Strain difference in the induction of T-cell activation-associated, interferon gamma-dependent hepatic injury in mice

A single intravenous injection of concanavalin A (Con A) induces T-cell activation-associated inflammatory injury selectively in the liver. This study investigated the strain difference in the development of Con A-induced hepatic injury. Normal C57BL/6 and BALB/c spleen cells produced comparable levels of T-cell-derived lymphokines (interferon gamma [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], and interleukin-2 [IL-2]) following in vitro stimulation with Con A. A single intravenous injection of Con A to C57BL/6 mice induced the plasma levels of TNF-alpha and IL-2 comparable with or slightly higher than those observed in BALB/c mice, whereas the same treatment resulted in an apparently lower level of IFN-gamma production in C57BL/6 mice. RNA from livers of Con A-treated C57BL/6 mice exhibited lower levels of IFN-gamma mRNA than RNA of BALB/c livers. Unexpectedly, a dramatic difference in the severity of hepatic injury was observed between C57BL/6 and BALB/c. Namely, the peak alanine transaminase (ALT) level was more than 15,000 U/L and inducible as early as 8 hours after injection of 0.2 mg Con A per mouse in the C57BL/6 strain, whereas the peak was approximately 3,000 U/L and induced as late as 24 hours after Con A injection in the BALB/c strain. The increase in plasma ALT levels was limited to less than 10% by injection of anti-IFN-gamma monoclonal antibody (mAb) in both strains. The C57BL/6 strain inducing lower levels of IFN-gamma exhibited higher IFN-gamma responsiveness as exemplified by the intrahepatic expression of an IFN-gamma-inducible gene, an inducible type of nitric oxide (NO) synthase (iNOS). These results indicate that, while IFN-gamma produced in vivo by activated T cells induces hepatic injury, there exists a striking strain difference in the induction of IFN-gamma-dependent hepatic injury.     

Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice

Viral infection often activates the interferon (IFN)-gamma-inducible gene, nitric oxide synthase 2 (NOS2). Expression of NOS2 can limit viral growth but may also suppress the immune system and damage tissue. This study assessed each of these effects in genetically deficient NOS2(-/-) mice after infection with influenza A, a virus against which IFN-gamma has no known activity. At inocula sufficient to cause consolidating pneumonitis and death in wild-type control mice, NOS2(-/-) hosts survived with little histopathologic evidence of pneumonitis. Moreover, they cleared influenza A virus from their lungs by an IFN-gamma-dependent mechanism that was not evident in wild-type mice. Even when the IFN-gamma-mediated antiviral activity was blocked in NOS2(-/-) mice with anti-IFN-gamma mAb, such mice failed to succumb to disease. Further evidence that this protection was independent of viral load was provided by treating NOS2(+/+) mice with the NOS inhibitor, Nomega-methyl-L-arginine (L-NMA). L-NMA prevented mortality without affecting viral growth. Thus, host NOS2 seems to contribute more significantly to the development of influenza pneumonitis in mice than the cytopathic effects of viral replication. Although NOS2 mediates some antiviral effects of IFN-gamma, during influenza infection it can suppress another IFN-gamma-dependent antiviral mechanism. This mechanism was observed only in the complete absence of NOS2 activity and appeared sufficient to control influenza A virus growth in the absence of changes in cytotoxic T lymphocyte activity.     

Demonstration of luteotrophic responses of human recombinant gamma interferon in porcine corpora lutea using an in-vivo microdialysis system

Conceptuses from several mammalian species prior to implantation secrete proteins belonging to the family of interferons. The main species of interferons known to be secreted by the pig blastocyst is interferon gamma (IFNgamma), the precise role of which is unclear. We decided to explore its effects on corpus luteum (CL) function using the novel microdialysis technique in vivo. Six cycling miniature pigs were monitored for estrus by daily plasma progesterone analysis and visual symptoms. On day nine of the cycle (day zero being the day of ovulation) the animals underwent surgery, and microdialysis tubing (vitafiber, Amicon U.S.A, cut off mol. wt. 1 million) were implanted in 17 corpora lutea. The inlets and outlets of all tubings were exteriorized and the entry and exit points of tubings in the CLs sealed with tissue glue. The afferent extension tubings were connected to a fraction collector and the system was continuously flushed with Ringer at a flow rate of 2.4 ml/h. After an initial flushout phase of 8 h, fractions were collected every half hour over 3 days. On days 10, 11 and 12 post estrus 12 CLs were stimulated for 4 h with 10(-7) M, 2 x 10(7) M and 4 x 10(-7) M human recombinant IFNgamma (Pharma Biotechnologie) respectively. Simultaneously, fractions were also collected from the remaining five unstimulated corpora lutea which served as controls. Progesterone concentrations in the dialysates were estimated by a sensitive enzymeimmunoassay (EIA). A significant increase (P < 0.01) in progesterone release was observed in all 3 days following stimulation. The progesterone increase was more marked on the first day of stimulation (1 x 10[-7] M) with the hormone levels rising further even after the end of stimulation. The overall increase in progesterone concentration was 2-fold on day 10 in comparison to 15-30% on subsequent days even though IFN concentrations for stimulation were 2- and 4-fold higher. In the unstimulated CLs, a gradual decline (P < 0.01) in progesterone levels were observed over days. In conclusion, these data provide evidence that the early conceptus signals its presence by way of IFNgamma to maintain the CL in pigs.     

