bluuebunny/crossref_metadata_2025 huggingface dataset:
Human leucocyte interferon‐α in chronic hepatitis C resistant to recombinant or lymphoblastoid interferon‐α: a randomized controlled trial
Authors: Gaeta G. B. , Virgilio D. Di , Russo G. , Stornaiuolo G. , Nicolella U. , Colella F. , Grimaldi M. , Pasquale G. , Giust G.
Published: November 2003

Patients with biopsy‐proven chronic hepatitis C, who failed to respond to a previous course of either recombinant (rIFN‐α) or lymphoblastoid (Ly IFN‐α) interferon‐α, were randomized to receive either leucocyte (Le) IFN‐α (patients) or a second course of the same IFN‐aL (controls), to compare the efficacy and safety of these treatment schedules. All patients received the same dose of IFN‐α as was used during their previous treatment (3 million units (MU) or 6 MU three times weekly) for 6 months. Patients with a normal alanine aminotransferase (ALT) value at month 6 were treated for a further 6 months. All patients were followed‐up for 12 months after treatment. A total of 69 patients were enrolled, 44 in the Le IFN‐α group and 25 in the control group. At the end of the treatment period, 13 of the 44 patients (29.5%) in the Le IFN‐α group had a biochemical response (normal ALT) and six of 44 (13.6%) patients had undetectable serum hepatitis C virus (HCV) RNA. At the end of the follow‐up period, 10 patients (22.7%) had normal ALT values and serum HCV RNA was undetectable in three (6.8%). None of the patients in the control group showed normal ALT values at any time. Genotype lb tended to be more frequent among non‐responders (61 vs 45%); basal γ‐glutamyl transpeptidase (γ‐GT) values were lower in responders than in non‐responders (33.3 ± 11.70 Ul‐1vs 58.4 ± 33.04; P= 0.01). Le IFN‐α was well tolerated by all patients. These results support the use of Le IFN‐α in patients with chronic hepatitis C who are non‐responders to a previous treatment with recombinant or lymphoblastoid IFN‐α.
N‐acetyl aspartate estimation: a potential method for determining neuronal loss in the transmissible spongiform encephalopathies
Authors: Chung Y.‐L. , Barr J. , Bhakoo K. , Williams S. C. R. , Bell J. D. , Fraser J. R.
Published: November 2003

Neurodegenerative pathology is typical of the transmissible spongiform encephalopathies (TSEs), and is thought to underlie clinical disease. Some morphometric studies have shown early focal neurone loss, but the full extent of TSE induced neuronal loss in the central nervous system is not known, and can only be accurately estimated using intensive morphometric techniques. We have used a murine scrapie model in which we determined the levels of N‐acetyl aspartate (NAA), a putative neuronal marker, by both high‐performance liquid chromatography and high resolution, proton magnetic resonance spectroscopy in samples taken sequentially from the hippocampus. This scrapie model develops severe neuronal loss in the hippocampus, and the NAA levels showed a significant positive correlation with our previous morphometric estimates of neurone number. NAA measurement may therefore provide a practical alternative to intensive morphometric techniques in the investigation of neurodegeneration in the TSEs.
Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein ɛ4
Authors: Tsuboi Y. , Wszolek Z. K. , Graff‐Radford N. R. , Cookson N. , Dickson D. W.
Published: November 2003

Olfactory dysfunction increases with disease severity in Alzheimer's disease (AD), is early and independent of disease severity in Parkinson's disease (PD), but is absent in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Previous histopathologic studies of olfactory bulbs in AD have shown neurofibrillary tangles (NFTs) and senile plaques while Lewy bodies (LBs) have been described in PD. Little is known about olfactory bulb pathology in PSP and CBD. Tau and α‐synuclein pathology was assessed with immunohistochemistry in olfactory bulbs of AD (N = 15), Lewy body disease (LBD; N = 10), LBD with concurrent AD (AD/LBD; N = 19), PSP (N = 27), CBD (N = 3) and cases with no significant neurodegenerative pathology (NSP; N = 15). The Braak NFT stage, counts of senile plaques and NFT in cortical and hippocampal sections, and counts of LBs in amygdala and cortical sections were recorded for each case. Apolipoprotein E (APOE) genotypes were determined on DNA prepared from frozen brain tissue. All AD and AD/LBD cases and nine of 10 LBD cases had tau pathology in the anterior olfactory nucleus (AON), but it was uncommon in PSP (9/27), CBD (0/3) and NSP (5/15). Multiple linear regression analysis demonstrated that tau pathology in the AON correlated with Braak stage (P < 0.001), cortical LB counts (P < 0.001), as well as APOE ɛ4. Tau pathology is common in the olfactory bulb of AD and LBD but is minimal or absent in PSP and CBD. It correlates with APOE ɛ4, severity of tau pathology in the brain and surprisingly with cortical and amygdala LBs, suggesting a possible synergistic effect between tau and synuclein in the AON in cases with both pathologic processes.
Accumulation of flotillin‐1 in tangle‐bearing neurones of Alzheimer's disease
Authors: Girardot N. , Allinquant B. , Langui D. , Laquerrière A. , Dubois B. , Hauw J.‐J. , Duyckaerts C.
Published: November 2003

