bluuebunny/crossref_metadata_2025 huggingface dataset:
Atypical pituitary adenoma (silent corticotroph pituitary adenoma)
Authors: Al‐Sarraj S. , King A. , Harris P. , Lantos P.
Published: March 2003

Introduction:  Pituitary adenomas are benign neoplasms with clinical behaviour and recurrence depending on the size of the tumour, therefore it is more common in nonfunctioning macroadenoma adenomas.

Material and methods:  Patient 1: A 40‐year female presented originally with visual field disturbance and underwent transphenoidal resection of pituitary macroadenoma in 1995. The tumour recurred in 1997 and 1998. Despite aggressive radiotherapy, the tumour metastasized to the vertebra in 1999. Patient 2: A 46‐year female presented with clinically nonfunctioning pituitary macroadenoma. She required two transphenoidal operations in 1998 and 1999, and underwent radiotherapy.

Results:  Patient 1: The initial biopsy shows silent corticotroph pituitary adenoma with occasional mitotic figures and Ki67 labelling index 2%. The recurrences in 1997 and 1998 showed increased nuclear pleomorphism, mitotic activity and Ki67 labelling (5% and 8%). The p53 was positive. The metastatic deposit in the vertebra showed similar histology but with Ki67 labelling of 15% and p53 immunoreactivity of 10%. Patient 2: The initial biopsy in 1998 showed silent corticotroph adenoma with Ki67 of 1%. The recurrence in 1999 showed increased mitotic figure, Ki67 labelling of 5% and p53 immunoreactivity.

Conclusion:  Silent corticotroph adenoma could be regarded as atypical pituitary adenoma with aggressive behaviour and high recurrence rate.
Inhibitory interneurons in focal cortical dysplasia and microdysgenesis
Authors: Thom M. , Sisodiya S. M. , Lin W.‐R. , Cross H. , Harding B.
Published: March 2003

Commonly identified cortical malformations in patients undergoing epilepsy surgery for intractable seizures include focal cortical dysplasia (FCD) and microdysgenesis (MD). Both are characterized by abnormalities in the cortical laminar architecture and in FCD the presence of dysplastic neurons and balloon cell glia are also observed. The aetiology and mechanisms of seizure genesis in these lesions is still questioned, as is the distinction of cellular changes that are developmental rather than a consequence of seizures. We investigated the distribution of calcium binding protein (calbindin‐CB, parvalbumin‐PV and calretinin‐CR), Neuropeptide Y and reelin positive cells in 12 cases of FCD and in 12 temporal lobectomy specimens from patients with hippocampal sclerosis with or without additional MD. The majority of FCD cases showed a reduction in PV interneurons but abnormal PV puncta around dysplastic neurons. Hypertrophic multipolar CB cells were commonly seen in FCD cases whereas smaller multipolar CB cells were present in MD. Altered NPY patterns were observed in FCD and a prominent superficial NPY plexus in some MD. Significantly higher numbers of reelin positive cells were present in layer I in MD compared with controls (P < 0.05) but were more variable in FCD with reduction of layer I reelin in some FCD cases.
Neuropathology of septic shock
Authors: Gray F. , Sharshar T. , De La Grandmaison G. Lorin , Annane D.
Published: March 2003

Introduction:  Septic shock is the most frequent cause of death in intensive care units. It is often complicated by an encephalopathy and there is increasing evidence that central autonomic nervous system (CANS) dysfunction plays a crucial role in the onset and persistance of the haemodynamic failure. However, only a few neuropathological studies are available; they are always retrospective and often disagree.

Material and methods:  Twenty consecutive patient who died from septic shock were examined and compared with eight patients who died from nonseptic shock in the same unit and five ‘normal’ controls collected from the Forensic Medicine Service.

Results and conclusion:  A variety of lesions, including microabscesses, multifocal necrotizing leukoencephalopathy, haemorrhages and disseminated intravascular coagulation, were found, and were most probably related to the biological disturbances associated with sepsis. These lesions may contribute to the ‘septic encephalopathy’. Ischaemic changes in ‘susceptible’ areas were comparable in septic shock and in nonseptic shock. In contrast, ischaemic changes in the nuclei of the CANS were significantly more severe in septic shock than in nonseptic shock. Neuronal apoptosis in these nuclei was significantly more frequent and more severe in septic shock; apoptosis did not correlate exactly with neuronal ischaemia and was associated with only mild microglial activation suggesting that circulating factors may also play a role in its causation.
Differential neuronal responses between brain nuclei after blunt head‐injury
Authors: Mitchell Y. , Pennington K. , Maxwell W. , Graham D. I.
Published: March 2003

Introduction:  Stereological evidence for loss of neurons after human blunt head‐injury is lacking. A quantitative analysis of total numbers of neurons in two different brain regions in nonhead‐injured control (n = 10) and severely head‐injured patients (n = 24) (age range 18–64) was undertaken.

Material and methods:  8 µm paraffin sections of the left and right thalami and of the left hippocampus from all patients were cut and cresyl violet stained. The neuronal size in subfields of the hippocampus, and dorsomedial, lateral and ventral thalamic nuclei was measured to determine the size of the counting box and, within this, the total number of neurons was counted. Statistical analysis used the Student's t‐test.

Results:  At 1 week, pyramidal neurons were lost from hippocampal subfields CA1 (P = 0.012), CA3 (P = 0.003) and CA4 (P = 0.002), but not from CA2. Further loss occurred at 6 months but only in CA1 (P = 0.033) and CA4 (P = 0.013). No evidence for loss of neurons from any thalamic nucleus was obtained.