Demonstration and analysis of an alarm pheromone in mice.

In an experiment with 31 C57Bl/6J mice, Ss exposed to the odor of a stressed conspecific communicator-S were averse to the source of the odor, although prior to the stress they preferred the source of the communicator's odor. No correlation existed between the communicator urinating or defecating and the recipient showing an aversion to the odor. Ss that were socially isolated for 12 wk. after weaning could emit the odor when stressed, but responded inappropriately. After 15 wk. of social experience, the odor aversion of these isolates improved, but was not restored to normal. Removal of the olfactory mucosa abolished the odor aversion, indicating the presence of a true pheromone. (19 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Immune response to mouse mammary tumor virus in mice lacking the alpha/beta interferon or the gamma interferon receptor

Mouse mammary tumor virus (MMTV) is a retrovirus which induces a strong immune response and a dramatic increase in the number of infected cells through the expression of a superantigen (SAg). Many cytokines are likely to be involved in the interaction between MMTV and the immune system. In particular, alpha/beta interferon (IFN-alpha/beta) and gamma interferon (IFN-gamma) exert many antiviral and immunomodulatory activities and play a critical role in other viral infections. In this study, we have investigated the importance of interferons during MMTV infection by using mice with a disrupted IFN-alpha/beta or IFN-gamma receptor gene. We found that the SAg response to MMTV was not modified in IFN-alpha/betaR(0/0) and IFN-gammaR(0/0) mice. This was true both for the early expansion of B and T cells induced by the SAg and for the deletion of SAg-reactive cells at later stages of the infection. In addition, no increase in the amount of proviral DNA was detected in tissues of IFN-alpha/betaR(0/0) and IFN-gammaR(0/0) mice, suggesting that interferons are not essential antiviral defense mechanisms during MMTV infection. In contrast, IFN-gammaR(0/0) mice had increased amounts of IL-4 mRNA and an altered usage of immunoglobulin isotypes with a reduced frequency of IgG2a- and IgG3-producing cells. This was associated with lower titers of virus-specific antibodies in serum early after infection, although efficient titers were reached later.     

Cytomegalovirus encephalitis in an immunocompetent adult

Cytomegalovirus encephalitis in immunologically normal patients is rarely reported in the literature. Only seven cases have been previously reported. CMV infection was diagnosed in a 24-year-old, immunologically normal female presenting a severe clinical picture due to encephalitis. Diagnosis was based on detection of CMV DNA in the CSF with the polymerase chain reaction. Administration of ganciclovir was followed by an immediate improvement.     

BK virus encephalitis in an immunocompetent patient

OBJECTIVES: To describe a previously healthy patient now suffering from monophasic encephalitis caused by a primary infection with BK virus and to discuss possible risk factors for developing BK virus encephalitis. DESIGN: Case report. SETTING: Referral hospital. PATIENT: The patient was examined on referral. MAIN OUTCOME MEASURES: The main diagnostic tests performed were serology, polymerase chain reaction on cerebrospinal fluid samples, and cranial magnetic resonance imaging. RESULTS: During the course of the patient's encephalitis, an IgM titer developed against polyomavirus, followed by anti-polyomavirus IgG. Wild-type BK virus was demonstrated in cerebrospinal fluid samples. Cranial magnetic resonance imaging showed diffuse reversible white matter changes most prominent on T2-weighted images. CONCLUSION: We conclude that diagnostic tests for BK, a human polyomavirus, should be included in the screening program for encephalitogenic pathogens.     