The protein flotillin‐1 is associated with the ‘lipid rafts’, that is, membrane microdomains that are enriched in cholesterol and sphingolipids. We compared flotillin‐1 immunoreactivity in the hippocampus, amygdala and isocortex (Brodmann area 22) of six controls and 13 Alzheimer's disease (AD) cases (10 sporadic and three familial). A diffuse labelling of the neuropil was observed in most of the samples. The intensity of this labelling was not correlated with the density of neurofibrillary tangles (NFT) or of senile plaques. Some neuronal cell bodies were diffusely labelled in patients as in controls. Immunostained granular bodies were found in the cell body of a few neurones. The density of neuronal profiles containing large granular bodies (diameter ≥ 2 µm) was significantly higher in AD cases and was correlated with the density of NFTs in the three regions that were studied. Sections stained by double immunofluorescence methods and examined with confocal microscopy suggested that flotillin‐1 accumulated most often in tangle‐bearing neurones (76% of flotillin‐1‐positive neurones contained a NFT). Flotillin‐1 immunoreactivity, even when found in a tangle‐bearing neurone, was not colocalized with tau protein indicating that the two proteins were not in close contact and probably in different subcellular compartments. Flotillin‐1‐positive granular bodies were also found in neurones containing Pin1‐positive vesicles but were not colocalized with them. Flotillin‐1 immunoreactivity was colocalized with cathepsin D, a lysosomal marker. These data indicate that flotillin‐1, a marker of rafts, accumulates in lysosomes of tangle‐bearing neurones in the course of AD.
Role of interferon‐γ and nitric oxide in the neuropathogenesis of avirulent Semliki Forest virus infection
Authors: Keogh B. , Atkins G. J. , Mills K. H. G. , Sheahan B. J.
Published: November 2003

Semliki Forest virus (SFV) infection of mice provides a useful model for the analysis of viral neuropathogenesis. In this study, the roles of interferon (IFN)‐γ and nitric oxide (NO) in the pathogenesis of SFV infection were assessed using mice deficient in inducible nitric oxide synthase (iNOS–/–), an enzyme important in the production of NO, and mice deficient in IFN‐γ receptor (IFN‐γR–/–). Gene‐knockout and wildtype mice were infected intranasally with the avirulent A7 strain of SFV and neuropathological lesions were correlated with levels of IFN‐γ, tumour necrosis factor (TNF)‐α and interleukin (IL)‐10 in the olfactory bulbs and frontal cortex. Lesions in IFN‐γR–/– mice were characterized by higher levels of neuronal necrosis than in wildtype mice. The higher levels of neuronal necrosis were associated with increased levels of SFV antigen in neurones and increased numbers of macrophages and B cells. Relative differences in the severity of demyelination between IFN‐γR–/– and wildtype mice were not detected. Similar levels of neuronal necrosis and SFV antigen labelling occurred in iNOS–/– mice and wildtype mice and levels of demyelination and macrophage infiltration in the iNOS–/– mice were lower than those in the wildtype strain. A rapid, but transient increase in the concentration of IFN‐γ was demonstrated in the frontal cortex of all infected mice samples. IL‐10 levels in the frontal cortex and olfactory bulbs of SFV‐infected iNOS–/– mice exceeded those present in the wildtype mice. This study, taken with our previous reports, provides further evidence that type 1 T cell responses are important in the control of brain viral clearance and the prevention of neuronal necrosis, but not in the development of demyelination.
Month of birth as an independent variable in the sudden infant death syndrome
Authors: Douglas A. S. , Gupta Ramyani , Helms Peter , Jolliffe Ian
Published: November 2003

Well‐known epidemiological features of sudden infant death syndrome (SIDS) are age at death and the increased numbers in winter. There are more SIDS deaths in late autumn/early winter and there is a seasonal rhythm of births with a peak in late summer and early autumn. The data set was 14 033 SIDS deaths from Scotland, England and Wales over the 11 years 1982–92. Using log‐linear models, which accounted for age at death and month of death, birth month was found to be a statistically significant risk factor for SIDS independent of age at death and winter environment (P<0.001). Although winter season had the largest effect (relative risk 2.7 in January compared with August), the independent effect of birth month was of clinical as well as statistical significance with a relative risk for August births of 1.37 compared with those born in April. The analysis of each birth month cohort revealed a change in age distribution with infants born in early winter (December) dying at a younger age (mean 108 days) than those born in midsummer (June) (mean 146 days). Although winter season and age are the most influential factors, the substantial effect of month of birth requires explanation and points to as yet unidentified environmental influences during pregnancy.
Neonatal respiratory distress syndrome in Karachi: some epidemiological considerations
Authors: Bhutta Zulfiqar Ahmed , Yusuf Kamran
Published: November 2003

Although respiratory distress syndrome (RDS) is a leading cause of neonatal morbidity and mortality in the west, there are few data on the prevalence and spectrum of RDS from developing countries. Available evidence suggests that the disorder may be less common than the overall 1% incidence reported from developed countries. In a prospective study of the prevalence of RDS in a consecutive 10 134 births at the Aga Khan University Hospital, we documented the disorder in 127 (1.2% births), with a prevalence of 12.8% among low birthweight infants. The overall mortality for this group was 39%, with the highest mortality rate (68%) among newborn infants 1000 g birthweight. Our data from a large and relatively well‐nourished hospital‐born population in Karachi suggest that RDS is a significant cause of morbidity and mortality in preterm infants with a similar prevalence rate to western figures.
Qualitative effects of patchy stomatal conductance distribution features on gas‐exchange calculations
Authors: BUCKLEY T. N. , FARQUHAR G. D. , MOTT K. A.
Published: November 2003