Conclusions:  Loss of neurons from different nuclei of the brain after blunt head‐injury occurs both with a different timescale and to a different extent. Anecdotal evidence of damage to thalamic nuclei after head‐injury has not been supported using stereology.
Influence of ApoE genotype on cerebral amyloid angiopathy after closed head‐injury
Authors: Leclercq P. D. , Graham D. I. , Nicoll J. A. R. , Gentleman S. M.
Published: March 2003

Introduction:  Possession of an ε4 allele of the apolipoprotein E gene is a recognized genetic risk factor for Alzheimer's disease but has also been linked to traumatic brain injury, dementia pugilistica, cerebrovascular diseases and stroke.

Materials and methods:  In this study, we have combined morphological and quantitative analysis to investigate the effect of the genotype on the pathology observed after fatal closed head‐injury in a cohort of 88 patients.

Results:  Quantification of the amyloid‐β (Aβ) pathology in these cases has confirmed the original qualitative observations made by Nicoll et al. (Nat Medicine 1995) that the amount of Aβ pathology correlates with the ε4 gene dose. More striking, however, was the fact that the presence of cerebral amyloid angiopathy (CAA) was very strongly associated with the possession of the ε4 allele. Seven out of eight cases with CAA were ε4 carriers and half of them were ε4 homozygotes.

Conclusion:  Over the total HI cohort, ε4 carriers had 8.75 times more chance of developing CAA after brain trauma than non‐ε4 carriers.
Microglial colonization of the developing mouse brain: the effect of CD11b deletion
Authors: Jeetle J. K. , Hagger G. N. , Topps S. S. , Male D. K. , Rezaie P.
Published: March 2003

Introduction:  Microglia are resident mononuclear phagocytes of the central nervous system, which colonize the brain both prenatally and after birth. It is proposed that they enter the brain initially via the surrounding mesenchyme, via ventricles and later through blood vessels, but the mechanisms of entry and signals used for migration are still to be established. Previous studies have shown that ligands for some integrin adhesion molecules expressed on blood vessels in the developing nervous system (particularly ICAM‐1 and ICAM‐2 which bind CD11a/LFA‐1 and CD11b/Mac‐1), may act as potential recruiting signals for microglial precursors. This study addressed whether CD11b is influential on the migration of microglial precursors into the developing CNS.

Material and methods:  Ricinus communis agglutinin‐1 (RCA‐1) lectin histochemistry was employed to anatomically map the distribution of amoeboid and ramified microglia from embryonic day 15 (E15) to birth. Embryonic mouse brains from CD11b knockout (−/−) (n = 42), and heterozygote (+/−) (n = 52) mice generated on a C57/BL6 background (Melo et al. Cell Immunol 2000; 205: 13–23) and wild‐type (+/+) (n = 37) litter mates were fixed in Bouin's solution, processed to paraffin wax and serially sectioned at 15–40 µm. To investigate further potential signals for recruiting microglial precursors, brains were immunochemically screened for integrins CD11a, CD11b, CD18, αX, VLA‐4 and the chemokine MCP‐1.

Results:  Microscopic analysis revealed the morphological transition of microglia from predominantly amoeboid forms at E15–E16 to a flourishing population of ramified cells at E19–E20. RCA‐1 histochemistry showed no clear differences in microglial distribution or timing of colonization between CD11b (−/−) and wild‐type mice from E15 to birth. Although CD11b deletion did not influence the timing of microglial ramification, there appeared to be fewer ramified cells in (−/−) mice within comparative brain regions. This requires further quantitative morphometric analysis. Of the integrins investigated, none were restricted to microglia and only VLA‐4 and αX showed reactivity within the CNS. However, MCP‐1 was notably localized to the cortical plate within all genotypes, consistent with previous findings in human foetal CNS (Rezaie & Male. Microsc Res Tech 1999; 45: 359–382).

Conclusion:  The results suggest that CD11b has little influence on the timing or regional distribution of microglia in the developing murine CNS. It is more likely that CD11b is only one of several factors that influence the migration and differentiation of these cells.
Expression of mos in astrocytic tumours and its potential role in neoplastic progression
Authors: Perunovic B. , Athanasiou A. , Quilty R. D. , Gourgoulis V. G. , Kittas C. , Love S.
Published: March 2003

Introduction:  Mos, the product of the C‐mos gene, is a component of the mitogen‐activated protein‐kinase transduction pathway, and is involved in the control of meiosis and mitosis. High levels have been reported to cause p53‐mediated growth arrest and apoptosis. Apart from a study on lung carcinomas, there is little information about its role in human neoplasia. The aim of this study was to investigate expression of mos in astrocytic tumours and to correlate it with the accumulation of p53.

Material and methods:  We studied the expression of mos in 62 cases of supratentorial diffuse astrocytic tumours and correlated this with tumour grade, survival and accumulation of p53.

Results:  Intracytoplasmic immunopositivity for mos was found in 28 (45%) cases: 3/20 (15%) grade 2 astrocytomas, 9/20 (45%) grade 3 anaplastic astrocytomas and 16/22 (73%) glioblastomas. Immunopositivity for mos correlated significantly (P < 0.01) with tumour grade but not with p53 expression. In contrast to the findings in relation to lung carcinomas, immunopositivity for mos in astrocytic tumours did not predict recurrence‐free or overall survival time. Cytoplasmic immunostaining was observed in scattered large cortical neurons adjacent to tumours, possibly as a result of ‘stress’‐induced abortive entry into the cell cycle.

