 months. The long-lasting MV transmission which affected predominantly unvaccinated individuals in different hard-to-reach groups and in the general population is not consistent with the measles elimination goal. Additional efforts are necessary to meet the elimination target in the EUR.

Lower seroreactivity to European than to North American H3N2 swine influenza viruses in humans, Luxembourg, 2010.

Seroreactivity to H3N2 swine influenza viruses (SIVs)was evaluated in serum samples collected from 843 people aged 0 to 100 years in 2010 in Luxembourg.Sera were analysed by haemagglutination inhibition(HI) and virus neutralisation (VN) assays targeting a European H3N2 SIV, a North American H3N2 variant of swine origin (H3N2v) and human seasonal H3N2 viruses isolated in 1975, 1995 and 2005. HI antibodies(titre ≥ 10) against European H3N2 SIV were almost exclusively detected in those born before 1990, of whom 70% were seropositive. HI antibodies against H3N2v were predominantly found in those born before 2000, with 86% seropositive. Titres against the North American H3N2v were higher than against the European H3N2 SIV. VN patterns were similar, but with higher rates and titres. We also demonstrated lower seroreactivity to European H3N2 SIV than to North American H3N2v virus. Finally, we found a strong correlation between HI titres against the European H3N2SIV and H3N2v and their respective human ancestors,A/Victoria/3/75 and A/Nanchang/933/95. This finding and the minimal contacts between humans and pigs in Luxembourg suggest that anti-SIV antibodies inhuman serum samples reflect serological cross-reactivity with historical human H3N2 viruses. Our findings help assess the pandemic risk of H3N2 SIV.

Occult hepatitis B infections among blood donors in Lao PDR.

BACKGROUND AND OBJECTIVES: In Lao People's Democratic Republic, hepatitis B virus is highly endemic. However, blood donations are only screened for HBsAg, leaving a risk of transmission by HBsAg-negative occult infected donors. Here, we characterized first-time blood donors to assess prevalence of hepatitis B virus infections and occult infected donors. MATERIALS AND METHODS: Sera were screened for HBsAg, HBeAg and anti-HBs, anti-HBc and anti-HBe antibodies. Occult HBV infections (OBIs) were assessed in HBsAg-negative sera by PCR, and sera of HBsAg positive and occult infected donors were phylogenetically characterized. RESULTS: 9·6% of the donors were HBsAg positive, and 45.5% were positive for at least one of the hepatitis B virus serum markers. More than 40% HBsAg carriers were HBeAg positive, with HBeAg seroconversion occurring around 30 years of age. Furthermore, 10·9% of HBsAg-negative, anti-HBc and/or anti-HBs-positive donors were occult infected with hepatitis B virus. Thus, at least 3·9% of blood donations would potentially be unsafe, but hepatitis B virus DNA copy numbers greatly varied between donors. CONCLUSION: In Lao People's Democratic Republic, a sizable proportion of HBsAg-negative and anti-HBc antibody-positive blood donations are potentially DNA positive and infective for hepatitis B.

Mumps outbreak in the Federation of Bosnia and Herzegovina with large cohorts of susceptibles and genetically diverse strains of genotype G, Bosnia and Herzegovina, December 2010 to September 2012.

A mumps outbreak reported from the Federation of Bosnia and Herzegovina involved 7,895 cases between December 2010 and September 2012. This was the largest outbreak in the country since the introduction of the measles, mumps and rubella vaccine in 1980. The highest disease incidence was found among 15 to 19 year-olds. About 39% (3,050/7,895) of cases reported to be unvaccinated; the vaccination status of 31% (2,426/7,895) was unknown. A seroprevalence study among 150 asymptomatic contacts to mumps cases showed that about one third (45/150) were susceptible to mumps. Among 105 clinically suspected mumps patients hospitalised at the Clinical Centre of the University of Sarajevo, orchitis (60% of all males: 51/85) and meningitis (9%: 9/105) were the most common complications. Among 57 outbreak sequences obtained for the small hydrophobic gene, eight different variants of genotype G viruses were identified. The outbreak affected mainly age groups comprising individuals who were not vaccinated during or after the Bosnian war, as well as cantons with single dose immunisation policies until 2001. In addition to issues related to vaccination of individuals, differential responses to vaccines and vaccine strains, waning of antibodies and potentially also the genetically diverse variants of genotype G may have compounded the size and duration of the outbreak. Our report emphasizes the need for supplementary immunisation programmes in particular for adolescents and young adults.