The qualitative influence of patchy stomatal conductance distributions on the values of photosynthesis (A) and intercellular CO2 concentration (ci) as determined by gas‐exchange measurements were investigated using computer modelling. Gas‐exchange measurements were simulated for different conductance distributions by modelling photosynthesis explicitly for each patch, summing these rates, and inferring ci from a diffusion equation. Qualitative relationships are presented between conductance distribution features and the difference between assimilation rates measured for patchy and homogeneous leaves at the same ci (Ap and Ah, respectively). These data show that, although most conductance distributions have little effect on the value of A measured for a given ci, some distribution features (which we have termed ‘bimodality’, ‘position’, ‘skewness’ and ‘range’) play a key role in controlling the magnitude of these effects. Distributions that are more nearly bimodal, span regions of lower conductance, are right‐skewed, or have broader conductance ranges are associated with larger effects on the A(ci) relationship. To clarify our mathematical analysis and illustrate some of the trends it predicts, we present conductance distributions and gas‐exchange data from leaves of Malus dolgo var. Spring Snow Dial were treated with ABA. The results are discussed in the light of recent controversy over the effect of patchy stomatal conductance on gas‐exchange data.
Induction of CD8+ CTL Recognizing Mycobacterial Peptides
Authors: VORDERMEIER H. M. , ZHU X. , HARRIS D. P.
Published: November 2003

Mycobacterium tuberculosis is the single, most important cause of morbidity attributable to a single infectious organism. CD8+ T cells play an important role in anti‐tuberculous immune responses in both mice and humans. Data concerning the identity of mycobacterial antigens recognized by CD8+ T cells is limited; consequently, few CTL epitopes have been characterized. The authors identified allele‐specific (H‐2b and d) MHC class I binding motifs in six prominent M. tuberculosis protein antigens (the 19 and 38 kDa lipoglycoproteins and the 10, 16, 65 and 70 kDa stress proteins). These predicted epitopes were tested for MHC binding as well as their ability to elicit peptide‐specific CTL following in vivo priming. The authors were able to identify eight previously undescribed mycobacterial CTL epitopes by using spleen cells from peptide‐immunized mice. In addition, CTL specific for at least one of these epitopes also recognized the naturally processed epitope presented on transfected EL4 target cells. These mycobacteria‐derived CTL epitopes could be important for future analysis of the involvement of CD8+ T cells in M. tuberculosis infection, pathogenesis and vaccine development.
Cutaneous Delayed Type Hypersensitivity in SCID Mice Adoptively Transferred with Lymphocytes is B Cell Independent and H‐2 Restricted
Authors: TAUBE M. , CARLSTEN H.
Published: November 2003

Severe combined immunodeficiency (SCID) mice are largely devoid of functional T and B lymphocytes but have normal antigen presenting cell (APC) capacity. The authors have examined the requirements for cutaneous delayed type hypersensitivity (DTH) in SCID recipients by i.p. transfer of freshly isolated naive mature T cells or non‐fractionated spleen cells of H‐2 compatible or incompatible origin. Recipient SCID mice were epicutaneously sensitized with oxazolone (OXA) within 24 h after cell transfer. SCID mice injected with as few as 105 H‐2 compatible BALB/c (H‐2d) spleen cells were able to mount DTH ear swelling reaction upon sensitization and challenge with OXA. Non‐fractionated spleen cells from H‐2 incompatible B6 or NZW mice were also able to restore DTH capacity in SCID recipients. However, when thymocytes were transferred, only donor mice expressing H‐2d, but not H‐2b and H‐2z, haplotype restored DTH reactivity. Serum levels of IgM and IgM anti‐OXA antibodies in SCID mice 27 days post‐transfer with 107 BALB/c spleen cells were similar to that of intact donor mice. In contrast, specific antibodies of IgG isotype were approximately only one‐tenth of that found in BALB/c controls. The results of this study show that for the development of cutaneous DTH, in SCID mice transferred with T cells, H‐2 restricted APC‐T cell interaction is required, whereas B cells are not mandatory. Also, SCID mice transferred with splenocytes show signs of defect immunoglobulin switch function. The authors believe that this model of DTH will be useful in delineating the effects of immunomodulatory substances in vivo on distinct host versus donor cell populations.
Antidepressant‐induced mania: an overview of current controversies
Authors: Goldberg Joseph F , Truman Christine J
Published: November 2003

Objective:  The prevalence, characteristics, and possible risk factors associated with antidepressant‐induced mania remain poorly described. The present review sought to identify published rates of antidepressant‐induced mania and describe risk factors for its emergence.

Methods:  A MedLine search was conducted of journals that focused on mania or hypomania associated with recent antidepressant use. Data from published reports were augmented with relevant findings from recent clinical trials presented at scientific conferences.

Results:  Antidepressant‐induced manias have been reported with all major antidepressant classes in a subgroup of about 20–40% of bipolar patients. Lithium may confer better protection against this outcome when compared with other standard mood stabilizers, although switch rates have been reported with comparable frequencies on or off mood stabilizers. Evidence across studies most consistently supports an elevated risk in patients with (i) previous antidepressant‐induced manias, (ii) a bipolar family history, and (iii) exposure to multiple antidepressant trials.

