Imported dengue virus infections in German tourists

Dengue viruses (DEN) are increasingly becoming endemic and epidemic in tropical and subtropical countries. In this study, 17 serologically confirmed clinical cases of DEN infection diagnosed in German tourists over the period from May 1993 until May 1994 are presented. Thirteen out of 17 (76.5%) infections occurred in southeast Asia (Thailand 58.9%), and 4/17 (23.5%) in Central and South America. All sera screened by means of the indirect immunofluorescence assay (IIFA) were positive for anti-DEN IgM. Acute infection was confirmed by demonstrating anti-DEN IgM using a "mu-capture assay". Sixteen out of 17 (94.1%) of patients presenting with fever upon admission were positive for anti-DEN IgG, with titres of > or = 128 in the IIFA. This report indicates the rising significance of DEN as a travel-associated infection in German tourists.     

Prognostic value of vasodilator myocardial perfusion imaging in patients with left bundle-branch block

BACKGROUND: The prognostic value of tomographic myocardial perfusion imaging with dipyridamole or adenosine in patients with left bundle-branch block has not been established. METHODS AND RESULTS: The study group consisted of 245 patients with left bundle-branch block who underwent tomographic (single photon emission tomography) myocardial perfusion imaging with thallium-201 (n=173) or technetium-99m sestamibi (n=72) and either dipyridamole (n=153) or adenosine (n=92) stress. Patients were prospectively classified into two groups. Patients were classified as "high risk" if they had (1) a large severe fixed defect (n=28), (2) a large reversible defect (n=36), or (3) cardiac enlargement and either increased pulmonary uptake (thallium) or a decreased resting ejection fraction (sestamibi) (n=20). The remaining 161 patients (66% of the study group) were at "low risk." Follow-up was 99% complete at 3+/-1.4 years. Three-year overall survival was 57% in the high-risk group compared with 87% in the low-risk group (P<.0001). Survival free of cardiac death/nonfatal myocardial infarction/cardiac transplantation was 55% in the high-risk group and 93% in the low-risk group (P<.0001). The presence of a high-risk scan had significant incremental prognostic value after adjustment for age, sex, diabetes, and previous myocardial infarction (P<.0001). Patients with a low-risk scan had an overall survival that was not significantly different from that of a US age-matched population (P=.86). CONCLUSIONS: Tomographic myocardial perfusion imaging with adenosine or dipyridamole stress provides important prognostic information in patients with left bundle-branch block, which is incremental to clinical assessment.     

Prospective identification of myocardial stunning using technetium-99m sestamibi-based measurements of infarct size

OBJECTIVES: We sought to prospectively identify patients with stunning and hyperkinesia at hospital discharge on the basis of mismatches between left ventricular (LV) function and infarct size as assessed by technetium-99m (Tc-99m) sestamibi perfusion tomographic imaging. BACKGROUND: Mechanical indexes of LV function may not accurately reflect myocardial damage after acute myocardial infarction (MI) because of myocardial stunning and compensatory hyperkinesia in noninfarct-related territories. Myocardial perfusion techniques are unaffected by these variables. METHODS: Eighty-four patients with acute MI underwent hospital admission and discharge Tc-99m-sestamibi tomographic imaging. Global LV ejection fraction (LVEF) was measured at hospital discharge and 6 weeks later. The perfusion defect size was quantified and expressed as a percentage of the LV. The discharge perfusion defect, which is a measure of infarct size, was used to predict the 6-week LVEF for each patient based on a previously reported regression equation. Patients were classified into one of three groups depending on whether their LVEF at hospital discharge fell within, above or below one standard error (6.8 LVEF points) of the predicted 6-week LVEF. RESULTS: There were 48 patients classified as having a "match" between function and infarct size; these patients demonstrated no significant change in LVEF at 6 weeks. There were 21 patients (25%) classified as "mismatch stunned" who had discharge LVEFs lower than those predicted by infarct size. These patients demonstrated a significant improvement in mean LVEF at 6 weeks (mean [+/-SD] discharge LVEF 0.41 +/- 0.08, 6-week LVEF 0.47 +/- 0.10; p = 0.003). Fifteen patients (18%) were classified as "mismatch-hyperkinetic." The mean LVEF for these patients significantly declined at 6 weeks (discharge LVEF 0.64 +/- 0.06, 6-week LVEF 0.58 +/- 0.09; p = 0.002). There was a marked increase in LVEF within the infarct zone (8 +/- 15 LVEF points; p = 0.03) for patients predicted to have stunning and a marked decline in LVEF outside the infarct zone (9 +/- 15 LVEF points; p = 0.06) in patients predicted to have hyperkinesia. Both discharge LVEF (p < 0.0001) and group classification (p = 0.005) were independent predictors of LVEF 6 weeks later. CONCLUSIONS: Perfusion imaging with Tc-99m-sestamibi can identify post-MI patients at hospital discharge in whom LV function is discordant with the measured infarct size. Patients with stunning have late increases in LVEF; patients with hyperkinesia have late decreases. This methodology, performed at discharge, is predictive of late changes in LV function.     

Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6

Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy. Linkage to the HLA complex on chromosome 6p21.3 and an allelic association with HLA-DR13 and -DQB1 alleles suggest that a susceptibility locus for JME, designated as "EJM1," is located within or near the HLA region. However, further studies revealed controversial results, and genetic heterogeneity has been suspected. The present study was designed to evaluate the validity of the association and linkage findings and to refine the map position of EJM1. Our association analysis showed no significant difference of the frequency of HLA-DR13 carriers in 62 German JME patients compared with that in 77 German controls (X2 = 0.98, df = 1, p = 0.161, one-tailed). Multipoint linkage analysis with use of microsatellite markers from the chromosomal region 6p25-q13 in 29 German families of JME patients provided significant evidence that an epilepsy locus (EJM1) close to the HLA locus confers susceptibility to "idiopathic" generalized seizures (Zmax = 3.27 at theta max = 0.033 centromeric to the HLA-DQ locus), assuming an autosomal dominant mode of inheritance with 70% penetrance. Haplotype analyses revealed key recombinations in five families, which locate EJM1 to the centromeric side of the HLA-DQ locus. This study confirms a causative role of EJM1 in the pathogenesis of idiopathic generalized seizures in the majority of German families of JME patients and refines a candidate region of 10.1 cM in the chromosomal region 6p21 between the flanking loci HLA-DQ and D6S1019. A possible explanation for the current controversial results in families of different populations might be ethnic variation of interfering polygenic effects that could be permissive for heterogeneous susceptibility alleles.     

Technically accurate intracavitary insertions improve pelvic control and survival among patients with locally advanced carcinoma of the uterine cervix

The purpose of this study was to document whether the technical qualities of a brachytherapy application impacts on the outcome of patients with locally advanced cervix cancer treated by definitive irradiation. A previous report from the patterns of care study demonstrated the importance of brachytherapy in the treatment of locally advanced cervix cancer. Locally advanced disease was defined as FIGO stages Ib (if tumor diameter was < or = 4 cm), IIb (if disease was bilateral or involved the lateral aspect of either parametrium), and III. Localization films from 128 patients with locally advanced squamous cell carcinoma of the cervix were reviewed by a radiation physicist and a radiation oncologist with expertise in gynecologic radiotherapy. All patients received external beam irradiation followed by one brachytherapy application (median point A dose = 8040 cGy; range, 4083-10,020 cGy). Brachytherapy parameters assessed were (a) the distance between the right colpostat source and the distal tandem source, (b) the distance between the left colpostat source and the distal tandem source, and (c) the symmetry of colpostat placement. Implants were scored as "ideal" (n = 8) when all three parameters were deemed satisfactory, "unacceptable" (n = 17) when none of the parameters was deemed satisfactory, and "adequate" (n = 41) in all other cases. Significantly improved 5-year local control was seen when comparing ideal and adequate placements to unacceptable placements (68% vs 34%, P = 0.02). A strong trend toward improved 5-year survival was also noted among the group with ideal and adequate implants as opposed to unacceptable implants (60% vs 40%). Multivariate analysis showed that the technical adequacy of the brachytherapy implant was the most important prognostic discriminant of local control. In conclusion, these analyses demonstrate the direct influence of competent technical implant performance on tumor control and even survival. While only a small fraction of implants for cervical cancer are performed poorly in the United States, there is a need for continued emphasis of the principles for proper implant technique.     

Mechanism-based inactivation of cytochrome P-450-3A4 by mifepristone (RU486)

Mifepristone (RU486), an 11beta-substituted nor-steroid containing a 17alpha-1-propynyl group used clinically as an antiprogestin agent for medical abortions, was demonstrated to be a selective mechanism-based inactivator of human cytochrome P-450-3A4 (CYP-3A4). The loss of testosterone 6beta-hydroxylation activity was time- and concentration-dependent as well as requiring metabolism of mifepristone in a purified CYP-3A4 reconstituted system. The inactivation exhibited pseudofirst-order kinetics. The values for KI and kinactivation were 4.7 microM and 0.089 min-1, respectively. The reduced-CO spectrum of CYP-3A4 was decreased by 76%, whereas approximately 81% of the activity was lost following incubation with mifepristone in the reconstituted system in the presence of NADPH. However, the Soret peak of the inactivated CYP-3A4 was slightly increased. High-performance liquid chromatography analysis of the incubation mixture showed that the peak containing the heme dissociated from the inactivated CYP3A4 was almost identical with that seen for the -NADPH control. Covalent binding of [3H]mifepristone to apoCYP3A4 was demonstrated by SDS-PAGE and high-pressure liquid chromatography analyses of the reconstituted system containing CYP-3A4, NADPH-CYP reductase, cytochrome b5 and lipids in the presence of NADPH. The stoichiometry was determined to be approximately 1 mol of mifepristone bound per 1 mol of CYP-3A4 inactivated. Therefore, the mechanism of inactivation of CYP-3A4 by mifepristone involves irreversible modification of the apoprotein at the enzyme active site instead of being the result of heme adduct formation or heme fragmentation. Mifepristone exhibits selectivity for CYP-3A4 as evidenced by the fact that it did not show mechanism-based inactivation of CYPs 1A, 2B, 2D6, and 2E1, although a competitive inhibition of CYP 2B1 and 2D6 was observed.     

