Tick-Borne Encephalitis sequelae at long-term follow-up: a self-reported case-control study.

BACKGROUND: Tick-borne encephalitis (TBE), caused by the TBE virus (TBEV), is a major neurotropic infection throughout Europe and Asia, with a considerable risk of neurological sequelae. Our aim was to study the symptoms in patients with TBE in Western Gotaland between 1997 and 2012 in the acute phase and at follow-up after 2-15 years (median: 5.5 years). METHODS: The medical records of 96 patients with TBE were studied. Phone-based interviews were held with 92 patients and 58 controls, matched by age, gender and residential area. The Encephalitis Support Group Questionnaire (ESGQ) 2000 was used, further developed with dimensions and scoring 1-4, where a high score is related to better outcome. Patients and controls also answered a written survey regarding functional outcome of sleep (FOSQ). RESULTS: Of the patients, 35% had a mild disease, 56% moderate and 7.3% severe disease. At the follow-up, patients scored significantly lower than controls in the dimensions of memory/learning, executive functions, vigilance and physical impairments. In addition, the answers concerning tiredness/fatigue, poor concentration/attention, reduced initiative/motivation, balance disturbances, coordination problems, difficulties with short- and long-term memory, learning difficulties and problems with fine motor skills resulted in significantly lower scores in the patients compared with the controls. The patients scored lower than the controls in the FOSQ dimension social outcome. CONCLUSIONS: At the long-term follow-up, the patients scored significantly lower in a diversity of neurocognitive and motor symptoms, in comparison with controls. These sequelae and their pathogenesis should be further explored and specific neurocognitive assessment tests are needed.

Cytomegalovirus seropositivity is negatively associated with multiple sclerosis.

BACKGROUND: Epidemiological data suggest a role for common viruses in the pathogenesis of multiple sclerosis (MS), and recent data showed a negative association of past cytomegalovirus (CMV) infection on pediatric MS risk. OBJECTIVE: Our aim was to analyze the association of CMV infection with MS risk in an adult case-control material. A meta-analysis was performed to validate our findings. METHODS: Epidemiological Investigation in MS (EIMS) is a case-control study with incident cases and population-based controls. Anti-CMV antibody titers were measured with ELISA, and HLA-A and DRB1 genotyping was performed with SSP-PCR, in 658 MS cases, who all fulfilled the McDonald criteria for MS, and 786 controls. RESULTS: CMV seropositivity was associated with a decreased MS risk, OR = 0.73 (0.58-0.92 95% CI), p = 0.005, adjusted for index age, gender, smoking, sun exposure, EBNA1 IgG titer and HLA-A*02 and DRB1*15. When we removed all cases and controls younger than 18 years at index, the protective effect was still apparent. CONCLUSIONS: CMV is negatively associated with adult-onset MS pathology, consistent with results from a study on pediatric MS cases. It remains to be shown whether this negative association is due to a true protective effect of CMV infection on MS risk.

Monitoring of seasonality of norovirus and other enteric viruses in Cameroon by real-time PCR: an exploratory study.

We studied the seasonal fluctuation of norovirus and other enteric viruses in Cameroon. Two hundred participants aged between 1 and 69 years were prospectively followed up. Each participant provided monthly faecal samples over a 12-month period. A total of 2484 samples were tested using multiplex real-time PCR assay for the detection of norovirus, rotavirus and enterovirus. The effect of weather variables and risk factors were analysed by Pearson correlation and bivariate analysis. Overall, enterovirus was the most commonly detected virus (21·6% of specimens), followed by norovirus (3·9%) and rotavirus (0·4%). Norovirus and enterovirus were detected throughout the year with a peak of norovirus detection at the beginning of the rainy season and a significant alternation of circulation of norovirus genogroups from one month to the next. Age <5 years and consumption of tap water were risk factors for norovirus infection. Better understanding of factors influencing transmission and seasonality may provide insights into the relationship between physical environment and risk of infection for these viruses.

Recent origin of HLA-DRB1 alleles and implications for human evolution.