Aspergillus spondylodiscitis in an immunocompetent paraplegic patient

A case of an immunocompetent 60 year old patient is reported, who suffered extensive thoracic spinal injury and paraplegia after polytrauma. In the course of rehabilitation he developed aspergillus spondylodiscitis in a part of the thoraco-lumbar spine which was primarily uninjured. The diagnostic assessment and therapeutic approach of this rare disorder is elucidated and discussed in the context of paraplegia and polytrauma. Possible mechanisms of inoculation and spreading of the moulds as well as predisposing factors of the disease are discussed in this paper and a review of the recent literature is provided.     

Effect of antibiotics on interferon production in mice

Neomycin, chloramphenicol, gentamycin, rifampicin and oxytetracycline were tested for their influence on virus induced interferon (IF) production in mice. Repeated intraperitoneal (i.p.) injections of antibiotics were given to produce significant serum concentrations during the time of IF production, induced by i.p. injections of Newcastle disease virus (NDV). IF titres in antibiotic-treated mice determined 6 hours after induction were compared to titres in control mice given NDV only. The IF production was not significantly modified in most of the antibiotic treated mice. Only the highest dose of chloramphenicol (2500 mug/mouse) appeared to cause a reduction in IF production (p less than 0.10). Addition of antibiotics in vitro did not alter the antiviral titres of IF.     

Response to Pneumocystis infection in an immunocompetent host

Cell swelling is now admitted as being a new principle of metabolic control but little is known about the energetics of cell swelling. We have studied the influence of hypo- or hyperosmolarity on both isolated hepatocytes and isolated rat liver mitochondria. Cytosolic hypoosmolarity on isolated hepatocytes induces an increase in matricial volume and does not affect the myxothiazol sensitive respiratory rate while the absolute value of the overall thermodynamic driving force over the electron transport chain increases. This points to an increase in kinetic control upstream the respiratory chain when cytosolic osmolarity is decreased. On isolated rat liver mitochondria incubated in hypoosmotic potassium chloride media, energetic parameters vary as in cells and oxidative phosphorylation efficiency is not affected. Cytosolic hyperosmolarity induced by sodium co-transported amino acids, per se, does not affect either matrix volume or energetic parameters. This is not the case in isolated rat liver mitochondria incubated in sucrose hyperosmotic medium. Indeed, in this medium, adenine nucleotide carrier is inhibited as the external osmolarity increases, which lowers the state 3 respiration close to state 4 level and consequently leads to a decrease in oxidative phosphorylation efficiency. When isolated rat liver mitochondria are incubated in KCl hyperosmotic medium, state 3 respiratory rate, matrix volume and membrane electrical potential vary as a function of time. Indeed, matrix volume is recovered in hyperosmotic KCl medium and this recovery is dependent on Pi-Kentry. State 3 respiratory rate increases and membrane electrical potential difference decreases during the first minutes of mitochondrial incubation until the attainment of the same value as in isoosmotic medium. This shows that matrix volume, flux and force are regulated as a function of time in KCl hyperosmotic medium. Under steady state, neither matrix volume nor energetic parameters are affected. Moreover, NaCl hyperosmotic medium allows matrix volume recovery but induces a decrease in state 3 respiratory flux. This indicates that potassium is necessary for both matrix volume and flux recovery in isolated mitochondria. We conclude that hypoosmotic medium induces an increase in kinetic control both upstream and on the respiratory chain and changes the oxidative phosphorylation response to forces. At steady state, hyperosmolarity, per se, has no effect on oxidative phosphorylation in either isolated hepatocytes or isolated mitochondria incubated in KCl medium. Therefore, potassium plays a key role in matrix volume, flux and force regulation.     

Progressive outer retinal necrosis in an immunocompetent patient

Progressive outer retinal necrosis syndrome is a variant of necrotizing herpetic retinopathy, a group of retinal infections caused by the herpes viruses. It has been described only in immunosuppressed patients. We present a healthy immunocompetent 16-year-old male who suffered a bilateral progressive outer retinal necrosis. Varicella-zoster virus infection was confirmed on the basis of serologic study. Treatment with intravenous acyclovir and oral prednisone was successful.     