Identification of enolases and aldolases as important fish allergens in cod, salmon and tuna: component resolved diagnosis using parvalbumin and the new allergens.

BACKGROUND: The majority of fish-allergic patients are sensitized to parvalbumin, known to be the cause of important IgE cross-reactivity among fish species. Little is known about the importance of fish allergens other than parvalbumin. OBJECTIVE: The aim of this study was to characterize hitherto undefined fish allergens in three commonly consumed fish species, cod, salmon and tuna, and to evaluate their importance for in vitro IgE-diagnosis in addition to parvalbumin and fish gelatin. METHODS: Sixty-two patients were diagnosed by clinical history, skin prick tests and specific IgE to fish extracts. Two new fish allergens from cod, salmon and tuna were identified by microsequencing. These proteins were characterized by immunoblot, ELISA and mediator release assay. Purified parvalbumin, enolase, aldolase and fish gelatin were used for quantification of specific IgE in ELISA. RESULTS: Parvalbumin and two other allergens of 50 and 40 kDa were detected in IgE-immunoblots of cod, salmon and tuna extracts by most patient sera. The 50 and 40 kDa proteins were identified as beta-enolase and fructose-bisphosphate aldolase A respectively. Both purified enzymes showed allergenic activity in the mediator release assay. Indeed, 72.6% of the patients were sensitized to parvalbumin, 20% of these had specific IgE to salmon parvalbumin only. IgE to enolases were found in 62.9% (0.5-95.0 kUA /L), to aldolases in 50.0% (0.4-26.0 kUA /L) and to fish gelatin in 19.3% (0.4-20.0 kUA /L) of the patients. Inter-species cross-reactivity, even though limited, was found for enolases and aldolases by IgE-inhibition ELISA. CONCLUSIONS AND CLINICAL RELEVANCE: Fish enolase and aldolase have been identified as important new fish allergens. In fish allergy diagnosis, IgE to enolase and aldolase are especially relevant when IgE to parvalbumin are absent.

An outbreak of rubella in the Federation of Bosnia and Herzegovina between December 2009 and May 2010 indicates failure to vaccinate during wartime (1992-1995).

A rubella outbreak involving 1900 cases was recorded in the Federation of Bosnia and Herzegovina between mid-December 2009 and the end of May 2010. Sera from 389 suspected rubella cases were examined for the presence of rubella-specific IgM and IgG antibodies. A total of 32 throat swabs from suspected rubella cases were tested by RT-PCR and were used to attempt virus isolation. Most patients (945/1900, 49·73%) had never received rubella vaccination or had an unknown vaccination status (563/1900, 29·63%). About 45% (178/389) of suspected rubella patients were IgM positive. From 13 of the throat swabs a virus isolate and E1 gene sequences attributed to genotype 2B were obtained. The rubella outbreak was due to failure to vaccinate during the war period (1992-1995) and emphasizes the need for additional vaccination opportunities.

Avian flu: multiple introductions of H5N1 in Nigeria.

As the avian influenza virus H5N1 swept from Asia across Russia to Europe, Nigeria was the first country in Africa to report the emergence of this highly pathogenic virus. Here we analyse H5N1 sequences in poultry from two different farms in Lagos state and find that three H5N1 lineages were independently introduced through routes that coincide with the flight paths of migratory birds, although independent trade imports cannot be excluded.

Ongoing large mumps outbreak in the Federation of Bosnia and Herzegovina, Bosnia and Herzegovina, December 2010 to July 2011.