Conclusion:  About one‐quarter to one‐third of bipolar patients may be inherently susceptible to antidepressant‐induced manias. Bipolar patients with a strong genetic loading for bipolar illness whose initial illness begins in adolescence or young adulthood may be especially at risk. Further efforts are needed to better identify high‐vulnerability subgroups and differentiate illness‐specific from medication‐specific factors in mood destabilization.
The bipolar spectrum: a clinical perspective
Authors: Katzow Jacob J , Hsu Douglas J , Nassir Ghaemi S
Published: November 2003

The relative misdiagnosis and underdiagnosis of bipolar disorder is due in part to the ‘soft’ symptoms of bipolarity that characterize patients with non‐classical bipolar disorder. While no agreement has been reached on the term for this group of patients, the most common classification used is ‘bipolar spectrum’, which shifts the emphasis in diagnosis away from polarity and toward other diagnostic validators. In order to recognize and properly treat patients with bipolar disorder, clinicians should focus on careful evaluation of patients with mixed anxiety/depressive symptoms or impulsivity conditions (substance abuse, borderline personality, bulimia, and attention deficit disorder). Furthermore, in the treatment of bipolar disorder, clinicians should also recognize that antidepressants can have a negative effect on patients by increasing the likelihood of more severe rapid cycling. While antidepressants may be useful in particularly difficult cases, emphasis should be placed on mood stabilizers for treatment of the bipolar spectrum.
Clinical consequences of under‐recognized bipolar spectrum disorder
Authors: Dunner David L
Published: November 2003

The prevalence of bipolar disorder is higher than previously believed, especially when bipolar spectrum disorders (BSD) are taken into account, and may approach rates as high as 5%. Difficulties in diagnosing bipolar II and BSD arise from complexities associated with defining and diagnosing hypomania. Additionally, bipolar disorder and BSD are often misdiagnosed because of symptoms that overlap with other psychiatric disorders, particularly unipolar depression. Recognition of the broader spectrum of bipolar disorders and their adequate treatment is paramount because bipolar disorder exacts such a high personal and societal toll, with high rates of suicide and interpersonal problems and a substantial economic burden. Recognition can be improved with active screening, and screening tools such as the Mood Disorders Questionnaire can be easily included in the initial assessment of patients who present with depressive symptoms. Depressive episodes are common in patients who experience BSDs, and increasingly treatment approaches designed specifically for bipolar depression are being studied.
Protective, Curative and Eradicant Activity of the Strobilurin Fungicide Azoxystrobin against Cercospora beticola and Erysiphe betae
Authors: Anesiadis T. , Karaoglanidis G. S. , Tzavella‐Klonari K.
Published: November 2003

The protective, curative and eradicant activity of the strobilurin fungicide azoxystrobin against Cercospora beticola and Erysiphe betae on sugar beet was determined under growth chamber conditions. Difenoconazole and chlorothalonil were used as standard fungicides against C. beticola, while chlorothalonil was replaced by sulphur against E. betae. Fungicides were applied before (protective treatments) and after (curative treatments) inoculation at 24, 48 and 96 h intervals, respectively. An additional spray treatment was applied after the appearance of the symptoms to evaluate the eradicant activity of the fungicides tested. Applications of azoxystrobin at 16 μ/ml provided 89–94% and 95–97% disease control against C. beticola and E. betae, respectively. Curative treatments of azoxystrobin either at 8 or 16 μg/ml provided control of Cercospora leaf‐spot higher than 90% only when it was applied 24 h after inoculation of the plants. Comparatively, chlorothalonil (100 μg/ml) provided satisfactory control of C. beticola when applied in protective treatments (83–87% disease control) but showed little activity when applied after the inoculation of the seedlings (45–76% disease control). High control efficacy against E. betae was also obtained by protective applications of sulphur (600 μg/ml) but the fungicide failed to provide satisfactory disease control, particularly when applied for 48 or 96 h after inoculation of seedlings. Difenoconazole (8 μg/ml) gave excellent protective and curative activity against both pathogens. Eradicative treatments with azoxystrobin provided high antisporulant activity of 94–96% and 85–93% against C. beticola and E. betae, respectively. Similarly, high antisporulant activity was also provided by difenoconazole, while postsymptom applications of chlorothalonil and sulphur provided significantly lower antisporulant activity against C. beticola and E. betae, respectively. Such results encourage the evaluation of azoxystrobin under field conditions to determine optimal treatment schedules and to select possibly partner fungicides for use in mixtures.
The Phytopathogenic Fungus Ramularia collo‐cygni Produces Biologically Active Rubellins on Infected Barley Leaves
Authors: Miethbauer S. , Heiser I. , Liebermann B.
Published: November 2003

The anamorph fungus Ramularia collo‐cygni Sutton and Waller, the cause of a leaf spot disease on barley, produces biologically active rubellins on infected leaves, the main component of which is the anthraquinone derivate rubellin B. In severely infected barley leaves originating from Germany and Austria we found approximately 2–6 μg rubellin B per cm2 leaf area. Rubellin B isolated for the first time from mycelium and culture filtrate of R. collo‐cygni acts as reference substance. As already shown for rubellin D, the isomeric compound rubellin B induces symptoms in barley leaves only in the light. The light‐dependency of symptom expression can be explained by the photodynamic formation of reactive oxygen species by rubellin B and D which was demonstrated in a model system.
An Integrated Approach to the Evaluation of the Efficacy of Fungicides Against Fusarium culmorum, the Cause of Head Blight of Wheat
Authors: Chala A. , Weinert J. , Wolf G. A.
Published: November 2003

