The effect of neonatal BCG vaccination on atopy and asthma at age 7 to 14 years: an historical cohort study in a community with a very low prevalence of tuberculosis infection and a high prevalence of atopic disease

BACKGROUND: There are conflicting reports on the effect of BCG vaccination on the subsequent development of atopy and asthma. There are no data on the effects of neonatal BCG vaccination on cytokine responses of lymphocytes that are exposed in vitro to allergens. OBJECTIVES: We sought to test the hypothesis that neonatal BCG vaccination or, alternatively, evidence of an immunologic memory of this vaccination is associated with a reduced prevalence of allergic sensitization, asthma, eczema, and hay fever during childhood. METHODS: An historical cohort study was conducted among 7- to 14-year-old children who were born in 2 districts in Sydney, Australia, and whose mothers were born in southeast Asia. One district had routinely administered BCG vaccination to infants born to overseas-born mothers and the other had not. Eligible subjects were identified from birth registers. Consenting subjects completed questionnaires, performed spirometric and airway hyperresponsiveness testing, and had allergen skin prick testing and tuberculin skin testing. Blood was collected to measure total serum IgE levels and for in vitro lymphocyte culture in the presence of an extract of house dust mite, the dominant allergen in this region, and purified protein derivative of Mycobacterium tuberculosis (tuberculin). IL-4, IL-5, IL-10, and IFN-gamma were measured in the culture supernatant. RESULTS: The cohort included 309 BCG-vaccinated subjects and 442 non-BCG-vaccinated subjects. BCG-vaccinated subjects did not have a lower rate of allergic sensitization than nonvaccinated subjects. However, among the subgroup of subjects with a family history of rhinitis or eczema, BCG vaccination was associated with a lower prevalence of current asthma (defined as recent wheezing plus airway hyperresponsiveness; relative risk, 0.46; 95% CI, 0.22-0.95). BCG vaccination was also associated with lower levels of allergen-stimulated IL-10 production in vitro. Among the BCG-vaccinated subjects, the 44 (14.3%) who had tuberculin skin test reaction sizes of 5 mm or greater and the 31 (18.3%) who demonstrated an in vitro IFN-gamma response to purified protein derivative of M tuberculosis did not have lower rates of allergic sensitization and, overall, did not have a lower prevalence of allergic disease than tuberculin skin test or IFN-gamma nonreactors. CONCLUSION: We conclude that neonatal BCG vaccination has an effect on T-cell allergen responsiveness 7 to 14 years after vaccination and that among a subgroup of subjects with an inherited predisposition to allergic disease, this is associated with clinically relevant beneficial effects. The findings of this study encourage the view that external influences on the immune system in the neonatal period have consequences that extend into later childhood and influence the expression of asthma. Genetic factors are likely to modify the effect of those external factors.     

Collision tumour of the oesophagus: a challenge for histological diagnosis.

An unusual case of mantle cell lymphoma metastasising to squamous cell carcinoma of the oesophagus, in a 62 year old Chinese man, is reported. A histological diagnosis based on examination of a small endoscopic biopsy specimen, in the absence of detailed clinical information, may be difficult, as the lymphoma component can be mistaken for reactive lymphoid infiltrate which is sometimes present adjacent to squamous cell carcinoma. Correlation with the clinical history, careful assessment of the subtle histological changes, and use of ancillary methods such as immunohistochemistry are most helpful in making the correct diagnosis. This case also illustrates further the possible occurrence of lymphomatous infiltrates surrounding other lesions in patients with a previous or concurrent history of lymphoma.     

Adrenal pseudocysts: Evidence of their posthemorrhagic nature

Hemorrhagic adrenal pseudocysts are uncommon nonneoplastic lesions that have been reported as secondary to intraparenchymal hemorrhage or alternatively related to endothelial (vascular) cysts. Ultrastructural and immunohistochemical evidence in support of the latter has been presented, but the exact nature of hemorrhagic adrenal pseudocysts remains poorly defined. We evaluated six surgical specimens of hemorrhagic adrenal pseudocysts using immunohistochemical staining for CD31 and CD34, as well as conventional histochemistry. All six cases had hemorrhagic contents within a wall of variable thickness possessing focal areas of linear, disrupted elastin, and smooth muscle. Three cases demonstrated extensive thrombosis with organization, including papillary endothelial hyperplasia, simulating angiosarcoma. In these cases, CD31 and CD34 staining decorated areas of papillary endothelial hyperplasia as well as foci of the internal cyst lining, whereas the other cases were negative for both antibodies. Of interest is the history of FNA prior to surgical resection in three cases of hemorrhagic adrenal pseudocysts, two of which showed papillary endothelial hyperplasia. The presence of papillary endothelial hyperplasia and our immunohistochemical findings support, the conclusion that adrenal pseudocysts are posthemorrhagic and derive from vascular disruption. Furthermore, FNA or other interventional studies may be associated with papillary endothelial hyperplasia in hemorrhagic adrenal pseudocysts.     

