Protective effect of curcumin against cytomegalovirus infection in Balb/c mice.

Curcumin has been found to suppress the activity of human cytomegalovirus (HCMV) in vitro, whereas its protective effects against HCMV infection in vivo remain unclear. In this study, we aimed to investigate the protective effects of curcumin against HCMV infection in Balb/c mice. Mice were randomly divided into the control, model, model+ganciclovir (positive control), and model+high-dose, model+middle-dose, and model+low-dose curcumin groups. In the model groups, each mouse was given HCMV by tail injection intravenously. Positive control animals were given ganciclovir. Animals in the curcumin treatment groups were given different concentrations of curcumin. The anti-HCMV activities of ganciclovir and curcumin were assessed by serological examination and pathology. Ganciclovir and curcumin treatment reduced the HCMV IgM level and HCMV DNA load; decreased the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), and lactate dehydrogenase (LDH) as well as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) generation in infected mice. These treatments also suppressed malondialdehyde (MDA) content and upregulated superoxide dismutase (SOD) and glutathione (GSH) levels. In addition, both treatments prevented pathological changes of the lung, kidney, liver, and heart tissues in infected mice. Our findings indicate that curcumin protected Balb/c mice against HCMV infection possibly by its anti-inflammatory and antioxidant effects.

Human cytomegalovirus infant infection adversely affects growth and development in maternally HIV-exposed and unexposed infants in Zambia.

BACKGROUND: Human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV) coinfections have been shown to increase infant morbidity, mortality, and AIDS progression. In HIV-endemic regions, maternal HIV-exposed but HIV-uninfected infants, which is the majority of children affected by HIV, also show poor growth and increased morbidity. Although nutrition has been examined, the effects of HCMV infection have not been evaluated. We studied the effects of HCMV infection on the growth, development, and health of maternally HIV-exposed and unexposed infants in Zambia. METHODS: Infants were examined in a cohort recruited to a trial of micronutrient-fortified complementary foods. HIV-infected mothers and infants had received perinatal antiretroviral therapy to prevent mother-to-child HIV transmission. Growth, development, and morbidity were analyzed by linear regression analyses in relation to maternal HIV exposure and HCMV infection, as screened by sera DNA for viremia at 6 months of age and by antibody for infection at 18 months. RESULTS: All HCMV-seropositive infants had decreased length-for-age by 18 months compared with seronegative infants (standard deviation [z]-score difference: -0.44 [95% confidence interval {CI}, -.72 to -.17]; P = .002). In HIV-exposed infants, those who were HCMV positive compared with those who were negative, also had reduced head size (mean z-score difference: -0.72 [95% CI, -1.23 to -.22]; P = .01) and lower psychomotor development (Bayley test score difference: -4.1 [95% CI, -7.8 to -.5]; P = .03). HIV-exposed, HCMV-viremic infants were more commonly referred for hospital treatment than HCMV-negative infants. The effects of HCMV were unaffected by micronutrient fortification. CONCLUSION: HCMV affects child growth, development, and morbidity of African infants, particularly in those maternally exposed to HIV. HCMV is therefore a risk factor for child health in this region.

Antitumor-promoting activity of lignans: inhibition of human cytomegalovirus IE gene expression.

BACKGROUND: Chemoprevention is a promising new approach to cancer prevention. Since the beginning of chemoprevention studies, short-term in vitro models used in the study of carcinogenesis have been applied in the identification of antitumor-promoting agents. MATERIALS AND METHODS: The lignans threo-4,4'-dihydroxy-3-methoxylignan, (-)-dihydroguaiaretic acid, 4'-hydroxy-3,3',4-trimethoxylignan, 3,3',4,4'-tetramethoxylignan, 4,4'-diacetyl-3,3'-dimethoxylignan, talaumidin, heliobuphthalmin, (-)-dihydro-cubebin, and hinokinin were evaluated for their ability to inhibit human cytomegalovirus (HCMV) IE-antigen expression in lung cancer cells (A549). RESULTS: Most of the evaluated compounds reduced IE-antigen expression of HCMV, the best result being obtained with 4,4'-dihydroxy-3-methoxylignan. However, a dose-dependent significant increase of IE-antigen expression was found for the derivative (-)-dihydrocubebin. CONCLUSION: The results of this study suggest that some of these lignans might be valuable as potential cancer chemopreventive agents.

Cytomegalovirus prostatitis: a series of 4 cases.

