Probing the ability of the coat and vertex protein of the membrane-containing bacteriophage PRD1 to display a meningococcal epitope

Bacteriophage PRD1 is an icosahedral dsDNA virus with a diameter of 740 A and an outer protein shell composed of 720 copies of major coat protein P3. Spike complexes at the vertices are composed of a pentameric base (protein P31) and a spike structure (proteins P5 and P2) where the N-terminal region of the trimeric P5 is associated with the base and the C-terminal region of P5 is associated with receptor-binding protein P2. The functionality of proteins P3 and P5 was investigated using insertions and deletions. It was observed that P3 did not tolerate changes whereas P5 tolerated changes much more freely. These properties support the hypothesis that viruses have core structures and functions, which remain stable over time, as well as other elements, responsible for host interactions, which are evolutionally more fluid. The insertional probe used was the apex of exposed loop 4 of group B meningococcal outer membrane protein PorA, a medically important subunit vaccine candidate. It was demonstrated that the epitope could be displayed on the virus surface as part of spike protein P5.     

The relationship between job-related burnout and depressive disorders--results from the Finnish Health 2000 Study

BACKGROUND: Depression and burnout are common health problems in working populations today. They appear to be interrelated, and the need for their differential diagnosis has been highlighted in many reviews. We analysed the overlap of job-related burnout and depressive disorders, i.e., major depressive disorder, dysthymia, and minor depressive disorder. METHODS: We used the population-based 'Health 2000 Study' in Finland. Our nationally representative sample comprised 3276 employees aged 30-64 years. Burnout was assessed with the Maslach Burnout Inventory-General Survey. Diagnoses of depressive disorders were based on the Composite International Diagnostic Interview. RESULTS: Burnout and depressive disorders were clearly related. The risk of depressive disorders, especially major depressive disorder (12-month prevalence), was greater when burnout was severe. Half of the participants with severe burnout had some depressive disorder. Those with a current major depressive episode suffered from serious burnout more often than those who had suffered a major depressive episode earlier. LIMITATIONS: This study was cross-sectional. CONCLUSIONS: The concepts of burnout and depression complement each other and cover partly overlapping phenomena. Depressive disorders are related to job-related burnout, particularly when it is severe. A current major depressive episode is likely to be associated with the experience of burnout. When encountering working patients, it is recommended to assess both the occurrence of burnout and of depressive disorders.     

Quantitative measurement of regional lung gas volume by synchrotron radiation computed tomography

The aim of this study was to assess the feasibility of a novel respiration-gated spiral synchrotron radiation computed tomography (SRCT) technique for direct quantification of absolute regional lung volumes, using stable xenon (Xe) gas as an inhaled indicator. Spiral SRCT with K-edge subtraction using two monochromatic x-ray beams was used to visualize and directly quantify inhaled Xe concentrations and airspace volumes in three-dimensional (3D) reconstructed lung images. Volume measurements were validated using a hollow Xe-filled phantom. Spiral images spanning 49 mm in lung height were acquired following 60 breaths of an 80% Xe-20% O2 gas mixture, in two anaesthetized and mechanically ventilated rabbits at baseline and after histamine aerosol inhalation. Volumetric images of 20 mm lung sections were obtained at functional residual capacity (FRC) and at end-inspiration. 3D images showed large patchy filling defects in peripheral airways and alveoli following histamine provocation. Local specific lung compliance was calculated based on FRC/end-inspiration images in normal lung. This study demonstrates spiral SRCT as a new technique for direct determination of regional lung volume, offering possibilities for non-invasive investigation of regional lung function and mechanics, with a uniquely high spatial resolution. An example of non-uniform volume distribution in rabbit lung following histamine inhalation is presented.     

Whole-exome sequencing of Finnish patients with vascular cognitive impairment

Cerebral small vessel disease (CSVD) is the most important cause of vascular cognitive impairment (VCI). Most CSVD cases are sporadic but familial monogenic forms of the disorder have also been described. Despite the variants identified, many CSVD cases remain unexplained genetically. We used whole-exome sequencing in an attempt to identify novel gene variants underlying CSVD. A cohort of 35 Finnish patients with suspected CSVD was analyzed. Patients were screened negative for the most common variants affecting function in NOTCH3 in Finland (p.Arg133Cys and p.Arg182Cys). Whole-exome sequencing was performed to search for a genetic cause of CSVD. Our study resulted in the detection of possibly pathogenic variants or variants of unknown significance in genes known to associate with CSVD in six patients, accounting for 17% of cases. Those genes included NOTCH3, HTRA1, COL4A1, and COL4A2. We also identified variants with predicted pathogenic effect in genes associated with other neurological or stroke-related conditions in seven patients, accounting for 20% of cases. This study supports pathogenic roles of variants in COL4A1, COL4A2, and HTRA1 in CSVD and VCI. Our results also suggest that vascular pathogenic mechanisms are linked to neurodegenerative conditions and provide novel insights into the molecular basis of VCI.Subject terms: Stroke, Sequencing, Genetics research, Dementia     

Genome of the European elk papillomavirus (EEPV)

The genome of the European elk papillomavirus (EEPV) was found to be 8,095 base pairs (bp) long and its genetic organization was similar to that of other papillomaviruses. Ten open reading frames (ORFs), designated E1-E7 and L1-L3, were identified in the genome, all located on one strand. The presence of the L3 ORF is rare among the papillomaviruses and to date has only been identified in the genomes of EEPV, the deer papillomavirus (DPV) and the Cottontail papillomavirus (CRPV). The ORF is well conserved beteeen DPV and EEPV with regard to both length and sequence. Potential promoter regions were identified at the 5-end of the E6 ORF, at the 3-end of the E1 ORF and downstream of the L1 ORF. Furthermore, two potential polyadenylation signals were found, one located in the long control region (LCR), downstream of the L1 ORF, and another preceding the L2 ORF. The EEVP genome is closely related to the genome of the DPV, the most highly conserved regions being ORFs E1 (70%), E5 (69%), and L1 (74%).     