The HLA class I and class II loci are the most highly polymorphic coding regions in the human genome. Based on the similarity of the coding sequences of alleles between species, it has been claimed that the HLA polymorphism is ancient and predates the separation of human (Homo) and chimpanzee (Pan), 4-7.4 Myr ago. Analysis of intron sequences, however, provides support for a more recent origin and for rapid generation of alleles at the HLA class II DRB1 locus. The human DRB1 alleles can be divided into groups (allelic lineages); most of these lineages have diverged from each other before the separation of Homo and Pan. Alleles within such a lineage, however, appear to be, on average, 250,000 years old, implying that the vast majority (greater than 90%) of the more than 135 contemporary human DRB1 alleles have been generated after the separation of Homo and Pan. The coalescence time of alleles within allelic lineages indicates that the effective population size (Ne) for early hominids (over the last 1 Myr) was approximately 10(4) individuals, similar to estimates based on other nuclear loci and mitochondrial DNA. With a single exception, the genetic mechanisms (gene conversion and point mutation) that have diversified the exon-2 sequences do not appear to extend into the adjacent intron sequences. The part of exon 2 encoding the beta-sheet evolves in concert with the surrounding introns, while the alpha-helix appears to have been subjected to gene conversion-like events, suggesting that such exchange events are highly localised and occur over extremely short sequence tracts.

Enveloped virus but not bacteria block IL-13 responses in human cord blood T cells in vitro.

Infections that occur early in life may have a beneficial effect on the immune system and thereby reduce the risk of allergen sensitization and/or allergic disease. It is not yet clear to what extent specific virus and/or bacteria can mediate this effect. The purpose of this study was to assess the role of virus and bacteria in CD4(+) T cell-derived cytokine production in newborns. We compared the effects of five bacteria (Staphlococcus aureus, Escherichia coli, Clostridium difficile, Lactobacillus rhamnosus and Bifidobacterium bifidus) and seven virus (adenovirus, coronavirus, cytomegalovirus, herpes simplex virus, influenza virus, morbillivirus and poliovirus) on the Th1/Th2 cytokine production in mixed lymphocyte reactions using CD4(+) T cells from cord blood cocultured with allogenic myeloid or plasmacytoid dendritic cells. When comparing the baseline cytokine production prior to microbial stimulation, we observed that cord plasmacytoid DC were stronger inducers of Th2 cytokines (IL-5 and IL-13) compared with cord myeloid DC and to adult DC. When adding microbes to these cultures, bacteria and virus differed in two major respects; Firstly, all enveloped viruses, but none of the bacteria, blocked Th2 (IL-13) production by cord CD4(+) cells. Secondly, all Gram-positive bacteria, but none of the virus, induced IL-12p40 responses, but the IL-12p40 responses did not affect Th1 cytokine production (IFN-γ). Instead, Th1 responses were correlated with the capacity to induce IFN-α secretion, which in cord cells were induced by S. aureus and influenza virus alone. These data imply that enveloped virus can deviate Th2 responses in human cord T cells.

The recurrent Guillain-Barré syndrome: a long-term population-based study.

OBJECTIVES: To describe a population-based material of patients with recurrent Guillain-Barré syndrome (RGBS), examine the long time course, and search for factors predisposing to recurrence. MATERIALS AND METHODS: We performed a follow-up study of the neurology and neurophysiology and a systematic study of the acute microbial serology of patients with RGBS. These parameters were compared with the results of a previous study of monophasic GBS. RESULTS: The patients with RGBS (n = 15) were retrieved from admissions of 229 patients with GBS during a 17-year period. They had 2-7 (median 3) episodes occurring at irregular intervals over decades. Of the 11 patients who accepted a follow-up examination, six were in full remission, and five had moderate sequelae. Nine had a demyelinating subtype, one had an axonal motor variant, and one patient with incomplete Miller Fisher syndrome had associated arachnoiditis. Two patients showed ultimate transition to a course similar to chronic inflammatory demyelinating polyneuropathy. Episodes were generally shorter in RGBS than in GBS, and an initial episode duration <45 days was predictive of recurrence and related to a younger onset age (univariate P = 0.005-0.009). Triggering infections occurred in all patients, in 32 of 41 episodes (78%) with few examples of etiological promiscuity. Serological findings did not differ from those in GBS. CONCLUSIONS: Episodes in RGBS were shorter than in monophasic GBS. We were unable to identify further immunological predisposing factors for recurrence beyond the previously demonstrated relationship to a weaker respiratory burst. We observed no obvious tendency for the recurrence frequency to wane.