Cytomegalovirus (CMV) prostatitis is very rare with only 1 report of biopsy-proven CMV prostatitis in the literature. The authors report 4 cases, 3 detected on needle biopsy and 1 detected on transurethral resection. Patients were 36, 41, 48, and 71 years old. All patients were immunosuppressed, including 1 with AIDS and 3 undergoing immunosuppressive therapy following organ transplantation. CMV inclusions were seen in secretory cells of the prostatic glands, endothelial cells of small vessels, and prostatic stromal cells associated with a dense lymphoid inflammation. Only very rarely is CMV prostatitis detected on clinical specimens, typically in immunosuppressed hosts undergoing immunosuppressive therapy following organ transplantation. Patients with CMV prostatitis may harbor multiple infections or have other serious medical conditions adversely affecting their prognosis.

Therapeutic effect of a traditional Chinese medicine, ren-shen-yang-rong-tang (Japanese name: Ninjin'yoeito) on nitric oxide-mediated lung injury in a mouse infected with murine cytomegalovirus.

The therapeutic effect of a traditional Chinese medicine ren-shen-yang-rong-tang (Japanese name: Ninjin'yoeito, NYT) on murine cytomegalovirus (MCMV)-associated pneumonitis was examined. In MCMV-pneumonitis, IFN-gamma-induced nitric oxide (NO) mediates its pathogenesis. When mice, which had been infected with 0.2LD(50) of MCMV at 28 days previously, were intraperitoneally injected with anti-CD3 monoclonal antibody (mAb), MCMV-pneumonitis was induced in the lung, where high amounts of IFN-gamma-producing cells thereafter accumulated, accompanied by an elevation in the NO level in the serum and abundant expression of inducible NO synthase (iNOS) mRNA, thus resulting in all mice eventually dying. When the mice were orally treated with NYT (1000 mg/kg/day) once on the day of mAb injection and once the day after, the expression level of iNOS-mRNA was suppressed and NO level in the serum decreased. The survival rate improved from 0% to 57.1%. The pathological findings of the lungs in the NYT-treated mice were comparable to those of the uninfected controls. In contrast, NYT itself did not affect either the ratio of IFN-gamma-producing cells or MCMV titer. As a result, NYT had a therapeutic effect on MCMV-pneumonitis by decreasing the degree of inflammation mediated by the IFN-gamma-induced NO. It is also interesting to note that only two oral administrations of NYT had a therapeutic effect on viral disease.

[Effect of oxymatrine on pathological change in brain tissue of newborn mice infected by cytomegalovirus].

OBJECTIVE: To study the effect of oxymatrine on pathological change in brain tissue of newborn mice infected by cytomegalovirus (CMV). METHODS: CMV of TCID50 was inoculated into the brain of the newborn mice, and the morphological change in the brain tissue infected by CMV was observed with light microscope and transmission electron microscope. RESULTS: In the model control group, the results showed that there were some inflammatory cellular infiltration and focal necrosis in the brain tissue of newborn mice infected by CMV. The ultrastructure change in the brain tissue showed that the nuclear membrane of cerebral neurons sunk, the chromatin deformed and fused into masses, the cytoplasm vacuolated, the endoplasmic reticulum disarranged and the Nissl's body was blurred or disappeared. After being treated with oxymatrine (50 mg/kg, ip) for 15 days, those pathological changes of the brain tissue in the newborn mice could be significantly improved. CONCLUSION: Oxymatrine has an obvious inhibition on CMV in vivo.

An animal model of neonatal cytomegalovirus infection.

Cytomegalovirus (CMV) is the most common cause of congenital infection in the developed world and can lead to a life-threatening disease. We therefore developed an animal model to evaluate candidate anti-CMV drugs and to further define the pathogenesis of CMV infections. Newborn guinea pigs were infected by intraperitoneal administration of 10(6) pfu of a virulent salivary gland (SG) passaged guinea pig CMV (gpCMV) within 48 h of birth. Inoculation of animals produced 50% overall mortality. A lack of weight gain was also a hallmark of infection. By day 14 after inoculation the weight of gpCMV-infected animals was significantly less than controls (152.9+/-45 g versus 254.7+/-38.5 g, P<0.0001). The most consistent isolation and highest titers of virus were found in the liver and spleen early while lung titers were maximal at day 10. A quantitative competitive PCR (qcPCR) assay confirmed the presence of a high CMV viral load in infected organs. Antiviral treatment with cyclic HPMPC (cHPMPC) for 7 days significantly reduced mortality (1/20 versus 14/20, P<0.001) and viral replication but did not improve weight gain. This model should be useful for further evaluations of the pathogenesis of CMV infections and for evaluation of antiviral drugs and vaccines.

Massive lower gastrointestinal hemorrhage caused by CMV disease as a presentation of HIV in an infant.