From December 2010 until the end of July 2011, 5,261 mumps cases were recorded in the Federation of Bosnia and Herzegovina, Bosnia and Herzegovina, leading to an incidence of 225.8 per 100,000. Fifteen to 19 year-olds (43%) were most affected and 62% of cases were male. Mumps-specific IgM antibodies were found in about 70% of sera investigated, complications were reported in 41% of 81 hospitalised patients. The outbreak affected mainly those unvaccinated or unaware of their vaccination status and is probably due to vaccination failures during the war and postwar period (1992­1998).

[Molecular epidemiology of parvovirus infection in Belarus].

The paper analyzes a 994 nucleotide fragment of the NS1/VP1u region junction of 84 parvovirus B19 samples obtained from the sera of erythema infectiosum patients in Belarus in 2006. All the strains belong to genotype 1 as defined by Servant et al. (2002) and form two major clusters within this genotype (1A and 1B) with a clearly distinct geographic distribution. Cluster 1A mainly included B19 strains from Minsk where an outbreak of erythema infectiosum was observed during sample collection. Cluster 1B comprises parvovirus B19 strains obtained from sporadic cases in different parts of the country. The nucleotide variability within cluster 1B (1.1%) was almost two times higher than that within cluster 1A (0.6%). The comparison of the Belarus strains with all parvovirus B19 sequences from the GenBank revealed 22 unique nucleotide substitutions in the new strains, 18 (81.8%) of which were nonsynonymous. A high percentage of parvovirus B19 IgM positive sera were also PCR positive (94.0%; n = 63/67) indicating that both methods are suitable for diagnosis of the infection.

Serelaxin activates eNOS, suppresses inflammation, attenuates developmental delay and improves cognitive functions of neonatal rats after germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMH-mediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats. We investigated whether effects of Serelaxin are mediated by its ability to activate the GMH-suppressed eNOS pathway resulting in attenuation of inflammatory marker overproduction. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U). Seven day old Sprague-Dawley rat pups (P7) were used (n = 63). GMH animals were divided in vehicle or serelaxin treated (3 µg once, 30 µg once, 30 µg multiple, i.p., starting 30 after GMH and then daily). Sham operated animals were used. We monitored the developmental profile working memory and spatial function (T-maze and open field test respectively). At day 28, all rats underwent MRI-scans for assessment of changes in cortical thickness and white matter loss. Effects of Serelaxin on eNOS pathway activation and post-GMH inflammation were evaluated. We demonstrated that Serelaxin dose-dependently attenuated GMH-induced developmental delay, protected brain and improved cognitive functions of rats after GMH. That was associated with the decreased post-GMH inflammation, mediated at least partly by amelioration of GMH-induced eNOS inhibition.

The role of cortical serotonin in anxiety and locomotor activity in Wistar rats.

The brain's serotonergic system is known to play an important role in the modulation of anxiety. While the role of serotonin (5-HT) in subcortical structures is well investigated, little is known about the function of cortical 5-HT. The present series of studies used local injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the medial prefrontal cortex (mPFC), entorhinal cortex (EC), or occipital cortex (OccC) of rats to chronically reduce 5-HT neurotransmission in these brain areas. The animals were tested for anxiety-like behavior on the elevated plus-maze and open field. An 82% depletion of 5-HT from the mPFC increased anxiety-like behavior, while no general motor effects were evident. In contrast, a 63% 5-HT-depletion of the EC or a 78% 5-HT-depletion of the OccC did not have any effects on emotional or exploratory behaviors. These findings are in line with a proposed role of 5-HT in the mPFC in the modulation of anxiety- and stress-mediated behavior and demonstrate a functional differentiation between different cortical 5-HT projections.

Light-induced activity in the activity box is not aversively motivated and does not show between-trial habituation.

