Swine as a principal reservoir of hepatitis E virus that infects humans in eastern China

BACKGROUND AND METHODS: Genotype IV hepatitis E virus (HEV) has been isolated from humans and swine. To study the relationship between the human and swine reservoirs, we estimated their respective viral burden, analyzed the genetic makeup of the virus populations, and assessed the risk of infection associated with swine farming. RESULTS: In 2 swine-farming districts of eastern China, 9.6% of swine and 0.3% of healthy human subjects excreted HEV in stool, as did 68.8% of patients with confirmed HEV infection. The virus population circulating in humans consisted of genotype I and at least 4 phylogenetically distinct subgroups of genotype IV viruses, 2 of which concurrently circulated among swine. Persons engaged in occupations related to swine farming were found to have a 74% higher risk of infection than those engaged in other occupations, and persons living in communities downstream of the swine farms were found to have a 29% higher risk of infection than persons living in communities upstream. CONCLUSIONS: Genotype IV HEV is freely transmitted between humans and swine. Because the size of the swine population and its viral burden are much larger than those of humans, transmission of the virus most likely is directed from swine to humans. Infection can be acquired through contact with swine and their waste.     

Usefulness of the total cholesterol to high-density lipoprotein cholesterol ratio in predicting angiographic coronary artery disease in women

To investigate the relation between lipids and angiographic coronary artery disease (CAD) in women, fasting lipid profiles were obtained on 108 women undergoing coronary angiography (group I). CAD, defined as ≥25% luminal diameter narrowing in a major coronary artery, was present in 57 (53%). Neither serum total cholesterol nor triglyceride levels correlated with the presence of CAD. Mean total/high-density lipoprotein (HDL) cholesterol ratio was higher among women with than without CAD (5.5 ± 0.3 vs 4.2 ± 0.2, p < 0.0001). Multiple regression analyses identified a higher total/HDL cholesterol ratio as the variable most predictive of the presence (p < 0.001), extent (number of narrowed arteries) (p < 0.0001), and severity (% maximum stenosis) (p < 0.001) of CAD. Age and lack of estrogen use were also independently associated with the presence of CAD, age and lowdensity lipoprotein cholesterol level were additional indicators of extent, and age was the only other discriminator of severity of CAD.

In 56 women with total cholesterol <200 mg/dl (group II), mean total/HDL cholesterol ratio was higher in women with (n = 24) than without CAD (4.3 ± 0.2 vs 3.5 ± 0.2, P = 0.01). Higher total/HDL cholesterol ratio was the variable most predictive of the presence of CAD (p = 0.01), and the tone variable associated with severity (p < 0.001) after adjustment for other risk factors. Age was independently associated with presence and extent, and hypertension was also independently related to extent. Thus, among these women, total/HDL cholesterol ratio is the best predictor of the presence, severity and extent of CAD in general, and is the best predictor of presence, and severity in patients with total cholesterol <200 mg/dl.     

CT and MRI findings of cystadenofibromas of the ovary

The aim of this study was to assess imaging findings on CT or MR images of histologically proven ovarian cystadenofibromas. In the period 1995–2001, 32 histologically proven ovarian cystadenofibromas were identified in 28 women. Of the 32 ovarian cystadenofibromas, 16 tumors were purely cystic and the remaining 16 were complex cystic on CT or MR images. Solid components of 16 complex cystic tumors were seen as nodular (n=8) or trabecular (n=9) solid areas. One tumor had both nodular and trabecular solid components. Among 16 complex cystic tumors, 14 had thick or irregular septa; thus, half of ovarian cystadenofibromas had morphological imaging features of malignancy on CT or MR images. On histology, solid components in the cystic tumors were correlated with fibrous stromas that occasionally made a false-positive result for malignancy on imaging.     

Alteration of intramolecular electronic transition via deboronation of carbazole-based o-carboranyl compound and intriguing ‘turn-on’ emissive variation