The gastrointestinal (GI) manifestations of acquired immunodeficiency syndrome in children are related to opportunistic infections like cytomegalovirus (CMV). CMV disease of the GI tract is a major cause of morbidity and mortality in immunocompromised patients: it typically produces mucosal ulcerations that can result in pain, bleeding, diarrhea, and GI perforation, often around the cecum. Preoperative diagnosis may be difficult, plain films and barium enema are often non-specific, and endoscopic evaluation is impossible when there is massive bleeding. The patient usually needs surgery to establish the correct diagnosis and initiate appropriate treatment. The use of gancyclovir for CMV disease in the postoperative period has improved the prognosis.

Electrophysiology and pathology evaluation of the Yucatan pig as a non-rodent animal model for regulatory and mechanistic toxicology studies.

Six male and six female Yucatan pigs were utilized to investigate the feasibility of this species as a non-rodent model for routine regulatory and mechanistic toxicology studies. This study evaluated disease surveillance and computerized electrophysiology, along with possible gross and micropathology changes. Two pigs were used as sentinel animals to evaluate the microbiological status of the vendor upon arrival; the other pigs were maintained as biomonitors and to provide baseline clinical chemistry, urinalysis, pathology and electrophysiology data. The electrophysiology tests conducted included electrocardiography (ECG), electroretinography (ERG) and quantitative electroencephalography (qEEG), which achieved consistent baseline values with acceptable intrasubject variation. Tissue cholinesterase and histochemical staining were done to determine their suitability for testing cholinesterase compounds. Evaluation of the serum chemistry profile demonstrated increased CPK and LDH, which was likely associated with slight haemolysis or minor subclinical muscle stress during handling. There were no additional clinical chemistry changes or findings in haematology, urinalysis parameters or gross pathology. Micropathology found an absence of background lesions which would interfere with routine toxicology studies, except for a mild rhinitis. The aetiological agent was identified by electron microscopy as being consistent with inclusion body rhinitis of swine, previously unreported in miniature swine. This would most notably interfere with inhalation studies. The anatomical and physiological similarities of the Yucatan pig, along with its ability to accept the performance of electrophysiology tests allow this species to be considered as a suitable model for organ system testing in toxicology studies.

Histological diagnosis of cytomegalovirus hepatitis in liver allografts.

AIMS--To determine the incidence of histologically documented cytomegalovirus (CMV) hepatitis following orthotopic liver transplantation (OLT) and to assess the effectiveness of immunohistochemistry and in situ hybridisation (ISH) in detecting CMV. To describe the histological pattern most frequently associated with CMV hepatitis in order to select the biopsy group in which these modern techniques are most effective. METHODS--A prospective histological study was carried out on 853 biopsy specimens, obtained from 191 liver allografts (160 patients). Specimens were stained with haematoxylin and eosin and immunohistochemically (avidin-biotin complex) using monoclonal antibodies directed against early and late CMV antigens. A retrospective selection was made of 23 specimens with viral inclusion bodies in cytomegalic cells (group A) to characterise the most frequently associated histological pattern, and of 34 other specimens without viral inclusion bodies (group B) but with the same microscopic features as group A. Re-cuts from both specimen groups were studied using immunohistochemistry and ISH with a CMV specific complementary DNA probe. RESULTS--CMV infection was confirmed in 35 specimens (29 by immunohistochemistry, 23 by presence of inclusion bodies in haematoxylin and eosin stained sections, 16 by ISH) from 27 patients (incidence 16.9%). CMV hepatitis was diagnosed within 46 +/- 19 (range 21-114) days posttransplant. Twenty on (91.3%) of the 23 biopsy specimens with inclusion bodies (group A) displayed heterogeneous inflammatory foci disseminated throughout the hepatic lobule. Nineteen specimens (82.6%) were positive by immunohistochemistry and 14 (60.9%) by ISH. In eight (23.5%) of the 34 group B specimens CMV infection was confirmed by immunohistochemistry (n = 6) or ISH (n = 2). Another 12 (35.3%) of the group B specimens negative on staining with haematoxylin and eosin, immunohistochemistry and ISH came from allografts in which previous or subsequent biopsy specimens were CMV positive. CONCLUSIONS--Demonstration of cytomegalic inclusion bodies in haematoxylin and eosin sections is sufficient for a diagnosis of CMV hepatitis. The routine use of immunohistochemistry in all allograft biopsy specimens in more sensitive than demonstration of inclusion bodies by staining with haematoxylin and eosin but may yield false negative results because of the focal distribution of positive cells. ISH was less sensitive than staining with haematoxylin and eosin and/or immunohistochemistry. A histological picture of "disseminated focal hepatitis" without viral inclusion bodies selects a group of allograft biopsy specimens in which immunohistochemistry and/or ISH may improve detection of CMV.