T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens

We show here that T cell cross-reactivity between heterologous viruses influences the immunodominance of virus-specific CD8(+) T cells by two mechanisms. First, T cells specific for cross-reactive epitopes dominate acute responses to viral infections; second, within the memory pool, T cells specific for cross-reactive epitopes are maintained while those specific for non-cross-reactive epitopes are selectively lost. These findings suggest an immunological paradigm in which viral infections shape the available T cell repertoire, causing alterations in the hierarchies of both the primary and memory CD8(+) T cell responses elicited by subsequent viral infections. Thus, immunodominance is a function of the host's previous exposure to unrelated pathogens, and this may have an impact on protective immunity and immunopathology.     

High levels of estradiol impair spatial performance in the Morris water maze and increase 'depressive-like' behaviors in the female meadow vole

The present study investigated sex differences and the effect of a high level of estradiol in the female meadow vole on performance in the forced swim test (FST) and the Morris water maze in meadow voles. Female meadow voles were ovariectomized (OVX) and administered either vehicle (sesame oil) or estradiol for 2 days prior to performing the FST. Four days following the FST, all animals were run in the Morris water maze. Results indicated that estradiol-injected female meadow voles showed more 'depressive-like' behaviors in the FST (greater time spent immobile and less time spent swimming) than vehicle-treated female or male meadow voles. In addition, estradiol-treated females had impaired performance (greater latencies and distance swam to reach the hidden platform) than both vehicle-treated female and male meadow voles, consistent with previous data. Despite the fact that estradiol administration increased 'depressive-like' behaviors in the FST and impaired performance in the Morris water maze, there was no correlation between the two behaviors indicating that 'depressive-like' behaviors did not account for the differences seen in spatial performance in the Morris water maze. To our knowledge, this is the first demonstration in rodents indicating that estradiol-mediated changes in behavior in the FST is not indicative of subsequent performance in the Morris water maze.     

Retardation of cerebral dopamine turnover after morphine withdrawal and its enhanced acceleration by acute morphine administration in rats

Summary To clarify the effects of withdrawal from chronic morphine treatment on cerebral dopamine (DA) turnover, we have measured the -methyl-p-tyrosine (MT)-induced depletion of DA in five brain areas of male Wistar rats given morphine twice daily for 40 or 60 days. After the last morphine dose (50 or 70 mg/kg) the rats were withdrawn for 1, 2 or 4 days. In order to study the development of tolerance some of the rats were challenged with 10 mg/kg of morphine.Withdrawal of morphine retarded the MT-induced DA depletion in the limbic forebrain and after long enough chronic treatment in the striatum, too. The challenge dose of morphine accelerated the cerebral DA depletion slightly less in rats withdrawn for 1 day from 60-day chronic morphine treatment than in rats treated chronically with saline, but it enhanced the DA depletion more in rats withdrawn from morphine for 2 and 4 days than in chronic saline rats. This enhancement was clearest in rats withdrawn for 4 days from 60-day treatment. Thus withdrawal from morphine seems to sensitize the rats to the DA depletion accelerating effect of morphine.Our results show that repeated administration of morphine creates no marked tolerance to the DA depletion accelerating effect of morphine. In contrast, the dopaminergic neurones of the chronically treated rats seem to depend on continuous morphine administration for their normal functioning. Furthermore, the retarded DA turnover after discontinuation of morphine treatment seems to sensitize the dopaminergic neurones to the DA depletion accelerating effect of morphine. The limbic dopaminergic neurones are more easily affected by both acute and chronic morphine treatment than the striatal ones.     

Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants

Background: Reactive oxygen species have been considered to play a role in several clinical complications in pre-term infants. The aim of this study was to determine the pharmacokinetics of intravenous N-acetylcysteine in pre-term neonates. This information is needed to evaluate the use of N-acetylcysteine as an antioxidant in this patient group. Methods: N-acetylcysteine was infused intravenously in ten patients (gestational age 24.9–31.0 weeks, weight 500–1384 g) for 24 h (3.4–4.6 mg/kg/h), starting 2.0–11.2 h from birth (study I) and in six patients (gestational age 25.9–29.7 weeks, weight 520–1335 g) for 6 days (0.3–1.3 mg/kg/h), starting at the age of 24 h (study II). Arterial plasma N-acetylcysteine and cyst(e)ine concentrations were determined from timed samples taken during (study I and II) and after (study I) the N-acetylcysteine infusion. Results: In study I, the mean elimination half-life of N-acetylcysteine was 11 h (range 7.8–15.2 h). The mean plasma clearance of N-acetylcysteine was 37 ml/kg/h (range 13–62 ml/kg/h) and the mean volume of distribution was 573 ml/kg (range 167–1010 ml/kg). The plasma clearance and volume of distribution correlated with weight (r = 0.81, P < 0.01, and r = 0.78, P < 0.01, respectively) and with gestational age (r = 0.71, P < 0.05, and r = 0.64, P < 0.05, respectively). In study II, the steady-state concentration of N-acetylcysteine was reached in 2–3 days in five of six patients during a constant infusion. Conclusions: The pharmacokinetics of N-acetylcysteine in pre-term infants depend markedly on weight and gestational age. The elimination of N-acetylcysteine is much slower in pre-term new-borns than in adults. Received: 12 April 1999 / Accepted in revised form: 18 August 1999