All the registered Strobilurin‐containing chemicals and one Azole known for its higher efficacy to control the pathogen were compared in a fungicide trial in 2001 on wheat inoculated with Fusarium culmorum. Two application times (BBCH 39 and BBCH 51) were used for the Strobilurin fungicides, whereas the Azole was applied at BBCH 65. Visual disease assessment, enzyme‐linked immunosorbent assay (ELISA), a mycotoxin test, 1000‐grain weight and yield assessment were used for evaluation, and all the techniques in different ways revealed differences in the efficacy of the chemicals. Whereas visual disease assessment showed the effect of the chemicals on symptom development, ELISA and the mycotoxin test indicated differences in the treatments on grain contamination by the pathogen and its mycotoxin, respectively. Assessment on 1000‐grain weight and yield also showed the impact of the treatments in reducing the effect of the pathogen on grain production. Correlation coefficients calculated for the different parameters were significantly higher, indicating that a strong relationship existed among the various parameters used for evaluation. It was thus assumed that any of the techniques can be used to make general recommendations about the effect of chemicals on plant pathogenic fungi such as F. culmorum.
IL‐4 from Th2‐type cells suppresses induction of delayed‐type hypersensitivity elicited shortly after immunization
Authors: Jacysyn Jacqueline F , Abrahamsohn Ises A , Macedo Mahasti S
Published: November 2003

The pure delayed‐type hypersensitivity reaction obtained in 4‐day ovalbumin‐sensitized mice after antigen challenge in the footpad was abrogated by transfer of in vitro expanded, antigen‐specific lymphoblasts derived from ovalbumin‐hyperimmunized donors (high antibody producers), 12 h before immunization. This effect was specific inasmuch as Trypanosoma cruzi‐specific blasts derived from Tc‐Ag‐hyperimmunized mice did not inhibit delayed‐type hypersensitivity in ovalbumin‐immunized recipients. The ovalbumin‐specific blasts displayed a Th2 cytokine profile, secreting IL‐4 and IL‐10 upon restimulation in vitro with ovalbumin, but not IFN‐γ or IL‐2. In addition, recipients of such cells produced much more IgG1 and IgE antibodies. When the frequency of T‐cell blasts was enriched among these cells, transfer of four million cells was enough to prevent the induction of delayed‐type hypersensitivity. Neutralization of IL‐4 alone just before cell transfer not only restored the delayed‐type hypersensitivity reaction, but also maintained it in a plateau for at least 72 h after challenge. Recipients treated in this way also showed a shift back towards a Th1 phenotype, indicated by the increase in IL‐2, IFN‐γ and IL‐12 synthesis. No synergistic action was observed when IL‐4 and IL‐10 were concomitantly neutralized. These results indicate that activation of Ag‐specific Th2 cells early in the course of the immune response to a protein antigen provides an immunological environment rich in IL‐4, thus leading to the inhibition of cell‐mediated immunity.
Listeria species escape from the phagosomes of interleukin‐4‐deactivated human macrophages independent of listeriolysin
Authors: Neumann Katja , Eppler Elisabeth , Filgueira Luis , Groscurth Peter , Gasal Eduard , Schaffner Andreas , Schoedon Gabriele , Schneemann Markus
Published: November 2003

Listeria monocytogenes is the causative agent of infections like sepsis and meningitis, especially in immunocompromised hosts. Human macrophages are able to phagocytose and digest L. monocytogenes but IL‐4 prevents human macrophages from killing the bacteria, the mechanisms of which are unknown. In the present study, we examined various listeria species and strains including wild‐type and deletion mutants in human macrophages pretreated with IL‐4. To analyse the IL‐4‐mediated deactivation process, we combined quantitative infection assays with various morphologic methods. IL‐4 facilitates survival and escape of the pathogenic L. monocytogenes wild‐type strain 10403S from the macrophage phagosomes. In untreated macrophages, the isogenic listeriolysin deletion mutant strain DP‐L2161 was killed and did not escape from the phagolysosomes. However, after macrophage deactivation with IL‐4 DP‐L2161 survived and escaped from the phagosomes. This was also the case, but to a lesser extent, even for the naturally avirulent L. innocua. As detected by confocal laser‐scanning fluorescence microscopy and electron microscopy, IL‐4 permitted the escape of all listeria species tested, including DP‐L2161 and L. innocua from the phagosomal compartment of the macrophages. We conclude that escape from the phagosome and survival of the listeria species tested in IL‐4‐deactivated human macrophages is independent of the virulence factor listeriolysin.
Subcortical hematoma caused by cerebral amyloid angiopathy: Does the first evidence of hemorrhage occur in the subarachnoid space?
Authors: Takeda Shigeki , Yamazaki Kazunori , Miyakawa Teruo , Onda Kiyoshi , Hinokuma Kaoru , Ikuta Fusahiro , Arai Hiroyuki
Published: November 2003

Six autopsy cases of subcortical hematoma caused by CAA were examined to elucidate the primary site of hemorrhage. Immunohistochemistry for amyloid β‐protein (Aβ) revealed extensive CAA in the intrasulcal meningeal vessels rather than in the cerebral cortical vessels. All of the examined cases had multiple hematomas in the subarachnoid space, mainly in the cerebral sulci, as well as intracerebral hematomas. Each intracerebral hematoma was connected to the subarachnoid hematomas at the depth of cerebral sulci or through the lateral side of the cortex. There was no debris of the cerebral cortical tissue in the subarachnoid hematomas. In case 2, another solitary subarachnoid hematoma, which was not connected to any intracerebral hematoma, was seen. In all of these subarachnoid hematomas, many ruptured Aβ‐immunopositive arteries were observed. These ruptured arteries did not accompany any debris of the brain tissue, some of them were large in diameter (250–300 µm), and several of them were far from the cerebral cortex. Therefore, it was considered that they were not cortical arteries but meningeal arteries. Within the cerebral cortex, there were only a few ruptured arteries associated with small hemorrhages. There were no ruptured vessels within the intracerebral hematomas. There was a strong suggestion that all of the subarachnoid hematomas, including the solitary one in case 2, originated from the rupture of the meningeal arteries. The present study indicates that in some cases of subcortical hematoma caused by CAA, the primary hemorrhage occurs in the subarachnoid space, in particular the cerebral sulci, because of rupture of multiple meningeal arteries. Infarction occurs subsequently in the cortex around the hematoma, the hematoma penetrates into the brain parenchyma, and finally, a subcortical hematoma is formed.
Primary frontal‐lobe germinoma appearing as a large cyst
Authors: Kawasaki Koichi , Yamada Mitsunori , Hara Naoyuki , Okamoto Kouichirou , Tanaka Ryuichi , Takahashi Hitoshi
Published: November 2003