The conversion of closo-o-carborane–containing compounds to the nido-o-species via deboronation causes photophysical changes that could be used for sensing applications. 9-Methyl-9H-carbazole–based closo- (closo-Cz) and nido-o-carboranyl (nido-Cz) compounds were prepared and fully characterised by multinuclear NMR spectroscopy and elemental analysis, and the solid-state molecular structure of closo-Cz was analysed by X-ray crystallography. Although the closo-compound exhibited an emissive pattern centred at λ_em = ca. 530 nm in the rigid state only (in THF at 77 K and as a film), nido-Cz demonstrated intense emission in the near-UV region (λ_em = ca. 380 nm) in both solution and film states at 298 K. The positive solvatochromic effect of nido-Cz and the results of theoretical calculations for both the o-carboranyl compounds supported that these emissive features originate from intramolecular charge transfer (ICT) corresponding to the o-carborane. Furthermore, the calculations verified that the electronic role of the o-carboranyl unit changed from acceptor to donor upon deboronation from closo-Cz to nido-Cz. Investigations of the radiative decay mechanisms of closo-Cz and nido-Cz according to their quantum efficiencies (Φ_em) and decay lifetimes (τ_obs) suggested that the ICT-based radiative decays of closo-Cz and nido-Cz readily occur in the film (solid) and solution state, respectively. These observations implied that the emission of closo-Cz in the solution state could be drastically enhanced by deboronation to nido-Cz upon exposure to an increasing concentration of fluoride anions. Indeed, turn-on emissive features in an aqueous solution were observed upon deboronation, strongly suggesting the potential of closo-Cz as a turn-on and visually detectable chemodosimeter for fluoride ion sensing.

Deboronation of a 9-methyl-9H-carbazole–based closo-o-carboranyl compound to the nido-o-carborane in an aqueous solution results in a ratiometric turn-on response in the deep-blue emission region with moderate reactivity.     

Dual Roles of CD40 on Microbial Containment and the Development of Immunopathology in Response to Persistent Fungal Infection in the Lung