Conclusions:  The correlation of mos immunopositivity with tumour grade may reflect the expansion of more malignant mos‐positive clones. This study provides evidence that mos may be involved in the neoplastic progression of a proportion of astrocytic tumours.
The human perirhinal cortex in semantic memory: an in vivo and postmortem volumetric magnetic resonance imaging study in semantic dementia, Alzheimer's disease and matched controls
Authors: Davies R. R. , Xuereb J. H. , Hodges J. R.
Published: March 2003

Introduction:  Studies in macaque monkeys indicate that the perirhinal cortex is critical for processes analogous to human semantic memory (i.e. memory for words, objects, faces and concepts). It is selectively impaired in semantic dementia (SD), the temporal lobe variant of fronto‐temporal dementia, and less consistently in Alzheimer's disease (AD).

Materials and methods:  In vivo volumetric magnetic resonance imaging (MRI) data were collected from 30 cases (10 SD, 10 AD, 10 controls). Regions were outlined on successive scan slices and volumes calculated. Hippocampus, temporopolar, perirhinal and entorhinal cortices were measured bilaterally (using the protocol of Insausti et al. Am J Neuroradiol; 19: 23). High‐resolution MR images from six cadaver brains have also been obtained. These will further clarify the relationship between cytoarchitectonic boundaries and gyral/sulcal landmarks.

Results:  Initial analyses indicate greater atrophy of the perirhinal cortex in SD than in AD (P < 0.00002). There is also a trend towards greater atrophy of posterior than of anterior entorhinal cortex in AD vs. SD.

Conclusions:  Cortical regions of the medial temporal lobe, defined by reference to cytoarchitecture, have been measured on MRI. As predicted by primate studies, but for the first time in man, perirhinal cortex atrophy is correlated with a neuropsychologically defined syndrome of semantic memory impairment.
Astrocyte characterization in the multiple sclerosis glial scar
Authors: Holley J. E. , Gveric D. , Newcombe J. , Gutowski N. J.
Published: March 2003

Introduction:  Dense astrocytic scarring in chronic multiple sclerosis (MS) plaques inhibits tissue repair. However, at the rim of a lesion the glial scar fails to form despite the presence of reactive astrocytes. Animal studies have shown that astrocyte antigen expression varies depending on astrocyte type and location. Characterization of human astrocytes in MS tissue may identify markers relevant to the glial scar.

Materials and methods:  Astrocyte antigenic phenotype was investigated in subventricular white matter by immunocytochemistry and Western blotting. Snap‐frozen tissue from normal controls (n = 4), MS normal appearing white matter (n = 5) and lesions [acute (n = 7), subacute (n = 7) and chronic (n = 13)] was studied.

Results:  As expected, glial fibrillary acidic protein and vimentin expression was elevated in scar astrocytes. In addition there was increased expression of nestin, embryonic neural cell adhesion molecule, epidermal growth factor receptor, nerve growth factor and its receptor p75, and in a subpopulation of scar astrocytes, basic fibroblast growth factor.

Conclusion:  Changes in expression of proteins associated with development, growth factors and growth factor receptors are characteristic of the scar astrocyte phenotype in chronic MS lesions. These proteins may be of relevance to glial scar formation and tissue repair.
Efficacy of leukaemia inhibitory factor in experimental autoimmune neuritis
Authors: Laurà M. , Gregson N. A. , Smith K. , Hughes R. A. C.
Published: March 2003

Objective:  To test the efficacy of leukaemia inhibitory factor (LIF) in experimental autoimmune neuritis (EAN), an animal model of Guillain–Barrè Syndrome.

Background:  Growth factors might be promising treatment in human inflammatory neuropathy. LIF is a cytokine, which exerts neurotrophic and myotrophic properties.

Materials and methods:  EAN was induced in 24 Lewis rats by the injection of peripheral bovine myelin. At the onset of the disease they were injected in pairs on a random basis either with placebo or murine LIF 10 µg/kg. The injections continued until day 25 when they were killed. The clinical course of the disease and histological pattern of the cauda equina were examined.

Results:  The severity of the disease was slightly less in the LIF treated group and these animals also had a more rapid recovery. The main pathological features in the cauda equina of both groups were demyelination and remyelination with varying degrees of axonal degeneration, but there were no significant differences in the pathological changes between the groups.

Conclusion:  The administration of LIF showed a slight, but not significant, improvement in the clinical course of EAN, but no significant evidence on nerve histology. Further investigation of the therapeutic role of LIF would be worthwhile in view of its favourable effects in nerve regeneration.
Mitochondrial dysfunction in myofibrillar myopathy
Authors: Reimann Jens , Kunz Wolfram S. , Vielhaber Stefan , Kappes‐Horn Karin , Schröder Rolf
Published: March 2003

J. Reimann, W. S. Kunz, S. Vielhaber, K. Kappes‐Horn and R. Schröder (2003) Neuropathology and Applied Neurobiology 29, 45–51