Y chromosome microdeletions, in azoospermic or near-azoospermic subjects, are located in the AZFc (DAZ) subregion

Submicroscopic deletions of the Y chromosome and polymorphisms of the androgen receptor (AR) gene in the X chromosome have been observed in men with defective spermatogenesis. To further define the subregions/genes in the Y chromosome causing male infertility and its relationship to polymorphisms of the AR polyglutamine tract, we screened the genomic DNA of 202 subfertile males and 101 healthy fertile controls of predominantly Chinese ethnic origin. Y microdeletions were examined with 16 sequence-tagged site (STS) probes, including the RBM and DAZ genes, spanning the AZFb and AZFc subregions of Yq11, and related to the size of trinucleotide repeat encoding the AR polyglutamine tract. Y microdeletions were detected and confirmed in three out of 44 (6.8%) of azoospermic and three out of 86 (3.5%) severely oligozoospermic patients. No deletions were detected in any of the patients with sperm counts of >0.5 x 10(6)/ml, nor in any of the 101 fertile controls. All six affected patients had almost contiguous Y microdeletions spanning the entire AZFc region including the DAZ gene. The AZFb region, containing the RBM1 gene, was intact in five of the six subjects. Y deletions were not found in those with long AR polyglutamine tracts. Our study, the first in a Chinese population, suggest a cause and effect relationship between Y microdeletions in the AZFc region (possibly DAZ), and azoospermia or near-azoospermia. Y microdeletions and long AR polyglutamine tracts appear to be independent contributors to male infertility.      

Clinicopathologic significance of genetic alterations in hepatocellular carcinoma

Hepatocarcinogenesis may involve multiple mutations with distinctive pathogenetic and clinicopathologic significance. To test this hypothesis, 68 cases of hepatocellular carcinoma (HCC) were studied prospectively for genetic-clinicopathologic correlation. Ten pathologic characteristics were evaluated. TP53 (alias p53) gene mutation was studied by a polymerase chain reaction (PCR)-single-strand conformation polymorphism-sequencing; CDKN2B (alias p15) and CDKN2A (alias p16) gene methylation by methylation-specific PCR; and genetic imbalances by comparative genomic hybridization (CGH). TP53 gene mutations occurred in 25% of cases, more than half being codon 249 G to T transversion. Methylation of CDKN2A was frequent (61.7%); of CDKN2B, rare (5.9%). The CGH analysis showed a median of nine aberrations per case, with amplifications more frequent than deletions. Isochromosomes might be involved in about 25% of cases. Amplifications of 1q and 8q were most frequent. Clinicopathologic correlations showed that CDKN2A methylation was significantly associated with tumors arising in cirrhotic livers; amplifications of 17q was significant in multiple parameters of tumor invasiveness (size, venous invasion, poor cellular differentiation, microsatellite formation); other amplifications (1q, 6p, 10p, and 20p) were also significant in tumor invasion; and deletions (at 1p, 11q, 4q, and 14q) were significant in tumor growth. Consistent patterns of genetic alterations were defined in HCC, which might represent distinctive pathways in hepatocarcinogenesis.     

"Waste" follicular aspirate from fertility treatment--a potential source of human germline stem cells?

Fertility clinics worldwide routinely produce a large volume of 'waste' follicular aspirate, which is potentially an abundant source of immature ovarian follicles. Current attempts to cultivate these further in vitro to yield viable mature oocytes for fertility treatment have not yet achieved much success. Instead, recent lines of evidence have emerged that are suggestive of a potential stem cell niche within such immature ovarian follicles. The recent discovery of follicular renewal and putative germ-line stem cells within the postnatal mammalian ovary shook the foundations of reproductive biology by challenging the established dogma that mammalian females lose the capacity for germ cell renewal during fetal life, such that a fixed reserve of germ cells (oocytes) enclosed within follicles is endowed at birth. More intriguingly, another recent study in the Drosophila model provided compelling evidence that somatic progenies (nurse cells) of germ-line stem cells had the ability to revert back to the stem-cell-like state. This introduces the exciting possibility that within the mammalian ovarian follicle, similar somatic progenies of germ-line stem cells may also possess a greater intrinsic ability to revert back into functional stem cells. If this is the case, then a favored candidate would be the cumulus/granulosa of immature ovarian follicles, since such cells are true homologues of nurse cells found within the Drosophila ovary. The successful elucidation of a human germ-line stem cell niche within immature ovarian follicles is likely to have huge ramifications in stem cell biology and regenerative medicine.     