Viral and bacterial aetiologies of male urethritis: findings of a high prevalence of Epstein-Barr virus.

Male urethritis is one of the most common sexually transmitted infections (STIs). However, the aetiology is still unclear in many cases. In this study the prevalences of Epstein-Barr virus (EBV), herpes simplex virus type 1 (HSV-1), HSV-2, cytomegalovirus (CMV), adenovirus, Chlamydia trachomatis, Mycoplasma genitalium and Ureaplasma urealyticum (including subtyping) were investigated. Samples from 112 male STI attendants with microscopically verified urethritis and from a control group of 103 men without clinical or microscopic signs of urethritis were analysed. Prevalences in the urethritis group compared with the controls were as follows: EBV 21%, 6% (P < 0.01); C. trachomatis 15%, 3% (P < 0.01); M. genitalium 6%, 1% (P = 0.067) and U. urealyticum 10%, 10% (ns). The results for HSV-1, HSV-2, CMV and adenovirus were negative in patients, and therefore not analysed in the controls. EBV was shown to be an independent predictor of urethritis and may play a role in its pathogenesis.

Herpes simplex virus infection downmodulates NKG2D ligand expression.

Herpes simplex virus (HSV) type 1 infection may cause orofacial infections in humans. The virus resides in a latent form in neural ganglia and occasionally reactivates and infects epithelial cells. Natural killer (NK) cells have been implicated in immune control of herpes virus infections, possibly by downmodulating major histocompatibility complex (MHC) class I and by other, as yet unidentified, mechanisms. Upon HSV-1 infection of cell lines, surface levels of NKG2D ligands MHC class I related proteins (MIC) A and UL16 binding protein 2 were downmodulated due to late viral gene product(s). As also MHC class I levels were reduced by HSV-1, NK cell recognition of HeLa cells was not affected by infection. Total cellular MICA contents remained unchanged, suggesting masking, internalization or intracellular retention of MICA as possible mechanisms of viral downregualtion of MICA surface levels. Furthermore, NK cells from patients with active HSV-1 infection had a tendency towards increased expression level of the activating receptor NKG2D. These data support a role for NKG2D-MICA interactions in immune responses to HSV-1 reactivation.

The pharmacokinetic and tolerability profile of varenicline in healthy Chinese volunteers.

OBJECTIVE: Varenicline is a selective, nicotinic alpha4beta2 acetylcholine receptor partial agonist that has been licensed as a smoking cessation drug in more than 70 countries worldwide. The current study was conducted in order to evaluate its pharmacokinetic (PK) properties and tolerability in healthy volunteer Chinese smokers. METHODS: This was an open-label, non-randomized study conducted over 17 days at a single center in China. Male and female subjects (18 - 45 years old) received a single, 1 mg dose of varenicline on days 1 and 10 as well as 1 mg varenicline twice daily (12-h dosing interval) on Days 4 - 9. RESULTS: A total of 14 subjects (50% male) received varenicline as per study protocol for 8 days. The mean maximum plasma concentration of varenicline (Cmax) was 1.93-fold larger at steady state (reached on Day 8, after 4 days of repeat dosing) than following a single dose, showing accumulation of varenicline on repeat administration. Median values of tmax (time of occurrence of Cmax) were similar for both dosing regimens (3.0 and 2.5 h following single and multiple dosing, respectively). The mean elimination half-life following single and multiple dosing was 15.2 and 18.3 h, respectively. There was no evidence of time- or concentration-dependence in the PK of varenicline upon repeat dosing as the ratio of the area under the plasma concentration vs time curve (AUC) from time 0 - 12 h at steady state to the AUC from time 0 - 8 on Day 1 was nearly 1. The 2-sided 95% confidence intervals for this comparison included 1, demonstrating the linearity of the PK of varenicline for the single and multiple doses. Varenicline was safe and well-tolerated, adverse events were mild in severity and there were no abnormal laboratory tests. CONCLUSIONS: Varenicline 1 mg twice daily was safe and well-tolerated in a cohort of healthy male and female, 18- to 45-year-old Chinese smokers and demonstrated PK properties that were stable and reproducible and similar to those observed previously in Western subjects.