 Mitochondrial dysfunction in myofibrillar myopathy

‘Myofibrillar myopathy’ defines a myopathic condition with focal myofibrillar destruction and accumulation of degraded myofibrillar elements. Despite the fact that a number of mutations in different genes as well as cytotoxic agents lead to the disease, abnormal accumulation of desmin is a typical, common feature. Pathological changes of mitochondrial morphology and function have been observed in animal models with intermediate filament pathology. Therefore, in the present study we tested for mitochondrial pathology in skeletal muscle of five patients with the pathohistological diagnosis of myofibrillar myopathy. Screening for large‐scale mtDNA deletions and the frequent MERRF (myoclonic epilepsy; ragged red fibres) and MELAS (mitochondrial encephalomyopathy; lactic acidosis; stroke) point mutations was negative in all patients. Histologically, all muscle biopsies showed nonspecific abnormalities of the oxidative/mitochondrial enzyme stainings (histochemistry for reduced nicotinamide adenine dinucleotide, succinic dehydrogenase, cytochrome c oxidase), only one of them had ragged red fibres and a significant number of cytochrome c oxidase‐negative fibres. Upon biochemical investigation, four of our patients showed pathologically low respiratory chain complex I activities. Only one of our patients had a pathologically low complex IV activity, while the measurements of the others were within low normal range. The single patient with pathological values for both complex I and IV was the one with the clear histological hallmarks (ragged red and cytochrome c oxidase‐negative fibres) of mitochondrial pathology. She also was the only patient with clinical signs hinting at a mitochondrial disorder. Together with data from observations in desmin‐ and plectin‐deficient mice, our results support the view that desmin intermediate filament pathology in these cases is closely linked to mitochondrial dysfunction in skeletal muscle.
Survival of infants born with Down’s syndrome: 1980–96
Authors: Leonard  , Bower  , Petterson  , Leonard
Published: March 2003

The improved life expectancy of people with Down’s syndrome as a result of the greater availability of surgery and advances in medical care has been widely documented. However, there has been no evaluation of survival in the Australian Down’s syndrome population since the 1980s. This study aimed to evaluate the changes in survival from birth in cases of Down’s syndrome notified to the Birth Defects Registry in Western Australia. Babies born with Down’s syndrome between 1980 and 1996 (inclusive) and registered with the Birth Defects Registry were studied. Survival status was obtained in several ways. Cases were stratified into three cohorts for comparison. Survival curves were constructed using the methods of Kaplan and Meier. For infants born during 1980–96, survival to 1 year is now > 91%, and 85% can expect to survive until the age of 10 years. Although survival in those with heart disease showed improvement over the period studied, overall this was still a strong predictor of mortality. Survival in Aboriginal children with Down’s syndrome was significantly poorer than in non‐Aboriginal children, mirroring the pattern in the general population. Mortality was greater in females and in those with a low birthweight. There was no statistically significant difference in the survival between those born in metropolitan and in rural areas.

There has been a considerable improvement in survival of infants born with Down’s syndrome in Western Australia. This improvement is similar to findings in recent international studies. The difference in survival between Aboriginal and non‐Aboriginal children is particularly disturbing. These findings are useful for both clinicians and families who need to plan for the long‐term care of these children.
Preterm birth research: from disillusion to the search for new mechanisms
Authors: Buekens Pierre , Klebanoff Mark
Published: March 2003

No intervention has been shown to decrease the rate of preterm birth. There was thus a need for a new research agenda. The new emphasis is on social and biological mechanisms, including the impact on stress of racism and poverty, and gene–environment interactions. New markers are also under study, and pertain mostly to infection and inflammation. The impact on preterm birth of broad contextual factors, such as universal social protection, will need to be explored further. The recent trends toward increased rates of preterm births deserve much attention. New policies and interventions to decrease medically indicated preterm births should be urgently developed and evaluated. The failure to prevent preterm deliveries has been so disappointing that there is a risk that high rates of preterm births will be seen as unavoidable. The research programme launched by March of Dimes is a timely effort to foster new enthusiasm, to test new ideas and to generate new hypotheses.
Hospital admissions during pregnancy in two urban areas of Ukraine
Authors: Little R. E. , Little A. S. , Chislovska N. , Hulchiy O. P. , Monaghan S. C. , Gladen B. C.
Published: March 2003

Hospital admissions are generally regarded as a marker of severe pregnancy complications, and a low ratio of antenatal admissions to deliveries is considered an indicator of maternal–fetal well‐being. We investigated the reasons for hospital admissions in a sample of deliveries from Ukraine, a country of the former eastern bloc. All hospitalisations were traced among 3099 women who delivered live singletons of at least 20 weeks gestation in two urban areas of Ukraine and data were abstracted from their medical records. More than a third of the women were admitted to hospital during their pregnancy, and 91% of the admissions were for a pregnancy complication, primarily threatened abortion or early labour. Median length of stay for all admissions was 12 days. The ratio of admissions to deliveries was 52 per 100. The Ukrainian ratio of hospitalisations to deliveries is notably higher than any that have been published in studies from the United States and Australia, reflecting patterns of care that stress hospital‐based treatment. This high ratio does not necessarily mean that Ukrainian women are sicker, although that may be the case. The comparison of hospitalisation to delivery ratios is meaningful only when other factors, such as resources, patterns of care, costs and access, are taken into account.
Malnutrition and susceptibility to enteroparasites: reinfection rates after mass chemotherapy
Authors: Saldiva S. R. M. , Carvalho H. B. , Castilho V. P. , Struchiner C. J. , Massad E.
Published: March 2003