Genomic detection of new yeast pre-mRNA 3'-end-processing signals

To investigate Saccharomyces cerevisiae 3'-end-processing signals, a set of 1352 unique pre-mRNA 3'-end-processing sites, corresponding to 861 different genes, was identified by alignment of expressed sequence tag sequences with the complete yeast genome. Nucleotide word frequencies in the vicinity of the cleavage sites were analyzed to reveal the signal element features. In addition to previously recognized processing signals, two previously uncharacterized components of the 3'-end-processing signal sequence were discovered, specifically a predominance of U-rich sequences located on either side of the cleavage site. One of these, the downstream U-rich signal, provides a further link between the 3'-end-processing mechanisms of yeast and higher eukaryotes. Analysis of the complete set of 3'-end-processing sites by means of a discrimination function supports a 'contextual' model in which the sum total effectiveness of the signals in all four elements determines whether or not processing occurs.     

Interspecific and intraspecific competition as causes of direct and delayed density dependence in a fluctuating vole population

A 3- to 5-year cycle of vole abundances is a characteristic phenomenon in the ecology of northern regions, and their explanation stands as a central theoretical challenge in population ecology. Although many species of voles usually coexist and are in severe competition for food and breeding space, the role of interspecific competition in vole cycles has never been evaluated statistically. After studying community effects on the population dynamics of the gray-sided vole (Clethrionomys rufocanus) in the subarctic birch forest at Kilpisj?rvi, Finland, we report statistical results showing that both interspecific and intraspecific effects are important in the direct year-to-year density dependence. However, interspecific effects are not detectable in the 2-year delayed density dependence that is crucial for generating the characteristic cycles. Furthermore, we show that most of the competition takes place during the winter. The results are evaluated against two models of community dynamics. One assumes that the delayed effects are caused by an interaction with a specialist predator, and the other assumes that they are caused by overgrazing food plants. These statistical results show that vole cycles may be generated by a species-specific trophic interaction. The results also suggest that the gray-sided vole may be the focal species in the birch-forest community, as field voles may be in the taiga and as lemmings may be on the tundra.     

Innervation and control of the adenohypophysis by hypothalamic peptidergic neurons in teleost fishes: EM immunohistochemical evidence

Previous light microscopic studies have revealed neuropeptide-immunoreactive neurosecretory fibers in the teleostean neurohypophysis, and ultrastructural work has reported direct innervation of endocrine cells by the terminals of fibers penetrating the adenohypophysis. This paper reviews our recent data from ultrastructural, immunohistochemical, receptor localization, and superfusion studies, which suggest a role for neuropeptides in the control of teleost pituitary secretion. We have used a combination of pre- and post-embedding electron microscopic immunolabeling methods to determine which neuropeptides are present in fibers innervating the pituitaries of three species: Poecilia latipinna, Dicentrarchus labrax, and Clarias gariepinus. Numerous axon profiles with immunoreactivity for the neurosecretory peptides vasotocin and isotocin formed large Herring bodies and terminal-like boutons in contact with corticotropic, growth hormone, thyrotropic, and pars intermedia cells. Numerous melanin-concentrating hormone-immunoreactive fibers and scarcer neurotensin and corticotropin-releasing factor-immunoreactive fibers showed similar distributions, terminating close to pars intermedia and corticotropic cells. Somatostatin, cholecystokinin, galanin, substance P, neuropeptide Y, growth hormone-releasing factor, thyrotropin-releasing hormone, and gonadotropin-releasing hormone-immunoreactivities were found in small calibre fibers penetrating among growth hormone, thyrotropic, and gonadotropic cells. These morphological findings have been supplemented by autoradiographic studies, which showed the distribution of binding sites for vasotocin, isotocin, galanin, and neuropeptide Y ligands over specific groups of pituitary cells, and superfusion studies that showed growth hormone release was stimulated by growth hormone-releasing factor and thyrotropin-releasing hormone, but inhibited by somatostatin. The implications of these results for neuropeptidergic control of teleostean pituitary secretions are discussed.