The genetic contribution to canine personality.

The domestic dog may be exceptionally well suited for behavioral genetic studies owing to its population history and the striking behavior differences among breeds. To explore to what extent and how behavioral traits are transmitted between generations, heritabilities and genetic correlations for behavioral traits were estimated in a cohort containing over 10,000 behaviorally tested German shepherd and Rottweiler dogs. In both breeds, the pattern of co-inheritance was found to be similar for the 16 examined behavioral traits. Furthermore, over 50% of the additive genetic variation of the behavioral traits could be explained by one underlying principal component, indicating a shared genetic component behind most of the examined behavioral traits. Only aggression appears to be inherited independently of the other traits. The results support a genetic basis for a broad personality trait previously named shyness-boldness dimension, and heritability was estimated to be 0.25 in the two breeds. Therefore, breeds of dogs appear to constitute a valuable resource for behavioral genetic research on the normal behavioral differences in broad personality traits.

Physicochemical study of percutaneous absorption enhancement by dimethyl sulfoxide: dimethyl sulfoxide mediation of vidarabine (ara-A) permeation of hairless mouse skin.

Dimethyl sulfoxide's (DMSO) concentration-dependent influences on its own permeation rate through hairless mouse skin and on the concurrent permeation rates of water and the antiviral drug vidarabine (ara-A) have been studied at 37 degrees C using in vitro diffusion cells. Solubilities of ara-A in DMSO-water mixtures were also determined in order to assess ara-A's relative thermodynamic activity in the binary solvent media used in the mass transfer studies. Solubilities increased exponentially with increasing percentages of DMSO. Activity coefficients decreased accordingly. When the same DMSO medium was placed in each side of diffusion cell (balanced solvent configuration) permeability coefficients for ara-A decreased exactly as ara-A's solubility increased up to a 50% DMSO concentration, indicating the observed decreases in the mass transfer coefficients have thermodynamic origins. When DMSO media were placed in either the donor or receiver side of the cell up to the same 50% concentration point and opposed by a normal saline medium on the other side (asymmetric solvent configurations), the permeability of ara-A did not decrease and at some DMSO levels was substantially increased, behavior in marked departure from thermodynamic control. The behavior disparity between the 2 configurations of the cell suggests that cross-currents of solvents play a role in permeability enhancement. Regardless of solvent configuration, permeability coefficients for ara-A at 90 and 100% DMSO strengths were exaggeratedly large, consistent with severe impairment of the stratum corneum. Similar overall permeability behavior was observed for the 2 solvents, water and DMSO. Possible underlying mechanisms for these effects and the relative importance of the various mechanisms of DMSO enhancement as a function of DMSO's concentration and configuration are discussed.

A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS.