In the present case, a primary frontal‐lobe germinoma in a 20‐year‐old man is reported. This is the first such case to be investigated by autopsy. The tumor appeared on a CT scan as a large cystic lesion in the frontal‐lobe white matter. At autopsy, the typical two‐cell histology pattern was seen mainly in the area of the cyst wall. Although cyst formation is a frequent feature of germinomas, the presence of a large cystic lesion in the cerebral white matter, as demonstrated in the present case, is very rare. The present case provides further radiographic data that might be useful for the future diagnosis of this tumor, which is radiosensitive and potentially curable.
Expression of extracellular matrix markers in benign meningiomas
Authors: Das Asha , Tan Wan‐Loo , Smith Duncan R
Published: November 2003

Meningiomas have mesenchymal differentiation and studies have confirmed that meningiomas express intermediate filaments of both mesenchymal and epithelial types including vimentin and keratin. To further characterize their mesenchymal properties, particularly the role of factors requiring adhesion, extracellular matrix degradation, and migration, meningiomas were examined for a panel of extracellular matrix markers. Immunoreactivity to the matrix metalloproteinases, MMP‐2 and MMP‐9, and their tissue inhibitor, TIMP‐1, and to an adhesion factor, galectin‐3 were found in the majority of cases. The present study suggests that expression of these factors in benign meningiomas is ubiquitous and unrelated to tumor location. Therefore, these factors of the extracellular matrix may be potential targets of future therapy.
Brain tissue microarrays in dementia research: White matter microvascular pathology in Alzheimer's disease
Authors: Sjöbeck Martin , Haglund Mattias , Persson Annette , Sturesson Kerstin , Englund Elisabet
Published: November 2003

Tissue microarrays (TMA) consist of up to 1000 cylindrical tissue cores from different donor paraffin blocks relocated into one recipient block, allowing for efficient histopathological studies by fluorescence in situ hybridization, RNA in situ hybridization or immunohistochemistry. On the background of the increasing interest of the TMA technique in cancer research and the suggestion of its application also in studies of non‐neoplastic intracranial disorders, the technique was applied to pathologic white matter in AD brains. Eight cases with AD and concomitant white matter pathology were neuropathologically diagnosed on whole brain coronal slides. The TMA technique was used to grade severity of white matter pathology and to quantify small vessels with traditional staining and immunohistochemical markers. These measurements were compared with the whole brain neuropathological assessment. The technique produced good results with preserved tissue structures as confirmed by the whole brain evaluation. Severity of white matter pathology evaluated on the TMA cores correlated negatively with small vessel quantities, and statistically significant differences in vessel quantities paralleled different grades of white matter pathology. It is concluded that the TMA technique could be further utilized in studies of dementing disorders, and may have its advantages in large, clinically well‐characterized materials (e.g. in quantitative mapping of white matter changes).
Measuring the degree of spatial correlation between histological features in thin sections of brain tissue
Authors: Armstrong Richard A
Published: November 2003

Histological features visible in thin sections of brain tissue, such as neuronal perikarya, blood vessels, or pathological lesions may exhibit a degree of spatial association or correlation. In neurodegenerative disorders such as AD, Pick's disease, and CJD, information on whether different types of pathological lesion are spatially correlated may be useful in elucidating disease pathogenesis. In the present article the statistical methods available for studying spatial association in histological sections are reviewed. These include tests of interspecific association between two or more histological features using χ2contingency tables, measurement of ‘complete’ and ‘absolute’ association, and more complex methods that use grids of contiguous samples. In addition, the use of correlation matrices and stepwise multiple regression methods are described. The advantages and limitations of each method are reviewed and possible future developments discussed.
Pick body disease and Pick syndrome*
Authors: Uchihara Toshiki , Ikeda Kenji , Tsuchiya Kuniaki
Published: November 2003

Diagnostic criteria for Pick's disease have been criticized from many different viewpoints. This confusion is mainly derived from the ambiguity of this term ‘Pick's disease’ (PD), which may imply either purely histological findings, such as Pick body (PB), or a characteristic clinical syndrome that could occur even in the absence of PB. This taxonomic confusion will be circumvented by introducing the diagnostic term ‘Pick body disease’ to designate patients with the characteristic argyrophilic inclusions purely on histological grounds. In parallel, employment of ‘Pick syndrome’ to describe the time‐honored clinical features may be more convenient and less confusing than PD because PD implies either the presence of PB or the clinical features, two aspects not necessarily linked to each other. Three‐dimensional reconstruction of PB confirmed that tau‐like immunoreactivity was accentuated at their periphery, as was recognized with the Bodian method. Preferential affinity of three‐repeat tau pathology, as seen in Pick body disease, to the Bodian over the Gallyas method is distinct from the reversed affinity (the Gallyas over the Bodian method) of four‐repeat tau pathology, as seen in corticobasal degeneration and in argyrophilic grains. This preference of silver staining is compatible with the mixed three‐ and four‐repeat tau pathology, as seen in NFT of the Alzheimer's type, which are stained with both the Bodian and Gallyas staining. This will provide a practical basis on which to differentiate these disorders based on their distinctive tau species and possible relation of tau species to staining profile on these silver methods.
Association of hepatocyte growth factor expression with salivary gland tumor differentiation
Authors: Tsukinoki Keiichi , Yasuda Masanori , Asano Shigeyuki , Karakida Kazunari , Ota Yoshihide , Osamura R. Yoshiyuki , Watanabe Yoshihisa
Published: November 2003