The evidence that relates malnutrition to enteroparasite infections arises from studies that demonstrate the improvement of nutritional indicators after antiparasitism treatment. However, the role of malnutrition as an aggravating factor to the susceptibility to enteroparasite infections is still not fully understood. We investigated the correlation between malnutrition and enteroparasite infection after mass chemotherapy, in a poor city of São Paulo State, Brazil. The sample comprised 759 children between 1 and 10 years of age of whom 585 were followed up for a period of 1 year and periodically assessed for reinfection with enteroparasites. One year of follow‐up after mass chemotherapy demonstrated that 38% of the undernourished children were reinfected with enteroparasites, as compared with 25% of the eutrophic children (P
= 0.033). The survival multivariate analysis demonstrated that, after controlling
for the potential confounding variables, maternal literacy and per capita income
rate, malnutrition was associated with susceptibility to reinfection (P = 0.13). We demonstrate that, although maternal literacy and per capita income rate are indeed confounding variables, malnutrition contributes to an increase in the risk of enteroparasite infections.
Effects of changing risk factors on increasing asthma prevalence in southern Taiwan
Authors: Tsuang Hui‐chun A. , Su Huey‐Jen Jenny , Kao Fei‐Fei , Shih H. C.
Published: March 2003

The study sought to identify factors with consistent relationships with the prevalence of asthma and postulate causes for the increasing prevalence. Reduplication of prevalence surveys was conducted among children of similar ages (6–12 years) from the same area (Tainan City, Taiwan). A total of 7523 primary school children from 1993 and 7224 from 1997 participated in the study. The reported prevalence of diagnosed asthma increased from 6.46% in 1993 to 8.45% in 1997 (relative risk 1.31, 95% CI 1.16, 1.47). Among all environment‐ and heredity‐related factors examined, only four showed consistent relationships with childhood asthma, and all appeared to be a related hereditary condition. Dander allergy is the only factor that increased correspondingly with the prevalence of childhood asthma; therefore, it seems to be the most likely key factor responsible for the increasing trend. The investigation of the interactive effects imposed by the environment‐ (dander exposure) and heredity‐related (atopic sensitisation) factors are recommended for further studies.
Ultrasonographic and serologic studies of experimental cysticercosis in rats infected with Taenia taeniaeformis
Authors: ITO AKIRA , SAKAKIBARA YOSHIMI , MA LIANG , ASANO KAZUHITO , TAKIGUCHI MITSUYOSHI , YASUDA JUN , HASHIMOTO AKIRA
Published: March 2003

Rats experimentally infected with Taenia taeniaeformis were followed‐up until 14 weeks post inoculation with eggs (PIE) by hepatic ultrasonographic (US) image and serum antibody response analyses. Parasitic cysts could be imaged as small (2 mm in diameter) anechoic areas with or without a parenthesis‐like echogenic small line from two weeks PIE. Immunoblot analysis using antigens from oncospheres (TtO), 30‐day‐old (TtM‐30) and 300‐day‐old metacestodes (TtM‐300) revealed that: (1) these three different developmental stages showed their own unique patterns suggesting the presence of stage‐specific antigens; (2) faint IgM antibody responses to some components of TtO and TtM‐30 or TtM‐300 could be detected from one and two weeks PIE, respectively, and (3) IgG responses to some major components of both TtO and TtM‐300, and TtM‐30 were easily detected from four and five weeks PIE onwards, respectively. Both TtO and TtM (especially TtM‐300) appeared to be highly useful for detection of antibody responses in experimentally infected rats. Due to the easiness in preparation of antigens, fully developed metacestodes may be the best candidate antigens for serodiagnosis. These results strongly suggest that both US image and antibody analyses using antigens from fully developed metacestodes are useful for detection of the early stage of cysticercosis in laboratory animal model.
Role of neutrophils in innate resistance to Entamoeba histolytica liver infection in mice
Authors: VELAZQUEZ CARLOS , SHIBAYAMA‐SALAS MINEKO , AGUIRRE‐GARCIA JESUS , TSUTSUMI VICTOR , CALDERON JESUS
Published: March 2003

In order to define the role of neutrophils in the innate resistance to Entamoeba histolytica liver infection in mice, we examined the pattern of liver lesion induced by direct injection of E. histolytica trophozoites in normal mice and in neutrophil‐depleted mice. A variety of histological lesions were found, the extent of liver damage was considerably higher in the neutrophil‐depleted mice. Livers from neutrophil‐depleted mice displayed areas of liquefactive (lytic) necrosis containing a large number of amoebae and absence of neutrophils or mononuclear cells. By contrast, in the liver of normal mice, neutrophils were seen associated to E. histolytica at early stages of infection. In both mouse groups, areas of TUNEL‐positive dead hepatocytes were observed and a characteristic internucleosomal banding pattern of genomic DNA consistent with apoptosis was detected in DNA harvested from amoebic liver lesions. These data suggest that neutrophils play an important role in the mechanisms of resistance to amoebic liver infection in mice. In addition, our histological analysis suggests that E. histolytica is capable of producing liver damage in the absence of inflammatory cells.
Human antibodies to the 19 kDa C‐terminal fragment of Plasmodium falciparum merozoite surface protein 1 inhibit parasite growth in vitro
Authors: EGAN ANDRÉA F. , BURGHAUS PETRA , DRUILHE PIERRE , HOLDER ANTHONY A. , RILEY ELEANOR M.
Published: March 2003