OBJECTIVE: To evaluate the effect of treatment with the antiherpes drug valacyclovir on MRI-evident lesions in patients with relapsing-remitting MS in a phase 2, randomized, double-blind, placebo-controlled study. BACKGROUND: It has been postulated from virologic studies that herpesvirus infection could play a role in the progression of MS. METHODS: Patients were eligible for the study if they had had two or more MS relapses in the 2-year period before enrollment. Seventy patients with Expanded Disability Status Scale scores of 0 to 5.5 were randomly assigned to receive 1 gram of valacyclovir (n = 36) or placebo (n = 34) three times daily for 24 weeks. Patients underwent MRI every fourth week for 32 weeks: twice during pretreatment, six times during treatment, and once after treatment. Scoring of neurologic disability was performed at the start and end of the treatment period. The primary endpoint was the number of new active MRI-evident lesions over 24 weeks of treatment. Secondary endpoints included other MRI measures and clinical endpoints. RESULTS: The mean number of new active lesions +/- SD per patient during 24 weeks of treatment with valacyclovir was 11.9 +/- 17.6 and that during placebo treatment was 14.5 +/- 21.4. A protocol-planned exploratory analysis stratified patients according to baseline activity; this analysis showed that patients with high levels of disease activity in the valacyclovir treatment group (n = 17) developed fewer new active lesions per scan than did those in the placebo treatment group (n = 11). The median number (Q(1), Q(3) range) of active lesions was 2.0 (1.38, 3.96) in the valacyclovir treatment group and 6.5 (2.63, 9.0) in the placebo treatment group. CONCLUSIONS: Valacyclovir treatment did not reduce the formation of active lesions in patients with relapsing-remitting MS who had two or more relapses during the previous 2-year period. In a subgroup of patients with high levels of disease activity who had more than one active MRI-evident lesion during 4 weeks, valacyclovir treatment was associated with a reduced number of new active MRI-evident lesions and with an increase in the number of scans free of new active lesions. The results of the exploratory subgroup analysis provide support for further studies of antiherpes therapy for patients with MS and high levels of MRI-evident disease activity.

Cerebrospinal fluid anti-cerebellar soluble lectin antibodies in human immunodeficiency virus type 1 infection.

Cerebrospinal fluid samples from 14 human immunodeficiency type 1 (HIV-1) seropositive patients in various stages of HIV infection were tested for the presence of autoantibodies to an endogenous manose-binding protein, the cerebellar soluble lectin (CSL), which has recently been found to be detected in a high proportion of patients with multiple sclerosis. An immunoblotting test was used with rat CSL as antigen. Seven patients were positive for anti-CSL and seven were negative. The seven anti-CSL-positive patients had signs of intrathecal immunoglobulin G production measured as an elevated IgG index, while the seven anti-CSL-negative patients had a normal IgG index. There was no apparent relation between infectious stage and the presence of anti-CSL. Immunological reactions such as anti-CSL autoantibodies may be a similar pathogenic mechanism in HIV and multiple sclerosis brain disease.

Increasing intrathecal lymphocytosis and immunoglobulin G production in neurologically asymptomatic HIV-1 infection.

Cerebrospinal fluid from 34 human immunodeficiency virus (HIV-1) seropositive patients, only four of whom had HIV-related neurological symptoms, was examined by cytology, protein quantification, isoelectric focusing and specific serological tests. CSF lymphocytosis and evidence of intrathecal IgG production, found in 21 and 20 respectively of the 34 patients, correlated significantly with the duration of the infection. Increasing IgG index was found in two patients with repeated CSF examinations during greater than 7 years. Intrathecal HIV antibodies were detected on Western blot in 32/34 patients. HIV antigen test positive in 5/34 sera was negative in all 34 CSF samples. Intrathecal B cell activation seems to increase during the early HIV infection.

Quantification of cytomegalovirus DNA in BAL fluid: a longitudinal study in lung transplant recipients.

STUDY OBJECTIVES: Cytomegalovirus (CMV) infection is common in patients receiving solid organ transplants, and it is associated with increased morbidity as well as risk for development of chronic rejection. A rapid and sensitive diagnostic method would improve the therapeutic management of CMV infection, including the monitoring of treatment effects. We investigated whether longitudinal determinations of CMV DNA quantities in BAL fluid could be useful for this purpose. DESIGN: CMV DNA levels in 340 BAL samples from 35 consecutive lung transplant recipients were studied during a median of 18 months. Seventeen (49%) of the patients developed CMV disease with pneumonitis. Twenty-seven CMV disease episodes were diagnosed. RESULTS: Patients with CMV disease had a significantly higher mean level of CMV copies per milliliter BAL fluid (1,120 +/- 4,379) compared with those without (180 +/- 1,177, p < 0.01). Viral load as well as acute rejection requiring treatment (>/= A2) were independent risk factors associated with CMV disease. Differences between the groups concerning HLA-DR matching, basic immunosuppressive therapy, and CMV serologic status D/R -/+ vs D/R +/+ were not significant. A diagnostic definition of normality based on the mean level of all episodes without CMV disease +2 SD would discriminate only 9 of the 27 CMV episodes. CONCLUSIONS: Although the viral load is increased during episodes of clinical CMV disease in lung transplant recipients, the quantitative PCR assessment of CMV DNA in BAL fluid is not discriminative enough to be useful as a diagnostic tool for CMV disease.