To clarify the significance of hepatocyte growth factor (HGF) expression in salivary gland tumors, HGF distribution in tissue sections and HGF concentrations in saliva and serum were examined. Sixty salivary gland adenomas, 61 salivary gland carcinomas and three autopsy fetuses were studied. Hepatocyte growth factor expression was observed in the duct‐type luminal cells by immunohistochemical staining and in situ hybridization. However, HGF failed to be expressed in acinar cells and myoepithelium of normal salivary gland tissue. Hepatocyte growth factor tended to be expressed more intensely in benign salivary gland tumors than in malignant salivary gland tumors (P < 0.0001). In highly malignant tumors, the expression was limited in some cases. Salivary and serological HGF concentrations of 18 patients, comprised of 12 benign cases and six malignant cases, were analyzed before and after operation by an ELISA system. The concentrations were distinctly elevated after operation, in both saliva and serum, compared to before operation (P < 0.0005). However, there were no significant relationships between HGF concentration and histology, age, gender, size or location. Our findings suggest that HGF may play an important role in the development of salivary ducts of normal salivary tissues and differentiation of ductal structures of their neoplasms, while HGF kinetics in saliva and serum would be less likely to reflect the neoplastic character, benign or malignant.
Adrenocorticotropin‐producing pulmonary tumorlets with lymph node metastasis
Authors: Liu Shian‐Min , Wu Hsing‐Hsien , Wu Chieh‐Jen , Kuo Chien‐Long , Mo Lein‐Ray
Published: November 2003

A case of pulmonary tumorlets with ectopic adrenocorticotropin (ACTH) production and lymph node metastasis in a bronchiectatic patient is reported. A 65‐year‐old man underwent right lower lobe lobectomy because of a sudden attack of cough and hemoptysis. Histological study revealed multiple discrete uniform small nests of tumor cells surrounding dilated bronchioles. Tumor nests were also found in the hilar lymph node. Immunohistochemically, the proliferating cells were confirmed to be neuroendocrine in origin with ectopic ACTH production, despite being clinically silent. The findings in the present case suggest that the clinical behavior of pulmonary tumorlets may be like a carcinoid, and need to be treated as tumor‐like lesions. Ectopic hormonal production in the present case suggests pulmonary tumorlets should be considered in the differential diagnosis of Cushing's syndrome.
Proliferative funiculitis with a prominent infiltration of mast cells
Authors: Shintaku Masayuki , Ukikusa Minoru
Published: November 2003

A surgical case of proliferative funiculitis (pseudosarcomatous myofibroblastic proliferation of the spermatic cord) with a prominent mast cell infiltration is reported. A 67‐year‐old man with a history of right inguinal herniorrhaphy 7 years earlier was operated on for diffuse swelling of the inguinal region and scrotum. A large lipoma was found in the inguinal region, and a nodular lesion, measuring 2.7 cm in maximal dimension, was firmly attached to the right spermatic cord. The nodular lesion showed diffuse proliferation of fibroblasts and myofibroblasts associated with the deposition of collagen. A diffuse infiltration of numerous mast cells was found throughout the lesion. Lesions that belong to the group of inflammatory pseudotumors are rarely accompanied by a prominent mast cell infiltration, and the differentiation from mast cell neoplasms is often problematic in such cases. The present case is the first example of proliferative funiculitis associated with this rare phenomenon.
Epithelial differentiation in medulloblastoma: Comparison with other embryonal tumors of neuroectodermal origin
Authors: Sugita Yasuo , Tokunaga Osamu , Terasaki Mizuhiko , Morimatsu Minoru , Shigemori Minoru
Published: November 2003

Three cases of medulloblastoma characterized by epithelial differentiation are described in patients 6‐months‐, 1‐month‐ and 8‐years‐old. Histologically, tumors from the two infant patients showed a perivascular arrangement without apparent radiated cytoplasmic processes from the vessels. Tumor cells displayed round and/or pleomorphic vesicular nuclei and a more abundant eosinophilic cytoplasm than that found in classic medulloblastoma. Neither Homer–Wright rosettes nor ependymal or ependymoblastic rosettes were noted in these tumors. The tumor in the 8‐year‐old patient exhibited a classic medulloblastoma component intermingled with abundant eosinophilic cytoplasm forming a tubular structure. Immunohistochemically, tumor cells in all cases were positive for cytokeratin, synaptophysin, and vimentin. In the third case involving the 8‐year‐old patient, epithelial tumor cells were positive for cytokeratin, whereas classic medulloblastoma components were negative for cytokeratin. Positive staining for melanoma‐specific antigen was seen only in the third case, where strong reactivity of tumor cells formed a tubulus. However, the classic medulloblastoma component was negative for melanoma‐specific antigen. Ultrastructurally, basal laminae were observed around tumor cells in the 6‐month‐old patient. These morphological and immunohistochemical features suggest that medulloblastoma with epithelial differentiation is a rare but distinct variant of medulloblastoma, and that some of these tumors should show differentiation in ocular pigment epithelium.
Introduction of autopsy imaging redefines the concept of autopsy: 37 cases of clinical experience
Authors: Ezawa Hidefumi , Yoneyama Ryuichi , Kandatsu Susumu , Yoshikawa Kyosan , Tsujii Hirohiko , Harigaya Kenichi
Published: November 2003