The 19 kDa, C‐terminal fragment of the major surface protein of Plasmodium falciparum (PfMSP119) is a candidate for inclusion in a subunit malaria vaccine. In this study, we show that PfMSP119‐specific antibodies, affinity purified from malaria‐immune human serum, can: (i) compete with invasion‐inhibitory monoclonal antibodies for binding to PfMSP119 and (ii) mediate inhibition of parasite growth in vitro, in the absence of complement and mononuclear cells, at physiological antibody concentrations (100 μg/ml). Parasites expressing either the K1 or 3D7 allele of PfMSP119 were equally susceptible to inhibition of merozoite invasion, indicating that the target epitopes of inhibitory antibodies are conserved or cross‐reactive. These studies suggest that vaccines designed to induce antibodies to PfMSP119 may protect against the high levels of malaria parasitaemia which are associated with clinical disease.
Protection against Fasciola hepatica in the intestine is highly correlated with eosinophil and immunoglobulin G1 responses against newly excysted juveniles
Authors: VAN MILLIGEN FLORINE J. , CORNELISSEN JAN B.W.J. , BOKHOUT BEN A.
Published: March 2003

Rats were infected with Fasciola hepatica and challenged at regular intervals up to 38 weeks using an ex vivo gut loop, a technique developed in our laboratory. The kinetics of the observed immune responses against F. hepatica in gut tissue and serum were investigated and correlated to protection. Immunohistochemical methods were used to measure the frequency of eosinophils, immunoglobulin (Ig)E‐positive cells, and mucosal mast cells in the gut loop, and to determine whether the newly excysted juveniles were coated with IgG antibodies or surrounded by eosinophils, or both. Enzyme‐linked immunosorbent assays and a radioimmuno assay were used to measure serum antibody reactive with newly excysted juveniles. Results showed that protection was highly correlated with the frequency of eosinophils and IgE‐positive cells in the gut, but was only moderately correlated with the frequency of mucosal mast cells. Newly excysted juveniles taken from rats exhibiting high levels of protection were always coated with IgG antibodies and surrounded by eosinophils. Protection was highly correlated with titers of serum IgG1 antibodies directed against newly excysted juveniles, but was only weakly correlated with titers of serum IgA and IgE antibodies. Because protection was highly correlated with IgG1 in gut tissue and serum, and with eosinophils in gut tissue, we suggest that IgG1 and eosinophils are important in protecting rats against F. hepatica.
Secondary alveolar echinococcosis in lymphotoxin‐α and tumour necrosis factor‐α deficient mice: exacerbation of Echinococcus multilocularis larval growth is associated with cellular changes in the periparasitic granuloma
Authors: Amiot Franck , Vuong Phat , Defontaines Marie , Pater Clotilde , Dautry François , Liance Martine
Published: March 2003

The availability of mice carrying a deletion of LT‐α and tumour necrosis factor (TNF)‐α genes enabled us to investigate the role of the TNF during alveolar echinococcosis. We compared the growth rate of Echinococcus multilocularis in LT‐αTNF‐α +/+ mice to that of mice having either no or only one LT‐αTNF‐α functionnal allele. LT‐αTNF‐α−/− mice harboured a significantly higher parasite burden than did the other two populations at 5, 10, and 15 weeks of infection, and they did not survive thereafter. Liver metacestodes removed from these mice were alive and the dehydrogenase activities of peritoneal metacestodes were decreased. Liver lesions regressed in most wild‐type mice. Indeed, dead parasites were cordoned by granulomas containing numerous macrophages and lymphocytes leading to focal liver fibrosis at an early stage of infection. In contrast, most of LT‐αTNF‐α−/− mice harboured metacestodes interspersed with leucocytes, realising purulent abscesses with secondary extensive irregular fibrosis at a late stage of infection. Heterozygous mice had behavioural characteristics intermediate between homozygous mutants and wild‐type mice. Levels of E. multilocularis‐specific delayed‐type hypersensitivity and serum antibodies were slightly decreased in LT‐αTNF‐α−/− mice. This study shows that TNF‐α and/or LT‐α genes play an essential role in the immune protection mechanisms against E. multilocularis at the site of infection.
Immunotherapy with live BCG plus heat killed Leishmania induces a T helper 1‐like response in American cutaneous leishmaniasis patients
Authors: Cabrera Maira , M.blackwell Jenefer , Castes Marianella , Trujillo Dinorah , Convit Jacinto , Shaw Marie‐Anne
Published: March 2003

Previous work has shown that American cutaneous leishmaniasis (ACL) patients treated with viable BCG plus heat killed promastigotes of Leishmania amazonensis show the same rate of cure as patients receiving conventional chemotherapy. The treatment is safe and economical, but the immunological correlates of cure have not been examined. In the present study, T cell responses have been analysed in 43 ACL patients, including patient groups sampled before and after therapy, and in 10 endemic controls. Lymphocyte proliferation, interferon (IFN)‐γ and interleukin (IL)‐5 responses to crude antigen (L. amazonensis, MEL; Mycobacterium tuberculosis PPD; M. bovis BCG) stimulation, and serum IL‐5 levels, were analysed. In endemic volunteers, proliferative responses to BCG were high and IFN‐γ responses low. In contrast, localized cutaneous (LCL) and mucocutaneous (MCL) patients showed low proliferative and high IFN‐γ responses to BCG. Treatment enhanced the IFN‐γ response and further decreased the proliferative response to BCG, especially in MCL patients. LCL and MCL patients showed an increase in proliferative and IFN‐γ responses to MEL with treatment, but the response was not exaggerated in MCL patients, either before or after treatment, compared to LCL patients. IL‐5 production was low in T cell assays, and > 62% of untreated patients had very low serum IL‐5 levels. There were no significant changes in serum IL‐5 with treatment. Overall results show enhanced antigen‐specific IFN‐γ responses to the two components of the immunotherapy, live M. bovis BCG and heat killed L. amazonensis, which is consistent with a shift in balance of T cell response towards a T helper 1 response and clinical cure mediated by IFN‐γ.
Immunogenicity and immunolocalization of the 22.6 kDa antigen of Schistosoma japonicum
Authors: Li Yuesheng , Auliff Alyson , Jones Malcolm K. , Yi Xinyuan , McManus Donald P.
Published: March 2003