Rectal perforation after barium enema in a patient with cytomegalovirus colitis--a case report.

The very rare complication of rectal perforation during the barium enema of an immunocompetent Chinese man with cytomegalovirus (CMV) colitis is described. Rectal biopsy performed over three weeks earlier was unlikely to have been related to the perforation. Histopathological examination of the colonic mucosa showed features of active chronic colitis and CMV infection. After treatment with Ganciclovir, there was cessation of symptoms with eradication of the virus on repeat biopsy samples. It is suggested that presence of CMV colitis predisposed to rectal perforation. The clinical presentation, course of disease and response to treatment supported the concept of CMV as a primary aetiological agent. This complication should be borne in mind when performing barium enemas in patients with clinical features of colitis, especially if they are immunocompromised.

In situ DNA hybridization for cytomegalovirus in colonoscopic biopsies.

We reviewed colonoscopic biopsies of the lower gastrointestinal tract performed during a two-year period. Those representing neoplasia were excluded. Formalin-fixed paraffin-embedded biopsy specimens from 53 patients were studied by in situ DNA hybridization for cytomegalovirus (CMV) using commercially available biotinylated DNA probes detected by an avidin-biotin peroxidase technique. Nine of the patients were severely immunocompromised: four had acquired immunodeficiency syndrome, three had ulcerative colitis and were receiving high-dose steroid therapy, one was a bone marrow transplant recipient, and one had idiopathic pulmonary fibrosis and was receiving therapy with prednisone and cyclophosphamide. Four of these had evidence of CMV infection by routine histology and DNA hybridization. Three additional immunocompromised patients had evidence of CMV infection by DNA hybridization alone. Forty-four patients had inflammatory conditions or ulcerations of the lower gastrointestinal tract. Six of these had evidence of CMV by DNA hybridization alone. Histologically normal as well as enlarged and cytomegalic cells were probe positive, and the cells were sparse to numerous in number. They were found in the epithelium and/or lamina propria. This technique was demonstrated to be applicable to routinely processed colonic biopsy specimens.

Cytomegalovirus colitis in AIDS: radiographic findings in 11 patients.

Radiographic findings in 11 proved cases of cytomegalovirus (CMV) colitis were reviewed and correlated with colonoscopic and pathologic findings. Patients were chronically ill homosexual men with multiple systemic opportunistic infections. Endoscopies showed focal or diffuse inflammation, hemorrhagic plaques, and superficial colonic ulcers. Biopsies revealed inflammatory cells associated with cytoplasmic and intranuclear inclusion bodies. Barium enema examinations showed mucosal granularity, superficial erosions, thickened folds, and spasticity. Disease was either diffuse (four patients) or segmental (two patients), or it involved the cecum exclusively (three patients). Two patients had normal barium enema studies. Computed tomography scans in two patients demonstrated marked colonic wall thickening and mucosal ulcerations. In the homosexual population with acquired immunodeficiency syndrome, CMV colitis should be part of the differential diagnosis of diffuse colitis, segmental colitis, or typhlitis.

Double encephalitis with herpes simplex virus and cytomegalovirus in an adult.

A 51-year-old housewife developed symptoms of a cold followed by high fever, delirium, coma, rigidity of extremity muscles, positive Babinski sign and generalized convulsions, while complement-fixing antibody titre to herpes simplex virus in the sera raised over 128 X and declined to 8 X in the course. She finally expired of bronchopneumonia following status epilepticus after 94 days of illness. Severe necrosis with extensive hemorrhage in the white matter was predominant in the temporal, insular and orbitofrontal cortex, thalamus and globus pallidus. Focal rarefaction of the cerebral cortex with a very few eosinophilic intranuclear inclusions in the oligodendroglia and nerve cells, nerve cell destruction in the substantia nigra with glial nodules and perivascular inflammatory cell cuffs were observed. Abundant cytomegalic inclusion cells, originating from hypertrophic astrocytes, were present in the necrotic areas of cerebrum as well as in the rarefied tissue in the subependymal layers of the brainstem and cerebellum. Electron-microscopic study of the cytomegalic cells demonstrated the presence of numerous virions in both nucleus and cytoplasm. Fortuitour infection of the brain by cytomegalovirus with necrotizing encephalitis by herpes simplex virus is unique. The cause of double viral infections and severe lesions by less virulent strains is discussed.