A new autopsy imaging (AI) system was introduced at the Research Center Hospital for Charged Particle Therapy (RCCPT) in January 2000. Autopsy imaging is a postmortem and preautopsy diagnostic procedure using magnetic resonance imaging (MRI). Scanning is performed with a 1.5 Tesla MRI system before autopsy. The AI results are reported to the pathologist and, in light of this information, autopsy is performed with minute precision. Autopsy imaging was performed on 37 cancer cases. In seven cases, AI was less informative than the autopsy, but in 30 cases, more precise reports on the final diagnosis were available with the combined application of autopsy and AI than autopsy alone, particularly in eight limited autopsy cases. Thus, AI provides critical and supplementary information for autopsy; furthermore, AI itself is a unique imaging system of great importance.
Small cell carcinoma of the extrahepatic bile duct: Case report and immunohistochemical analysis
Authors: Kuraoka Kazuya , Taniyama Kiyomi , Fujitaka Tsuguo , Nakatsuka Hirofumi , Nakayama Hirofumi , Yasui Wataru
Published: November 2003

A small cell carcinoma of the extrahepatic bile duct in a 75‐year‐old Japanese man is reported. The patient suffered from obstructive jaundice, and percutaneous transhepatic cholangiography‐drainage (PTCD) revealed a massive lesion in the lower common bile duct. Because it was diagnosed as a malignant tumor, pancreaticoduodenectomy was performed. A nodular infiltrating tumor measuring 4.5 × 3.0 × 2.0 cm was located in the intrapancreatic portion of the extrahepatic bile duct. Histologically, the tumor was composed of a dense proliferation of small atypical cells with a little region of high‐grade dysplasia in the adjacent epithelium of the common bile duct. Tumor cells were immunoreactive to neuroendocrine markers such as chromogranin A, synaptophysin, CD56, and Leu7. Although carcinoma cells invaded into pancreas and duodenum, there were no histological findings that indicated the carcinoma arose from the mucosa of either the pancreatic duct or duodenum. These results indicated that the tumor was a small cell carcinoma derived from the epithelium of the extrahepatic bile duct; a rare neoplasm with only a few cases reported. A few neuroendocrine cells were recognized in the adjacent epithelium of the extrahepatic bile duct, suggesting that the tumor cells might be derived from them. Using immunohistochemical examination, no p53 abnormality was found. Tumor cells showed positive nuclear staining for p16, while negative for cyclin D1, suggesting that functional retinoblastoma protein (pRB) might be lost in the p16/pRB pathway, as in small cell lung cancer.
Central sleep apnoea and heart failure (Part II)
Authors: BURGESS Keith
Published: November 2003

Central sleep apnoea (CSA) in congestive heart failure is sleep state dependent and occurs typically in stages I and II of non‐REM sleep. The pre‐requisites are hypocapnia and some prolongation of the circulation time. It is not certain whether abnormalities in after‐discharge activity in the brainstem are also important. The presence of CSA in patients with left ventricular dysfunction is a poor prognostic sign and associated with a higher mortality in that group compared to age, sex and ejection fraction matched patients with congestive cardiac failure alone. It is reasonable to speculate that the CSA causes an increase in sympathetic nervous system activity which would maintain afterload at a high level or tend to increase it with time. The application of a high afterload to an impaired left ventricle leads over time to a further reduction in ejection fraction. From other studies, particularly ACE inhibitor studies, it is known that ejection fraction and prognosis are almost linearly related. It could therefore be said that once CSA has developed it may lead to a vicious circle of increasing afterload and further reduction in ejection fraction, causing worsening CSA and further increases in afterload. A number of treatments have been shown to be of benefit: supplemental nocturnal oxygen therapy, acetazolamide and nasal CPAP therapy have all been shown to reduce CSA. In addition nasal continuous positive airways pressure (CPAP) has been shown by two groups in Canada to also improve ejection fraction. The beneficial effects on ejection fraction in particular, persist after the treatment has been withdrawn, which suggests either remodelling of the left ventricular musculature or a resetting of the baseline sympathetic nervous system activity. The impressive increase in ejection fraction due to three months nasal CPAP therapy in one study (an average 35% increase) is both dramatic and exciting for the future. It is reasonable to expect improvement in prognosis for patients with CCF whose ejection fraction rises with CPAP treatment. Finally, only a limited number of studies have been published. Unfortunately the impressive results from Canada have not yet been reproduced in other centres around the world.
Angiotensin converting enzyme inhibitor cough: Lessons from heart–lung transplantation
Authors: GABBAY E , SMALL T , CORRIS PA
Published: November 2003

Coughing is a frequent side‐effect of angiotensin converting enzyme (ACE) inhibitors. Its pathogenesis is thought to be related to the local accumulation of tachykinins although the role of extrinsic cholinergic pathways is unclear. The development of an ACE inhibitor induced cough in two patients who have undergone heart–lung transplantation and in whom cholinergic pathways remain denervated supports the hypothesis of a ‘local’ mechanism.