The 22.6 kDa tegumental‐associated antigens of Schistosoma mansoni (Sm22.6) and Schistosoma japonicum (Sj22.6) are of recognized interest in schistosomiasis vaccine development, although no direct vaccination/challenge experiments using either Sm22.6 or Sj22.6 had been previously described. We report that Escherichia coli‐expressed reSj22.6 failed to protect mice or water buffaloes against subsequent challenge with S. japonicum cercariae. This was despite the fact that specific IgG (buffaloes) and IgG and IgE (CBA mice) antibodies were generated against the 22.6 kDa molecule, observations consistent with some of our earlier findings. We could find no evidence from immunolocalization studies that Sj22.6 is expressed or exposed on the surface of the adult parasite since it appears to be restricted to the apical cytoplasm of the tegument and is not associated with the apical or basal membrane or any membrane‐bound structures in the apical cytoplasm. Nevertheless, Sj22.6 must be released to the immune system during the course of infection because specific anti‐Sj22.6 IgG antibodies were present in the sera of nonvaccinated but challenged mice. We conclude that it may be necessary to produce reSj22.6 in a more relevant expression system, such as baculovirus, to further establish its vaccine potential and that detailed immunochemical and immunolocalization studies of early developmental stages may be necessary to determine how Sj22.6 is released or shed in S. japonicum infections.
Human Bancroftian filariasis: loss of patent microfilaraemia is not associated with production of antibodies to microfilarial sheath
Authors: Satapathy A.K. , Sahoo P.K. , Babu Geddam J.J. , Mohanty M.C. , Ravindran B.
Published: March 2003

Antisheath antibodies have been incriminated in elimination of circulating microfilariae in human filariasis since a very significant inverse association has been consistently demonstrated between the two parameters. An attempt was made in the present study to seek empirical proof for the above proposal. Two cohorts of 43 and 73 microfilariae (mf) carriers were examined after 13 and 10 years, respectively, for mf as well as antisheath antibodies. The first cohort was also examined for the presence of circulating filarial antigen (CFA). Of the 43 mf carriers examined after 13 years, 62·8% were free of circulating mf although only 3·7% of them had demonstrable antisheath antibodies. Approximately 93% of this cohort (with or without current microfilaraemia) tested positive for CFA after 13 years indicating continued presence of adult filarial worms in the host after loss of mf in circulation. When the second cohort of 73 mf carriers were examined after 10 years, 30 were found to be amicrofilaraemic and only 6·66% of them had demonstrable antisheath antibodies. We conclude that, in human Bancroftian filariasis, elimination of circulating microfilariae may not be mediated by antibodies to microfilarial sheath.
Protective immunity to Schistosoma japonicum infection depends on the balance of T helper cytokine responses in mice vaccinated with γ‐irradiated cercariae
Authors: Osada Y. , Janecharut Tuenta , Hata H. , Mahakunkij‐Charoen Yuvadee , Chen X.‐W. , Nara T. , Kita K. , Kojima S.
Published: March 2003

Although the strain difference in protection of mice to Schistosoma mansoni infection has been described, limited information is available in the case of Schistosoma japonicum. In the present study, we compared the protective immunity to S. japonicum infection and cytokine production in various strains of mice vaccinated with γ‐irradiated cercariae. A significant reduction in worm recovery was observed in male and female mice of DBA/2 at a 6‐week interval between vaccination and a challenge infection, whereas vaccinated mice of C57BL/6, C57BL/10, (C57BL/6 × DBA/2) F1 (B6D2F1) and (C57BL/10 × DBA/2) F1 (B10D2F1) showed no detectable level of protection. No sex‐linked difference in development of resistance was observed in any of the strains so far examined. Vaccination with γ‐irradiated cercariae twice with a 3‐week interval also induced significant protection against a challenge infection in DBA/2 but not in BALB/c or C57BL/6 strains. Further studies demonstrated that spleen cells of vaccinated C57BL/6 mice produced lower levels of IFN‐γ compared to the cells of vaccinated BALB/c and DBA/2. On the other hand, production of IL‐10 by spleen cells was relatively higher in BALB/c mice than in the other two strains. Macrophages that had been stimulated with spleen cell culture supernatants derived from vaccinated DBA/2 damaged schistosomula more effectively than cells stimulated with supernatants derived from the other strains. These results suggest that different levels of protection observed among strains of mice depend on the balance of cytokine responses which consequently activate or suppress macrophage‐mediated damage to schistosomula.
Transmission intensity and human immune responses to lymphatic filariasis
Authors: King Christopher L.
Published: March 2003

Our understanding of how the host immune response influences the risk of developing disease has changed dramatically over the past decade. Previously, the spectrum of disease associated with lymphatic filariasis was largely attributed to the nature of the host immune response. Now, we appreciate that the duration and intensity of infection and possibly the direct influence of parasite‐derived molecules also determine the risk of disease. Individuals chronically infected with lymphatic filariasis generally have an impaired lymphocyte proliferation response to filarial antigens and favour Th2‐type cytokine responses. This ability to down‐modulate the host immune response may help protect the host from disease. Defects in antigen‐presenting cell (APC) function appear to participate in this acquired immune hyporesponsiveness, although the mechanisms as to how this occurs are poorly understood. Here, we present evidence that repeated exposure to infective stage larvae and their secreted products may stimulate basophils and mast cells to related products that may impair APC function.
Fasciola hepatica cathepsin L cysteine proteinase suppresses Bordetella pertussis‐specific interferon‐γ production in vivo
Authors: O'Neill Sandra M. , Mills Kingston H.G. , Dalton John P.
Published: March 2003