Herpesviruses--a rationale for antiviral treatment in multiple sclerosis.

In multiple sclerosis (MS), the extensive and long lasting search for viruses or other pathogens has hitherto failed to identify a common etiological agent. However, the beneficial effects by interferon-beta treatment in MS, although suggested to depend mainly on immunomodulation, might lend support to a viral involvement in the pathogenesis. The human herpesviruses have attracted interest since their recurrent modes of infection share some similarity with the relapsing-remitting course of MS, most members are readily detected within the brain, and several of these viruses may induce demyelination within the central nervous system in human hosts as well as in animal models. Accumulated diagnostic and epidemiological data are compatible with a role for the herpesviruses as possible cofactors rather than etiological agents, and recent studies showing early neuronal damage in MS patients focus attention on the neurotropic alpha-herpesviruses. Antiviral treatment trials with safe and effective drugs such as valaciclovir offer a possibility of testing the hypotheses concerning herpesviral involvement in MS.

Pigmented iris angiography.

A small volume of concentrated fluorescein was used in a technique of fluorescein angiography in rabbits. The procedure is not accompanied by the usual risks of general anesthesia in rabbits. Angiographic findings demonstrated that the pigmented rabbit iris vessel pattern is similar to that found in albino rabbits.

The effects of subconjunctival mitomycin-C on glaucoma filtration surgery in rabbits.

A prospective, randomized, masked, placebo-controlled study was performed to determine whether a single, intraoperative subconjunctival application of a 0.5-mg/mL solution of mitomycin-C enhances the success of full-thickness filtration surgery in rabbits. Compared with control eyes, mitomycin-C-treated eyes showed significant increases in bleb duration from 8.1 +/- 2.4 to 68.0 +/- 20.8 days and in intraocular pressure reduction from 6.0 +/- 3.0 to 63.6 +/- 21.5 days. Histopathologic evaluation confirmed the inhibitory effects of mitomycin-C on fibrovascular, fibrocellular, and collagenous organization of the filtering blebs that resulted in their preservation. Transient, superficial, corneal vascularization anterior to the bleb occurred in all mitomycin-C-treated eyes. No other clinical or pathologic signs of undesirable side effects were noted. We studied the effectiveness and safety of a single intraoperative application of mitomycin-C in prolonging the success of filtration surgery in rabbits and its potential for similar use in humans.

Relation between polymerase chain reaction findings and morphological changes during cytomegalovirus infection in transplanted lung.

Cytomegalovirus (CMV) can be present as a latent or productive infection resulting in disease. The polymerase chain reaction (PCR) is a sensitive technique to document the presence of CMV (DNA). Negative reactions are indicative of its absence. The presence of CMV (DNA) was assessed longitudinally in 261 transbronchial lung biopsy (TBB) specimens from 37 patients over a 6-month period. The TBB specimens from six serologically CMV-negative recipients who received lungs from serologically CMV-negative donors never showed a positive CMV-PCR(DNA) reaction during the study. Based on a study of their TBB specimens, 10 serologically CMV-positive recipients who received lungs from serologically CMV-negative donors all developed a CMV-PCR(DNA)-positive reaction and five (50%) morphologically manifested CMV disease. The remaining 21 serologically CMV-positive recipients who received lungs from serologically CMV-positive donors all developed a CMV-PCR(DNA)-positive reaction and 15 (71%) developed CMV pneumonitis. The data show that development of a positive CMV-PCR(DNA) reaction in a TBB sample within the first month after transplantation indicates a greatly increased risk of developing CMV disease. In addition, a positive CMV-PCR(DNA) reaction preceded morphologically manifest disease on average by 2 weeks. Comparisons between TBB and bronchoalveolar lavage show the former to provide a more dependable template.