Persistent pulmonary infection with Cryptococcus neoformans in C57BL/6 mice results in chronic inflammation that is characterized by an injurious Th2 immune response. In this study, we performed a comparative analysis of cryptococcal infection in wild-type versus CD40-deficient mice (in a C57BL/6 genetic background) to define two important roles of CD40 in the modulation of fungal clearance as well as Th2-mediated immunopathology. First, CD40 promoted microanatomic containment of the organism within the lung tissue. This protective effect was associated with: i) a late reduction in fungal burden within the lung; ii) a late accumulation of lung leukocytes, including macrophages, CD4⁺ T cells, and CD8+ T cells; iii) both early and late production of tumor necrosis factor-α and interferon-γ by lung leukocytes; and iv) early IFN-γ production at the site of T cell priming in the regional lymph nodes. In the absence of CD40, systemic cryptococcal dissemination was increased, and mice died of central nervous system infection. Second, CD40 promoted pathological changes in the airways, including intraluminal mucus production and subepithelial collagen deposition, but did not alter eosinophil recruitment or the alternative activation of lung macrophages. Collectively, these results demonstrate that CD40 helps limit progressive cryptococcal growth in the lung and protects against lethal central nervous system dissemination. CD40 also promotes some, but not all, elements of Th2-mediated immunopathology in response to persistent fungal infection in the lung.CD40, a 48-kDa type I transmembrane protein and member of the tumor necrosis factor receptor family, is a well-described costimulatory molecule expressed on B cells, dendritic cells (DC), macrophages, basophils, and platelets as well as nonhematopoietic cells including fibroblasts, epithelial, and endothelial cells. The ligand for CD40, known as CD154 or CD40L, is a type II transmembrane protein member of the tumor necrosis factor (TNF) superfamily expressed primarily by activated T cells, B cells, and platelets.^1,2,3 CD40 can be induced on DC, monocytes, and macrophages under inflammatory conditions.^4,5 Signaling via the CD40/CD40L pathway exerts numerous biological effects including: i) increased cytokine expression (especially TNF-α and Th1 cytokines interleukin (IL)-12 and interferon (IFN)-α) and nitric oxide production; ii) upregulation of additional costimulatory molecules (CD80 and CD86) on antigen-presenting cells (APC); iii) enhanced cell survival (particularly of B and T cells, DC, and endothelial cells); iv) Ig isotype switching; and v) somatic hypermutation of Ig.^1,4,5The CD40/CD40L signaling pathway contributes to adaptive Th1 immune responses required to clear Leishmanisa spp.,^6,7,8 Trypanosoma spp.,^6,7,8,9 Shistosoma mansoini,¹⁰ and the fungi Candida albicans¹¹ and Pneumocystis spp.¹² The enhanced production of IFN-γ, TNF-α, and nitric oxide associated with CD40/CD40L signaling is thought to be responsible for this protective effect. However, other studies have suggest that CD40/CD40L signaling is not required for successful host defense against Listeria monocytogenes,^13,14 Toxoplasma gondi,¹⁵ lymphocytic choriomeningitis virus,^16,17 or the fungus Hisoplasma capsulatum.^18,19 In models of Mycobacterium spp. infection, CD40 appears dispensable for clearance of an i.v. infection,^20,21 but essential for clearing the organism in response to aerosolized infection in the lungs.^22,23 Thus, the role of CD40 in antimicrobial host defense varies and depends not only on the specific pathogen but also on the primary site of infection.Cryptococcus neoformans, an opportunistic fungal pathogen acquired through inhalation, causes significant morbidity and mortality primarily in patients with AIDS, lymphoid or hematological malignancies, or patients receiving immunosuppressive therapy secondary to autoimmune disease or organ transplantation.^24,25 Infection in non-immunocompromised patients has been reported.^26,27,28 Murine models of cryptococcal infection in CBA/J or BALB/c mice demonstrate that development of a Th1 antigen-specific immune response characterized by IFN-γ production and classical activation of macrophages is required to eradicate the organism.^{29,30,31,32,33,34,35,36,37,38,39,40} In contrast, a model of persistent cryptococcal infection has been developed using C57BL/6 mice;^{41,42,43,44,45,46,47} this model reflects many features observed in humans diagnosed with allergic bronchopulmonary mycosis.⁴⁸ Specifically, these mice fail to clear the organism from the lung and develop characteristic Th2-mediated immunopathology including: i) tissue eosinophilia; ii) airway hyperreactivity, mucus production, and fibrosis; and iii) alternative macrophage activation associated with YM1 crystal deposition.The molecular mechanisms responsible for the immunopathologic response associated with persistent cryptococcal infection are not clearly defined. These features are abrogated in the absence of IL-4,⁴⁵ whereas more severe Th2-mediated lung injury occurs in the absence of IFN-γ.^29,41 TNF-α exerts a protective effect by enhancing IFN- γ production and the subsequent classical activation of lung macrophages.^31,35,49,50 Lymphocytes are critical mediators of this Th2 response as the pathological features of chronic cryptococcal infection are substantially diminished in CD4 T cell-depleted mice despite no change in fungal clearance.⁴²Although interactions between CD4 T cells and APC are critical determinants of T cell polarization in response to cryptococcal lung infection,^{49,51,52,53,54,55} the contribution of specific costimulatory molecules including the CD40/CD40L signaling pathway has not been fully elucidated. In vitro studies suggest that activation of the CD40/CD40L pathway in response to Cryptococcus promotes IFN-γ production by T cells and TNF-α, and nitric oxide (NO) production by monocytes.⁵⁶ In the absence of CD40L, primary pulmonary infection with a weakly virulent strain of C. neoformans was associated with impaired fungal clearance; however, measurements of immune function at the site of infection in the lung or evidence of systemic fungal dissemination were not evaluated.⁵⁷ The potential to target CD40 therapeutically is highlighted by studies showing that treatment of mice with disseminated or intracerebral cryptococcal infection with an agonist antibody to CD40 in combination with IL-2 improves survival.^58,59 In this study, we used gene-targeted CD40-deficient mice (on a C57BL/6 genetic background), a clinically relevant model, and assessments of immune function and histopathology in the lung to identify two unique roles for the CD40-signaling pathway in response to persistent cryptococcal lung infection.     

Effects of exercise training on pathological cardiac hypertrophy related gene expression and apoptosis

This study determined whether exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial and apoptosis-associated genes. We used spontaneously hypertensive rats (n=15, non-exercise SHR), exercise-trained SHR (n=15, treadmill exercise for 12 weeks), and sedentary Wistar-Kyoto (WKY) rats (n=15). Exercise-trained SHR expressed adaptive changes such as reduced body weight, heart rate, blood pressures, left ventricle wall thickness, lipid profiles, and homocysteine level. The mRNA expression of angiotensin converting enzyme, endothelin-1, and brain natriuretic peptides in the heart was lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR, whereas mRNA expression of caveolin-3 and eNOS in the heart was higher. Bcl-2 protein was higher in the exercise-trained SHR than in the WKY and the non-exercise SHR. In contrast, Bax protein levels were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. Furthermore, the levels of the active forms of caspase-3 (20 kDa) were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. These findings suggest that exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial genes and that it interferes with a signal transduction pathway of apoptosis secondary to the pathological cardiac hypertrophy.