基于互信息的医学图像配准实验

基于互信息的配准方法，包括互信息和归一化互信息方法，是目前医学图像配准中无创、自动且精度很高的一种方法。已经被广泛应用。但是在其目标函数中存在着一定程度的幅值振荡现象。特别是在单模态图像配准中。我们研究发现，产生这种振荡的原因除了插值赝像外，还有由配准过程中图像重叠部分发生变化而引起的熵的变化不确定性。由插值赝像所带来的振荡基本上可以被消除掉；由熵的变化不确定性所带来的振荡很难被消除，但是这种振荡作用在归一化互信息中影响不大。归一化互信息比互信息具有更高的稳健性，适合于更广的应用范围。     

Immunological efficacy of a three-dose schedule of hepatitis A vaccine in HIV-infected adults: HEPAVAC study

BACKGROUND: The immunogenicity of vaccines, including vaccine against hepatitis A virus (HAV), is impaired in patients with HIV infection, requiring revised immunization regimens. METHODS: We evaluated the immunological efficacy and safety of a 3-dose schedule of hepatitis A vaccine in HIV-infected adults. HAV-seronegative HIV-infected adults were randomized to receive either 3 doses of 1440 UI of hepatitis A vaccine (HAVRIX; GlaxoSmithKline, Marly le Roi, France) at weeks 0, 4, and 24 (46 patients) or 2 doses 24 weeks apart (49 patients). RESULTS: At week 28, seroconversion, defined as an anti-HAV antibody >or=20 mIU/mL, occurred in 82.6% and 69.4% of patients in the 3-dose and the 2-dose group, respectively (P = 0.13, intent-to-treat analysis, missing data = nonresponder), and in 88.4% and 72.3% of patients in the 3-dose and the 2-dose group, respectively (P = 0.06, observed analysis). Only 37.9% of patients experienced seroconversion after 1 vaccine dose (intent-to-treat analysis). Anti-HAV antibody geometric mean titers were 323 and 132 mIU/mL in the 3-dose group and 138 and 67 mIU/mL in the 2-dose group, respectively, 28 (P = 0.03) and 72 weeks (P = 0.05) after the first vaccine dose. There were no serious adverse events associated with the vaccine. Multivariate analysis showed no treatment group effect but indicated that absence of tobacco smoking (odds ratio = 2.92, 95% confidence interval: 1.07 to 7.97; P = 0.04) was an independent predictor of response to HAV vaccine. CONCLUSIONS: In HIV-infected adults, immunogenicity of hepatitis A vaccine is poor. Three doses of vaccine were safe and increased antibody titers.     

Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: a retrospective study of 61 cases

Purpose To evaluate lymphangiogenesis in patients with breast carcinoma, explore the underlying mechanism, and study the relationship between lymphangiogenesis and progression of breast carcinoma. Methods Sixty-one cases of breast carcinoma with complete clinical and pathological data were analyzed. Using an anti-podoplanin monoclonal antibody, an immunohistochemical study was made of all specimens to detect lymphatic vessel density (LVD) and to investigate its clinicopathological and prognostic value. VEGF-C and VEGF-D were observed by RT-PCR and immunostaining to investigate their clinicopathological and prognostic values and their relationship with lymphangiogenesis. Results LVD in breast carcinoma (6.28 ± 3.73) was significantly higher than in benign mammary lesions (0.50 ± 1.27), P < 0.01 and was significantly associated with lymphatic metastasis and high TNM stage, P < 0.01. The level of VEGF-C and VEGF-D expression was also significantly higher in breast carcinomas than in benign mammary lesions, P < 0.01. LVD increased significantly with higher expression of VEGF-C and VEGF-D, P < 0.01. Patients with high expression of VEGF-C and VEGF-D were observed to be more likely to have a bad outcome, P < 0.05. Conclusions Lymphangiogenesis was significantly associated with lymph node metastasis, high TNM, and poor outcome in breast carcinoma. LVD may serve as a predictor of lymph node metastasis and a prognostic factor in breast carcinoma. VEGF-C and VEGF-D play an important role in lymphangiogenesis making the carcinoma more aggressive and leading to a poor prognosis.     

The common variants of E-selectin gene in Graves' disease

Adhesion molecules are involved in cell invasion in autoimmune thyroid disease. It was also reported that patients with untreated Graves' disease (GD) had high serum level of soluble form of E-selectin (sE-selectin), the concentration of which correlated with the activity of the disease. The aim of the present study was to elucidate whether the common variants in E-selectin gene (SELE) were associated with the development of GD. Six tagSNPs within SELE were studied in 297 patients with GD and 208 healthy subjects in Chinese population. Our data showed that common SELE variants were associated with GD (P=0.012-0.036). Haplotype analysis of the single nucleotide polymorphisms revealed an association of a haplotype ATAACC with GD (P=0.005). Furthermore, quantitative trait analysis showed a significant association of SELE haplotype with sE-selectin levels (P=0.0438). This study therefore could provide us to a certain degree the insight that common SELE variants may be associated with susceptibility to GD in Chinese population, though the limitation of sample size and multiple test problems exists.     

Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas

A number of recent reports have demonstrated that only CD133-positive cancer cells of glioblastoma multiforme (GBM) have tumor-initiating potential. These findings raise an attractive hypothesis that GBMs can be cured by eradicating CD133-positive cancer stem cells (CSCs), which are a small portion of GBM cells. However, as GBMs are known to possess various genetic alterations, GBMs might harbor heterogeneous CSCs with different genetic alterations. Here, we compared the clinical characteristics of two GBM patient groups divided according to CD133-positive cell ratios. The CD133-low GBMs showed more invasive growth and gene expression profiles characteristic of mesenchymal or proliferative subtypes, whereas the CD133-high GBMs showed features of cortical and well-demarcated tumors and gene expressions typical of proneuronal subtype. Both CD133-positive and CD133-negative cells purified from four out of six GBM patients produced typical GBM tumor masses in NOD-SCID brains, whereas brain mass from CD133-negative cells showed more proliferative and angiogenic features compared to that from CD133-positive cells. Our results suggest, in contrast to previous reports that only CD133-positive cells of GBMs can initiate tumor formation in vivo CD133-negative cells also possess tumor-initiating potential, which is indicative of complexity in the identification of cancer cells for therapeutic targeting.     

Galactose residues on the lipooligosaccharide of Moraxella catarrhalis 26404 form the epitope recognized by the bactericidal antiserum from conjugate vaccination

Lipooligosaccharide (LOS) from Moraxella catarrhalis has the potential to elicit bactericidal antibodies against the pathogen. We generated LOS-based conjugate vaccines that elicited bactericidal antibodies in animal models. However, epitopes on the LOS recognized by the functional anti-LOS antibodies remain unidentified. In this study, a mutant strain, D4, which lost the recognition by a bactericidal anti-LOS rabbit serum in Western blotting was generated from a serotype C strain 26404 by random transposon mutagenesis. Sequence analysis revealed there was an insertion of a kanamycin resistance gene in the lgt2 gene of D4, which encodes beta(1-4)-galactosyltransferase. An isogenic lgt2 mutant, 26404lgt2, was constructed. Structural analysis indicated that the mutant strain produced a truncated LOS lacking terminal galactoses from 4- and 6-linked oligosaccharide chains of strain 26404. Further studies showed that the antiserum lost the recognition of both mutant cells and LOSs in Western blotting, an enzyme-linked immunosorbent assay (ELISA), or a flow cytometry assay. The antiserum also lost the ability to kill the mutant strain in a bactericidal assay, whereas it showed a bactericidal titer of 1:80 to strain 26404. In an inhibition ELISA, d-(+)-galactose or 26404lgt2 LOS showed no inhibition. However, the 26404 LOS and a serotype A O35E LOS with terminal galactoses on its 6-linked oligosaccharide chain showed >90% inhibition, while a serotype B 26397 LOS showed >60% inhibition. These studies suggest that the terminal alpha-Gal-(1-->4)-beta-Gal on the 6-linked oligosaccharide chain of 26404 LOS plays a critical role in forming the epitope recognized by the bactericidal antiserum induced by immunization with our conjugate vaccine.     

The sodium-activated potassium channel Slack is modulated by hypercapnia and acidosis

Slack (Slo 2.2), a member of the Slo potassium channel family, is activated by both voltage and cytosolic factors, such as Na(+) ([Na(+)](i)) and Cl(-) ([Cl(-)](i)). Since the Slo family is known to play a role in hypoxia, and since hypoxia/ischemia is associated with an increase in H(+) and CO(2) intracellularly, we hypothesized that the Slack channel may be affected by changes in intracellular concentrations of CO(2) and H(+). To examine this, we expressed the Slack channel in Xenopus oocytes and the Slo 2.2 protein was allowed to be inserted into the plasma membrane. Inside-out patch recordings were performed to examine the response of Slack to different CO(2) concentrations (0.038%, 5%, 12%) and to different pH levels (6.3, 6.8, 7.3, 7.8, 8.3). In the presence of low [Na(+)](i) (5 mM), the Slack channel open probability decreased when exposed to decreased pH or increased CO(2) in a dose-dependent fashion (from 0.28+/-0.03, n=3, at pH 7.3 to 0.006+/-0.005, n=3, P=0.0004, at pH 6.8; and from 0.65+/-0.17, n=3, at 0.038% CO(2) to 0.22+/-0.07, n=3, P=0.04 at 12% CO(2)). In the presence of high [Na(+)](i) (45 mM), Slack open probability increased (from 0.03+/-0.01 at 5 mM [Na(+)](i), n=3, to 0.11+/-0.01, n=3, P=0.01) even in the presence of decreased pH (6.3). Since Slack activity increases significantly when exposed to increased [Na(+)](i), even in presence of increased H(+), we propose that Slack may play an important role in pathological conditions during which there is an increase in the intracellular concentrations of both acid and Na(+), such as in ischemia/hypoxia.     