We have previously demonstrated that Fasciola hepatica infection significantly reduced Bordetella pertussis‐specific interferon (IFN)‐γ production in mice coinfected with B. pertussis or immunized with a pertussis whole cell vaccine (Pw). In the present study, we have identified parasite molecules capable of mimicking this suppressive effect of F. hepatica. Parenteral injection of mice with culture medium in which adult F. hepatica were maintained (excretory/secretory, ES, products) suppressed B. pertussis‐specific IFN‐γ production in mice immunized with Pw. The suppressive effect of ES was abrogated by coinjecting ES with the cysteine proteinase inhibitor, Z‐Phe‐Ala‐diazomethylketone. Furthermore, purified cathepsin L proteinase (FheCL), a major component of ES products, was capable of suppressing IFN‐γ production. The suppressive effect of FheCL was attenuated in interleukin (IL)‐4 defective (IL‐4−/–) mice. Therefore, FheCL released by F. hepatica is involved in the suppression of Th1 immune responses and this suppression may be dependent upon IL‐4.
Human T and B cell epitope mapping of Taenia solium paramyosin
Authors: Vázquez‐Talavera José , Solís Carlos F. , Medina‐Escutia Edith , López Zoila Morales , Proaño Jefferson , Correa Dolores , Laclette Juan Pedro
Published: March 2003

Taenia solium paramyosin is an immunodominant antigen in human and porcine cysticercosis that has shown promise as a vaccine candidate against schistosomiasis and some filariasis. There are few studies to identify the immunologically relevant regions of paramyosin. In this work, we characterize the humoral and cellular response of neurocysticercotic patients against T. solium paramyosin. Western blots using different recombinant fragments of T. solium paramyosin, showed that the sera from neurocysticercotic patients were strongly reactive against the carboxyl end region, with poor recognition of the central and amino regions. In contrast, the cellular immune response of patients did not show preferential recognition of any region of paramyosin.
In vitro indomethacin administration upregulates interleukin‐12 production and polarizes the immune response towards a Th1 type in susceptible BALB/c mice infected with Leishmania mexicana
Authors: Pérez‐Santos José Luis Martín , Talamás‐Rohana Patricia
Published: March 2003

The immune response in Leishmania infected BALB/c mice is associated with a Th2 type cellular response, which has been characterized by the absence of interleukin (IL)‐12, interferon (IFN)‐γ, and nitric oxide (NO) and the presence of IL‐10 and IL‐4. Prostaglandins (PGs) can modulate the immune response inhibiting the development of Th1 response and enhancing the development of Th2 response. We investigated the production of PGs and their effects on cytokine and NO production by spleen cells from Leishmania mexicana infected BALB/c and C57BL/6 mice. Increased production of PGs was noted as early as 1 week after infection in BALB/c mice, whereas in infected C57BL/6 mice PGs were not detected. In vitro administration of indomethacin (INDO), a specific inhibitor of PGs synthesis, reduced PGs production at normal levels, and increased IL‐12, IFN‐γ, and NO production in infected BALB/c mice. Whereas, IL‐10 and IL‐4 were not affected. Moreover, INDO did not modulate cytokine and NO production in infected C57BL/6. INDO addition induced the intracellular killing of parasites in infected BALB/c mice. Together, these results suggest that suppression of PGs by INDO may promote the development of a protective Th1 type response in susceptible mice by a mechanism, which involves an enhancement of IL‐12, IFN‐γ and NO production. These findings were confirmed by smaller lesions in BALB/c mice, when treated with INDO.
Natural resistance of 129/SvJ mice to Strongyloides venezuelensis infection
Authors: Nakamura‐Uchiyama Fukumi , Nagao Toshikage , Obara Akio , Ishiwata Kenji , Nawa Yukifumi
Published: March 2003

The susceptibility of 129/SvJ mice to infection with Strongyloides venezuelensis was compared with that of C57BL/6 mice. After a primary infection, daily egg output in faeces (EPG) from 129/SvJ mice was lower and terminated earlier than that from C57BL/6 mice. Adult worm recovery from the small intestine of 129/SvJ mice on day 7 was also lower than that of C57BL/6 mice. When the numbers of larvae recovered from the lungs were examined on days 2, 3 and 4 after a primary infection, they were comparable between the two strains. On the other hand, when an equal number of larvae recovered from the lungs of each strain on day 3 were implanted orally into homologous strain mice, the magnitude of EPG and the number of adult worms in the small intestine on day 5 after implantation were significantly lower in 129/SvJ than in C57BL/6 mice. The number of mucosal mast cells in the jejunum was not significantly different between 129/SvJ and C57BL/6 naive mice. Total chondroitin sulphate concentration in the gut washings obtained from naive mice was significantly higher in 129/SvJ (11·34 ± 9·48) than in C57BL/6 mice (1·09 ± 0·77, P < 0·05). These results indicate that the natural resistance of 129SvJ mice to S. venezuelensis infection is expressed at the intestine, probably due to higher concentration of chondroitin sulphate, which prevents establishment of S. venezuelensis.