The induction of behaviour by sensory stimuli, i.e. sensorimotor stimulation, is a fundamental aspect of behaviour. Recently, it was found that the presentation of white-light stimuli to a rat in an activity box reliably induces locomotor activity, and, thus, may be able to serve as a paradigm to measure basal, non-aversively motivated sensorimotor processing. However, light can be an aversive stimulus to a rat. In order to test if there is a stressful component in light-induced activity, a retreat-box was introduced into the test-apparatus in experiment 1, so that the animals had the opportunity to escape the light stimuli. It was found, that light-induced activity was also shown, when a retreat-box was available in the activity box, and that light-stimulation did not lead to an increase of entries into or the time spent in the retreat box. Experiment 2 examines the stability of the response to light over trials. Three light-induced activity test-trials were conducted with one day between each test. There was no effect of repeated testing on light-induced activity, which was evident during each of the three test-sessions. It is concluded that stress/anxiety does not significantly contribute to the increase of locomotor behaviour induced by light stimulation under the present conditions. Thus, the paradigm appears to involve a non-aversively motivated behavioural response. Furthermore, light-induced activity did not habituate over at least three test trials, and may, therefore, serve for repeated testing.

Ongoing rubella outbreak in Bosnia and Herzegovina, March-July 2009--preliminary report.

Between 24 March and 31 July 2009, 342 clinically diagnosed cases of rubella were notified in five municipalities in Republika Srpska, Bosnia and Herzegovina. Fourteen cases were laboratory-confirmed by positive IgG against rubella virus. Four virus isolates were obtained and identified as genotype 2B strains, with one isolate differing by a single mutation in the region of the E1 gene. This ongoing outbreak revealed gaps in the immunisation programme during the war in BiH (1992-1995) and highlights the need to revise legislation to permit immunisation of children above 14 years of age with measles, mumps, rubella (MMR) vaccine and to introduce supplemental immunisation activities.

Genetic variability and mRNA editing frequencies of the phosphoprotein genes of wild-type measles viruses.

The sequences of the nucleoprotein (N) and hemagglutinin (H) genes are routinely used for molecular epidemiologic studies of measles virus (MV). However, the amount of genetic diversity contained in other genes of MV has not been thoroughly evaluated. In this report, the nucleotide sequences of the phosphoprotein (P) genes from 34 wild-type strains representing 15 genotypes of MV were analyzed and found to be almost as variable as the H genes but less variable than the N genes. Deduced amino acid sequences of the three proteins encoded by the P gene, P, V and C, demonstrated considerably higher variability than the H proteins. Phylogenetic analysis showed the same tree topography for the P gene sequences as previously seen for the N and H genes. RNA editing of P gene transcripts affects the relative ratios of P and V proteins, which may have consequences for pathogenicity. Wild-type isolates produced more transcripts with more than one G insertion; however, there was no significant difference in the use of P and V open reading frames, suggesting that the relative amounts of P and V proteins in infected cells would be similar for both vaccine and wild-type strains.

Role of medial prefrontal, entorhinal, and occipital 5-HT in cocaine-induced place preference and hyperlocomotion: evidence for multiple dissociations.

RATIONALE: Application of cocaine or exposure to cocaine-related stimuli induces widespread activation of the cortex in neuroimaging studies with human subjects. In accordance to these findings, it was reported in previous microdialysis experiments that cocaine increased serotonin (5-HT) and dopamine in various cortical brain areas. The present series of studies set out to investigate the functional role of the observed increases in 5-HT in the medial prefrontal cortex (mPFC), the entorhinal cortex (EC), and the occipital cortex (OccC) in the mediation of cocaine-induced conditioned place preference (CPP) and hyperactivity. MATERIALS AND METHODS: To reduce 5-HTergic neurotransmission in circumscribed brain areas, bilateral local infusions of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), were made into the mPFC, EC, or OccC. Two weeks following surgery, cocaine-induced (10 mg/kg; i.p.) CPP was measured in an unbiased design. RESULTS: The 90% depletion of 5-HT in the mPFC significantly attenuated the preference for the cocaine-associated environment and the hyperlocomotor response to cocaine. A 61% depletion of 5-HT in the EC reduced conditioned place preference without modulation of hyperactivity, while a 78% 5-HT depletion of the OccC cortex had no effect on cocaine-induced CPP and hyperactivity. No lesion affected general activity, habituation learning, or visual stimulation-induced behavioral activation. CONCLUSION: These results indicate an important role of cortical 5-HT in the mediation of cocaine-induced CPP and specify the region-dependent contribution of a neurochemical response to cocaine-mediated behavior.