Spinal N-methyl-D-aspartate receptors and nociception-evoked release of primary afferent substance P

Dorsal horn N-methyl-D-aspartate (NMDA) receptors contribute significantly to spinal nociceptive processing through an effect postsynaptic to non-primary glutamatergic axons, and perhaps presynaptic to the primary afferent terminals. The present study sought to examine the regulatory effects of NMDA receptors on primary afferent release of substance P (SP), as measured by neurokinin 1 receptor (NK1r) internalization in the spinal dorsal horn of rats. The effects of intrathecal NMDA alone or in combination with D-serine (a glycine site agonist) were initially examined on basal levels of NK1r internalization. NMDA alone or when co-administered with D-serine failed to induce NK1r internalization, whereas activation of spinal TRPV1 receptors by capsaicin resulted in a notable NK1r internalization. To determine whether NMDA receptor activation could potentiate NK1r internalization or pain behavior induced by a peripheral noxious stimulus, intrathecal NMDA was given prior to an intraplantar injection of formalin. NMDA did not alter the formalin-induced NK1r internalization nor did it enhance the formalin paw flinching behavior. To further characterize the effects of presynaptic NMDA receptors, the NMDA antagonists DL-2-amino-5-phosphonopentanoic acid (AP-5) and MK-801 were intrathecally administered to assess their regulatory effects on formalin-induced NK1r internalization and pain behavior. AP-5 had no effect on formalin-induced NK1r internalization, whereas MK-801 produced only a modest reduction. Both antagonists, however, reduced the formalin paw flinching behavior. In subsequent in vitro experiments, perfusion of NMDA in spinal cord slice preparations did not evoke basal release of SP or calcitonin gene-related peptide (CGRP). Likewise, perfusion of NMDA did not enhance capsaicin-evoked release of the two peptides. These results suggest that presynaptic NMDA receptors in the spinal cord play little if any role on the primary afferent release of SP.     

BDNF improves the effects of neural stem cells on the rat model of Alzheimer's disease with unilateral lesion of fimbria-fornix

In this study, neural stem cells (NSCs) were obtained from the hippocampus using the serum-free culturing. NSCs labeled with 5'-bromo-2'-deoxyuridine (BrdU) were transplanted into transected rat basal forebrain followed by the injection of brain-derived neurotrophic factor (BDNF) into the lateral ventricle. Nestin staining and double-labeling immunohistochemistry were used to detect cell survival and neuronal differentiation of the BrdU labeled cells in the basal forebrain and it was observed that labeled NSCs differentiated into neurons and astrocytes in the basal forebrain. Immunohistochemical detection of p75(NGFR) indicated that the number of cholinergic neurons of the combination groups treated by NSCs, BDNF, and NSCs groups had more significant improvement than that of the injured groups in medial septum (MS) and vertical diagonal branch (VDB). Learning and memory abilities were also measured by Y-maze test and the results support that BDNF can enhance the treatment effects of NSCs transplanted into brain lesion model.     

Assessment of diagnostic accuracy and feasibility of dynamic telepathology in China

To assess the feasibility, including diagnostic accuracy and time cost, of a real-time telepathology system with pathologic slides, 600 cases covering a wide spectrum of lesions from 16 organ systems were tested. The "correct" diagnosis (gold standard) was established as a consensus by 2 experienced pathologists. The cases were first examined by 4 pathologists at different levels of experience with dynamic telepathology. Cases were then reviewed by the same pathologists using light microscopy in a blinded fashion 3 weeks to 2 months later. A diagnosis, together with reading times for telepathology and light microscopy, was recorded for each case. Diagnostic accuracy by telepathology was 94.8% (569/600), 93.3% (560/600), 91.6% (550/600), and 97% (388/400) for pathologists A, B, C, and D, respectively. Telepathologic diagnosis was concordant with the gold standard and with direct microscopy, with a mean of 94.2% and 99.26%, respectively. Most cases (510 or 85%) were diagnosed in 15 to 40 minutes by telepathology, with a mean of 17.0 minutes. The time needed to review a slide by telepathology was 3 to 4 times longer than that of standard light microscopy. All 4 pathologists were able to render a diagnosis in all cases. Our results showed that robotic telepathology is sufficiently accurate for primary diagnosis in surgical pathology, but modifications in laboratory protocols, telepathology hardware, and internet speed are needed to reduce the time necessary for diagnosis by telepathology before this method may be deemed suitable for use in a busy practice.