Failure to reject an allografted tumor after elimination of macrophages in mice

After an i.p. transplantation of an allogeneic tumor (Meth A) to C57BL/6 mice, a macrophage (M phi)-rich, non-T, non-NK cell population is induced as the major infiltrate and cytotoxic cells. We here evaluated the role of the M phi s in the rejection of allografted Meth A cells and characterized the M phi s in comparison with other well-known M phi s. At all time intervals after transplantation, the highest cytotoxic activities against Meth A tumor were obtained with the M phi-rich population. In addition, the lymphocyte-rich population had a significant but low cytotoxic activity, whereas two other population types, granulocytes and large granular cells, were inactive. When the M phi-rich or the T cell-depleted M phi-rich population was i.p. transplanted simultaneously with Meth A cells into untreated C57BL/6 mice, the tumor cells were rejected without growth. After specific elimination of M phi s by in vivo application of dichloromethylene diphosphonate-containing liposomes, the cytotoxic activity against Meth A cells was hardly induced at the transplantation site of Meth A cells and the allografted Meth A tumor continued to grow, indicating that a type of M phi is the effector cell essential for the rejection. In contrast to other well-known M phi s, the cytotoxic activity against Meth A cells was cell-to-cell contact dependent and soluble factor (e.g., NO and TNF-alpha) independent. Moreover, the cytotoxic activity of the M phi s (H-2b) against 51Cr-labeled Meth A (H-2d) cells was inhibited by the addition of unlabeled H-2d, but not H-2b, H-2k or H-2h, lymphoblasts as well as Meth A cells, implying the specific interaction of the M phi s with H-2d cells.     

Dynamics of interferon induction in albino mice by interferon inducer ridostin administered by various routes

The time dependence of interferon production in blood, tissues of the respiratory tract, brain and olfactory tract of mice BALB/c was investigated after administration of the interferon inductor ridostin by various routes. Intraperitoneal injection of ridostin in a dose of 5 mg/kg induced intensive accumulation of interferon in the blood serum with the peak in 8 hours (2560 U/0.2 ml) while no interferon was detected in the tissues of the respiratory tract and brain of the animals. Intracerebral injection of ridostin in the same dose induced accumulation of interferon in both the tissues of the brain (maximum 160 U/0.2 ml in 24 hours) and the blood serum (maximum 1280 U/0.2 ml in 8 hours). After respiratory administration of ridostin interferon was detected only in the site of the administration in the tissues of the upper respiratory tract and lungs of the mice.     

Chronic pulmonary nocardiosis with eosinophilia in an immunocompetent host

A 75-year-old man who worked at a horse racing track, had an abnormal shadow on a chest radiography. He had a history of dilated cardiomyopathy and mitral regurgitation but had not had any respiratory or systemic symptoms for two years. Chest radiographs and CT scans showed slowly increasing consolidation with internal areas of low attenuation, and without cavity formation, at the left S8. The erythrocyte sedimentation rate, C-reactive protein level, WBC count, percentage of eosinophils, and IgE level were 35 mm/hr, negative, 8400, 17%, and 3628 IU/ml, respectively. Eosinophils were found in samples of sputum. His immunological status was normal. Transbronchial lung biopsy yielded necrotic tissue, along with gram-positive and irregular acid-fast branching filaments that grew in culture. The microorganism was identified as Nocardia asteroides. Occupational inhalation of soil may have caused his disease.     

French system of drug surveillance

The French drug surveillance system is characterized by: a network of thirty one regional drug surveillance centres, located to provide convenient proximity to health care professionals; a causality assessment method, compulsory for all persons involved in drug surveillance, to assess the causal relationship between an adverse effect and one or more drugs; if necessary, an additional evaluation of the causal relationship will be performed using pharmaco-epidemiology methods; a Technical committee and a National Commission of Drug Surveillance which centralize and assess all the data in order to provide a consensual advice to the relevant authorities on necessary measures, to prevent, or reduce a drug related adverse effect; in the case of an inquiry, the drug surveillance department of the pharmaceutical company and the network of regional drug surveillance centers will pool their data with the aim to exchange information and ideas.     

Isolated bilateral renal aspergillosis: an unusual presentation in an immunocompetent host

A 35 year old apparently immunocompetent farmer developed isolated bilateral renal aspergillosis. He presented with acute renal failure due to granulomatous interstitial nephritis and had bilateral renal abscesses on CT scan. Diagnosis came from renal histology and was confirmed on serology. The patient responded quite satisfactorily to single agent antifungal chemotherapy with IV amphotericin B.     

Isolated limb perfusion of an irradiated foot with tumor necrosis factor, interferon, and melphalan

A 57-year-old woman presented with the second recurrence of a high-grade malignant fibrous histiocytoma of the right foot, following previous local resection plus curative adjuvant radiotherapy. The first recurrence of the lesion was treated by isolated limb perfusion with cisplatin; the second recurrence was treated by isolated limb perfusion with tumor necrosis factor, interferon, and melphalan. The tumor and the area that had been irradiated showed a bluish color a few hours after tumor necrosis factor perfusion. Amputation of the right foot and leg below the knee had to be performed because of severe necrosis.