Endometrial and subendometrial blood flow measured during early luteal phase by three-dimensional power Doppler ultrasound in excessive ovarian responders

BACKGROUND: Impaired implantation in assisted reproduction cycles with high serum estradiol (E(2)) concentrations may be related to suboptimal endometrial perfusion. Endometrial and subendometrial blood flow were compared between excessive responders (serum E(2) on the day of HCG >20 000 pmol/l) and moderate responders (E(2) < or =20 000 pmol/l). METHODS: Three-dimensional (3D) ultrasound examination with power Doppler was performed 2, 4 and 7 days after HCG in 32 patients who did not have embryo transfer in order to measure endometrial thickness, pulsatility index (PI)/resistance index (RI) of uterine vessels, and endometrial volume, vascularization index (VI)/flow index (FI)/vascularization flow index (VFI) of endometrial and subendometrial regions. RESULTS: Excessive responders tended to have lower endometrial and subendometrial VI/VFI on HCG +2 and more absent endometrial/subendometrial blood flow. They had significantly higher endometrial FI and subendometrial VFI than moderate responders on HCG +7. Only in the excessive responder group, uterine PI/RI declined significantly from HCG +2 to HCG +7 and endometrial VI/VFI increased significantly from HCG +4 to HCG +7. CONCLUSION: Changes in uterine Doppler flow indices, and endometrial and subendometrial 3D power Doppler flow indices during the early luteal phase were significantly different between moderate and excessive responders.     

Neural progenitor cells lack immunogenicity and resist destruction as allografts

Multipotent, self-renewing stem and progenitor cells isolated from the mammalian central nervous system (CNS) have been shown to survive as allografts following transplantation to sites throughout the neuraxis. However, studies of this type shed little light upon the immunologic properties of the cells themselves, primarily because little is learned about the intrinsic immunogenic properties of a cell when it is grafted into an immune-privileged site. We have therefore investigated the immunogenic and antigenic properties of CNS progenitor cells by grafting them into a conventional (i.e., non-immune-privileged) site, namely, beneath the kidney capsule. Our results indicate that allogeneic CNS progenitor cells survive at least 4 weeks in a conventional site, during which time they neither sensitize their hosts nor express detectable levels of major histocompatibility complex (MHC) class I or II. These in vivo data are in accord with flow cytometric results showing that CNS progenitor cells do not express MHC class I or class II, either at baseline or upon differentiation in 10% serum. Exposure to interferon gamma, however, reversibly upregulates expression of these key transplantation antigens. Together, these results reveal CNS progenitor cells to possess inherent immune privilege. Since CNS progenitor cell allografts were rejected beneath the kidney capsule following specific sensitization of the host, CNS progenitor cells were able to display alloantigens, albeit not in an immunogenic form.     

Rat self administration of ethanol: Enhancement by darkness and exogenous melatonin

Using an FT 60 schedule, rats on 100% free feeding tested in the dark phase of a 12:12 light-dark cycle were trained to self-administer ethanol intravenously. The effect was dose-dependent with 20% ethanol being the preferred dose as measured by the number of infusions. Daily administration of 1.5 mg/kg melatonin significantly increased ethanol self-injection in the dark but not in the light. The time of day of testing and/or drug administration may be an important variable in studies on self-administration of drugs. Testing in the dark may eliminate the need for reducing body weight when inducing self-administration of ethanol.     

Three-dimensional pseudospectral modelling of cardiac propagation in an inhomogeneous anisotropic tissue

Various investigators have used the monodomain model to study cardiac propagation behaviour. In many cases, the governing non-linear parabolic equation is solved using the finite-difference method. An adequate discretisation of cardiac tissue with realistic dimensions, however, often leads to a large model size that is computationally demanding. Recently, it has been demonstrated, for a two-dimensional homogeneous monodomain, that the Chebyshev pseudospectral method can offer higher computational efficiency than the finite-difference technique. Here, an extension of the pseudospectral approach to a three-dimensional inhomogeneous case with fibre rotation is presented. The unknown transmembrane potential is expanded in terms of Chebyshev polynomial trial functions, and the monodomain equation is enforced at the Gauss-Lobatto node points. The forward Euler technique is used to advance the solution in time. Numerical results are presented that demonstrate that the Chebyshev pseudospectral method offered an even larger improvement in computational performance over the finite-difference method in the three-dimensional case. Specifically, the pseudospectral method allowed the number of nodes to be reduced by ≈85 times, while the same solution accuracy was maintained. Depending on the model size, simulations were performed with ≈18–41 times less memory and ≈99–169 times less CPU time.